[Federal Register Volume 72, Number 121 (Monday, June 25, 2007)]
[Rules and Regulations]
[Pages 34752-34958]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 07-3039]



[[Page 34751]]

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Part II





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Part 111



Current Good Manufacturing Practice in Manufacturing, Packaging, 
Labeling, or Holding Operations for Dietary Supplements; Final Rule



Petition To Request an Exemption From 100 Percent Identity Testing of 
Dietary Ingredients; Interim Final Rule

Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules 
and Regulations

[[Page 34752]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

[Docket No. 1996N-0417] (formerly Docket No. 96N-0417)
RIN 0910-AB88


Current Good Manufacturing Practice in Manufacturing, Packaging, 
Labeling, or Holding Operations for Dietary Supplements

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
regarding current good manufacturing practice (CGMP) for dietary 
supplements. The final rule establishes the minimum CGMPs necessary for 
activities related to manufacturing, packaging, labeling, or holding 
dietary supplements to ensure the quality of the dietary supplement. 
The final rule is one of many actions related to dietary supplements 
that we are taking to promote and protect the public health.

DATES: This rule is effective August 24, 2007.
    Compliance Dates: The compliance date is June 25, 2008; except that 
for businesses employing fewer than 500, but 20 or more full-time 
equivalent employees, the compliance date is June 25, 2009; and except 
that for businesses that employ fewer than 20 full-time equivalent 
employees, the compliance date is June 25, 2010.

FOR FURTHER INFORMATION CONTACT: Vasilios H. Frankos, Center for Food 
Safety and Applied Nutrition (HFS-810), Food and Drug Administration, 
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1696.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background and Related Information
II. How is the Final Rule Organized?
III. What Does the Final Rule Do?
    A. Overview of CGMP
    B. Highlights of the Final Rule
IV. What General Comments Did We Receive?
    A. What Comments Did We Receive on the Structure and Organization 
of the Rule?
    B. What Comments Did We Receive on the Need for Dietary Supplement 
CGMP Requirements?
    C. What Comments Did We Receive on Written Procedures?
    1. Overview
    2. Written Procedures That Are Required by This Final Rule
    3. Written Procedures That Are Not Required by This Final Rule
    D. Other Comments on Written Procedures
    E. What Other General Comments Did We Receive?
V. What Legal Authority Comments Did We Receive?
    A. Modeled After CGMP for Food
    B. Records Authority
    C. Public Health Service Act Authority
    1. The Communicable Disease Risk Posed by Dietary Supplements
    2. Activities For Which We Are Asserting Legal Authority Under the 
PHS Act
    D. The Interstate Commerce Nexus for the Final Rule
    1. The PHS Act
    2. The Act
    3. Commerce Clause
    E. Fifth Amendment
    F. Miscellaneous
VI. What Comments Did We Receive on the General Provisions? (Subpart A)
    A. Organization of Final Subpart A
    B. Who Is Subject to This Part? (Final Sec.  111.1)
    C. What Definitions Apply to This Part? (Final Sec.  111.3)
    1. Actual Yield
    2. Batch
    3. Batch Number, Lot Number, or Control Number
    4. Component
    5. Contact Surface
    6. Ingredient
    7. In-Process Material
    8. Lot
    9. Microorganisms
    10. Must
    11. Pest
    12. Physical Plant
    13. Product Complaint
    14. Quality
    15. Quality Control
    16. Quality Control Personnel
    17. Representative Sample
    18. Reprocessing
    19. Reserve Sample
    20. Sanitize
    21. Theoretical Yield
    22. Water Activity
    23. We
    24. You
    25. What Other Terms Did the Comments Want Defined?
    26. What Definitions Did the Comments Want Us to Delete?
    D. Do Other Statutory Provisions and Regulations Apply? (Final 
Sec.  111.5)
    E. What Sections Did We Remove From the Rule, and Why?
    1. ``What Are These Regulations Intended to Accomplish?'' (Proposed 
Sec.  111.2)
    2. ``Exclusions'' (Proposed Sec.  111.6)
VII. Comments on Personnel (Final Subpart B)
    A. Organization of Final Subpart B
    B. Highlights of Changes to the Proposed Requirements for Personnel
    1. Revisions
    2. Changes After Considering Comments
    C. General Comments on Proposed Subpart B
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.8)
    E. What Requirements Apply for Preventing Microbial Contamination 
From Sick or Infected Personnel and for Hygienic Practices? (Final 
Sec.  111.10)
    1. Final Sec.  111.10(a)
    2. Final Sec.  111.10(b)
    F. What Personnel Qualification Requirements Apply? (Final Sec.  
111.12)
    G. What Supervisor Requirements Apply? (Final Sec.  111.13)
    H. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.14)
VIII. Comments on Physical Plant and Grounds (Final Subpart C)
    A. Organization of Final Subpart C
    B. Highlights of Changes to the Proposed Requirements for Physical 
Plant and Grounds
    1. Revisions
    2. Changes After Considering Comments
    C. General Comments on Proposed Subpart C
    D. What Sanitation Requirements Apply to Your Physical Plant and 
Grounds? (Final Sec.  111.15)
    1. Final Sec.  111.15(a)
    2. Final Sec.  111.15(b)(1)
    3. Final Sec.  111.15(c)
    4. Final Sec.  111.15(d)
    5. Final Sec.  111.15(e)
    6. Final Sec.  111.15(f)
    7. Final Sec.  111.15(g)
    8. Final Sec.  111.15(h)
    9. Final Sec.  111.15(i)
    10. Final Sec.  111.15(j)
    11. Final Sec.  111.15(k)
    E. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.16)
    F. What Design and Construction Requirements Apply to Your Physical 
Plant? (Final Sec.  111.20)
    1. Final Sec.  111.20(a) and (b)
    2. Final Sec.  111.20(c)
    3. Final Sec.  111.20(d)
    4. Final Sec.  111.20(e)
    5. Final Sec.  111.20(f)
    6. Final Sec.  111.20(g)
    7. Final Sec.  111.20(h)

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    G. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.23)
IX. Comments on Requirements Related to Equipment and Utensils (Subpart 
D)
    A. Organization of Final Subpart D
    B. Highlights of Changes to the Proposed Requirements for Equipment 
and Utensils
    1. Revisions
    2. Revisions Associated With the Reorganization
    3. Changes After Considering Comments
    C. General Comments on Proposed Subpart D
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.25)
    E. What Requirements Apply to the Equipment and Utensils That You 
Use? (Final Sec.  111.27)
    1. Final 111.27(a)
    2. Final Sec.  111.27(b)
    3. Final Sec.  111.27(c)
    4. Final Sec.  111.27(d)
    F. Reorganization of Certain Paragraphs in Proposed Sec.  111.25
    G. What Requirements Apply to Automated, Mechanical, or Electronic 
Equipment? (Final Sec.  111.30)
    1. Comments on the Organization and Framework of Proposed Sec.  
111.30
    2. Comments Specific to Proposed Sec.  111.30
    3. Reorganization of Certain Paragraphs in Proposed Sec.  111.30
    H. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.35)
    1. Final Sec.  111.35(a)
    2. Final Sec.  111.35(b)(1) and (b)(2)
    3. Final Sec.  111.35(b)(3)
    4. Final Sec.  111.35(b)(4)
    5. Final Sec.  111.35(b)(5)
    6. Final Sec.  111.35(b)(6)
X. Comments on Requirement to Establish a Production and Process 
Control System (Final Subpart E)
    A. Reorganization of Proposed Sec.  111.35 Into Final Subpart E
    B. General Comments on Proposed Sec.  111.35
    C. Final Subpart E and Highlights of Changes to the Proposed 
Regulations
    D. What Are the Requirements to Implement a Production and Process 
Control System? (Final Sec.  111.55)
    E. What Are the Design Requirements for the Production and Process 
Control System? (Final Sec.  111.60)
    F. What Are the Requirements for Quality Control Operations? (Final 
Sec.  111.65)
    G. What Specifications Must You Establish? (Final Sec.  111.70)
    1. Final Sec.  111.70(a)
    2. Final Sec.  111.70(b)
    3. Final Sec.  111.70(c)
    4. Final Sec.  111.70(d)
    5. Final Sec.  111.70(e)
    6. Final Sec.  111.70(f)
    7. Final Sec.  111.70(g)
    H. What is Your Responsibility for Determining Whether Established 
Specifications Are Met? (Final Sec.  111.73)
    I. What Must You Do to Determine Whether Specifications Are Met? 
(Final Sec.  111.75)
    1. Final Sec.  111.75(a)
    2. Final Sec.  111.75(b)
    3. Final Sec.  111.75(c) and (d)
    4. Final Sec.  111.75(e)
    5. Final Sec.  111.75(f)
    6. Final Sec.  111.75(g)
    7. Final Sec.  111.75(h)
    8. Final Sec.  111.75(i)
    J. What Must You Do if Established Specifications Are Not Met? 
(Final Sec.  111.77)
    1. Final Sec.  111.77
    2. Final Sec.  111.77(a)
    3. Final Sec.  111.77(b)
    4. Final Sec.  111.77(c)
    K. Comments on Shelf Life
    L. What Representative Samples Must You Collect? (Final Sec.  
111.80)
    1. Final Sec.  111.80(a)
    2. Final Sec.  111.80(b)
    3. Final Sec.  111.80(c)
    4. Final Sec.  111.80(d)
    5. Final Sec.  111.80(e)
    M. What Are the Requirements for Reserve Samples? (Final Sec.  
111.83)
    1. Final Sec.  111.83(a)
    2. Final Sec.  111.83(b)(1)
    3. Final Sec.  111.83(b)(2)
    4. Final Sec.  111.83(b)(3)
    5. Final Sec.  111.83(b)(4)
    N. Who Conducts a Material Review and Makes a Disposition Decision? 
(Final Sec.  111.87)
    O. What Requirements Apply to Treatments, In-Process Adjustments, 
and Reprocessing When There is a Deviation or Unanticipated Occurrence 
or When a Specification Established in Accordance With Sec.  111.70 Is 
Not Met? (Final Sec.  111.90)
    1. Final Sec.  111.90
    2. Final Sec.  111.90(a)
    3. Final Sec.  111.90(b)
    4. Final Sec.  111.90(c)
    P. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.95)
    1. Final Sec.  111.95(a)
    2. Final Sec.  111.95(b)
XI. Comments on Requirements for Quality Control (Final Subpart F)
    A. Organization of Final Subpart F
    B. Highlights of Changes to the Proposed Requirements for Quality 
Control Operations
    1. Revisions
    2. Changes Associated With the Reorganization
    3. Changes After Considering Comments
    C. General Comments on Proposed Sec.  111.37 (Final Subpart F)
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.103)
    E. What Must Quality Control Personnel Do? (Final Sec.  111.105)
    1. Final Sec.  111.105(a)
    2. Final Sec.  111.105(b), (c), (d), and (e)
    3. Final Sec.  111.105(f)
    4. Final Sec.  111.105(g)
    5. Final Sec.  111.105(h)
    6. Final Sec.  111.105(i)
    F. What Quality Control Operations Are Required for Laboratory 
Operations Associated With the Production and Process Control System? 
(Final Sec.  111.110)
    1. Final Sec.  111.110(a)
    2. Final Sec.  111.110(b)
    3. Final Sec.  111.110(c)
    G. What Quality Control Operations Are Required for a Material 
Review and Disposition Decision? (Final Sec.  111.113)
    1. Final Sec.  111.113(a)
    2. Final Sec.  111.113(b)
    3. Final Sec.  111.113(c)
    H. What Quality Control Operations Are Required for Equipment, 
Instruments, and Controls? (Final Sec.  111.117)
    1. Final Sec.  111.117(a) through (c)
    2. Final Sec.  111.117(d)
    I. What Quality Control Operations Are Required for Components, 
Packaging, and Labels Before Use in the Manufacture of a Dietary 
Supplement? (Final Sec.  111.120)
    1. Final Sec.  111.120(a)
    2. Final Sec.  111.120(b)
    3. Final Sec.  111.120(c)
    4. Final Sec.  111.120(d)
    5. Final Sec.  111.120(e)
    J. What Quality Control Operations Are Required for the Master 
Manufacturing Record, the Batch Production Record, and Manufacturing 
Operations? (Final Sec.  111.123)
    1. Final Sec.  111.123(a)(1)
    2. Final Sec.  111.123(a)(2)
    3. Final Sec.  111.123(a)(3)
    4. Final Sec.  111.123(a)(4)
    5. Final Sec.  111.123(a)(5)
    6. Final Sec.  111.123(a)(6)
    7. Final Sec.  111.123(a)(7)
    8. Final Sec.  111.123(a)(8)
    9. Final Sec.  111.123(b)
    K. What Quality Control Operations Are Required for Packaging and 
Labeling Operations? (Final Sec.  111.127)

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    1. Final Sec.  111.127(a) and (b)
    2. Final Sec.  111.127(c)
    3. Final Sec.  111.127(d)
    4. Final Sec.  111.127(e)
    5. Final Sec.  111.127(f) and (g)
    6. Final Sec.  111.127(h)
    L. What Quality Control Operations Are Required for Returned 
Dietary Supplements? (Final Sec.  111.130)
    1. Final Sec.  111.130(a)
    2. Final Sec.  111.130(a)(1) and (a)(2)
    3. Final Sec.  111.130(b)
    4. Final Sec.  111.130(c)
    5. Final Sec.  111.130(d)
    M. What Quality Control Operations Are Required for Product 
Complaints? (Final Sec.  111.135)
    N. What Records Must You Make and Keep? (Final Sec.  111.140)
    1. Final Sec.  111.140(a)
    2. Final Sec.  111.140(b)(1)
    3. Final Sec.  111.140(b)(2)
    4. Final Sec.  111.140(b)(3)
XII. Comments on the Production and Process Control System: 
Requirements for Components, Packaging, and Labels, and for Product 
That You Receive for Packaging or Labeling as a Dietary Supplement 
(Final Subpart G)
    A. Organization of Final Subpart G
    B. Highlights of Changes to the Proposed Requirements for 
Components, Packaging, and Labels, and Product That You Receive for 
Packaging or Labeling as a Dietary Supplement
    1. Revisions
    2. Changes After Considering Comments
    C. General Comments on Proposed Sec.  111.40 (Final Subpart G)
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.153)
    E. What Requirements Apply to Components of Dietary Supplements? 
(Final Sec.  111.155)
    1. Proposed Sec.  111.35(d)
    2. Final Sec.  111.155(a)
    3. Final Sec.  111.155(b)
    4. Final Sec.  111.155(c)
    5. Final Sec.  111.155(d)
    6. Final Sec.  111.155(e)
    F. What Requirements Apply to Packaging and Labels Received? (Final 
Sec.  111.160)
    1. Final Sec.  111.160(a)
    2. Final Sec.  111.160(b)
    3. Final Sec.  111.160(c)
    4. Final Sec.  111.160(d)
    5. Final Sec.  111.160(e)
    G. What Requirements Apply to a Product Received for Packaging or 
Labeling as a Dietary Supplement (and for distribution rather than for 
return to the supplier)? (Final Sec.  111.165)
    1. Final Sec.  111.165(a)
    2. Final Sec.  111.165(b)
    3. Final Sec.  111.165(c)
    4. Final Sec.  111.165(d)
    5. Final Sec.  111.165(e)
    H. What Requirements Apply to Rejected Components, Packaging, and 
Labels, and to Rejected Products That Are Received for Packaging or 
Labeling as a Dietary Supplement? (Final Sec.  111.170)
    I. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.180)
    1. Final Sec.  111.180(a)
    2. Final Sec.  111.180(b)(1)
    3. Final Sec.  111.180(b)(2)
    4. Final Sec.  111.180(b)(3)
XIII. Comments on the Production and Process Control System: 
Requirements for the Master Manufacturing Record (Final Subpart H)
    A. Organization of Final Subpart H
    B. Highlights of Changes to the Proposed Requirements for the 
Master Manufacturing Record
    1. Revisions
    2. Changes Associated With the Reorganization
    3. Changes After Considering Comments
    C. General Comments on Proposed Sec.  111.45 (Final Subpart H)
    1. Comments on Written Procedures
    2. Comments That Support Proposed Sec.  111.45
    D. What Is the Requirement to Establish a Master Manufacturing 
Record? (Final Sec.  111.205)
    1. Final Sec.  111.205(a)
    2. Final Sec.  111.205(b)(1)
    3. Final Sec.  111.205(b)(2)
    4. Final Sec.  111.205(c)
    E. What Must the Master Manufacturing Record Include? (Final Sec.  
111.210)
    1. Final Sec.  111.210(a)
    2. Final Sec.  111.210(b)
    3. Final Sec.  111.210(c)
    4. Final Sec.  111.210(d)
    5. Final Sec.  111.210(e)
    6. Final Sec.  111.210(f)
    7. Final Sec.  111.210(g)
    8. Final Sec.  111.210(h)(1)
    9. Final Sec.  111.210(h)(2)
    10. Final Sec.  111.210(h)(3)
    11. Final Sec.  111.210(h)(4)
    12. Final Sec.  111.210(h)(5)
    F. Quality Control Responsibility (Proposed Sec.  111.45(c))
XIV. Comments on the Production and Process Control System: 
Requirements for the Batch Production Record (Final Subpart I)
    A. Organization of Final Subpart I
    B. Highlights of Changes to the Proposed Requirements for the Batch 
Production Record
    1. Revisions
    2. Changes Associated With the Reorganization
    3. Changes After Considering Comments
    C. What Is the Requirement to Establish a Batch Production Record? 
(Final Sec.  111.255)
    D. What Must the Batch Record Include? (Final Sec.  111.260)
    1. Final Sec.  111.260(a)
    2. Final Sec.  111.260(b)
    3. Final Sec.  111.260(c)
    4. Final Sec.  111.260(d)
    5. Final Sec.  111.260(e) and (f)
    6. Final Sec.  111.260(g)
    7. Final Sec.  111.260(h)
    8. Final Sec.  111.260(i)
    9. Final Sec.  111.260(j)
    10. Final Sec.  111.260(k)
    11. Final Sec.  111.260(l)
    12. Final Sec.  111.260(m)
    13. Final Sec.  111.260(n)
    E. Review of Batch Production Record Deviations (Proposed Sec.  
111.50(d)(1), (e)(2), (e)(3), and (e)(4))
XV. Comments on Production and Process Control System: Requirements for 
Laboratory Operations (Final Subpart J)
    A. Organization of Final Subpart J
    B. Highlights of the Changes to the Proposed Requirements for 
Laboratory Operations
    1. Revisions
    2. Changes Associated With the Reorganization
    3. Changes After Considering Comments
    C. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.303)
    D. What Are the Requirements for the Laboratory Facilities That You 
Use? (Final Sec.  111.310)
    E. What Are the Requirements for Laboratory Control Processes? 
(Final Sec.  111.315)
    1. Final Sec.  111.315(a)
    2. Final Sec.  111.315(b)
    3. Final Sec.  111.315(c)
    4. Final Sec.  111.315(d)
    5. Final Sec.  111.315(e)
    F. What Requirements Apply to Laboratory Methods for Testing and 
Examination? (Final Sec.  111.320)
    1. Final Sec.  111.320(a)
    2. Final Sec.  111.320(b)
    G. Appropriate Test Method Validation (Proposed Sec.  
111.60(b)(1)(v))
    H. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.325)
    1. Final Sec.  111.325(a)
    2. Final Sec.  111.325(b)(1)
    3. Final Sec.  111.325(b)(2)
XVI. Comments on the Production and Process Control System: 
Requirements for Manufacturing Operations (Final Subpart K)
    A. Organization of Final Subpart K

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    B. Highlights of Changes to the Proposed Requirements for 
Manufacturing Operations
    1. Revisions
    2. Changes Made After Considering Comments
    3. Revisions Associated With the Reorganization
    C. General Comments on Manufacturing Operations
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.353)
    E. What Are the Design Requirements for Manufacturing Operations? 
(Final Sec.  111.355)
    F. What Are the Requirements for Sanitation? (Final Sec.  111.360)
    G. What Precautions Must You Take to Prevent Contamination? (Final 
Sec.  111.365)
    1. Final Sec.  111.365(a)
    2. Final Sec.  111.365(b)
    3. Final Sec.  111.365(c)
    4. Final Sec.  111.365(d)
    5. Final Sec.  111.365(e)
    6. Final Sec.  111.365(f)
    7. Final Sec.  111.365(g)
    8. Final Sec.  111.365(h)
    9. Final Sec.  111.365(i)
    10. Final Sec.  111.365(j)
    11. Final Sec.  111.365(k)
    H. What Requirements Apply to Rejected Dietary Supplements? (Final 
Sec.  111.370)
    I. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.375)
XVII. Comments on the Production and Process Control System: 
Requirements for Packaging and Labeling Operations (Final Subpart L)
    A. Organization of Final Subpart L
    B. Highlights of Changes to the Proposed Requirements for Packaging 
and Labeling Operations
    1. Revisions
    2. Changes Associated With the Reorganization
    3. Changes After Considering Comments
    C. General Comments on Proposed Requirements for Packaging and 
Labeling Operations
    D. General Comments on Requirements for What Must Be on the Product 
Label Rather Than for Labeling Operations
    E. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.403)
    F. What Requirements Apply to Packaging and Labels? (Final Sec.  
111.410)
    1. Final Sec.  111.410(a)
    2. Final Sec.  111.410(b)
    3. Final Sec.  111.410(c)
    4. Final Sec.  111.410(d)
    G. What Requirements Apply to Filling, Assembling, Packaging, 
Labeling, and Related Operations? (Final Sec.  111.415)
    H. What Requirements Apply to Repackaging and Relabeling? (Final 
Sec.  111.420)
    1. Final Sec.  111.420(a)
    2. Final Sec.  111.420(b) and (c)
    I. What Requirements Apply to a Packaged and Labeled Dietary 
Supplement That Is Rejected for Distribution? (Final Sec.  111.425)
    J. Under this Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.430)
    1. Final Sec.  111.430(a)
    2. Final Sec.  111.430(b)
XVIII. Comments on Holding and Distributing (Final Subpart M)
    A. Organization of Final Subpart M
    B. Highlights of Changes to the Proposed Requirements for Holding 
and Distributing
    1. Revisions
    2. Changes Associated With the Reorganization
    3. Changes After Considering Comments
    C. General Comments on Proposed Sec. Sec.  111.80, 111.82, 111.83, 
and 111.85
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.453)
    E. What Requirements Apply to Holding Components, Dietary 
Supplements, Packaging, and Labels? (Final Sec.  111.455)
    1. Final Sec.  111.455(a)
    2. Final Sec.  111.455(b)
    3. Final Sec.  111.455(c)
    F. What Requirements Apply to Holding In-Process Material? (Final 
Sec.  111.460)
    1. Final Sec.  111.460(a)
    2. Final Sec.  111.460(b)
    G. Proposed Requirement for Holding Reserve Samples of Components 
(Proposed Sec.  111.83(a))
    H. What Requirements Apply to Holding Reserve Samples of Dietary 
Supplements? (Final Sec.  111.465)
    1. Final Sec.  111.465(a)
    2. Final Sec.  111.465(b)
    I. What Requirements Apply to Distributing Dietary Supplements? 
(Final Sec.  111.470)
    J. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.475)
XIX. Comments on Returned Dietary Supplements (Final Subpart N)
    A. Organization of Final Subpart N
    B. Highlights of Changes to the Proposed Requirements for Returned 
Dietary Supplements
    1. Revisions
    2. Changes After Considering Comments
    C. General Comments on Proposed Sec.  111.85
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.503)
    E. What Requirements Apply When a Returned Dietary Supplement is 
Received? (Final Sec.  111.510)
    F. When Must a Returned Dietary Supplement be Destroyed, or 
Otherwise Suitably Disposed Of? (Final Sec.  111.515)
    G. When May a Returned Dietary Supplement Be Salvaged? (Final Sec.  
111.520)
    H. What Requirements Apply to a Returned Dietary Supplement That 
Quality Control Personnel Approve for Reprocessing? (Final Sec.  
111.525)
    I. When Must an Investigation Be Conducted of Your Manufacturing 
Processes and Other Batches? (Final Sec.  111.530)
    J. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.535)
    1. Final Sec.  111.535(a)
    2. Final Sec.  111.535(b)(1)
    3. Final Sec.  111.535(b)(2)
    4. Final Sec.  111.535(b)(3)
    5. Final Sec.  111.535(b)(4)
XX. Comments on Product Complaints (Final Subpart O)
    A. Organization of Final Subpart O
    B. Highlights of Changes to the Proposed Requirements for Product 
Complaints
    1. Revisions
    2. Changes After Considering Comments
    C. General Comments on Proposed Sec.  111.95 (Final Subpart O)
    D. What Are the Requirements Under This Subpart for Written 
Procedures? (Final Sec.  111.553)
    E. What Requirements Apply to the Review and Investigation of a 
Product Complaint? (Final Sec.  111.560)
    1. Final Sec.  111.560(a)(1)
    2. Final Sec.  111.560(a)(2), (b), and (c)
    F. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.570)
    1. Final Sec.  111.570(a)
    2. Final Sec.  111.570(b)(1)
    3. Final Sec.  111.570(b)(2)
    4. Final Sec.  111.570(b)(2)(i)
    5. Final Sec.  111.570(b)(2)(ii)
XXI. Comments on Records and Recordkeeping (Final Subpart P)
    A. Organization of Final Subpart P
    B. Highlights of Changes to the Proposed Requirements for Records 
and Recordkeeping
    1. Revisions
    2. Changes After Considering Comments
    C. General Comments on Proposed

[[Page 34756]]

Sec.  111.125
    D. What Requirements Apply to the Records That You Make and Keep? 
(Final Sec.  111.605)
    1. Final Sec.  111.605(a)
    2. Final Sec.  111.605(b)
    3. Final Sec.  111.605(c)
    E. What Records Must Be Made Available to FDA? (Final Sec.  
111.610)
    1. Final Sec.  111.610(a)
    2. Final Sec.  111.610(b)
XXII. Other Comments and Miscellaneous
    A. Comments on Guidance Documents To Be Used With the Final Rule
    B. Comments on Consideration for Other CGMP Programs
    C. Comments on Public Involvement
    D. Comments on Implementation and Enforcement
    E. Removal of References to Part 112
XXIII. Paperwork Reduction Act of 1995
XXIV. Analysis of Impacts
    A. Introduction
    1. Summary of the Economic Analysis
    2. Summary of Comments on the Economic Analysis
    B. Final Regulatory Impact Analysis
    1. The Need for the Final Current Good Manufacturing Practice Rule
    2. Regulatory Options
    3. Coverage of the Final Rule
    4. Baseline Practices
    5. Baseline Risk
    6. Benefits
    7. Costs
    8. Summary of Benefits and Costs
    9. Benefits and Costs of Regulatory Options
    10. Cost Effectiveness Analysis
    11. Uncertainties in the Analysis
    C. Final Regulatory Flexibility Analysis
    1. Introduction
    2. Economic Effects on Small Entities
    3. Regulatory Options
    4. Description of Recordkeeping and Reporting
    5. Summary
    D. Unfunded Mandates
XXV. Analysis of Environmental Impact
XXVI. Federalism
XXVII. References

I. Background and Related Information

    On October 25, 1994, the Dietary Supplement Health and Education 
Act (DSHEA) (Public Law 103-417) was signed into law. DSHEA, among 
other things, amended the Federal Food, Drug, and Cosmetic Act (the 
act) by adding section 402(g) of the act (21 U.S.C. 342(g)). Section 
402(g)(2) of the act provides, in part, that the Secretary of Health 
and Human Services (the Secretary) may, by regulation, prescribe good 
manufacturing practices for dietary supplements. Section 402(g) of the 
act also stipulates that such regulations shall be modeled after CGMP 
regulations for food and may not impose standards for which there are 
no current and generally available analytical methodology. The final 
rule establishes, in part 111 (21 CFR part 111), the minimum CGMPs 
necessary for activities related to manufacturing, packaging, labeling, 
or holding dietary supplements to ensure the quality of the dietary 
supplement. The final rule is one of many actions related to dietary 
supplements that we are taking to promote and protect the public 
health.
    In response to DSHEA, we issued an Advance Notice of Proposed 
Rulemaking (the 1997 ANPRM) in the Federal Register of February 6, 1997 
(62 FR 5700). The 1997 ANPRM contained a CGMP outline submitted to us 
on November 20, 1995, by representatives of the dietary supplement 
industry. The 1997 ANPRM also asked nine questions that addressed 
issues that the industry outline did not. For example, we asked if 
there is a need to develop specific defect action levels (DALs) for 
dietary ingredients. We also asked whether a CGMP rule should require 
manufacturers to establish procedures to document, on a continuing or 
daily basis, that they followed pre-established procedures for making 
dietary supplements.
    We received more than 100 comments in response to the 1997 ANPRM. 
We evaluated these comments before we drafted and ultimately issued a 
proposed rule on CGMPs for dietary ingredients and dietary supplements 
(which we discuss later in this section of this document).
    Additionally, during 1999, we conducted a number of outreach 
activities related to dietary supplements. We held several public 
meetings to develop our overall strategy for achieving effective 
regulation of dietary supplements, which could include establishing 
CGMP regulations. We also held public meetings focused specifically on 
CGMPs and the economic impact that any CGMP rule for dietary 
ingredients and dietary supplements might have on small businesses. 
Further, we toured several dietary supplement manufacturing facilities 
to better understand the manufacturing processes and practices that 
potentially would be subject to CGMP requirements for dietary 
ingredients and dietary supplements (Refs. 1 through 6). These 
activities contributed to our knowledge about the industry.
    In the Federal Register of March 13, 2003 (68 FR 12157), we 
published a proposed rule to establish CGMP requirements for dietary 
ingredients and dietary supplements (the 2003 CGMP Proposal). The 
preamble to the 2003 CGMP Proposal addressed the comments we had 
received regarding the nine questions in the 1997 ANPRM, discussed our 
legal authority to issue a CGMP rule, and described the basis for each 
proposed requirement.
    The 2003 CGMP Proposal specifically requested comment on a variety 
of areas, including the need for written procedures and recordkeeping 
requirements. Although the proposed rule's comment period was scheduled 
to end on June 11, 2003, in the Federal Register of May 19, 2003 (68 FR 
27008), we extended the comment period to August 11, 2003.
    After we published the proposed rule, we conducted and/or 
participated in outreach activities related to dietary supplements and 
dietary ingredients. We held public stakeholder meetings on April 29, 
2003, in College Park, MD, and on May 6, 2003, in Oakland, CA. We also 
held a public meeting, via satellite downlink, on May 9, 2003, with 
viewing sites at our district and regional offices throughout the 
country. These public meetings gave an overview of the proposed rule, 
and clarified specific points in the proposed rule. Since the public 
stakeholder meetings held as part of our outreach efforts, we also have 
participated in several meetings with industry and other interested 
parties which are reflected in the public docket.
    We received approximately 400 comments in response to the proposal. 
The comments came from trade associations, government organizations and 
officials, manufacturers of dietary supplements and dietary 
ingredients, health care practitioners, consumer groups, and 
individuals. In general, the comments supported the idea of CGMPs, 
although many comments disagreed with specific aspects of the proposal.
    Published elsewhere in this issue of the Federal Register we are 
also issuing an interim final rule that sets forth a procedure for 
requesting an exception to a CGMP requirement in this final rule. The 
interim final rule allows for submission to, and review by, FDA of an 
alternative to the required 100-percent identity testing of components 
that are dietary ingredients (as discussed in section X of this 
document (subpart E)), provided certain conditions are met. The interim 
final rule also includes a requirement for retention of records related 
to the FDA grant of an exception request.

[[Page 34757]]

II. How is the Final Rule Organized?

    The 2003 CGMP Proposal was divided into eight subparts, with each 
subpart devoted to a particular topic. For example, proposed subpart A 
was titled ``General Provisions'' and contained sections describing the 
rule's scope, purpose, definitions, applicability of other statutory 
and regulatory provisions, and exclusions. As another example, proposed 
subpart B was titled ``Personnel'' and described microbial 
contamination and hygiene requirements, personnel qualification 
requirements, and supervisor requirements.
    In response to comments seeking a simpler, more ``user-friendly'' 
final rule or seeking clarification of the rule's applicability to 
certain persons, items, or activities, and to reduce redundant 
provisions or combine similar provisions, we have reorganized the final 
rule into 16 subparts, with new subparts focusing on specific aspects 
of the manufacturing process or addressing specific issues. For 
example, the proposed rule placed all production and process control 
requirements for manufacturing, packaging, labeling, and laboratory 
operations in a single subpart (proposed subpart E). The final rule 
creates separate subparts for the specific operations to make it easier 
to find the relevant production and process control requirements for a 
particular activity.
    Table 1 of this document summarizes how we reorganized the rule. We 
are providing this information to help readers understand the 
structural changes we made between the proposed and final rules.

  Table 1.--Reorganization and Revisions: 2003 CGMP Proposal and Final
                                  Rule
------------------------------------------------------------------------
                                                 Final         Final
 Proposed Subpart    Proposed Sections  in   Subpart  and   Sections  in
     and Title            the Subpart            Title      the Subpart
------------------------------------------------------------------------
A--General                            111.1  A--General    111.1
 Provisions                           111.2   Provisions   111.3
                                      111.3                111.5
                                      111.5
                                      111.6
------------------------------------------------------------------------
B--Personnel                         111.10  B--Personnel  111.8 (new)
                                     111.12                111.10
                                     111.13                111.12
                                                           111.13
                                                           111.14 (new)
------------------------------------------------------------------------
C--Physical Plant                    111.15  C--Physical   111.15
                                     111.20   Plant and    111.16 (new)
                                              Grounds      111.20
                                                           111.23
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.15(d)(3)
                                                            and (e)(2))
------------------------------------------------------------------------
D--Equipment and                     111.25  D--Equipment  111.25
 Utensils                            111.30   and           (formerly
                                              Utensils      proposed
                                                            Sec.
                                                            111.25(c)(1)
                                                            and (e)(1))
                                                           111.27
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.25 (a),
                                                            (b), (d)\1\,
                                                            and (e))
                                                           111.30
                                                           111.35
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.25
                                                            (c)(1),
                                                            (c)(2), (d),
                                                            (f),
                                                            111.30(b)(2)
                                                            , (b)(5),
                                                            and (c),
                                                            111.50(c)(4)
                                                            )
------------------------------------------------------------------------

[[Page 34758]]

 
E--Production and                    111.35  E--Requireme  111.55
 Process Controls                    111.37   nt to         (formerly
                                     111.40   Establish a   proposed
                                     111.45   Production    Sec.
                                     111.50   and Process   111.35(a))
                                     111.60   Control      111.60
                                     111.65   System        (formerly
                                     111.70                 proposed
                                     111.74                 Sec.
                                                            111.35(b))
                                                           111.65
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.35(c))
                                                           111.70
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.35(e),
                                                            (f), (g),
                                                            and (k))
                                                           111.73
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.35(f),
                                                            (g), and (h)
                                                           111.75
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.35(e)
                                                            through (i),
                                                            (k), and
                                                            (l)), Sec.
                                                            111.37(b)(11
                                                            (iv), and
                                                            Sec.
                                                            111.40(a)(2)
                                                           111.77 (new)
                                                           111.80
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.37(b)(11
                                                            ))
                                                           111.83
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.37(b)(12
                                                            ),
                                                            111.50(h),
                                                            and
                                                            111.83(b)(2)
                                                            )
                                                           111.87
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.35(i)
                                                            and (n),
                                                            111.37(b)(5)
                                                            and (b)(14),
                                                            111.40(a)(3)
                                                            ,
                                                            111.50(d)(1)
                                                            , and
                                                            111.85(a)
                                                            and (c))
                                                           111.90
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.35(i)(4)
                                                            ,
                                                            111.50(d)(1)
                                                            , (f), and
                                                            (g), and
                                                            111.65(d))
                                                           111.95
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.35(o))
------------------------------------------------------------------------

[[Page 34759]]

 
                    .......................  F--Productio  111.103 (new)
                                              n and        111.105
                                              Process       (formerly
                                              Control       proposed
                                              System:       Sec.
                                              Requirement   111.37(a),
                                              s for         (b)(1),
                                              Quality       (b)(11), and
                                              Control       (b)(12))
                                                           111.110
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.37(b)(9)
                                                            and (b)(13))
                                                           111.113
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.35(i)(2)
                                                            , (i)(3),
                                                            (i)(4)(i),
                                                            (i)(4)(ii),
                                                            (j), and
                                                            (n),
                                                            111.37(b)(3)
                                                            and (c),
                                                            111.40(a)(3)
                                                            and (b)(2),
                                                            111.50(d)(1)
                                                            , 111.65(d),
                                                            and
                                                            111.70(c))
                                                           111.117
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.30(b)(4)
                                                            and
                                                            111.37(b)(6)
                                                            through
                                                            (b)(8))
                                                           111.120
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.35(i)(4)
                                                            (i) and
                                                            (i)(4)(ii),
                                                            111.37(b)(2)
                                                            and (b)(10),
                                                            111.40(a)(3)
                                                            and (b)(2),
                                                            and
                                                            111.50(e)(1)
                                                            )
                                                           111.123
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.35(e)(2)
                                                            , (f),
                                                            (i)(2), and
                                                            (o)(2)
                                                            111.37(a),
                                                            (b)(2),
                                                            (b)(4),
                                                            (b)(5), and
                                                            (b)(11),
                                                            111.45(c),
                                                            and
                                                            111.50(d)(1)
                                                            , (d)(2),
                                                            and (g))
                                                           111.127
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.37(b)(2)
                                                            , (b)(10),
                                                            and (b)(11),
                                                            111.40(a)(2)
                                                            and (a)(3),
                                                            and
                                                            111.70(c),
                                                            (d) and (e))
                                                           111.130
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.37(b)(2)
                                                            and (b)(15),
                                                            and
                                                            111.85(a))
                                                           111.135 (new)
                                                           111.140
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.35(j)
                                                            and
                                                            111.37(c)
                                                            and (d)
------------------------------------------------------------------------
                    .......................  G--Productio  111.153 (new)
                                              n and        111.155
                                              Process       (formerly
                                              Control       proposed
                                              System:       Sec.  Sec.
                                              Requirement   111.35(d)(1)
                                              s for         through
                                              Components,   (d)(5) and
                                              Packaging,    111.40(a)(1)
                                              and Labels    through
                                              and for       (a)(5))
                                              Product      111.160
                                              That You      (formerly
                                              Receive for   proposed
                                              Packaging     Sec.  Sec.
                                              or Labeling   111.35(e)(4)
                                              a Dietary     , and
                                              Supplement    111.40(a)(2)
                                                            and (b)(1)
                                                            through
                                                            (b)(4))
                                                           111.165
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.40(a)(1)
                                                            through
                                                            (a)(5))
                                                           111.170
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.74)
                                                           111.180
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.35(d)(4)
                                                            , and
                                                            111.40(c)(1)
                                                            (i) through
                                                            (c)(1)(iv)
                                                            and (c)(2))
------------------------------------------------------------------------
                    .......................  H--Productio  111.205
                                              n and         (formerly
                                              Process       proposed
                                              Control       Sec.
                                              System:       111.45(a)(1)
                                              Requirement   , (a)(2),
                                              s for the     and (d))
                                              Master       111.210
                                              Manufacturi   (formerly
                                              ng Record     proposed
                                                            Sec.
                                                            111.45(b))
------------------------------------------------------------------------

[[Page 34760]]

 
                    .......................  I--Productio  111.255
                                              n and         (formerly
                                              Process       proposed
                                              Control       Sec.
                                              System:       111.50(a),
                                              Requirement   (b), and
                                              s for the     (i))
                                              Batch        111.260
                                              Production    (formerly
                                              Record        proposed
                                                            Sec.  Sec.
                                                            111.35(i)(2)
                                                            , (j), (m),
                                                            and (o)(2),
                                                            111.37(b)(3)
                                                            , (b)(5),
                                                            (b)(9) and
                                                            111.50(c)(1)
                                                            through
                                                            (c)(11),
                                                            (c)(13),
                                                            (c)(14),
                                                            (d)(2), (e),
                                                            and (g), and
                                                            111.70(b)(6)
                                                            and (g))
------------------------------------------------------------------------
                    .......................  J--Productio  111.303 (new)
                                              n and        111.310
                                              Process       (formerly
                                              Control       proposed
                                              System:       Sec.
                                              Requirement   111.60(a))
                                              s for        111.315
                                              Laboratory    (formerly
                                              Operations    proposed
                                                            Sec.
                                                            111.60(b)(1)
                                                            )
                                                           111.320
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.60(c)
                                                            and (d))
                                                           111.325
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.60(b)(2)
                                                            and (b)(3))
------------------------------------------------------------------------
                    .......................  K--Productio  111.353 (new)
                                              n and        111.355
                                              Process       (formerly
                                              Control       proposed
                                              System:       Sec.
                                              Requirement   111.65(a))
                                              s for        111.360
                                              Manufacturi   (formerly
                                              ng            proposed
                                              Operations    Sec.
                                                            111.65(b))
                                                           111.365
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.65(c))
                                                           111.370
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.74)
                                                           111.375 (new)
------------------------------------------------------------------------
                    .......................  L--Productio  111.403 (new)
                                              n and        111.410
                                              Process       (formerly
                                              Control       proposed
                                              System:       Sec.
                                              Requirement   111.70(a),
                                              s for         (b)(6), and
                                              Packaging     (f))
                                              and          111.415
                                              Labeling      (formerly
                                              Operations    proposed
                                                            Sec.
                                                            111.70(b))
                                                           111.420
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.70(d)
                                                            and (e))
                                                           111.425
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.74)
                                                           111.430
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.70(g)
                                                            and (h))
------------------------------------------------------------------------
F--Holding and                       111.80  M--Holding    111.453 (new)
 Distributing                        111.82   and          111.455
                                     111.83   Distributin   (formerly
                                     111.85   g             proposed
                                     111.90                 Sec.
                                                            111.80)
                                                           111.460
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.82)
                                                           111.465
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.83(b)(1)
                                                            and (b)(2))
                                                           111.470
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.90)
                                                           111.475 (new)
------------------------------------------------------------------------

[[Page 34761]]

 
                    .......................  N--Returned   111.503 (new)
                                              Dietary      111.510
                                              Supplements   (formerly
                                                            proposed
                                                            Sec.
                                                            111.85(a))
                                                           111.515
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.85(b)
                                                            and (c))
                                                           111.520
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.37(b)(15
                                                            ))
                                                           111.525
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.50(g))
                                                           111.530
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.85(d))
                                                           111.535
                                                            (formerly
                                                            proposed
                                                            Sec.  Sec.
                                                            111.50(g)
                                                            and
                                                            111.85(e)
                                                            and (f))
------------------------------------------------------------------------
G--Consumer                          111.95  O--Product    111.553 (new)
 Complaints                                   Complaints   111.560
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.95(a)
                                                            through (d))
                                                           111.570
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.95(e)
                                                            and (f))
------------------------------------------------------------------------
H--Records and                      111.125  P--Records    111.605
 Recordkeeping                                and           (formerly
                                              Recordkeepi   proposed
                                              ng            Sec.
                                                            111.125((a)
                                                            and (b))
                                                           111.610
                                                            (formerly
                                                            proposed
                                                            Sec.
                                                            111.125(b)
                                                            and (c))
------------------------------------------------------------------------
\1\The reference to (d) is the second (d) in the proposed rule in this
  section due to a misnumbering in the proposed rule.

    We discuss all subparts and sections, and our reasons for amending 
or creating subparts and sections, in our discussion of the comments to 
the proposal.

III. What Does the Final Rule Do?

A. Overview of CGMP

    In considering the specific requirements necessary for dietary 
supplement CGMPs, we considered information from a variety of sources. 
We considered information from our outreach activities, as described in 
section I of this document; comments to the 2003 CGMP Proposal; our own 
knowledge and expertise about CGMP for foods, including dietary 
supplements; and characteristics of CGMP that apply to manufacturing, 
labeling, packaging, and holding operations.
    The general food CGMPs in part 110 (21 CFR part 110) largely 
address practices designed to ensure that food is manufactured, 
processed, packed, and held under sanitary conditions and that the food 
is safe, clean, and wholesome. Although the general food CGMPs in part 
110 apply to a variety of food products, including dietary supplements, 
they do not address the unique characteristics of certain specific 
types of food products. The agency has implemented separate, and more 
specific, CGMPs for various types of food products to provide for 
process controls in manufacturing that are not captured by the more 
general part 110 food CGMPs. (See discussion in section V of this 
document (``Legal Authority'') on product specific CGMP requirements). 
At the time DSHEA was enacted, there were four such additional, 
specific food CGMP regulations: Those for infant formula (part 106 (21 
CFR part 106)), thermally processed low-acid canned food (part 113 (21 
CFR part 113)), acidified food (part 114 (21 CFR part 114)), and 
bottled water (part 129 (21 CFR part 129)).
    Dietary supplements are a type of food product for which specific 
food CGMPs also are needed. Manufacturing process controls are needed 
to ensure that a dietary supplement contains what the manufacturer 
intends. Unlike most foods, the majority of dietary supplements are 
packaged into tablets, gelcaps, and capsules. Some dietary supplements 
may contain bioactive ingredients for which certain, controlled amounts 
are intended to be in each tablet or capsule. The process controls that 
must be in place to ensure the tablet or capsule contains what it 
purports to contain are different than those that must be in place to 
ensure a food is manufactured, processed, packed, and held under 
sanitary conditions. Process controls for dietary supplement 
manufacture include establishing and meeting specifications to ensure 
the finished dietary supplement contains the correct ingredient, 
purity, strength, and composition intended.
    Vitamins can present a concentrated source of biologically active 
components. A vitamin, for example, that contains too high a 
concentration, such as vitamin D at levels that are many times greater 
than intended, can lead to illness and hospitalization (Refs. 7 and 8). 
A manufacturer must establish a process for manufacturing a dietary 
supplement product in order to produce the product consistently and 
reliably each time. In order to achieve consistency and reliability, 
there must be process controls in place to ensure, for example, that 
appropriate tests and examinations are conducted, a master 
manufacturing record is prepared, each batch production follows the 
master manufacturing record, and the finished tablet or capsule is 
placed in the intended package with the intended label.
    These same types of controls are needed for herbal and botanical 
dietary supplements. Botanicals are often complex mixtures that can 
vary in

[[Page 34762]]

composition depending on factors such as the part of the plant used, 
the location of harvesting and growing conditions that can vary from 
year to year even in the same location. It can be difficult to 
distinguish between closely related species of botanicals, and the 
biological activity of components of an incorrectly identified species 
can lead to adverse consequences. In addition, different species may be 
present in different ratios or blends in a particular product. Various 
products might contain different parts of the plant--flower, leaf, 
root, stem, extract--and the test methods for each can vary in the 
nature, sensitivity, and specificity of the test.
    Well-established principles of CGMP require process controls at 
each step of the manufacturing process as early in the production 
process as possible. Quality cannot be tested into the product only at 
the end (Ref. 9). Instead, the quality of the dietary supplement must 
be built into the product throughout the manufacturing process; quality 
begins with the starting material and continues with the product being 
manufactured in a reproducible manner according to established 
specifications. It is not sufficient, nor effective, to rely solely on 
end product testing to assure the quality of the individual dietary 
supplement product sold to the consumer.
    CGMPs are intended to establish a comprehensive system of process 
controls, including documentation of each stage of the manufacturing 
process, that can minimize the likelihood of, or detect, problems and 
variances in manufacturing as they occur and before the product is in 
its finished form. These process controls that are a part of CGMPs are 
essential to ensure that the dietary supplement is manufactured, 
packaged, held, and labeled in a consistent and reproducible manner.
    Manufacturing according to CGMP means that the manufacturing 
process incorporates a set of controls in the design and production 
processes to assure a quality finished product. CGMPs specific to 
dietary supplements are necessary to help ensure that these products 
have the identity, purity, strength, and composition that meet 
specifications established in the master manufacturing record and that 
they are not adulterated.
    Many comments stressed that the most critical aspect of a 
successful CGMP system is effective process control. Comments asserted 
that, with effective process control, quality is built into a product 
throughout the entire production process. The term ``quality'' came up 
repeatedly in comments as the desired outcome of the dietary supplement 
manufacturing process.\1\ In fact, several comments asked us to define 
``quality'' and suggested various definitions, each of which related to 
a dietary supplement having the identity, purity, strength, and 
composition intended (see comment 49 in section VI of this document). 
Some comments distinguished the concept of quality from that of 
preventing adulteration. These comments objected to our statement that 
dietary supplement CGMP requirements are needed to prevent adulteration 
and stated that CGMP is focused on assuring that finished products are 
manufactured using quality procedures, but are not related to 
preventing adulteration. Other comments asked us to define 
``adulteration.''
---------------------------------------------------------------------------

    \1\ Throughout this final rule, we refer to the ``manufacture'' 
or ``manufacturing process'' of dietary supplements. We use these 
terms in the broad sense, i.e., the terms refer to those activities 
that may be done from receipt of raw ingredients through the 
distribution of a finished dietary supplement, including labeling, 
packaging, and holding activities. We discuss the various roles and 
responsibilities of those who ``manufacture'' dietary supplements in 
the context of final Sec.  111.1 ``Who is subject to this part?'' We 
also sometimes use the terms to apply to only part of the process, 
i.e., those operations other than labeling, packaging, and holding.
---------------------------------------------------------------------------

    We agree that a critical aspect of CGMP is achieving control over 
manufacturing processes. Controls are necessary to ensure that you 
manufacture what you intend so that the characteristics and/or 
attributes desired in a final product will be consistently and reliably 
achieved. We disagree with the comments to the extent that they were 
suggesting that quality is not related to preventing contamination in 
the manufacturing process that may adulterate the finished product. 
However, we have reconsidered, as discussed in this section, what types 
of adulteration and misbranding are necessary to control for in this 
dietary supplement CGMP rule.
    To clarify what dietary supplement CGMP requirements are intended 
to achieve, we have added a definition of quality in the final rule. As 
defined, quality means ``that the dietary supplement consistently meets 
the established specifications for identity, purity, strength, and 
composition and has been manufactured, packaged, labeled, and held 
under conditions to prevent adulteration under section 402(a)(1), 
(a)(2), (a)(3), and (a)(4) of the Federal Food, Drug, and Cosmetic 
Act.'' Ensuring the quality of the dietary supplement means that you 
consistently and reliably manufacture what you intend and that you 
establish manufacturing controls to prevent the dietary supplement from 
being adulterated under section 402(a)(1) of the act due to the 
presence of contaminants, under section 402(a)(2) of the act, for 
example, if it bears or contains any unintentionally added poisonous or 
deleterious substance, under section 402(a)(3) of the act if the 
dietary supplement consists in whole or in part of any filthy, putrid, 
or decomposed substance, or if it is otherwise unfit for food, or under 
section 402(a)(4) of the act if the dietary supplement has been 
prepared, packed, or held under insanitary conditions whereby it may 
have become contaminated with filth, or whereby it may have been 
rendered injurious to health. The definition of quality limits to 
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act the types of 
adulteration that you must control for in this CGMP final rule. The 
definition applies to the controls that are designed to prevent 
contamination of the product that you intend to manufacture.
    In the 2003 CGMP Proposal, we said that our purpose was to present 
a broad enough scope to the proposed rule so that we could receive the 
depth and breadth of comment needed to develop a final rule that would 
provide the proper balance of regulation (68 FR 12157 at 12161). We 
asked for comment on whether each of the provisions proposed was 
necessary to ensure the safety and quality of the dietary supplement 
and was adequate to protect the public health (id.). We stated that the 
proposed rule ``would establish the minimum CGMPs necessary to ensure 
that, if you engage in activities related to manufacturing, packaging, 
or holding dietary ingredients or dietary supplements, you do so in a 
manner that will not adulterate and misbrand such dietary ingredients 
or dietary supplements'' (68 FR 12157 at 12158). For example, we stated 
that the proposed rule would require the manufacturer to test for toxic 
compounds in botanicals that may likely be present to ensure that no 
such compounds are present that may adulterate the dietary supplement 
(68 12157 FR at 12162). Further, we included a requirement that the 
ingredients, other than dietary ingredients under section 201(ff) of 
the act, be lawful under the applicable food additive regulations or be 
generally recognized as safe (GRAS) (proposed Sec.  111.35(d).
    The approach that we set forth in the 2003 CGMP Proposal was 
designed to prevent a manufacturer, under CGMP regulations, from using 
an ingredient, whether a dietary ingredient or another

[[Page 34763]]

component, in the manufacture of a dietary supplement that would 
adulterate the product under relevant provisions of the act, such as 
section 402(a)(1) or (a)(2)(C). The manufacturer would have been 
required to establish specifications at any point, step, or stage in 
the manufacturing process where control is necessary to prevent 
adulteration (proposed Sec.  111.35(e)). Thus, the manufacturer would 
not have been able to establish a specification, consistent with 
proposed Sec.  111.35(e), for the use of an unlawful ingredient because 
such use would not prevent adulteration. In addition, the manufacturer 
would have to establish specifications for contaminants that may 
adulterate or that could lead to adulteration of the dietary 
supplement. The manufacturer would have to take necessary precautions 
to prevent the presence or level of contaminants, that would otherwise 
adulterate the dietary supplement under another provision of the act, 
from being present in the dietary supplement. The specifications were 
intended to ensure that adulterated and misbranded dietary supplements 
would not reach the marketplace (68 FR 12157 at 12197).
    In addition to the general specifications established under 
proposed Sec.  111.35(e), the proposed rule would have required the 
manufacturer to establish specifications for the identity, purity, 
quality, strength, and composition of the components received (proposed 
Sec.  111.35(e)(1)) and for the finished batch of dietary supplement 
(proposed Sec.  111.35(e)(3)). Although we stated that the proposed 
rule did not address questions related to the safety of dietary 
ingredients used (68 FR 12157 at 12172), if a dietary ingredient was 
deemed to be unsafe under the act--under section 402(a)(1) or another 
provision--a specification could not have been established for that 
dietary ingredient, consistent with proposed Sec.  111.35(e). Thus, a 
manufacturer would not be able to use, under dietary supplement CGMP, a 
dietary ingredient, or other component, that would otherwise adulterate 
the product under another provision of the act.
    Further, the proposed rule was designed to ensure that the correct 
label was applied during manufacture so that the dietary supplement 
label would accurately identify the dietary supplement (proposed 
Sec. Sec.  111.45(b)(7), 111.50(c)(12), and 111.70(b)(7)). The proposed 
rule also would have required the master manufacturing record to 
contain the identity of each ingredient that is required to be declared 
on the ingredient list in section 403 of the act (21 U.S.C. 343) 
(proposed Sec.  111.45(b)(4)).
    Several comments seemed to question why the dietary supplement CGMP 
rule would require that a manufacturer use lawful ingredients when 
other provisions of the act would require such use. In fact, some 
comments objected to the proposed requirement in the rule that required 
that a component, other than a dietary ingredient, be approved for use 
as a food additive or be GRAS. The comments stressed that such a 
provision was not necessary because the statute already requires that 
such an ingredient be approved as a food additive or be GRAS. In light 
of these comments, we reconsidered our interpretation of the scope of 
``prevent adulteration'' in the proposed rule and whether that 
interpretation should be narrowed. We also considered whether to 
require, as part of a CGMP requirement, that the label that accurately 
reflects the ingredients in the product be applied or whether such a 
requirement was not necessary, given our existing authority in section 
403 of the act.
    We determined that ensuring quality in dietary supplement CGMP, in 
part, means that you produce what you intend to produce. As stated in 
section V of this document, manufacturers must plan what they intend to 
produce, institute adequate controls to achieve the desired outcome, 
and ensure that the controls work so that the desired outcome is 
consistently achieved. Thus, for example, the manufacturer decides on 
the identity, purity, strength, and composition of the dietary 
supplement it manufactures. The focus of CGMP is on process controls to 
ensure that the desired outcome is consistently achieved, and not on 
the inherent safety of the ingredients used (which is addressed by 
other statutory prohibitions).
    We agree with the comments that the safety of a particular 
ingredient is governed by other provisions of the act. If you 
manufacture a dietary supplement, you have a responsibility as a 
manufacturer to evaluate the safety of the ingredients under, for 
example, section 402(f) of the act.\2\ Dietary supplement CGMP would 
require you to establish the identity, purity, strength, and 
composition specifications for the product and ensure that such 
specifications are met in the finished batch of dietary supplement. 
Nothing in the dietary supplement CGMPs relieves manufacturers from 
complying with any other substantive provisions of the act relating to 
the safety of ingredients and other components.
---------------------------------------------------------------------------

    \2\Under section 402(f) of the act, a dietary supplement is 
deemed to be adulterated if it is or contains a dietary ingredient 
that presents a significant or unreasonable risk of illness or 
injury under conditions of use recommended or suggested in labeling 
or, if no such conditions, under ordinary conditions of use.
---------------------------------------------------------------------------

    Quality not only means that you produce what you intend, but that 
you prevent contamination in your manufacturing process that could 
adulterate your product. Food CGMP regulations, after which the dietary 
supplement CGMP rule is modeled, require that the manufacturer take 
precautions to ensure that the manufacturer does not adulterate the 
product under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. 
For example, under Sec.  110.5 (food CGMP), the criteria and 
definitions apply in determining whether a food is adulterated under 
section 402(a)(3) and (a)(4) of the act. Specifically, Sec.  
110.80(a)(2) states that raw materials shall not contain levels of 
microorganisms that may produce food poisoning or other disease in 
humans, unless otherwise treated during manufacturing operations so 
that they no longer contain levels that would adulterate the product 
within the meaning of the act. In addition, Sec.  110.80(a)(3) states 
that raw materials and other ingredients susceptible to contamination 
with natural toxins must comply with current FDA regulations and action 
levels for poisonous or deleterious substances before such materials 
are incorporated into finished food. Under dietary supplement CGMP, we 
believe it is appropriate to require you to establish specifications 
that are designed to prevent adulteration under section 402(a)(1), 
(a)(2), (a)(3), and (a)(4) of the act from contamination during the 
manufacturing, packaging, labeling, and holding operations. For 
example, if you are manufacturing a dietary supplement that you know is 
likely to contain a contaminant, you would need to establish limits on 
the contaminant in your supplement, and you must design these limits to 
prevent the dietary supplement from being adulterated under section 
402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
    Quality, as the term is used for the purposes of this final rule, 
relates both to producing what is intended (i.e., establishing and 
ensuring that specifications for the identity, purity, strength, and 
composition are met) and to ensuring that the dietary supplement that 
you intend to produce has been manufactured, packaged, labeled, and 
held under conditions to prevent adulteration within the meaning of 
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. Thus, this 
final rule is not designed to specifically prevent all

[[Page 34764]]

types of adulteration that may occur under the act. Rather, this final 
rule is designed to prevent adulteration from those types of 
contamination that are commonly controlled in other food CGMP 
regulations. We do expect, however, that compliance with CGMP 
requirements in the final rule will help to avoid other types of 
adulteration. Also, nothing in this rule exempts a manufacturer from 
compliance with other relevant adulteration provisions of the act.
    We are replacing the phrase ``prevent adulteration'' in the 
codified with words that relate to ensuring the quality of the dietary 
supplement. Thus, for example, we have modified proposed Sec.  
111.35(e) (now final Sec.  111.70(a)) to read, ``You must establish a 
specification for any point, step, or stage in the manufacturing 
process where control is necessary to ensure the quality of the 
finished dietary supplement and that the dietary supplement is packaged 
and labeled as specified in the master manufacturing record'' instead 
of ``* * * necessary to prevent adulteration.'' This phrase is replaced 
in several codified provisions and an explanation of this change is not 
provided in the preamble of this document each time it is made.
    Moreover, you have a responsibility under CGMP to ensure that the 
label you specify in the master manufacturing record is applied to the 
product. Under section 403 of the act, you are required to ensure that 
your label accurately reflects the ingredients in the product. Because 
section 403 of the act provides that food, including dietary 
supplements, is misbranded if a label that does not contain accurate 
statements is applied, we do not need to impose the same requirement in 
this final rule. Thus, if the representative label in the master 
manufacturing record for the product does not identify the correct 
dietary ingredients and the label that lists inaccurate information is 
applied, that dietary supplement would be misbranded under section 403 
of the act. Such labeling would not be a violation of dietary 
supplement CGMP unless there is a mixup in your process control and you 
do not put the representative label specified in the master 
manufacturing record on the product. Such a mixup would be a violation 
of dietary supplement CGMP requirements (see e.g., final Sec. Sec.  
111.127(d), 111.160(e), 111.410(c), 111.415).
    Thus, in addition to stating ``ensure the quality of the dietary 
supplement,'' in the codified instead of ``prevent adulteration,'' we 
are adding the language ``and that the dietary supplement is packaged 
and labeled as specified in the master manufacturing record.'' Such 
change is intended to clarify that the use of the packaging and 
labeling that is stated in the master manufacturing record is what is 
required in this final rule.
    A failure to follow the requirements in this final rule, including 
a failure to establish required specifications, could result in an 
enforcement action by the agency under section 402(g) of the act 
because the dietary supplement is adulterated in that it was prepared, 
packed, labeled, or held under conditions that do not meet CGMPs for 
dietary supplements. The act establishes certain prohibited acts and 
enforcement mechanisms to remove adulterated product from the market 
and prevent manufacturers from continuing to manufacture adulterated 
product. Enforcement mechanisms currently available to us under the act 
are not affected by this final rule.
    Finally, we have included in this final rule the existing 
requirements in part 110 that we believe are common to dietary 
supplement manufacturing. For example, the requirements in subpart C, 
Physical Plant and Grounds, are similar to those in Sec.  110.20. We 
recognize that there may be operations related to the manufacturing of 
dietary supplements for which certain provisions in part 110 apply, but 
that we did not determine to be common to most dietary supplement 
manufacturing operations. For example, there may be some dietary 
supplements that are dehydrated and rely on the control of moisture 
consistent with Sec.  110.80(b)(14). A manufacturer would be expected 
to comply with the regulations in part 110 in addition to the 
regulations in part 111, unless the regulations conflict. To the extent 
that the regulations conflict, the dietary supplement manufacturer must 
comply with the regulation in part 111.

B. Highlights of the Final Rule

    The final rule:
    <bullet> Applies to persons who manufacture, package, label, or 
hold dietary supplements unless subject to an exclusion in Sec.  111.1;
    <bullet> Establishes minimum requirements for personnel, physical 
plant and grounds, and equipment and utensils;
    <bullet> Requires the establishment and use of written procedures 
for certain operations, including those related to equipment, physical 
plant sanitation, certain manufacturing operations, quality control, 
laboratory testing, packaging and labeling, and product complaints;
    <bullet> Requires the establishment of specifications in the 
production and process control system that will ensure dietary 
supplements meet the identity, purity, strength, and composition 
established in specifications and are properly packaged and labeled as 
specified in the master manufacturing record;
    <bullet> Provides for the option to use a certificate of analysis 
(for specifications other than the identity of a dietary ingredient) 
from a component supplier instead of having manufacturers conduct tests 
or examinations on the components they receive;
    <bullet> Requires testing of a subset of finished batches of 
dietary supplements based on a sound statistical sampling or, 
alternatively, testing all finished batches;
    <bullet> Requires implementation of quality control operations to 
ensure the quality of a dietary supplement;
    <bullet> Requires the preparation and use of a written master 
manufacturing record for each unique formulation of manufactured 
dietary supplement, and for each batch size, to ensure your 
manufacturing process is performed consistently and to ensure 
uniformity in the finished batch from batch to batch;
    <bullet> Requires the preparation of a batch production record 
every time a dietary supplement batch is made. The batch production 
record must accurately follow the appropriate master manufacturing 
record;
    <bullet> Requires the establishment and use of laboratory control 
processes related to establishing specifications and to the selection 
and use of testing and examination methods;
    <bullet> Requires reserve samples of dietary supplements to be held 
in a manner that protects against contamination and deterioration;
    <bullet> Requires identification and quarantine of returned dietary 
supplements until quality control personnel conduct a material review 
and make a disposition decision;
    <bullet> Requires quality control personnel to conduct a material 
review and make a disposition decision under certain circumstances;
    <bullet> Requires a qualified person to investigate any ``product 
complaint'' that involves a possible failure of a dietary supplement to 
meet any CGMP requirement, with oversight by quality control personnel; 
and
    <bullet> Requires records associated with the manufacture, 
packaging, labeling, or holding of a dietary supplement to be kept for 
1 year beyond the shelf life dating (when such dating is used, such as 
expiration dating, shelf life dating, or ``best if used by'' dating), 
or if shelf life dating is not used, for 2 years beyond the date of 
distribution of the last batch

[[Page 34765]]

of dietary supplements associated with those records.

IV. What General Comments Did We Receive?

    We received approximately 400 comments on the proposed rule. 
Although most comments support CGMP requirements for dietary 
supplements and dietary ingredients, others question the need for a 
regulation and many sought changes to the rule. We describe, in this 
section, comments on general aspects of the final rule. We include 
comments related to the structure and organization of the final rule, 
comments we received on why CGMP requirements are needed, and comments 
on written procedures. In addition, we describe some general comments 
we received on multiple sections of the proposed rule that we believe 
are better addressed in one response.
    To make it easier to identify comments and our responses, the word 
``comment,'' in parentheses, will appear before each comment, and the 
word ``response'' will appear before each response. We also have 
numbered the comments to make it easier to distinguish between 
comments; the numbers are for organizational purposes only and do not 
reflect the order in which we received the comments or any value 
associated with the comment.

A. What Comments Did We Receive on the Structure and Organization of 
the Rule?

    (Comment 1) Several comments seek to restructure or reorganize the 
rule. For example, one comment states we should simplify the entire 
section on production and process controls. The comment asserts it 
would be more logical to list contaminants that may adulterate a 
dietary supplement or lead to adulteration as part of the requirements 
for specifications (proposed Sec.  111.35(e)) than to list such 
contaminants as part of the testing requirements (proposed Sec.  
111.35(k)). Other comments say it would be more logical to list the 
tests that are considered appropriate as part of proposed Sec.  
111.35(h) (concerning appropriate tests or examinations to determine 
whether specifications are met) than to have a separate requirement for 
appropriate tests in proposed Sec.  111.35(l) (which listed the types 
of analyses that should be part of a test).
    Another comment claims the rule is too complex, asserting it would 
create chaos. Other comments say that the proposal's degree of detail 
required is unrealistic for small dietary supplement firms, and we 
should rewrite the rule to be more user friendly.
    Yet another comment says that any final rule we issue must clearly 
set forth CGMP requirements. This comment seems to suggest the 
requirements need to be more detailed in describing what is required. 
The comment asserts that ambiguities in interpretation could result in 
economic disadvantage for small businesses because they typically do 
not have in-house legal counsel and, thus, must be more conservative in 
interpreting ambiguous regulatory provisions.
    (Response) In response to these comments, as well as comments on 
specific subparts and provisions, we have reorganized the final rule 
and have re-phrased or introduced concepts in a ``user-friendly'' or 
plain language format. We also have eliminated certain redundant 
regulatory requirements and combined similar requirements. For example, 
rather than put all production and process control system requirements 
in a single subpart, we have reorganized the final rule to create a 
series of subparts that first describe the requirements for the overall 
design and implementation of the production and process control system 
and then describe the requirements of the individual operations 
associated with that system. We also present each requirement as a 
question rather than as a paragraph within a section. This question 
format will help readers focus on the subparts or sections that apply 
to specific operations.
    As another example, we reduced the redundancy associated with the 
interrelated nature of the proposed rule by combining most similar 
requirements. Both proposed Sec. Sec.  111.35(m) and 111.60(b)(2) would 
require you to keep testing and examination results. The final rule 
places this requirement in a single section (Sec.  111.325(b)(2)(ii)).
    The final rule also shortens the construction ``includes, but is 
not limited to'' to ``includes.'' We did this because the use of the 
word ``includes'' indicates that the specified list that follows is not 
exclusive. The phrase ``but is not limited to'' is unnecessary.
    Finally, some changes we have made to one specific section have an 
impact on other sections. For example, after considering the comments, 
we revised subpart B to require you to establish and follow written 
procedures to fulfill the requirements of subpart B. Those written 
procedures are records you must make and keep in accordance with the 
recordkeeping requirements of subpart P, thus we made changes to 
include that requirement of making and keeping records.

B. What Comments Did We Receive on the Need for Dietary Supplement CGMP 
Requirements?

    (Comment 2) Some comments state that dietary supplement CGMP 
requirements will protect consumers from supplements that contain 
inherently unsafe dietary ingredients. Other comments request that we 
take additional action to ensure the safety of dietary ingredients.
    (Response) This final rule focuses on the manufacturing practices 
of dietary supplements and not on whether certain dietary ingredients 
are or are not safe. Therefore, comments related to whether certain 
dietary ingredients are inherently unsafe and any request to take 
actions related to the inherent safety of dietary ingredients are 
outside the scope of this rule.
    (Comment 3) Some comments support the rule, explaining that it will 
address current problems with superpotent and subpotent dietary 
supplements, undeclared ingredients, and varying levels of ingredients. 
Others indicate the rule will better protect consumers and increase 
consumer confidence. One comment states that CGMP requirements for 
dietary supplements are not needed for responsible manufacturers 
because they already manufacture safe dietary supplements. Some 
comments state that dietary supplement CGMP requirements are not needed 
because the dietary supplements have a track record of safety. Other 
comments say there were more adverse events reported from drug use than 
from dietary supplement use and that a large number of Americans take 
dietary supplements, and on that basis suggested that dietary 
supplements are safer than foods or drugs.
    (Response) We agree the final rule will better protect consumers 
and help address the types of manufacturing problems identified in the 
preamble to the 2003 CGMP Proposal (see 68 FR 12157 at 12162 through 
12163) through consistent use of established production processes and 
controls.
    However, we disagree with the comments asserting dietary 
supplements have a track record of safety such that dietary supplement 
CGMP requirements are unnecessary. Section 402(g) of the act does not 
require us to establish a ``bad'' track record of safety in the 
manufacture of dietary supplements before we may issue a dietary 
supplement CGMP rule. Furthermore, we disagree with the comments 
comparing dietary supplement safety to drug safety; there

[[Page 34766]]

are different statutory requirements, different regulatory 
requirements, and different safety evaluations for dietary supplements 
and drugs.
    We also disagree that the final rule should apply only to 
manufacturers who cannot manufacture dietary supplements responsibly. 
Establishing who is or is not a responsible manufacturer is not a 
threshold requirement in section 402(g) of the act, and it would be 
impractical to regulate dietary supplement CGMP in such a manner, 
because parties may differ as to whether a particular manufacturer 
acted ``responsibly'' in a particular situation. All dietary supplement 
manufacturers are subject to this final rule, just as all dietary 
supplement manufacturers are subject to section 402(g) of the act. We 
therefore are not persuaded that dietary supplement CGMP requirements 
are not needed, or should only be applied to manufacturers who have not 
acted ``responsibly.''
    (Comment 4) Some comments state that our authority under the 
current food CGMP regulation in part 110 and our authority to take 
actions against adulterated and misbranded products generally are 
sufficient. Other comments state that DSHEA gives us the necessary 
legal authority to protect the public health and that additional 
regulatory requirements are unnecessary. Several comments object to our 
statement that dietary supplement CGMP requirements are needed to 
prevent adulteration. These comments suggest dietary supplement CGMP is 
focused on ensuring finished products are manufactured using quality 
procedures, but are not related to preventing adulteration. Other 
comments state we should enforce current food CGMP regulations rather 
than adopt new regulations.
    (Response) We disagree that dietary supplement CGMP requirements 
are not related to preventing adulteration. In fact, under the 
statutory scheme a dietary supplement is deemed to be adulterated under 
section 402(g)(1) of the act if it fails to meet CGMP requirements we 
promulgate by regulation. As we discussed in section III of this 
document, dietary supplement CGMP requirements are necessary to ensure 
the quality of the dietary supplement; ensuring quality includes 
ensuring that the dietary supplement has been manufactured, packaged, 
labeled, and held under conditions to prevent adulteration under 
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
    We also disagree with those comments stating that the requirements 
in part 110 are adequate and that no additional requirements are 
necessary. The comments do not explain why the specific requirements 
set forth in the proposed rule that are not also in part 110 are 
unnecessary. As discussed in greater detail in response to comments on 
our legal authority in section V of this document, the particular 
characteristics and hazards of dietary supplements call for CGMP 
requirements tailored to dietary supplements. Congress specifically 
provided independent authority under section 402(g) of the act for us 
to promulgate CGMP requirements for dietary supplements. That authority 
would have been unnecessary if Congress had concluded that part 110 was 
adequate.
    We also disagree that enforcement of part 110 would eliminate a 
need for dietary supplement CGMP requirements. The dietary supplement 
CGMP requirements include practices specifically tailored to the 
characteristics and hazards of dietary supplements and their 
manufacturers. The comments asserting that current food CGMP 
requirements in part 110 are sufficient provided no persuasive or 
compelling reasons for that assertion, or for why we should not 
implement dietary supplement CGMP requirements under section 402(g) of 
the act. For these reasons, we are not persuaded by the comments that 
these dietary supplement CGMP requirements are not needed.
    (Comment 5) Some comments object to the examples of manufacturing 
problems that we used to support the need for CGMP requirements. 
Specifically, some comments object to the Prevention magazine citation 
and also object to the nine examples we presented in the preamble to 
the 2003 CGMP Proposal (see 68 FR 12157 at 12161 through 12163). We 
cited the Prevention magazine survey on consumer use of dietary 
supplements to show that only 41 percent of surveyed consumers who use 
vitamins and minerals think those products are very safe, and only 50 
percent think the products are somewhat safe; among those using herbal 
products, only 24 percent thought the products were very safe, and only 
53 percent thought the products were somewhat safe. We noted that 74 
percent supported increased government regulation of dietary 
supplements (see, id.). As one example of adulterated dietary 
supplements caused by manufacturing practices, the preamble to the 2003 
CGMP Proposal mentioned an instance where a young woman suffered a 
life-threatening abnormal heart function that was traced to a 
mislabeled or contaminated dietary ingredient (68 FR 12157 at 12162). 
Another example involved recalls of super- and subpotent dietary 
supplements (id.).
    Comments objecting to the Prevention survey said it provided no 
rationale for why CGMP requirements are needed. Other comments said the 
nine examples we provided represent a failure to conform to an existing 
regulation and do not demonstrate a need for a new CGMP regulation for 
dietary supplements. One comment disagrees that the CGMP requirements 
would prevent adverse reactions, as one example suggested in the 
preamble to the 2003 CGMP Proposal (see 68 FR 12157 at 12162) because, 
the comment claims, most adverse reactions are not the result of 
manufacturing problems. Another comment states the example involving 
plantain (68 FR 12157 at 12162), where a raw material was labeled as 
``plantain'' when it was, in fact, Digitalis lanata (a plant that can 
cause life-threatening heart reactions), shows that, had there been a 
system in place to test finished product for purity and identity or to 
perform identity testing upon receipt, the manufacturer could have 
prevented that adulterated product from entering the market place. The 
comment states identity testing is necessary in the final rule.
    Another comment objects to the example of ``non-food grade 
chemicals'' (id.) because the reference supporting the example involved 
Gamma-Butyrolactone, a substance we have stated is an unapproved new 
drug and not a dietary supplement. Some comments say the risks cited in 
the justification for these regulations are hypothetical or theoretical 
and current statutory or regulatory authority is adequate.
    (Response) We disagree, in most part, with the comments. We cited 
the Prevention survey to illustrate consumer perception and support for 
increased government involvement in dietary supplement regulation. We 
did not describe the survey as illustrating CGMP problems associated 
with dietary supplements.
    We also disagree that the risks cited in the preamble to the 2003 
CGMP Proposal are merely hypothetical or theoretical. We provided 
actual examples of failures in the manufacturing of products marketed 
as dietary supplements. The comments may have misunderstood what the 
CGMP requirements for dietary supplements are intended to accomplish. A 
principal goal of the CGMP requirements is to have those who 
manufacture, package, label, or hold dietary supplements do so in a 
manner that ensures the quality of the

[[Page 34767]]

dietary supplement and that the dietary supplement is packaged and 
labeled as specified in the master manufacturing record. It is the 
manufacturer who needs to establish procedures for its manufacturing 
operations to ensure, for example, the final product is produced 
according to its specifications in the master manufacturing record, 
meets limits on contaminants, and is a quality dietary supplement. If a 
product does not meet its specifications, a manufacturer who observes 
the CGMP requirements should know that and be able to take corrective 
action before the dietary supplement enters the marketplace. The onus 
is on the manufacturer, and not simply on us, to take action to prevent 
the adulterated product from entering the market or, if the product has 
already been released, to remove the product from the market. The 
umbrella food CGMP requirements in part 110 do not contain specific 
provisions establishing specifications, requiring identity testing, or 
requiring in-process and/or finished product testing. Through this 
final rule, we are establishing a new CFR part regarding CGMP 
requirements specifically for dietary supplements.
    The examples we used in the preamble to the 2003 CGMP Proposal 
included adverse event reports associated with contamination with 
Digitalis lanata, the possible contamination of botanical ingredients 
with toxic compounds, the use of non-food grade chemicals, the 
manufacture of super- and subpotent dietary supplements, the presence 
of undeclared ingredients, and the variability of ingredients from what 
is declared on the label (Refs. 7, 8, and 10; see, also, 68 FR 12157 at 
12162 through 12163). These were all examples where products were 
manufactured, labeled, and sold to the consumer as dietary supplements. 
We disagree with the comments' assertions that all these problems can 
be adequately dealt with by the food CGMP requirements in part 110, but 
agree with the comment that, had there been a system in place ``to 
perform identity testing upon receipt, the manufacturer could have 
prevented that adulterated product from entering the market place.'' 
Most of these examples present situations in which the manufacturer 
could have identified these problems through the dietary supplement 
CGMP requirements for specifications and testing or examination, such 
as identity verification, and could have prevented such products from 
entering the market or at least provided a greater assurance that such 
products would not make it into the marketplace. The dietary supplement 
CGMP requirements ensure adequate controls are in place to identify 
many of these types of manufacturing errors before the product is in 
the marketplace and not through postmarketing adverse event reports or 
consumers' illnesses.\3\
---------------------------------------------------------------------------

    \3\Mandatory reporting to FDA of serious adverse events is now 
required as a result of the enactment of the ``Dietary Supplement 
and Non-Prescription Drug Consumer Protection Act'' (Public Law 109-
462) signed into law on December 22, 2006 (see discussion in section 
XX of this document).
---------------------------------------------------------------------------

    The dietary supplement industry is diverse, as are the number and 
types of products marketed as dietary supplements. As we stated in the 
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12163), given the 
wide range of public health concerns presented by the manufacturing 
practices for dietary supplements, a comprehensive system of controls 
is necessary. This final rule will set the standards for CGMP for 
dietary supplements that, if followed, will help ensure the quality of 
the dietary supplement and that the dietary supplement is packaged and 
labeled as specified in the master manufacturing record. The 
establishment of production and process controls and adherence to these 
and other CGMP requirements of this final rule will help to prevent the 
types of events (and others) we described in the nine examples 
presented in the preamble to the 2003 CGMP Proposal.
    (Comment 6) Several comments suggest that dietary supplements are 
no different in safety or physiologic effect and require no different 
requirements than conventional food with respect to CGMP. One comment 
disagrees with us that dietary supplements require different 
requirements than conventional food because dietary supplements are 
ground up or in powder form and may not be easily recognized or 
differentiated; the comment says the same is true of many food 
ingredients as well.
    (Response) We disagree with the suggestions by these comments that 
dietary supplement CGMP requirements need not differ from those for 
conventional foods. By definition, a dietary supplement is in a 
category of food separate and distinct from the category of 
conventional food. The definition of dietary supplement in section 
201(ff) of the act, in part, essentially describes a dietary supplement 
as a type of food that differs from conventional food. The definition 
refers to section 411(c)(1)(B)(i) and (c)(1)(B)(ii) of the act (21 
U.S.C. 350(c)(1)(B)(i) and (c)(1)(B)(ii)), which describes the forms 
that dietary supplements intended to be ingested may take, i.e., 
tablet, capsule, powder, softgel, gelcap, or liquid form, and if not in 
such a form, limitations on how dietary supplements can be represented, 
i.e., not as conventional food or as a sole item of a meal or the diet.
    Congress included separate additional provisions under section 402 
of the act (see section 402(f) and (g) of the act) for when a dietary 
supplement may be adulterated. Congress considered that dietary 
supplements may warrant CGMP requirements that are different than those 
for conventional food. Although dietary supplements may include 
substances that are used as ingredients in conventional foods, the 
amounts consumed as a dietary supplement and as a conventional food 
product may not be the same and, in fact, may be more concentrated, and 
in higher amounts, when taken as a dietary supplement. The forms in 
which dietary supplements are consumed differ (e.g., capsule, tablet), 
as may the frequency, when compared to conventional foods. The uses of 
dietary supplements also differ from use as conventional food. 
Consequently certain manufacturing practices considered to be a part of 
CGMP for dietary supplement manufacturing may not be necessary for all 
types of food.

C. What Comments Did We Receive on Written Procedures?

1. Overview
    In the 2003 CGMP Proposal (68 FR 12157 at 12165), we stated that 
written procedures were included in the dietary supplement CGMP outline 
submitted to us by industry, namely, the National Nutritional Foods 
Association standards (NNFA), the NSF International draft standards, 
and the United States Pharmacopoeia (USP) draft manufacturing 
practices. We also stated that, to limit the burden to manufacturers, 
we were not proposing to require written procedures for all the 
requirements. We invited comment on whether we should require written 
procedures for a variety of operations; specifically, for complying 
with the CGMP requirements, under proposed Sec.  111.10 for personnel 
hygiene and for preventing microbial contamination due to personnel (68 
FR 12157 at 12182); maintenance, cleaning, and sanitation for the 
physical plant under proposed Sec.  111.15 (68 FR 12157 at 12187); 
calibrating instruments and controls under proposed Sec.  111.25(b), 
(c), and (d) (68 FR 12157 at 12191); maintaining, cleaning, and 
sanitizing equipment and utensils under proposed Sec.  111.25(e) (68

[[Page 34768]]

FR 12157 at 12192); calibrating, inspecting, and checking automatic 
equipment under proposed Sec.  111.30 (68 FR 12157 at 12193); the 
duties of the quality control unit under proposed Sec.  111.37 (68 FR 
12157 at 12201); implementing the proposed requirements for receipt of 
components, dietary supplements, packaging, and labels under proposed 
Sec.  111.40(a) and (b) (68 12157 at FR 12203); preparing the master 
manufacturing record under proposed Sec.  111.45 (68 FR 12157 at 
12205); laboratory operations under proposed Sec.  111.60 (68 FR 12157 
at 12209); manufacturing operations under proposed Sec.  111.65 (68 FR 
12157 at 12211); packaging and labeling operations under proposed Sec.  
111.70 (68 FR 12157 at 12213); holding components, dietary supplements, 
packaging, labels, and in-process materials under proposed Sec. Sec.  
111.80 and 111.82 (68 FR 12157 at 12214); identifying, quarantining, 
and salvaging returned dietary supplements under proposed Sec.  111.85 
(68 FR 12157 at 12216); and receiving, reviewing, and investigating 
consumer complaints under proposed Sec.  111.95 (68 FR 12157 at 12217).
    We stated that if comments assert that written procedures are 
necessary, comments should include an explanation of why the 
requirement is necessary to prevent adulteration including how such a 
requirement would ensure the identity, purity, quality, strength, and 
composition of the dietary supplement. Conversely, if comments assert 
that written procedures are not necessary, we asked for an explanation 
of why and how, in the absence of the requirement, one can prevent 
adulteration and ensure the identity, purity, quality, strength, and 
composition of the dietary supplement.
    (Comment 7) Many comments stress the most critical aspect of a 
successful CGMP system is effective process control, which requires 
conducting key operations using written procedures. Several comments 
assert that written procedures are an important part of manufacturing 
operations to ensure uniform practices in production operations, from 
receiving through final operations. Several comments assert written 
procedures provide a sound basis for employee training and supervision. 
Several comments state that without a written training program, it is 
very likely that some employees may not receive sufficient training, or 
in some cases, any CGMP training at all. One comment specifically 
suggests that companies develop written procedures for the minimum CGMP 
training common to all departments.
    One comment points out that all well-recognized quality systems 
require establishment of written procedures to ensure consistent 
process control, and cites examples such as the International 
Organization for Standardization, the American National Standards 
Institute (ANSI), and the Malcolm Baldridge National Quality Award 
criteria. Other comments state that written procedures are necessary 
for the definition, operation, and documentation of a process control 
system, and that without such procedures it would be virtually 
impossible for any company, regardless of size, to consistently 
manufacture products that meet established requirements for identity, 
purity, quality, strength, and composition. The comments note that 
written procedures contain the necessary instructions for all employees 
to successfully execute their respective functions. Another comment 
supports a requirement for conducting key operations using written 
procedures and states that records document that operations were 
performed, but that written procedures show how the task is to be 
performed and at what frequency it should be performed. One comment 
states effective communication is essential to build quality into a 
process, and written procedures provide that throughout all levels of 
an organization. Another comment states it is difficult to imagine how 
the quality control unit could carry out its obligations under proposed 
Sec.  111.37(b)(1) to ``approve or reject all processes, 
specifications, controls, tests, and examinations, and deviations from 
or modifications to them * * *'' if these are not subject to written 
procedures.
    Many comments which present one or more of these general reasons 
for requiring written procedures also list operations that they believe 
should be conducted using written procedures. The operations that one 
or more comments list as key operations are:
    <bullet> Employee training;
    <bullet> Cleaning the physical plant, including pest control;
    <bullet> Maintenance, cleaning, and sanitizing of equipment and 
utensils;
    <bullet> Calibration of equipment used in manufacturing or testing;
    <bullet> All aspects of the production process, including a general 
procedure to document the minimum investigation, review, and approval 
requirements for failures in manufacturing or packaging operations;
    <bullet> All quality control operations;
    <bullet> Reprocessing of batches or start-up materials that do not 
conform to specifications;
    <bullet> Receipt, identification, examination, handling, sampling, 
testing, and approval or rejection of components, packaging, and 
labels;
    <bullet> Laboratory operations, including the establishment of 
specifications and descriptions of laboratory test methods used to 
ensure that components, in-process materials, and finished product meet 
established specifications;
    <bullet> Packaging and labeling operations, including issuance and 
use of appropriate labels, labeling, and packaging materials;
    <bullet> Holding and distribution procedures, including procedures 
for quarantine and parameters for storage;
    <bullet> Return and salvage operations;
    <bullet> Handling of consumer complaints; and
    <bullet> Procedures for product recall.
    Many comments assert an effective process control system that 
includes extensive written procedures would justify a decreased testing 
burden with respect to the finished product. One comment suggests we 
exempt manufacturers from the requirement to test each finished batch 
of product if they have a qualified manufacturing process that meets 
certain basic criteria, including a requirement for written procedures 
for each stage of the process. One comment notes it would be clearer to 
all parties if specific written procedures were listed as required and 
stresses the importance of having all companies know exactly what is 
procedurally expected of them.
    In addition to these general reasons for requiring that key 
operations be conducted using written procedures, several comments 
provide specific reasons for requiring that specific operations be 
conducted using written procedures. In response to our request for 
comment on whether written procedures should be required for complying 
with proposed Sec.  111.10 (personnel hygiene and for preventing 
microbial contamination due to personnel), one comment states that 
written procedures help to ensure compliance with the proposed hygiene 
requirements by clearly listing the requirements and requiring the 
employees to follow them on a consistent basis.
    In response to our request for comment on whether written 
procedures should be required for complying with the proposed 
requirements for maintenance, cleaning, and sanitation for the physical 
plant under proposed Sec.  111.15, one comment states that having 
written procedures in place to clean the physical plant will ensure 
that there is no cross-contamination. Another comment states utility 
areas such as effluent treatment, boilers, cooling towers, and water

[[Page 34769]]

treatment plants also should have documented procedures for cleaning in 
order to create a general awareness of cleanliness throughout the 
plant. Other comments state that such written procedures should not be 
required because they would not directly prevent contamination or 
ensure the identity, purity, quality, strength, and composition of the 
dietary supplement if, as the ``bottom line,'' a manufacturer maintains 
the physical plant in a clean and sanitary condition.
    Responding to our request for comment on whether written procedures 
should be required for complying with the proposed requirements for 
calibrating instruments and controls under proposed Sec.  111.25(b), 
(c), and (d), several comments assert we should require manufacturers 
to establish and follow written procedures for calibrating equipment 
and controls. According to these comments, such procedures would 
provide us with a written record that is sufficient to evaluate the 
adequacy of the company's calibration procedures and would provide the 
necessary controls to meet the underlying intent of the rule. These 
comments assert that written procedures will lessen the risk that 
adulterated products will be produced.
    In response to our request for comment on whether written 
procedures should be required for complying with the proposed 
requirements for maintaining, cleaning, and sanitizing equipment and 
utensils under proposed Sec.  111.25(e), several comments assert such 
written procedures are crucial. These comments claim that written 
procedures promote consistency, clearly lay out expectations for 
employees, facilitate training, and provide a reference for individuals 
in performing their job functions. One comment states that written 
procedures for maintaining, cleaning, and sanitizing equipment are an 
industry standard.
    In response to our request for comment on whether written 
procedures should be required for complying with the proposed 
requirements for preparing the master manufacturing record under 
proposed Sec.  111.45, one comment states that written procedures for 
in-process control and quality checks should ensure the addition of the 
proper ingredients in the proper amount, and proper blending and 
control of other critical points. Another comment states written 
procedures are a critical element for ensuring consistent 
implementation of proper corrective action. Other comments state they 
do not support a requirement for written procedures for preparing the 
master manufacturing record; and one comment suggests such a written 
procedure is not necessary because the proposed regulations for 
preparing the master manufacturing record already delineate the 
requirements for what information must be included in the master 
manufacturing record.
    In response to our request for comment on whether written 
procedures should be required for complying with the proposed 
requirements for laboratory operations under proposed Sec.  111.60, 
some comments specifically note the need for written procedures for the 
laboratory test methods used to ensure that components, in-process 
materials, and finished product meet established specifications. Some 
comments emphasize written procedures would create a standard for 
testing of products or groups of products and establishing parameters 
for passing or failing products.
    In response to our request for comment on whether written 
procedures should be required for complying with the proposed 
requirements for manufacturing operations under proposed Sec.  111.65, 
one comment asserts this is an effective way to train personnel and a 
means to hold operators accountable to a quality standard. Another 
comment states written procedures can improve quality and consistency 
in a manufacturing operation.
    In response to our request for comment on whether written 
procedures should be required for complying with the proposed 
requirements for packaging and labeling operations under proposed Sec.  
111.70, one comment asserts this is an effective way to train personnel 
and a means to hold operators accountable to a quality standard.
    Responding to our request for comment on whether written procedures 
should be required for complying with the proposed requirements for 
holding components, dietary supplements, packaging, labels, and in-
process materials under proposed Sec. Sec.  111.80 and 111.82, one 
comment asserts this is an effective way to train personnel and a means 
to hold operators accountable to a quality standard. Another comment 
states a company cannot be considered to be a CGMP operation without 
having written procedures for every product manufacturing activity, 
including holding and distributing. This comment states mixups and 
adulterations will be more likely to occur if there are no written 
procedures for control of storage locations, manner of storage, and 
container and storage location identification codes.
    In response to our request for comment on whether written 
procedures should be required for complying with the proposed 
requirements for returned dietary supplements, one comment states 
written procedures should govern all return and salvage operations to 
create a standard for quarantine and salvage and to establish 
parameters for proper salvage conditions.
    Responding to our request for comment on whether written procedures 
should be required for complying with the proposed requirements for 
handling consumer complaints, some comments state written procedures 
will encourage companies to handle consumer complaints in a uniform 
manner. One comment asserts written procedures should be required for 
handling consumer complaints because some complaints could relate to 
serious illness or injury. The comment states that written procedures 
would set out exactly what steps need to be taken when complaints are 
reviewed, and are the best way to ensure the essential information is 
captured.
    (Response) We agree with the comments that effective process 
control, using written procedures, is an important aspect of a 
successful CGMP program. We also agree requiring written procedures 
will help to ensure consistent practices in operations i.e., help to 
ensure the operation is conducted in the same manner regardless of who 
conducts the operation or when the operation is conducted. We also 
agree that written procedures provide a sound basis for employee 
training and supervision, are an effective communication tool, and 
enable quality control personnel to carry out the responsibility to 
approve or reject all processes, specifications, controls, tests, and 
examinations, and deviations from or modifications to them. In 
addition, written procedures establish expectations for each covered 
operation so the operation does not proceed in an ad-hoc manner. 
Written procedures provide specific guidance if there is an 
unanticipated occurrence and, thus, can play a key role in ensuring a 
quality product, because actions to correct the unanticipated 
occurrence can take place swiftly and with confidence in the outcome.
    This final rule establishes the minimum CGMPs necessary for 
activities related to manufacturing, packaging, labeling, and holding 
dietary supplements to ensure a quality

[[Page 34770]]

product. The operations required by this final rule must be conducted 
in a consistent manner, regardless of who is conducting an operation or 
when the operation is conducted. As discussed in the following 
paragraphs, with a few exceptions, we are requiring that you establish 
and follow written procedures to fulfill the requirements for the 
operations covered by this final rule. The exceptions include final 
subpart A, which addresses the scope of the rule, rather than 
operations covered by the rule; final subparts E, H, and I, in which we 
conclude that a requirement for written procedures would be redundant 
to other requirements; and final subpart P, which establishes 
requirements for making and keeping records, rather than for conducting 
operations.
    We believe requiring you to establish and follow written procedures 
to fulfill the requirements of subparts B through D, F, G, and J 
through O, when combined with other requirements of this final rule, 
justifies reduced requirements for testing finished batches of product 
compared to the proposed requirements for such testing as found in 
proposed Sec.  111.35. By establishing and following written 
procedures, you will focus your production and process control system 
on ensuring the quality of the finished product at each stage in the 
production process, rather than relying entirely on testing at the end 
of the process.
2. Written Procedures That Are Required by This Final Rule
    a. Written procedures for personnel (final subpart B). We believe 
that successful programs for process control are directly connected to 
appropriate training programs. Employee training must be conducted in a 
consistent manner, regardless of who conducts the training or when it 
is conducted. Failure to conduct employee training in a consistent 
manner could lead to a failure in ensuring product quality. For 
example, an employee who has not received appropriate training on how 
to conduct a specific physical examination to verify the identity of a 
dietary ingredient may erroneously report that the correct ingredient 
was received when, in fact, the received dietary ingredient is related 
to, but different from, the ingredient that is specified in the master 
manufacturing record.
    We also believe the requirements that apply to preventing microbial 
contamination due to sick or infected personnel and that apply to 
proper hygienic practices must be conducted in a consistent manner. For 
example, it is well known that foodborne illness can be transmitted by 
workers who are sick. For example, volunteer food workers at an outdoor 
music festival were found to be the source of contamination for an 
outbreak of Shigellosis (Ref. 11).
    We include in final subpart B a requirement (final Sec.  111.8) 
that you establish and follow written procedures for fulfilling the 
requirements of subpart B.
    b. Written procedures for cleaning the physical plant, including 
pest control (final subpart C). We agree with the comments that written 
procedures for cleaning the physical plant would reduce the potential 
for cross-contamination and that such written procedures must include 
written procedures for pest control. Cleaning operations and pest 
control must be conducted in a consistent manner, regardless of who 
conducts the operation or when it is conducted. Failure to conduct 
cleaning operations and pest control in a consistent manner could lead 
to failure in ensuring product quality. For example, application of a 
chemical such as a fumigating agent or rodenticide in a production area 
must be performed correctly to avoid contaminating dietary supplements. 
Therefore, we disagree that written procedures would not directly 
prevent contamination or ensure the identity, purity, strength, and 
composition of the dietary supplement even if a manufacturer maintains 
the physical plant in a clean and sanitary condition.
    We include in final subpart C a requirement that you establish and 
follow written procedures for cleaning the physical plant and for pest 
control (final Sec.  111.16).
    c. Written procedures for calibrating instruments and controls and 
for calibrating, inspecting, and checking automated, mechanical, or 
electronic equipment (final subpart D). Calibrating instruments and 
controls, and calibrating, inspecting, and checking automated, 
mechanical, or electronic equipment must be conducted in a consistent 
manner, regardless of who conducts the operation or when it is 
conducted. Without a consistent approach, the performance of these 
operations could lead to equipment that produces inaccurate results. 
For example, if a scale is out of calibration, the wrong amounts of 
components could be added to a mixer. We include in final subpart D a 
requirement that you establish and follow written procedures for 
calibrating instruments and controls that you use in manufacturing or 
testing a component or dietary supplement (final Sec.  111.25(a)) and 
for calibrating, inspecting, and checking automated, mechanical, and 
electronic equipment (final Sec.  111.25(b)). We note that the 
manufacturers of equipment often provide written procedures for 
calibrating equipment. Depending on your circumstances and 
applications, you may be able to rely on written procedures provided by 
the manufacturer of the equipment with little or no modification.
    Final Sec.  111.25(a), pertaining to establishing and following 
written procedures for calibrating instruments and controls used in 
manufacturing or testing components or dietary supplements, is similar 
to proposed Sec.  111.25(c)(1) which would provide an option, in 
relevant part, that you establish written procedures for calibrating 
such instruments and controls in addition to requiring you to document 
that the procedure was followed each time a calibration is performed.
    d. Written procedures for maintaining, cleaning, and sanitizing 
equipment and utensils (final subpart D). Maintaining, cleaning, and 
sanitizing equipment and utensils must be conducted in a consistent and 
appropriate manner, regardless of who conducts the operation or when it 
is conducted. Failure to clean and sanitize equipment and utensils in a 
consistent and appropriate manner could lead to a product that is 
adulterated because, for example, equipment and utensils that are not 
properly cleaned and sanitized could be a source of microorganisms, or 
could lead to cross-contamination of products. In addition, failure to 
maintain equipment in a consistent manner could lead to the failure to 
ensure product quality. For example, equipment that is properly 
maintained is less likely to malfunction than equipment that is not 
maintained, and using equipment that malfunctions could lead to errors 
in production, such as dispensing an incorrect amount of each 
ingredient.
    We include in final subpart D a requirement that you establish and 
follow written procedures for maintaining, cleaning, and sanitizing 
equipment and utensils (final Sec.  111.25(c)). Final Sec.  111.25(c) 
applies to equipment, utensils, and any other contact surfaces used in 
labeling operations as well as in manufacturing, packaging, and holding 
operations. Although the factors you must consider for maintaining, 
cleaning, and sanitizing equipment used for labeling operations likely 
are different from those for equipment used in manufacturing or 
packaging operations, you nevertheless must determine the appropriate 
steps to take to ensure that labeling equipment is appropriately 
maintained and does not become a source of contamination

[[Page 34771]]

for dietary supplements. For example, equipment used for labeling 
operations has a greater potential to contaminate a dietary supplement 
when labeling operations are carried out in concert with packaging 
operations, because the dietary supplement could be exposed to one or 
more contact surfaces during the packaging operations.
    Final Sec.  111.25(c) requires you to establish and follow written 
procedures for maintaining, cleaning, and sanitizing, as necessary, all 
equipment, utensils, and any other contact surfaces used to 
manufacture, package, label, or hold components or dietary supplements. 
Final Sec.  111.25(c) relates to proposed Sec.  111.25(e)(1) which 
would, in relevant part, require you to maintain, clean, and sanitize 
as necessary, all equipment, utensils, and contact surfaces used to 
manufacture, package, label, or hold components, dietary ingredients, 
or dietary supplements.
    (Comment 8) Some comments suggest that written procedures for 
maintaining, cleaning, and sanitizing equipment require visual 
inspection of equipment when more than one product is manufactured 
using the same equipment, and that the presence of residual components 
from one product in a different product could be harmful. The comments 
also suggest the written procedures include residual limits of 
components from different product lines to guarantee the safety of the 
dietary supplement.
    (Response) The final rule gives you flexibility to develop written 
procedures appropriate to your products and equipment. Consequently, 
final Sec.  111.25(c) neither requires nor prohibits any specific 
procedure, such as the visual inspection suggested by the comment.
    As for the residual limits, the comment provides no data or other 
information that would provide a basis for setting residual limits for 
any particular components. However, as we discuss more fully in the 
discussion of final Sec.  111.70(e) in section X of this document, the 
final rule requires you to establish and meet specifications for the 
identity, purity, strength, and composition of dietary supplements and 
for limits on contamination for dietary supplements that you 
manufacture. When considering the specifications you must establish to 
ensure the quality of the dietary supplements, you must take into 
account the need to ensure that components or dietary supplements are 
not contaminated as a result of using the same equipment. Such 
equipment could be a source of contamination if more than one product 
is manufactured using the equipment and it is not properly cleaned and/
or sanitized.
    e. Written procedures for quality control operations, including 
written procedures for conducting a material review and making a 
disposition decision and written procedures for approving or rejecting 
reprocessing (final subpart F). Quality control operations must be 
conducted in a consistent manner. Failure to carry out quality control 
operations in a consistent and appropriate way could lead to failure to 
ensure product quality and to ensure the dietary supplement is packaged 
and labeled as specified in the master manufacturing record. For 
example, you could use a component that should not have been released 
for use in manufacturing, or you could distribute a packaged and 
labeled dietary supplement that should not have been released for 
distribution.
    We include in final subpart F a requirement that you establish and 
follow written procedures for quality control operations (final Sec.  
111.103). We agree with the comments that there should be written 
procedures for investigating failures in manufacturing operations. In 
the 2003 CGMP Proposal, we referred to the process of investigating 
such failures as a ``material review'' and proposed a series of 
requirements related to a material review and the disposition decision 
that follows a material review. The review must be conducted in a 
consistent manner, and the criteria for making a disposition decision 
must be consistent, regardless of who is conducting the material review 
or when it is conducted, and regardless of who makes the disposition 
decision and when the decision is made. For example, if you do not have 
written criteria for determining whether a deviation from 
specifications has resulted in, or could lead to, adulteration, 
different individuals who conduct a material review could reach 
different decisions regarding the appropriate disposition of the 
affected dietary supplement, including decisions that incorrectly 
result in the release of an adulterated product. As discussed more 
fully in sections X and XI of this document, the final rule requires 
that quality control personnel conduct all required material reviews 
and make all required disposition decisions. Therefore, we are 
requiring that the written procedures for quality control operations 
include written procedures for conducting a material review and making 
a disposition decision (final Sec.  111.103).
    We considered the comments that suggest that there should be a 
requirement for you to establish and follow written procedures for 
reprocessing from two perspectives: (1) Determining whether 
reprocessing should be approved or rejected and (2) performing the 
reprocessing. In general, reprocessing is performed when there is a 
problem with the manufacturing process, such as when a specification is 
not met or any step in the master manufacturing record is omitted. 
Depending on the nature of the dietary supplement, the manufacturing 
process, and the problem, reprocessing may or may not be able to 
correct the problem. From the perspective of determining whether 
reprocessing should be approved or rejected, under the final rule it is 
quality control personnel who must approve or reject any reprocessing 
(see final Sec. Sec.  111.90, 111.113, 111.120, 111.123, and 111.130). 
The decision to approve reprocessing must be made in a consistent 
manner, regardless of who conducts the operation or when it is 
conducted. For example, if it is not possible to test the product at 
the finished batch stage to determine whether the reprocessing 
corrected the problem (because, for example, there is no scientifically 
valid method available to test for a specification that is directly 
related to the reason for reprocessing), you must have a clear basis to 
decide that reprocessing will actually correct the problem or you will 
not know if all required specifications can be met. Without written 
procedures for approving reprocessing, different individuals who 
approve or reject any reprocessing could make very different decisions 
on when reprocessing can correct a problem and when it cannot. 
Therefore, we are specifically requiring that the written procedures 
for quality control operations include written procedures for approving 
or rejecting any reprocessing.
    From the perspective of performing the reprocessing, we agree that 
any procedure for reprocessing must be written because, for example, 
quality control personnel may need to rely on the procedure that you 
followed to determine whether all specifications are met for the 
reprocessed material. However, the final rule requires you to document 
any reprocessing in the batch record (final Sec.  111.260(n)) rather 
than establishing and following written procedures to conduct 
reprocessing, because the actual procedure you follow to reprocess a 
dietary supplement likely will be different depending on the 
circumstances.
    f. Written procedures for components, packaging, labels, and 
product that is received for packaging and labeling as a dietary 
supplement (final subpart G). We agree with the comments that the

[[Page 34772]]

receipt, examination, quarantine, and release from quarantine of 
components, packaging, labels, and product that are received for 
packaging and labeling as dietary supplements must be conducted in a 
consistent manner, regardless of who conducts the operation or when it 
is conducted. Failure to carry out these operations in a consistent way 
could lead to failure to ensure product quality if, for example, you 
use a component that should not have been released for use in 
manufacturing.
    We include in final subpart G a requirement that you establish and 
follow written procedures for fulfilling the requirements of subpart G 
(final Sec.  111.153).
    g. Written procedures for laboratory operations (final subpart J). 
Testing and examination of components, packaging, labels, and product 
that are received for packaging or labeling as a dietary supplement, or 
packaged and labeled dietary supplements, must be conducted in a 
consistent manner, regardless of who conducts the operation or when it 
is conducted. The reason a firm conducts these tests and examinations 
is to ensure that a dietary supplement meets established 
specifications. Failure to conduct tests and examinations in a 
consistent manner could lead to failure in ensuring the quality of the 
dietary supplement. For example, a test designed to determine the 
concentration of a product before it is diluted to the appropriate 
concentration could provide different results if it is conducted in a 
different manner by different individuals.
    In addition, laboratory operations such as use of criteria for 
establishing appropriate specifications and use of sampling plans for 
obtaining representative samples must be conducted in a consistent 
manner, regardless of who conducts the operation or when it is 
conducted. For example, failure to consider that specifications are 
needed to ensure that a dietary supplement derived from a botanical 
source does not contain contaminants, such as an unlawful pesticide, 
could result in a dietary supplement that contains unsafe levels of a 
contaminant.
    We include in final subpart J a requirement that you establish and 
follow written procedures for laboratory operations, including written 
procedures for the tests and examinations that you conduct to determine 
whether specifications are met (final Sec.  111.303).
    h. Written procedures for manufacturing operations (final subpart 
K). We agree with the comments that written procedures for 
manufacturing operations would be an effective way to train personnel, 
provide a means to hold operators accountable to a quality standard, 
and improve quality and consistency in a manufacturing operation. The 
final provisions for manufacturing operations require you to design or 
select manufacturing processes to ensure that dietary supplement 
specifications are consistently achieved, conduct all manufacturing 
operations in accordance with adequate sanitation principles, and take 
all necessary precautions to prevent contamination of components and 
dietary supplements. These manufacturing operations must be conducted 
in a consistent manner, regardless of who conducts the operation or 
when it is conducted. Failure to perform these operations in a 
consistent way could lead to failure to ensure the quality of the 
dietary supplement. For example, surfaces that come in contact with a 
dietary supplement are potential sources of microbial contamination if 
consistent procedures are not in place to ensure good sanitary 
practices. We are including in final subpart K a requirement that you 
establish and follow written procedures for manufacturing operations 
(final Sec.  111.353).
    i. Written procedures for packaging and labeling operations (final 
subpart L). We agree with the comments that written procedures for 
packaging and labeling operations are an effective means to hold 
operators accountable to ensure the quality of the dietary supplement 
and that the dietary supplement is packaged and labeled as specified in 
the master manufacturing record. The final provisions for packaging and 
labeling operations require that you fill, assemble, package, label, 
and perform other related operations in a way that ensures the quality 
of the finished product, including practices such as cleaning and 
sanitizing all filling and packaging equipment, utensils, and 
containers; protecting manufactured dietary supplements against 
airborne contamination, using sanitary handling procedures; taking 
actions to prevent mixups; and suitably disposing of obsolete packaging 
and labels. These packaging and labeling operations must be conducted 
in a consistent manner, regardless of who conducts the operation or 
when it is conducted. Failure to perform these operations in a 
consistent way could lead to a failure to ensure the quality of the 
dietary supplement and that the dietary supplement is labeled and 
packaged as specified in the master manufacturing record. For example, 
if you do not have procedures for identifying filled, but unlabeled, 
containers of dietary supplements, mixups could occur before the labels 
are applied. The final product could contain ingredients other than 
those identified on the label specified in the master manufacturing 
record. Therefore, we include in final subpart L a requirement that you 
establish and follow written procedures for packaging and labeling 
operations (final Sec.  111.403).
    j. Written procedures for holding and distributing operations 
(final subpart M). We agree with the comments that written procedures 
for holding and distributing operations are an effective means to hold 
operators accountable to CGMP standards, and that mixups and other 
problems that affect the final product will be more likely to occur if 
there are no written procedures for operations such as control of 
storage locations, manner of storage, and container and storage 
location identification codes. The final provisions for holding and 
distributing operations require, among other things, that you hold 
components and dietary supplements under appropriate conditions of 
temperature, humidity, and light so that the identity, purity, 
strength, and composition of the components and dietary supplements are 
not affected; that you hold components, dietary supplements, and in-
process materials under conditions that do not lead to the mixup, 
contamination, or deterioration of components or dietary supplements; 
and that you distribute dietary supplements under conditions that will 
protect them against contamination and deterioration.
    These holding and distributing operations must be conducted in a 
consistent manner, regardless of who conducts the operation or when it 
is conducted. Failure to follow these requirements for holding and 
distributing in a consistent manner could lead to a failure to ensure 
the quality of the dietary supplement product. For example, if 
employees do not know how to store an in-process batch of a botanical 
dietary supplement to control humidity, the growth of mold could be 
promoted. Furthermore, if a distributor does not refrigerate a dietary 
supplement that requires refrigeration to ensure its strength, the 
dietary supplement may not meet its specification for strength. 
Therefore, we include in final subpart M a requirement that you 
establish and follow written procedures for holding

[[Page 34773]]

and distributing operations (final Sec.  111.453).
    k. Written procedures for returned dietary supplements (final 
subpart N). We agree with the comments that written procedures for 
returned dietary supplements would help to ensure appropriate handling 
of such supplements prior to a disposition decision. The final rule 
requires you, among other things, to identify and quarantine returned 
dietary supplements until quality control personnel conduct a material 
review and make a disposition decision. You must destroy, or otherwise 
suitably dispose of, any returned dietary supplement that quality 
control personnel do not approve for salvage or reprocessing. These 
operations for returned dietary supplements must be conducted in a 
consistent manner, regardless of who conducts the operation or when it 
is conducted. Failure to comply with these requirements for quarantine, 
salvage, and disposition in a consistent way could lead to a failure to 
ensure the quality of the dietary supplement. For example, if an 
investigation leads to a conclusion that a dietary supplement requiring 
refrigeration to ensure its strength was not refrigerated while held at 
a customer's warehouse, and this dietary supplement was not quarantined 
while quality control personnel conducted a material review, the 
dietary supplement could be inadvertently co-mixed with other 
containers of that same lot of product and then inadvertently 
redistributed. Therefore, we are including in final subpart N a 
requirement that you establish and follow written procedures to fulfill 
the requirements of subpart N (final Sec.  111.503).
    l. Written procedures for product complaints (final subpart O). We 
agree with the comments that written procedures for handling consumer 
complaints (now called product complaints) will encourage companies to 
handle product complaints in a consistent manner and help ensure the 
essential information is captured during investigation of a product 
complaint. The final rule requires you, among other things, to review 
all product complaints to determine whether the product complaint 
involves a possible failure of a dietary supplement to meet any of its 
specifications; investigate any product complaint that involves a 
possible failure of a dietary supplement to meet any of its 
specifications; and extend the review and investigation of the product 
complaint to all relevant batches and records. These operations must be 
conducted in a consistent manner, regardless of who conducts the 
operation or when it is conducted. Failure to comply with these 
requirements for review and investigation of a product complaint in a 
consistent way could lead to a failure to ensure the quality of the 
dietary supplement. For example, if you do not have a procedure in 
place to determine whether the product complaint involves a possible 
failure of a dietary supplement to meet any of its specifications, you 
may not recognize that a particular product complaint is indicative 
that a problem has occurred with one of your manufacturing processes. 
That undiscovered problem may lead to continued distribution of product 
that is contaminated or otherwise not consistent with your 
specifications in the master manufacturing record. Therefore, we 
include in final subpart O a requirement that you establish and follow 
written procedures to fulfill the requirements of subpart O (final 
Sec.  111.553).
3. Written Procedures That Are Not Required by This Final Rule
    a. Written procedures for final subpart E (``Requirement to 
Establish a Production and Process Control System''). In the CGMP 
proposal, we did not specifically request comments on whether we should 
require that you establish and follow written procedures to fulfill the 
requirements of proposed Sec.  111.35 (``What Production and Process 
Controls Must You Use?''), and we received no specific comments 
regarding whether we should establish and follow such written 
procedures. Given the strong support in the comments for the use of 
written procedures in a production and process control system, we 
nonetheless considered whether the requirements that we establish in 
final subpart E, Requirement to Establish a Production and Process 
Control System, would require written procedures.
    Final subpart E requires that you implement a system of production 
and process controls that covers all stages of manufacturing, 
packaging, labeling, and holding of the dietary supplements and that 
your system be designed to ensure the quality of the dietary supplement 
and that the dietary supplement is packaged and labeled as specified in 
your master manufacturing record (final Sec. Sec.  111.55 and 111.60); 
implement quality control operations to ensure the quality of dietary 
supplements and that the dietary supplement is packaged and labeled as 
specified in your master manufacturing record (final Sec.  111.65); 
establish specifications (final Sec.  111.70); determine whether 
specifications are met (final Sec. Sec.  111.73 and 111.75); collect 
representative samples (final Sec.  111.80); hold reserve samples of 
packaged and labeled dietary supplements (final Sec.  111.83); have 
quality control personnel conduct all required material reviews and 
make all required disposition decisions (final Sec.  111.87); and 
adhere to certain requirements for treatment, in-process adjustments, 
and for reprocessing (final Sec.  111.90).
    In considering whether we should require that you establish and 
follow written procedures to fulfill the requirements of final subpart 
E, we evaluated whether requirements in other subparts that address 
specific operations for the production and process control system 
substitute for the requirement of written procedures in final subpart 
E.
    Final subparts F through M establish specific requirements for 
manufacturing, packaging, labeling, and holding dietary supplements, 
including requirements for quality control operations (final subpart 
F); components, packaging, labels, and product that is received for 
packaging and labeling as a dietary supplement (final subpart G); 
establishing a written master manufacturing record and batch record 
(final subparts H and I); laboratory operations (final subpart J); 
manufacturing operations (final subpart K); packaging and labeling 
operations (final subpart L); and holding operations (final subpart M). 
We require you to establish and follow written procedures to fulfill 
the requirements of final subparts F, G, J, K, L, and M. Given these 
requirements, we conclude it would be redundant to require you to 
establish and follow written procedures to fulfill the requirements of 
final Sec. Sec.  111.55, 111.60, and 111.65 in subpart E.
    Final subpart J requires you to establish and follow laboratory 
control processes that include the use of criteria for establishing 
appropriate specifications (final Sec.  111.315(a)); use of sampling 
plans for obtaining representative samples (final Sec.  111.315(b)); 
use of criteria for selecting appropriate examination and testing 
methods (final Sec.  111.315(c)); use of criteria for selecting 
standard reference materials used in performing tests and examinations 
(final Sec.  111.315(d)); and use of test methods and examinations in 
accordance with established criteria (final Sec.  111.315(e)). In 
addition, under final Sec.  111.303 you must establish and follow 
written procedures for laboratory operations. Given the requirements of 
final subpart J, we conclude it would be redundant to require you to 
establish and follow written procedures to fulfill

[[Page 34774]]

the requirements of final Sec. Sec.  111.70, 111.75, and 111.80 in 
subpart E.
    Final subpart M establishes requirements for holding reserve 
samples. Under final Sec.  111.453, you must establish and follow 
written procedures for holding operations. Given the requirements of 
final subpart M, we conclude that it would be redundant to require you 
to establish and follow written procedures to fulfill the requirements 
of final Sec.  111.83 in subpart E for reserve samples.
    Final subpart F establishes requirements for quality control 
personnel to conduct a material review and make a disposition decision 
(final Sec.  111.113); approve any reprocessing (final Sec.  
111.123(a)(5)); and document any material review and disposition (final 
Sec.  111.140(b)(3)). In addition, as discussed, under final Sec.  
111.103 you must establish and follow written procedures for quality 
control operations. Given the requirements of final subpart F, we 
conclude that it would be redundant to require that you establish and 
follow written procedures to fulfill the requirements of final 
Sec. Sec.  111.87 and 111.90 in subpart E.
    We conclude that it would be redundant to require you to establish 
and follow written procedures for each of the requirements established 
in final subpart E. We, therefore, do not require you to establish and 
follow written procedures to fulfill the requirements established in 
subpart E.
    b. Written procedures for preparing the master manufacturing record 
(final subpart H) and for preparing the batch record (final subpart I). 
As discussed in the 2003 CGMP Proposal (68 FR 12157 at 12203), a master 
manufacturing record is analogous to a recipe that sets forth the 
ingredients to use, the amounts of ingredients to use, the tests to 
perform, and the instructions for preparing the quantity the recipe 
calls for. This master manufacturing record helps ensure that you 
manufacture each ingredient or dietary supplement in a consistent and 
uniform manner. If you neglect to follow the master manufacturing 
record, you might not add all of the necessary components in the 
appropriate strength or amount, and this could result in a final 
product not consistent with the master manufacturing record. Thus, you 
must follow a written master manufacturing record in a consistent 
manner, regardless of who conducts the operation or when it is 
conducted.
    However, we agree with the comments that the specific requirements 
for what must be in the master manufacturing record make it unnecessary 
to require written procedures for preparing the master manufacturing 
record. Under final subpart H, the master manufacturing record must 
include written instructions, including specifications for each point, 
step, or stage in the manufacturing process where control is necessary 
to ensure the quality of the dietary supplement and that the dietary 
supplement is packaged and labeled as specified in the master 
manufacturing record; procedures for sampling, testing, and 
examinations; specific actions necessary to perform and verify points, 
steps, or stages in the manufacturing process where control is 
necessary to ensure the quality of the dietary supplement and that the 
dietary supplement is packaged and labeled as specified in the master 
manufacturing record; special notations and precautions to be followed; 
and corrective action plans for use when a specification is not met. 
With all of this detail specified for the written instructions the 
master manufacturing record must include, we believe a written 
procedure for developing a master manufacturing record can be optional. 
Therefore, we do not require you to establish and follow written 
procedures for preparing the master manufacturing record.
    A batch is prepared by following the written instructions provided 
in the master manufacturing record. The master manufacturing record 
functions as a written procedure for the production of the batch. 
Therefore, we do not require you to establish and follow written 
procedures for the batch production record because such practices would 
be redundant to the requirements for the master manufacturing record in 
final subpart H.
    c. Written procedures for records and recordkeeping (final subpart 
P). Final subpart P establishes general requirements for making and 
keeping records required in other subparts. We did not request comments 
on written procedures, nor did we receive any comments that supported 
such a requirement. Because we believe that requiring written 
procedures to fulfill subpart P requirements would be redundant or 
unnecessary, we do not require such written procedures.
    d. Written procedures for product recalls. We acknowledge that a 
product recall by persons who manufacture, package, label, or hold 
dietary supplements must be conducted in a consistent manner, 
regardless of who conducts the operation or when it is conducted. 
However, the final rule does not establish any requirements for product 
recalls. Therefore, we do not require you to establish and follow 
written procedures for product recalls. However, we encourage you to 
refer to our ``Guidance for Industry: Product Recalls, Industry 
Removals and Corrections'' (Ref. 12) (available at http://www.fda.gov/opacom/7alerts.html).

D. Other Comments on Written Procedures

    (Comment 9) One comment stresses the need for flexibility in 
requiring written procedures, based on differences between individual 
activities and companies. The comment suggests companies should be 
required to review and determine the need for written procedures at 
each critical step of their operations and be prepared to defend those 
determinations as necessary.
    (Response) To the extent the comment suggests we do not require any 
written procedures specific to a particular function or requirement, 
and allow firms to decide when and when not to include them, we 
disagree. We believe that written procedures for the specific 
operations we have identified should not be optional. We have no 
objection if firms decide to establish and follow additional written 
procedures, beyond those we require in this final rule. Although we 
require written procedures for entire subparts, or specific 
requirements within certain subparts, we provide flexibility for firms 
to establish those written procedures that will ensure the requirements 
are met.
    (Comment 10) Some comments stress the importance of written 
procedures in enabling FDA to ensure compliance with the dietary 
supplement CGMP requirements.
    (Response) We believe written procedures will help us to ensure 
compliance with these CGMP requirements because they will clearly 
communicate the steps the firm must take to satisfy the requirements. 
During an inspection, we observe the practices that employees follow. 
However, to ensure that a firm is consistently complying with CGMP 
requirements, our investigators need access to records that both 
describe a firm's processes and procedures and demonstrate whether the 
firm has been following them. Under the final rule, we require you to 
make and keep records of the written procedures in each applicable 
subpart. Such records would be available to us under the requirements 
of final subpart P, Records and Recordkeeping.
    (Comment 11) Many comments object to FDA's stated reasons for not 
requiring written procedures for most activities, including concerns 
about cost control and burden reduction. The comments contend that 
written procedures

[[Page 34775]]

actually save time and other resources because they greatly facilitate 
employee training and ensure that activities are performed consistently 
and correctly. Some comments assert most companies already have written 
procedures in place, so start-up costs associated with such 
requirements would be minimal. One comment notes written procedures 
would be among the least costly of all the procedural requirements 
proposed by FDA.
    (Response) We agree that requiring that operations be conducted 
using written procedures can save time and other resources by 
facilitating employee training and ensuring operations are performed 
consistently and correctly. Because following written procedures can 
help ensure uniformity in the process and ensure the quality of the 
dietary supplement at every step, periodic end product testing can be 
sufficient to determine whether your manufacturing process is 
controlled. CGMP is premised upon quality assurance at every step of 
the process. It is less costly to establish and follow written 
procedures than it would be to test each finished batch for conformance 
with specifications. As suggested by these comments, our analysis 
(section XXIV of this document) shows that the overall costs are 
reduced, in part, because requiring that certain operations be 
conducted using written procedures enables us to reduce requirements 
for testing at the finished batch stage.
    (Comment 12) One comment states training employees on the required 
hygienic practices prior to their first day of handling product is 
critical to ensuring product safety.
    (Response) The requirement to establish and follow written 
procedures to fulfill the requirements of subpart B does not establish 
any fixed requirement for when an employee must receive such training 
relative to when the employee handles product. However, final Sec.  
111.12(c) requires that any person engaged in manufacturing, packaging, 
labeling, or holding, or in performing any quality control operations, 
must have the education, training, or experience to perform the 
person's assigned functions. We therefore assume that employees will 
have the necessary education, training, or experience for each 
operation that they perform before they perform it.
    (Comment 13) Some comments make recommendations for what written 
procedures should contain, including general parameters that should be 
included in all written procedures and specific parameters that should 
be included in specific written procedures. The general parameters 
include identification of the company; title that reflects the 
activities to be performed; identification or control number with a 
revision level code; effective date; the number of pages in the 
procedure (e.g., by a procedure such as listing page numbers using a 
convention such as ``page 1 of 4''); approval date and signature(s); 
references to linked or related procedures or forms; definitions of 
technical terms and acronyms; list of equipment, materials, and 
supplies needed in performing the task; who has the responsibility for 
performing each task; when and where a task is to be performed; concise 
step-by-step instructions for performing the task; the expected results 
from performing the task; what data to collect; and how to analyze, 
file, or report the collected data. In the specific case of written 
procedures for cleaning equipment and utensils, some comments suggest 
the written procedures include descriptions of appropriate cleaning 
agents, methods of cleaning, and the intervals and schedules for 
cleaning equipment.
    (Response) We agree the suggestions provided by these comments are 
useful to include in any written procedures. However, to provide the 
flexibility necessary to address diverse dietary supplement 
manufacturing processes, we are leaving details such as these to the 
judgment of the company rather than prescribing them within the final 
rule.
    (Comment 14) Some comments request the final rule include 
requirements for managing changes to written procedures. One comment 
states changes to written procedures should be reviewed, justified, 
documented, approved, and implemented in a defined manner. The comments 
explain that ``Change control procedures'' define what is and what is 
not covered by the written procedure and how proposed changes will be 
identified or recommended, processed, reviewed, and approved.
    (Response) As discussed in final subpart F, the final rule requires 
that quality control personnel approve all written procedures. ``All'' 
written procedures includes revisions to written procedures. As 
discussed in this section, the final rule requires you to establish and 
follow written procedures for quality control operations. We believe 
that procedures for managing changes to written procedures can be 
addressed within the written procedures for quality control operations.
    (Comment 15) Some comments assert the final rule should not require 
written procedures for key operations because the rule should stay 
focused on end results and not process.
    (Response) We disagree. The essence of good manufacturing practice 
that is established by this final rule is a production and process 
control system that is designed to ensure the quality of the dietary 
supplement.

E. What Other General Comments Did We Receive?

    (Comment 16) Some comments say any final rule should not require 
written procedures, should not propose a definition of appropriate 
tests, and generally should not include requirements for procedures 
better left to ``normal business practices.'' The comments cited 
Executive Order 12866 and the Small Business Regulatory Enforcement 
Flexibility Act (SBREFA). The comment added that there is no such 
requirement in the food CGMPs or in the 1997 ANPRM.
    (Response) We disagree the final rule violates either Executive 
Order 12866 or SBREFA and discuss this in section XXIV of this 
document. We address SBREFA's regulatory flexibility issues by 
staggering compliance dates so that certain businesses would have 24 
and 36 months, respectively, to comply with the final rule. As for the 
assertion that food CGMPs do not require written procedures, we discuss 
the requirements of food CGMPS in relation to the requirements of these 
dietary supplement CGMPs in section V of this document. The comment's 
assertion that the 1997 ANPRM did not contain written procedures is 
incorrect. The industry draft that we published in the 1997 ANPRM had 
multiple written procedures, including written procedures for:
    <bullet> Cleaning and maintaining equipment and utensils used in 
the manufacture of products;
    <bullet> The receipt, identification, examination, handling, 
sampling, testing, and approval or rejection of raw materials;
    <bullet> Appropriate tests and/or examinations to be conducted to 
assure the purity, composition, and quality of the finished product;
    <bullet> The method for reprocessing batches or operational start-
up materials that do not conform to finished goods standards or 
specifications;
    <bullet> The control procedures employed for the receipt, storage, 
handling, sampling, examination, and/or testing that may be necessary 
to assure the identity of labeling and the appropriate identity, 
cleanliness, and quality characteristics of packaging materials for 
dietary products;

[[Page 34776]]

    <bullet> Ensuring correct labels, labeling, and packaging materials 
are issued and used for dietary products; and
    <bullet> Describing the handling of all written and oral complaints 
regarding a product.
(62 FR 5700 at 5704 through 5706).
    (Comment 17) In the analysis of impacts in the 2003 CGMP Proposal 
(68 FR 12157 at 12222), we stated that we had considered imposing fewer 
CGMP requirements for the manufacture of vitamins and minerals. 
Although this issue arose as a discussion of regulatory options that we 
had considered and rejected, we received several comments on this 
subject. Some comments state we should not create different CGMP 
standards based upon the type of dietary ingredient. These comments 
state that one set of appropriately flexible standards would be more 
efficient and less confusing to industry than separate standards for 
each portion of the industry. Some comments say that different 
requirements for vitamins and minerals would cause problems because 
most people who use these products take a multivitamin/mineral 
preparation as their primary and sole dietary supplement, so the risk 
of adverse events arising from adulteration, misidentification, or 
misformulation of products would be much higher if vitamins and 
minerals were subject to fewer requirements compared to other dietary 
supplements. Other comments supported the concept of differing 
standards. Some comments assert, in order for the CGMP regulations to 
set minimum quality standards for all dietary supplements, we would 
have to regulate each facet of the manufacture, packaging, and storage 
of a dietary supplement independently of product type. These comments 
state reducing the requirements for vitamin and mineral manufacturers 
would not allow the development of minimum quality standards across the 
entire dietary supplement industry.
    (Response) The concept of fewer requirements for vitamins and 
minerals was simply one regulatory option we considered as part of the 
2003 CGMP Proposal's analysis of impacts (see 68 FR 12157 at 12220 
through 12223). We rejected it (id.). We disagree with the comments 
that there should be fewer CGMP requirements for vitamins and minerals. 
Neither the 2003 CGMP Proposal, nor this final rule, imposes fewer 
requirements on vitamin or mineral firms compared to firms that make 
other types of dietary supplements.

V. What Legal Authority Comments Did We Receive?

    Many comments were submitted from individuals, companies, and trade 
groups concerning our legal authority for this rule. Most of the 
comments question the scope of the rule based on the language in 
section 402(g) of the act (21 U.S.C. 342(g)) stating that ``regulations 
shall be modeled after current good manufacturing practice regulations 
for food.'' Other comments question our authority for records access. 
Some comments assert that certain provisions of the proposed rule are 
unconstitutionally vague, and therefore violate the Fifth Amendment. A 
few comments disagree with our rationale for why dietary supplements 
are different than conventional food and need separate CGMP 
requirements. We address these comments immediately below in this 
section.

A. Modeled After CGMP for Food

    (Comment 18) Some comments support our approach of proposing 
requirements that are more comprehensive than the CGMP requirements for 
food. One comment states that the current requirements for food CGMP 
are less comprehensive than the CGMP requirements in current use by 
both the food and dietary supplement industries and the current ``best 
practices'' should be incorporated into the dietary supplement CGMP 
rule. Several comments state that the requirements for dietary 
supplement CGMP do not need to be identical to the requirements in 
existing food CGMP regulations, that appropriate manufacturing controls 
are needed for dietary ingredients contained in dietary supplements to 
protect the public health, that some borrowing of drug CGMP concepts 
may be necessary, and that we should balance effective control with 
necessary flexibility in the dietary supplement CGMP rule. In addition, 
one comment states that the USP manufacturing guidelines, which contain 
wording from the drug CGMP requirements, are a model for dietary 
supplement CGMP for many in industry.
    Several comments express concern about not deviating too 
drastically from the requirements in existing food CGMP regulations. 
Although several comments recognize that additional CGMP provisions for 
dietary supplements, such as those related to identity, purity, 
strength, quality, and composition, are needed, the comments say that 
we should not regulate dietary supplement manufacturing in the same 
manner as drug manufacturing because it would entail overly burdensome 
methods for production and process controls. Some comments contend that 
some of the proposed rule requirements exceed the drug CGMP 
requirements.
    Most of the comments assert that the proposed dietary supplement 
CGMP requirements are not modeled after the CGMP regulations for food. 
The reasons for this assertion vary. Some assert that certain 
provisions in the proposed rule were not found in, or differ from, the 
provisions in part 110. Examples of proposed requirements that comments 
indicate exceeded food CGMP included batch testing, packaging and 
labeling, recordkeeping, consumer complaints, and the use of validated 
methods. Other comments state that the proposed requirements exceeded 
those for food because the proposed rule provided for finished testing 
of certain substances when used as dietary supplements, such as garlic 
and ginger, whereas no such testing is required under existing food 
CGMP regulations when those same substances are used as conventional 
food. One comment says the rule was modeled after juice hazard analysis 
and critical control point (HACCP) and therefore goes beyond existing 
food CGMP regulations.
    Some comments assert that the proposed requirements exceed the 
existing food CGMP regulations because certain proposed provisions 
contained a level of detail that is not in the food or the drug CGMP 
regulations, or because elements of a provision in the proposed rule 
were similar to a provision in part 210 (21 CFR part 210) (drug CGMP 
regulation). Other comments disagree with our rationale that the 
proposed rule was designed on the same principles as the existing food 
CGMP regulations to address the characteristics and hazards specific to 
dietary supplements, or to prevent adulteration in preparing, 
packaging, or holding dietary supplements. The comments also disagree 
that we may include provisions in the dietary supplement CGMP final 
rule that were not found in the food CGMP regulations at the time DSHEA 
was enacted.
    Several comments state that we exceed our legal authority for the 
proposed rule because it used too broad a definition of ``modeled 
after.'' Some comments offer their own definitions of ``model;'' others 
object to the use of the noun form ``model'' and provide dictionary 
definitions of the verb form ``modeled.'' A few comments assert that 
the meaning of ``model'' is clear, despite different dictionary 
meanings, and that the statute is not ambiguous under Chevron U.S.A. 
Inc. v. Natural Resources Defense Council, 467 U.S.

[[Page 34777]]

837 (1984) (``Chevron''). One comment states that, even if the language 
is ambiguous and our interpretation merits deference, our 
interpretation is too expansive and not based on a permissible 
construction of the statute. Another comment states that we did not 
explain why our interpretation was consistent with our congressional 
mandate.
    (Response) We agree with the comments stating that the dietary 
supplement CGMP requirements in this final rule need not be identical 
to the existing food CGMP regulations and that a system of 
manufacturing controls specific to dietary supplements is needed. We do 
not agree that we exceeded the scope of our authority under section 
402(g) of the act in issuing the proposed requirements for dietary 
supplement CGMP or these final requirements. Our interpretation of the 
language in section 402(g) of the act, including the ``modeled after'' 
language, as to what requirements of the act we have authority to 
issue, is based on a permissible construction of the statute.
    The comments present the following general questions: (1) Whether 
the statute gives us authority to promulgate CGMP requirements for 
dietary supplements that are not identical to the requirements in 
existing CGMP regulations for food and (2) if so, whether the 
requirements in this final rule that differ from those in existing CGMP 
regulations for food are fairly encompassed within Congress' direction 
that the dietary supplement regulations shall be ``modeled after'' food 
regulations and, therefore, are based on a permissible construction of 
the statute.
    Under section 402(g)(1) of the act, a dietary supplement is deemed 
to be adulterated if it has ``been prepared, packed, or held under 
conditions that do not meet current good manufacturing practice 
regulations, including regulations requiring, when necessary, 
expiration date labeling, issued by the Secretary under subparagraph 
(2).'' Section 402(g)(2) of the act authorizes the Secretary, by 
regulation, to ``prescribe good manufacturing practices for dietary 
supplements.'' Congress further provided that such regulations ``shall 
be modeled after current good manufacturing practice regulations for 
food'' and ``may not impose standards for which there is no current and 
generally available analytical methodology.''
    In construing the meaning of section 402(g) of the act, and, in 
particular, the language in that section stating that such regulations 
shall be ``modeled after current good manufacturing practice 
regulations for food,'' we are confronted with two questions. First, 
has Congress directly and unambiguously spoken to the precise question 
at issue? (``Chevron step one'') (see Chevron, 467 U.S. at 842.) To 
find no ambiguity, Congress must have clearly manifested its intention 
with respect to the particular issue (see Young v. Community Nutrition 
Institute, 476 U.S. 974, 980 (1986)). If Congress has spoken directly 
and plainly, we must implement Congress's unambiguously expressed 
intent (see Chevron, 467 U.S. at 842-843). Second, if the act is silent 
or ambiguous with respect to a particular issue in section 402(g) of 
the act, is our interpretation based on a permissible construction of 
the statute (``Chevron step two'') (Chevron, 467 U.S. at 843; FDA v. 
Brown & Williamson Tobacco Corp., 529 U.S. 120, 132 (2000))? When 
Congress leaves a gap for the agency to fill by regulation, the 
regulation will pass muster so long as it is not ``arbitrary, 
capricious, or manifestly contrary to the statute'' (Chevron, 467 U.S. 
at 843-844).
    We believe that the language in section 402(g) of the act provides 
an express delegation of authority to us to promulgate a regulation to 
``prescribe good manufacturing practices for dietary supplements'' so 
long as those regulations are ``modeled after the current good 
manufacturing practice regulations for food.'' The express language in 
section 402(g) of the act contemplates broad, but not unlimited, agency 
discretion as to what to include in a dietary supplement CGMP 
regulation.
    Congress has also spoken to the precise question of whether the 
dietary supplement CGMP requirements must be identical to the 
requirements in existing food CGMP regulations. If Congress had wanted 
dietary supplement CGMP to be identical to food CGMP, it easily could 
have required that by statute. Indeed, if Congress had intended for 
CGMPs for dietary supplements to be the same as food CGMPs, there would 
have been no need for Congress to have addressed the issue at all; as a 
type of food, dietary supplements would otherwise be governed by the 
food CGMPs. See section (ff) of the act (21 U.S.C. 321(ff)). Instead, 
the statute calls for us to issue regulations that are ``modeled 
after'' CGMP regulations for food. The plain meaning of a ``model'' or 
``modeled after,'' as discussed in the 2003 CGMP Proposal (68 FR 12157 
at 12165) and in the comments, relates to a pattern, plan, 
representation, or simulation. The use of the term ``modeled after'' 
makes it clear that the regulations need not be identical to the 
original, but instead are contemplated to differ from the original.
    Thus, the additional, independent authority to promulgate CGMP 
regulations for dietary supplements that Congress provided in section 
402(g) of the act, without delineating what requirements such a 
regulation could or could not include, left us with considerable 
authority to fill in the gaps in ways that recognize the differences 
between dietary supplements and other foods that warrant different 
manufacturing controls. A contrary interpretation, as some comments 
suggested, that the ``modeled after'' language means the requirements 
for dietary supplement CGMP must be precisely found in current part 
110, or other food CGMP regulations, would so narrowly circumscribe our 
discretion as to make it impossible to tailor the regulation to fit the 
products it is designed to address. Such an interpretation would lead 
to a rule that would ``frustrate the success of the regulation 
undertaken by Congress'' because it would not take into consideration 
the characteristics, hazards, and manufacturing practices specific to 
dietary supplements (American Trucking Ass'ns v. U.S., 344 U.S. 298, 
311 (1953)).\4\
---------------------------------------------------------------------------

    \4\The Senate Report on DSHEA states that Congress inserted 
section 402(g) because it recognized that ``dietary supplements may 
require different manufacturing and quality controls'' when compared 
to food CGMP (S. Rep. No. 140, 103rd Cong., 2d Sess., at 31 (1994)). 
However, the report is not considered legislative history. Congress 
issued a Statement of Agreement (140 Cong. Rec. S14801 (Oct. 7, 
1994), reprinted in 1994 U.S.C.C.A.N. 3523) that stated ``it is the 
intent of the chief sponsors of the bill * * * that no other reports 
or statements be considered as legislative history for the bill'').
---------------------------------------------------------------------------

    Congress has also spoken to the precise question of which 
requirements CGMP ``regulations for food.'' The plain meaning of 
``regulations'' is plural (more than one), and the plain meaning of 
``food'' is as Congress defined in section 201(f) of the act, including 
articles ``used for food or drink.'' At the time DSHEA was enacted, 
there were five food CGMP regulations: Those for infant formula (part 
106), thermally processed low-acid canned food (part 113), acidified 
food (part 114), bottled water (part 129), and general food (part 110, 
often referred to as the ``umbrella'' regulations). All of these 
regulations appear in Subchapter B of Chapter 1 of Title 21 of the Code 
of Federal Regulations, entitled ``Food for Human Consumption.'' 
Nothing in the language of section 402(g) or elsewhere suggests that 
Congress meant to limit the term CGMP ``regulations for food'' to only 
the regulation in part 110. Thus, it is

[[Page 34778]]

consistent with our statutory authority for us to look to all of our 
food CGMP regulations--including infant formula, low-acid canned foods, 
acidified foods, and bottled water, as well as our general food CGMP 
regulations--after which to model our dietary supplement CGMP 
regulations.
    Congress has not spoken to the precise question of what specific 
requirements for dietary supplements may be imposed under the ``shall 
be modeled after'' language. Given this ambiguity, therefore, under 
Chevron step two, we may determine what requirements to include in this 
final rule for dietary supplement CGMP, provided that our 
interpretation is not arbitrary, capricious, or manifestly contrary to 
the statute (Chevron, 467 U.S. at 844).
    Accordingly, we considered the types of requirements in the 
existing food CGMP regulations and used those as models for the dietary 
supplement CGMP requirements. We considered both the objectives and the 
means of achieving the objectives in the existing food CGMP 
regulations. These CGMP food regulations include those for infant 
formula (part 106), general food (``umbrella'' regulations) (part 110), 
thermally processed low-acid canned food (part 113), acidified food 
(part 114), and bottled water (part 129). Each of these food CGMP 
regulations provides objectives and means upon which we modeled the 
dietary supplement CGMP regulations. Just as the precise requirements 
of the other food CGMP regulations are tailored to the particular 
characteristics and hazards of the foods and manufacturing processes 
being addressed, the dietary supplement CGMP requirements are also so 
tailored.
    For example, the infant formula CGMP regulation is intended to 
ensure that the ``safety and nutritional potency'' of a formula are 
``built into the manufacturing process'' in order to establish a 
quality control system to make sure that infant formula products are 
properly manufactured (47 FR 17016 at 17017, April 20, 1982). The 
specific criteria in the regulations apply in determining whether the 
infant formula meets the safety, quality, and nutrient requirements of 
the act (Sec.  106.1(a)). The means to achieving the objectives in the 
infant formula regulations include, for example, requirements for 
ingredient control (through a supplier's guarantee or certification or 
through analysis of the ingredient) (Sec.  106.20); preparation of a 
master manufacturing order and a system to assure and verify the 
addition of each ingredient (Sec.  106.25); either in-process batch 
testing (Sec.  106.25(b)) or sampling and testing of each batch to 
ensure nutrient requirements are met (Sec.  106.30); and coding to 
enable ready identification of lots during their sale and distribution 
(Sec.  106.90).
    The infant formula CGMP regulation also includes numerous 
requirements that manufacturers maintain records, e.g., records on 
certain food-packaging materials; records on nutrient premix testing; 
certificate and guarantees from premix suppliers for required 
nutrients; records of results of testing conducted by suppliers; 
records of tests to establish the purity of each nutrient, the weight, 
and amounts of nutrients; records to ensure proper nutrient quality 
control; records to ensure required nutrient control at the final 
product stage; distribution records; records on microbiological quality 
and purity of raw materials; and records of audits (Sec.  106.100). The 
infant formula CGMP regulation also requires manufacturers to maintain 
procedures describing how complaints will be handled, to follow those 
procedures, and to investigate when a complaint shows a possible health 
hazard (Sec.  106.100(k)). Quality control records must contain enough 
information to permit a public health evaluation of any batch of infant 
formula (Sec.  106.100(o)). All required records must be available for 
authorized inspection (Sec.  106.100(l)).
    Many provisions of the dietary supplement CGMP final rule are 
similar in objective and means and are ``modeled after'' the provisions 
of the infant formula CGMP regulation. For example, like the infant 
formula regulation, the dietary supplement CGMP regulation is designed 
to establish a quality control system to make sure that dietary 
supplements are properly manufactured. The dietary supplement 
regulation uses similar means to ensure this goal, such as requirements 
for ingredient control (through supplier's certificate of analysis or 
testing or examination) (final Sec.  111.75(a)); preparation of a 
master manufacturing record (final Sec.  111.205); in-process batch 
monitoring (final Sec.  111.75(b)) or batch testing or examination 
(final Sec.  111.75(c)); and coding to provide a batch, lot, or control 
number (final Sec.  111.260(a)). Like the infant formula CGMP 
regulations, the dietary supplement CGMP final rule contains 
recordkeeping requirements related to packaging materials; certificates 
of analysis from suppliers; results of tests that you conduct, for 
example, on ingredients or the finished batch; and results of chemical, 
microbiological, or other tests that you conduct as necessary to 
prevent the use of contaminated components (final Sec. Sec.  111.95, 
111.180(b)(2), 111.260(h), 111.325(b)(2), and 111.365(d)). Also similar 
to the infant formula CGMP regulation, the dietary supplement CGMP 
final rule requires manufacturers to maintain procedures for handling 
complaints (final Sec. Sec.  111.553 and 111.570(b)(1)); to investigate 
certain complaints (final Sec.  111.560(a)(2)); and to keep records of 
complaints (final Sec.  111.570(b)(2)). Required dietary supplement 
records must also, as with infant formula records, be available for 
inspection by FDA (final Sec.  111.610(a)).
    The ``umbrella'' food CGMP regulation in part 110 details practices 
to ensure ``(1) that food is manufactured, processed, packed, and held 
under conditions that are sanitary, and (2) that such food is safe, 
clean, and wholesome'' (44 FR 33238 at 33239, June 8, 1979). 
Promulgated primarily under the adulteration provisions of section 
402(a)(3) and (a)(4) of the act, as well as section 361 of the Public 
Health Service Act (the PHS Act) (42 U.S.C. 264), the umbrella CGMP 
food regulation requires a quality control operation whose main purpose 
is ``to provide a systematic procedure for taking all actions necessary 
to prevent food from being adulterated within the meaning of the act'' 
(51 FR 22458 at 22461, June 19, 1986), as well as to prevent the spread 
of food-borne communicable diseases (44 FR 33239, June 8, 1979) (see 
Sec.  110.5(a)). Part 110 also ``specifies requirements that must be 
met to produce safe and wholesome food'' (51 FR 22461). These umbrella 
food CGMP requirements not only pertain to food safety, but also are 
``concerned with contamination by filth or decomposition which may or 
may not raise safety concerns'' (51 FR 22458 at 22462).
    The detailed requirements of the umbrella food CGMP regulation 
accomplish these objectives through a variety of means. For example, 
there are specific personnel provisions requiring employees who may be 
sources of microbial contamination to be excluded from certain 
operations (Sec.  110.10(a)); persons working in contact with food, 
food-contact surfaces, and food-packaging materials to follow hygienic 
practices (Sec.  110.10(b)); and that certain personnel have sufficient 
education or experience to produce clean and safe food (Sec.  
110.10(c)). The umbrella food CGMP regulation also includes detailed 
requirements concerning the grounds surrounding a food plant and the 
design of buildings and structures to protect against contamination or 
to maintain sanitary operations and produce safe food (Sec.  110.20). 
Detailed provisions also require that physical facilities be

[[Page 34779]]

maintained in sanitary condition and in sufficient repair to prevent 
food from being adulterated (Sec.  110.35). Any water that contacts 
food or food-contact surfaces must be ``safe and of adequate sanitary 
quality'' (Sec.  110.37(a)); plumbing, sewage, and other disposal, as 
well as toilet facilities, must also protect against contamination 
(Sec.  110.37(b), (c), and (d)). Similarly, equipment and utensils must 
be designed and maintained to preclude adulteration and food contact 
surfaces must be maintained to protect food from being contaminated by 
any source, including unlawful indirect food additives (Sec.  
110.40(a)). All operations for receiving, inspecting, transporting, 
segregating, preparing, manufacturing, packaging, and storing food must 
be conducted using adequate sanitation principles (Sec.  110.80). 
Appropriate quality control operations must be used to ensure that food 
is suitable for human consumption and that food-packaging materials are 
safe and suitable (Sec.  110.80). Foods must be stored and transported 
under conditions to protect against physical, chemical, and microbial 
contamination, as well as against deterioration of the food and the 
container (Sec.  110.93).
    The provisions of the umbrella food CGMP regulation serve as the 
model for many dietary supplement CGMP provisions. For example, the 
dietary supplement CGMP requirements concerning personnel and microbial 
contamination (final Sec.  111.10(a)); hygienic practices (final Sec.  
111.10(b)); and education, training, or experience (final Sec.  111.12) 
are very similar to provisions in part 110. In addition, the dietary 
supplement CGMP requirements concerning the grounds, physical plant 
facilities, cleaning materials, pest control, water supply, plumbing, 
sewage disposal, bathrooms, and trash disposal (final Sec. Sec.  111.15 
and 111.20) closely resemble the analogous part 110 requirements.
    Because of the particular hazards associated with low-acid canned 
foods and with acidified foods, the CGMP regulations for these foods 
contain detailed provisions to ensure safe manufacturing. Specifically, 
the CGMP regulations for these foods protect the public health against 
microbial contamination from these foods. Part 113 sets out safe 
manufacturing, processing, and packaging procedures for low-acid foods 
in hermetically sealed containers. The CGMP criteria in this part apply 
in determining whether the facilities, methods, practices, and controls 
used by commercial processors of such foods are operated ``in a manner 
adequate to protect the public health'' (Sec.  113.5). Processors of 
low-acid canned foods must have a ``scheduled process'' that is 
established by a qualified person and is ``adequate under the 
conditions of manufacture for a given product to achieve commercial 
sterility'' (Sec. Sec.  113.3 and 113.83). ``Commercial sterility'' of 
thermally processed food means a condition achieved by applying heat to 
render the food free of certain microorganisms (Sec.  113.3). Part 113 
requires that supervisors satisfactorily complete training at a school 
approved by FDA (Sec.  113.10).
    Part 113 also contains extremely detailed requirements on equipment 
and procedures. For example, each vessel used for pressure processing 
in steam must be equipped with a mercury thermometer that is tested for 
accuracy at least once a year, or more frequently if necessary, to 
ensure its accuracy (Sec.  113.40(a)(1)). Critical factors (variation 
of which may affect the attainment of commercial sterility) must be 
specified in the scheduled process and must be measured and recorded on 
processing records frequently enough to ensure that the factors are 
within the specified limits (at least every 15 minutes) (Sec. Sec.  
113.40(a)(13) and 113.83). Observations and measurements of certain 
operating conditions must be made and recorded at intervals of 
sufficient frequency to ensure that commercial sterility of the food 
product is being achieved (at least every hour) (Sec.  
113.40(g)(2)(ii)(c)). There must also be a system to stop packaging 
operations (or to segregate products) when the packaging conditions 
fall below scheduled processes (Sec.  113.40(g)(2)(ii)(b)). Regular 
observations of container closures are required to be made and recorded 
(Sec.  113.60). Each container must be coded ``to enable ready 
identification of lots during their sale and distribution'' (Sec.  
113.60(c)).
    Before using raw materials and ingredients susceptible to 
microbiological contamination, the low-acid food processor must ensure 
that they are ``suitable for use in processing low-acid food'' (Sec.  
113.81(a)). Complete records covering all aspects of the establishment 
of the scheduled process and of certain confirmation tests must be 
maintained permanently (Sec.  113.83). Scheduled processes must be 
readily available to any duly authorized FDA employee (Sec.  
113.87(a)). Whenever any process is less than the scheduled process or 
when critical factors are not in control, the low-acid food must be 
reprocessed or set aside for further evaluation as to public health 
significance (Sec.  113.89). Unless the evaluation demonstrates that 
the product is free of microorganisms of potential public health 
significance, the product either must be reprocessed to render it 
commercially sterile or destroyed (Sec.  113.89).
    All process deviations involving a failure to satisfy the minimum 
requirements of the scheduled process must be recorded and kept in a 
separate file detailing the deviations and actions taken (Sec.  
113.89). Detailed information on processing and production must be 
entered on forms (Sec.  113.100(a)). Not later than 1 working day after 
the actual process, and before the food is shipped or released for 
distribution, a qualified representative of management must review all 
processing and production records for completeness and to ensure that 
the product was subjected to the scheduled process (Sec.  113.100(b)). 
Records to identify the initial distribution of the finished product 
must be kept to facilitate segregation of lots that may have become 
contaminated or otherwise rendered unfit for their intended use (Sec.  
113.100(d)). Records must be maintained at the processing plant for at 
least 1 year after the date of manufacturing and at a reasonably 
accessible location for another 2 years (Sec.  113.100(e)).
    Similarly, the CGMP regulation for acidified food in part 114 
requires supervision by personnel trained at an FDA-approved school 
(Sec.  114.10); manufacturing in accordance with a scheduled process 
established by a qualified person (Sec. Sec.  114.80 and 114.83); 
processing sufficient to destroy the vegetative cells of certain 
microorganisms (Sec.  114.80(a)(1)); sufficient control, including 
frequent testing and recording of results, to ensure that the finished 
hydrogen-ion concentration (pH) values are not higher than 4.6 (Sec.  
114.80(a)(2)); testing and examinations of containers to ensure that 
the food is suitably protected from leakage or contamination (Sec.  
114.80(a)(4)); and coding to enable ready identification of lots during 
their sale and distribution (Sec.  114.80(b)).
    Whenever any acidified food process operation deviates from the 
scheduled process or the pH of the finished product exceeds 4.6, the 
processor must reprocess it, process it under part 113 requirements, or 
set it aside for evaluation as to any potential public health 
significance (Sec.  114.89). Unless the evaluation demonstrates that 
the food has undergone a process that has rendered it safe, the food 
must be fully reprocessed to render it safe or be destroyed (Sec.  
114.89).
    A record must be made of the procedures used in the public health

[[Page 34780]]

evaluation and the results of the evaluation (Sec.  114.89). Records 
must be kept of examinations of raw materials, packaging materials, and 
finished products, and of suppliers' guarantees or certifications that 
verify compliance with our regulations (Sec.  114.100(a)). Processing 
and production records showing adherence to scheduled processes must be 
maintained and must have sufficient additional information such as 
product code, date, container size, and product, to permit a public 
health hazard evaluation of the processes applied to each lot, batch, 
or other portion (Sec.  114.100(b)). Departures from scheduled 
processes having a possible bearing on public health or the safety of 
the food must be recorded and kept in a separate file or log, along 
with the action taken to rectify the departure and the product 
disposition (Sec.  114.100(c)). Records must be kept identifying 
initial distribution of the finished product to facilitate segregation 
of lots that may have become contaminated or otherwise unfit for their 
intended use. Copies of certain required records must be kept at a 
reasonably accessible location for 3 years from the date of manufacture 
(Sec.  114.100). The criteria in the part 114 regulation, as well as 
those in part 110, apply in determining whether an article of acidified 
food is adulterated under section 402(a)(3) of the act in that it has 
been manufactured under such conditions that it is unfit for food or 
under section 402(a)(4) of the act in that it has been prepared, 
packed, or held under insanitary conditions whereby it may have become 
contaminated with filth, or whereby it may have been rendered injurious 
to health (Sec.  114.5).
    Many provisions of parts 113 and 114 also serve as models for 
provisions in the dietary supplement final rule. In many instances, the 
analogous provision in the dietary supplement final rule allows more 
flexibility in the means to achieve the goal. For example, under final 
Sec.  111.13 qualified personnel must be assigned to supervise the 
manufacturing, packaging, labeling, or holding of dietary supplements. 
Although the supervisor must be qualified by education, training, or 
experience to supervise, the more restrictive requirement of parts 113 
and 114 to attend an FDA-approved school is not included. The 
``scheduled process'' for low-acid and acidified food manufacturing, 
processing, and packing is analogous to the required ``system of 
production and process controls'' that dietary supplement manufacturers 
must design and implement (final Sec. Sec.  111.55 and 111.60(a)). 
Similarly, the ``critical factors'' required to be specified in the 
scheduled process for low-acid and acidified foods are akin to the 
``specifications'' that dietary supplement manufacturers must establish 
for certain points in the manufacturing process (final Sec.  111.70). 
Just as low-acid food processors must establish procedures to ensure 
that ingredients are suitable for use, so too must dietary supplement 
manufacturers establish component and finished product specifications 
(final Sec.  111.70(b) and (e)). Just as containers for acidified food 
must ensure suitable protection from contamination, packaging that 
comes into contact with dietary supplements must be safe and suitable 
for use (final Sec.  111.70(d)). Dietary supplement in-process points, 
like the ``critical factors'' for low-acid and acidified food, must be 
monitored to detect any deviation or unanticipated occurrence that may 
result in adulteration (final Sec.  111.75(b)(2)).
    Rejected dietary supplements must also be held under quarantine 
(final Sec. Sec.  111.370 and 111.425); dietary supplements which have 
been reprocessed, treated, or which have had in-process adjustments 
must meet all established product specifications and be approved before 
release (final Sec.  111.90(c)). Similar to coding low-acid or 
acidified foods, dietary supplements must have assigned batch, lot, or 
control numbers (final Sec.  111.415(f)). The design, calibrations, and 
cleaning of equipment and utensils must also result in the equipment 
and utensils being suitable for their intended uses and not result in 
contamination of components or dietary supplements (final Sec.  
111.27). Written procedures for the various controls are required (see, 
e.g., final Sec. Sec.  111.8, 111.25, and 111.103), and required 
written records (see, e.g., final Sec. Sec.  111.14, 111.23, 111.35, 
and 111.95) must be kept for 1 year past the shelf life date, if shelf 
life dating is used, or 2 years after the date of distribution of the 
last associated batch of dietary supplement (final Sec.  111.605). All 
required dietary supplement CGMP records must be readily available for 
inspection and copying by FDA (final Sec.  111.610(a)).
    Finally, the bottled water CGMP regulation was promulgated to 
ensure the safety and sanitary quality of these products, which include 
all water processed and bottled for human consumption (38 FR 32563, 
November 26, 1973). The criteria in part 129, as well as in part 110, 
apply in determining whether the facilities, methods, practices, and 
controls used to process, bottle, hold, and ship bottled drinking water 
conform with good manufacturing practice ``to assure that bottled 
drinking water is safe and that it has been processed, bottled, held, 
and transported under sanitary conditions'' (Sec.  129.1). Part 129 
requires plant construction and design features, such as a separate 
bottling room and an enclosed room for washing and sanitizing 
containers, to protect against contamination (Sec.  129.20). All plant 
equipment and utensils must be suitable for their intended use (Sec.  
129.40(a)).
    Both the product water supply and the operations water supply must 
be of a ``safe, sanitary quality'' in conformance with ``the applicable 
laws and regulations of the government agency or agencies having 
jurisdiction'' (Sec.  129.35(a)). Samples of source water must be 
analyzed at least once a year for chemical contaminants and once every 
4 years for radiological contaminants (Sec.  129.35(a)(3)). Source 
water from other than a public water system must be sampled and 
analyzed for microbiological contaminants at least once a week (id.). 
The product water-contact surfaces of all containers and equipment must 
be clean and adequately sanitized and protected from contamination 
(Sec.  129.37(a) and (b)). Filling, capping, closing, sealing, and 
packaging of containers must be done so as to preclude contamination of 
the water (Sec.  129.37(d)). All product water contact surfaces must be 
nontoxic and in compliance with section 409 of the act (21 U.S.C. 348) 
(concerning food additives) (Sec.  129.40(a)(2)).
    Numerous production processes and controls for bottled water are 
also required. For example, all treatment of product water must be 
effective in accomplishing its intended purpose and in accordance with 
section 409 of the act (Sec.  129.80(a)). The treatment processes must 
be performed with equipment and substances that will not adulterate the 
product (Sec.  129.80). Product water samples must be taken before 
bottling and analyzed as often as necessary to assure uniformity and 
effectiveness of the processes performed by the plant (Sec.  
129.80(a)). Cleaning and sanitizing solutions must be sampled and 
tested to assure adequate performance (Sec.  129.80(c)).
    Each unit package from a batch or segment of continuous production 
run must be identified by a production code (Sec.  129.80(e)). The 
plant must maintain information on the kind of product, volume, date, 
lot code, and distribution of finished product to wholesale and retail 
outlets (id.). During the process of filling, capping, or sealing the 
containers, performance must be monitored and the filled containers 
inspected to assure that they are sound, properly capped or sealed, and 
coded

[[Page 34781]]

and labeled (Sec.  129.80(f)). All containers and closures must be 
sampled and inspected to ascertain that they are free from 
contamination (id.).
    To assure that the plant's production of bottled water complies 
with applicable standards, laws, and regulations, the plant must 
analyze product samples at specified intervals (Sec.  129.80(g)). The 
methods used to analyze the samples must be approved by the government 
agency with jurisdiction (Sec.  129.80(g)(3)). Records of the date of 
sampling, type of product sampled, production code, and results of 
analysis must be maintained (Sec.  129.80(g)(3)). All required records 
must be maintained at the plant for at least 2 years (Sec.  129.80(h)) 
and be available for official review by FDA at reasonable times (id.).
    Provisions of the bottled water CGMP regulation also serve as a 
model for provisions of the dietary supplement CGMP regulation. For 
example, water that is used in a manner such that the water may become 
a component of a dietary supplement must at a minimum comply with 
applicable Federal, State, and local requirements and not contaminate 
the dietary supplements (final Sec. Sec.  111.15(e)(2) and 111.365(c)). 
Precautions that must be taken to prevent contamination of components 
or dietary supplements include performing chemical, microbiological, or 
other testing (final Sec.  111.365(d)). Filling, assembling, packaging, 
labeling, and related operations must be performed to protect the 
dietary supplement against adulteration (final Sec.  111.415). 
Equipment and utensils must be suitable for their intended use (final 
Sec.  111.27(a)). Safe and adequate cleaning compounds and sanitizing 
agents must be used (final Sec.  111.15(c)(1)). Representative samples 
of each batch must be examined to ensure that the product meets 
established specifications (final Sec.  111.415(g)). Each lot of 
packaged and labeled dietary supplement must be assigned a batch, lot, 
or control number (final Sec.  111.415(f)).
    Moreover, our interpretation of permissible requirements for the 
dietary supplement CGMP regulation is also consistent with the use of 
the terms ``good manufacturing practice'' and ``current good 
manufacturing practice'' in section 402(g) of the act. Although these 
terms are not defined in the act, GMP is generally used to refer to 
methods used in, and the facilities and controls used for, product 
manufacturing and related activities.\5\ The umbrella food CGMP 
regulation, for example, defines the ``plant'' covered by the 
requirements of that regulation as the facility used for, or in 
connection with, ``the manufacturing, packaging, labeling, or holding 
of human food'' (Sec.  110.3(k)). As we have described in detail, the 
objectives of the existing food CGMP regulations and the precise means 
(or requirements) used to achieve the objectives vary depending on the 
particular hazards and characteristics of the products and their 
manufacturing. For example, the umbrella food CGMP regulation is 
specifically designed to ensure that food is manufactured, processed, 
packed, and held under sanitary conditions and that the food is safe, 
clean, and wholesome. Low-acid and acidified food CGMP requirements 
focus on facilities, methods, practices, and controls to protect the 
public health against the particular risks of microbial contamination 
from these foods. The infant formula CGMP regulation is aimed at 
ensuring both the safety and nutritional potency of these special 
foods. Infant formula is often the sole item in the diet. An infant 
formula that does not meet the requirements for nutritional potency may 
cause a hazard to the health of the infant (see 61 FR 36154, July 9, 
1996). The bottled water CGMP regulation embodies requirements for 
facilities, methods, practices, and controls used in processing, 
bottling, holding, and shipping of bottled water to ensure its safety 
and sanitary quality.
---------------------------------------------------------------------------

    \5\Although the act does not define ``current good manufacturing 
practice,'' the term is used elsewhere in the statute (see, e.g., 
sections 501(a)(2)(B) (drug CGMP) and 520(f)(1)(A) of the act 
(device CGMP) (21 U.S.C. 351(a)(2)(B) and 21 U.S.C. 360j(f)(1)(A), 
respectively). Case law supports the agency's view that ``current'' 
does not mean ``actually prevailing manufacturing practice'' in an 
industry and that such a practice need not be accepted by a majority 
of manufacturers (National Ass'n of Pharmaceutical Mfr's v. 
Department of Health and Human Services, 586 F. Supp. 740, 752 
(S.D.N.Y. 1984)). Nevertheless, the requirements of this final rule 
embody current practices of many food and dietary supplement 
manufacturers, as reflected in the comments supporting the 
provisions of the proposed rule.
---------------------------------------------------------------------------

    Like the food CGMP regulations after which they are modeled, the 
dietary supplement CGMP final rule contains criteria for facilities, 
methods, practices, and controls used in manufacturing, packaging, 
labeling, or holding dietary supplements to ensure the quality of the 
dietary supplement. Quality includes consistently meeting the 
established specifications for identity, purity, strength, and 
composition of the dietary supplement and limits on contaminants, in 
addition to manufacturing the dietary supplement under conditions to 
prevent adulteration. As Congress recognized in DSHEA, identity, 
purity, strength, and composition are essential characteristics for 
dietary supplements (see, e.g., section 403(s)(2) of the act (a dietary 
supplement is misbranded if its labeling fails to list the name and 
quantity of each dietary ingredient and if it fails to have the 
identity and strength or the quality, purity, or compositional 
specifications it is represented to meet)). Yet without information 
about the identity, purity, strength, or composition, the manufacturer 
could not know the final contents of the dietary supplements it 
manufactures or whether its processes are reliably and consistently 
producing the correct combination and amounts of ingredients in a 
dietary supplement. Accordingly, the final rule requires a manufacturer 
to establish specifications for the identity, purity, strength, and 
composition and for limits on contaminants of the dietary supplements 
it manufactures and ensure that such specifications are consistently 
met in the finished batch of dietary supplement (Sec.  111.75(e)). 
Dietary supplements, like infant formula, are relied upon by consumers 
not only to be safe, but also in many instances to provide specific and 
important claimed health benefits (see, e.g., section 403(r) of the 
act). In the preamble to the 2003 CGMP Proposal, we discussed a number 
of examples illustrating adulteration and improper formulation of 
dietary supplements caused by manufacturing, packaging, or holding 
practices (68 FR 12157 at 12162 and 12163). These dietary supplement 
CGMP requirements will help to protect consumers against similar types 
of adulteration and against reliance on products that are not properly 
formulated.
    Generally recognized principles underlying CGMP also support our 
interpretation of section 402(g) of the act. Our interpretation of 
permissible CGMP regulations is reasonable based on recognized 
principles for controlling the quality of manufactured products in 
general (Ref. 9). As many comments asserted, if the dietary supplement 
CGMP requirements are to be meaningful, they must ensure quality in the 
finished product (see, for example, the discussion in section X of this 
document of comments regarding the production and process control 
system). Controls to ensure quality include planning processes to 
determine desired product features or characteristics, a system of 
controls to ensure that the desired product will be consistently 
produced, and making necessary improvements to the process (section 2.6 
of Ref. 9). Manufacturers must plan what they intend to produce, 
institute adequate controls to achieve the desired outcome, and ensure 
that the controls

[[Page 34782]]

work so that the desired outcome is consistently achieved. If the 
outcome is not consistently achieved, corrective actions need to be 
implemented in order to reach the desired outcome.
    This final rule, like the other food CGMP regulations, embodies the 
basic concepts of controlling quality, i.e., planning, control, and 
improvement. As discussed earlier in the ``Overview of CGMP'' (section 
III.A of this document), we have defined the term ``quality'' for this 
dietary supplement CGMP regulation to mean ``that the dietary 
supplement consistently meets the established specifications for 
identity, purity, strength, and composition and has been manufactured, 
packaged, labeled, and held under conditions to prevent adulteration 
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the Federal 
Food, Drug, and Cosmetic Act.'' Identifying the desired characteristics 
of identity, purity, strength, and composition of a dietary supplement, 
as required in this final rule, is an essential part of the planning 
process to manufacture a dietary supplement. Without identifying 
specifications for each of these characteristics of a dietary 
supplement, it is not possible to control for, and repeatedly and 
reliably produce, the desired end product. Similarly, requirements for 
batch testing ensure that there is consistency from batch to batch. 
Packaging and labeling requirements ensure that suitable packaging is 
used and that the label identified in the master manufacturing record 
for the product is placed on the finished product. In addition, 
requirements related to consumer complaints help to ensure that 
manufacturers are made aware of problems related to their manufacturing 
processes, including those that may result in illness or injury, so 
that they can take corrective actions to prevent any future problems 
from occurring. The procedures for production and process control in 
this final rule also include as key elements measures to prevent 
contamination that could adulterate the product. Requirements to 
protect against contamination during the manufacturing, packaging, 
labeling, and holding operations help ensure that this aspect of 
``quality'' is also achieved for dietary supplements. In sum, this 
final rule embodies principles for controlling quality through 
requirements designed to ensure both that the dietary supplement meets 
its established specifications for identity, purity, strength, and 
composition and that it is not adulterated.
    The dietary supplement CGMP requirements are also reasonable 
because they take into consideration the different product forms in 
which these products will be manufactured. Unlike conventional foods, 
such as fruit, vegetables, cereals, and dairy products, dietary 
supplements will be sold in tablet, capsule, powder, or softgel form. 
They may also be sold as a concentrate, metabolite, constituent, or 
extract of a vitamin, mineral, herb, botanical, or dietary substance. 
Because dietary supplements are often sold in different forms than 
conventional foods, different processes and controls are needed to 
manufacture dietary supplements than to manufacture conventional foods. 
For example, equipment must be able to manufacture dietary supplements 
in tablet or softgel form. Therefore, the final rule requires that 
controls be established to ensure that the equipment functions in 
accordance with its intended use (final Sec.  111.30(e)) and will 
consistently manufacture a product in whatever form is desired. 
Consistent with basic CGMP principles, ensuring the quality of the 
dietary supplement product requires that the manufacturer establish 
precisely what it will produce (specifications for its product), how it 
will make the product (processes), and which process controls and tests 
it will use to ensure reliable, reproducible results. These CGMP 
requirements will help to achieve these results.
    The dietary supplement CGMP requirements are also reasonable when 
viewed in the context of the act as a whole. See Brown & Williamson, 
529 U.S. at 133. Our mission is, in part, to protect the public health 
by ensuring that foods are safe, wholesome, sanitary, and properly 
labeled (section 903(b)(2)(A) of the act) (21 U.S.C. 393(b)(2)(A))). 
Section 701(a) of the act (21 U.S.C 371(a)) gives us the authority to 
promulgate regulations for the efficient enforcement of the act in 
order to ``effectuate a congressional objective expressed elsewhere in 
the Act'' (Association of American, Physicians and Surgeons, Inc. v. 
FDA, 226 F. Supp. 2d 204 (D.D.C. 2002) (citing Pharm. Mfrs. Ass'n. v. 
FDA, 484 F. Supp. 1179, 1183 (D. Del. 1980)). The final rule is 
designed to help ensure that dietary supplements consistently are 
manufactured to produce the product established by the manufacturer, to 
bear the label identified in the master manufacturing record, and to 
prevent adulteration. The requirements are written to facilitate 
efficient and effective action to enforce their terms when necessary.
    Some provisions of the dietary supplement CGMP final rule may be 
similar to the existing drug CGMP regulations. However, we have not 
modeled these regulations after the drug CGMP regulations. Controls 
that relate to certain product forms (e.g., tablets, capsules, powder, 
softgel) are required in this final rule based on the specific 
characteristics of dietary supplements and the hazards associated with 
these forms, not, as some comments imply, based on a desire to emulate 
drug CGMP requirements. The act does not state that there may not be 
similarities between the dietary supplement CGMP requirements and the 
CGMP requirements for drugs or other non-food products. Inasmuch as 
food CGMP regulations and other CGMP regulations are all based on CGMP 
principles, it is neither surprising nor impermissible that there are 
similarities between the dietary supplement CGMP requirements and drug 
or device CGMP requirements. Although we do not agree that any of the 
CGMP requirements exceed drug GCMP requirements, even if a particular 
requirement did, it is not prohibited under the statute. As long as the 
CGMP final rule is ``modeled after'' the food CGMP regulations, we have 
satisfied the statutory requirements. As noted, our interpretation of 
``modeled after'' means that the dietary supplement CGMP final rule 
provisions share similar objectives and/or use similar means as the 
existing food CGMP regulations. To the extent that there are 
similarities to drug CGMP regulations, those similarities are 
appropriate and not prohibited by section 402(g) of the act.
    Consistent with our role ``to fill in, through interpretation, 
matters of detail related to [the statute's] administration,'' Barnhart 
v. Walton, 535 U.S. 212, 225 (2002), we applied our scientific 
expertise, policy judgment, and experience to promulgate dietary 
supplement CGMP requirements that will protect the public health and 
effectively implement our statutory authority to prescribe dietary 
supplement CGMP. See United States v. Mead, 533 U.S. 218, 227-228 
(2001); Nationsbank of North Carolina v. Variable Annuity Life Ins. 
Co., 513 U.S. 251, 256-58 (1995); Chevron, 467 U.S. at 844; Forester v. 
Consumer Product Safety Com., 559 F.2d 774, 783 (D.C. Cir. 1977).

B. Records Authority

    (Comment 19) Some comments state that requirements related to 
record keeping and access to such records are necessary to allow our 
inspectors to assess the adequacy of a dietary supplement 
manufacturer's practices. Additional comments state that access to 
records is necessary to ensure that CGMP requirements are followed and 
to protect the public health. Several comments identify specific types 
of

[[Page 34783]]

records we should require in a final rule, including written 
procedures, batch and master manufacturing records, distribution 
records, and lot numbers. Another comment states that training records 
should be required because the qualifications and training of employees 
affects product quality.
    Other comments, however, state that the record retention and access 
requirements seem to be modeled after drug CGMP and not food CGMP. 
Other comments state that, even though records may be necessary to 
ensure that CGMP requirements are followed, we do not have authority to 
require access to and copying of such records. Some comments assert the 
authority to establish regulations for dietary supplement CGMP does not 
imply there is authority to inspect records. Several comments state we 
cannot rely on section 701 of the act because there is not another 
section of the act that authorizes us access to company records for 
dietary supplement CGMP and section 701(a) of the act does not itself 
give us the authority we need to require records inspection. Another 
comment suggests that the absence of an express grant of records 
inspection authority means that records inspection is not necessary for 
the efficient enforcement of the act.
    Some comments assert that we have no record inspection authority 
under section 704(a) of the act (21 U.S.C 374(a)). A few comments 
suggest that, because records inspection authority was not expressly 
granted in DSHEA's statutory language, as it was for OTC drugs and 
medical devices, Congress provided no authority for records inspection 
for dietary supplement CGMP. The comments state that we have a 
longstanding interpretation that section 704 of the act does not give 
us access to a food manufacturer's records. Several comments state that 
it was sufficient to have voluntary records access, stating that many 
companies are willing to provide access to records.
    Other comments say that our record inspection authority for dietary 
supplement CGMP is limited to that under section 306(a) of the Public 
Health Security and Bioterrorism Preparedness and Response Act of 2002 
(Bioterrorism Act) (21 U.S.C. 350(c)), i.e., when we have a 
``reasonable belief that an article of food is adulterated and presents 
a threat of serious adverse health consequences * * *'' Another comment 
suggests an alternative standard to that in section 306(a) of the 
Bioterrorism Act of a ``reasonable belief that there is a public health 
hazard'' for when we may access records.
    One comment cites In the Matter of Establishment Inspection of 
Medtronic, Inc., 500 F. Supp 536 (D. Minn. 1980), to support its 
assertion that we exceeded our statutory inspection authority in the 
dietary supplement CGMP record requirements. One comment states that a 
warrantless inspection of dietary supplement CGMP records and criminal 
consequences that may be imposed under the act for failure to comply 
with the act provide a ``powerful argument against expanding the 
Agency's inspection authority any further'' and raise ``serious 
constitutional concerns.'' Several comments ask us to clarify our 
jurisdiction for records inspection requirements or delete proposed 
Sec.  111.125(c).
    Still other comments seek confirmation that the confidential and 
trade secret information obtained by us under the rule would be 
protected from disclosure under applicable statutes. Among other 
things, the comments cite the Trade Secrets Act, 18 U.S.C. 1905, and 
the Freedom of Information Act (FOIA), 5 U.S.C. 552(b)(4). Some 
comments express concern that records inspection would violate ``rights 
to privacy of corporate manpower'' or would compromise trade secrets. 
The comments request the rule specifically reconfirm our obligations 
under these laws.
    (Response) We disagree with the comments suggesting that we have no 
authority to require dietary supplement manufacturers to maintain 
records to comply with CGMP under section 402(g) of the act; that the 
absence of an express grant of records authority means records are not 
needed for the efficient enforcement of the act; and that Congress 
meant, by its silence, that we have no authority to issue records 
requirements. Clearly, just as Congress is not expected to express 
``every single evil sought to be corrected'' in a grant of authority to 
promulgate a rule, it can not be expected to articulate every 
requirement that is within an agency's delegated authority (American 
Trucking Assoc. v. United States, 344 U.S. 298, 309-10 (1953)).
    Agencies are expected to bring their expertise to bear on what 
requirements are necessary that will not ``directly frustrate the 
success of the regulation undertaken by Congress'' (id. at 311). In 
this instance, Congress has not expressed any specific intent regarding 
recordkeeping for dietary supplements but has directed FDA to use other 
food CGMP regulations, which require recordkeeping and FDA access to 
records, as models for these regulations. Congress has delegated 
substantial and sufficiently specific authority to us to promulgate 
recordkeeping and access regulations (Cf. United States v. Storer 
Broadcasting, 351 U.S. 192, 202-03 (1956) (upholding a rule that 
established limitations on broadcast licensing that were ``not 
specifically authorized by statute'')). As stated earlier in this 
section, the ``modeled after'' language in section 402(g) of the act is 
ambiguous with respect to what specific CGMP requirements we are to 
include in this final rule. At the time Congress enacted section 402(g) 
of the act there were several food regulations that contained 
recordkeeping and record access requirements. We included records 
requirements in the food CGMP regulations for infant formula (part 
106), low acid food (part 113), acidified food (part 114), and bottled 
water (part 129). Accordingly, the directive in section 402(g) of the 
act is sufficient authority for our recordkeeping requirements in this 
final rule. In addition, our authority to establish records 
requirements has been upheld under other provisions of the act, which 
lacked explicit recordkeeping authority for FDA, where we have found 
records to be necessary (National Confectioners Assoc. v. Califano, 569 
F.2d 690, 693-94 (D.C. Cir. 1978) (upholding requirements for source 
coding and distribution records based on the statutory scheme as a 
whole)).
    Moreover, records are an indispensable component of CGMP. The 
records required by this final rule provide the foundation for the 
planning, control, and improvement processes that constitute a quality 
control system. Implementation of these processes in a manufacturing 
operation serves as the backbone to CGMP. The records will show what is 
to be manufactured; what was, in fact, manufactured; and whether the 
controls that the manufacturer put in place to control the identity, 
purity, strength, and composition and limits on contaminants and to 
prevent adulteration were effective. Further, records will show whether 
and what deviations from control processes occurred, facilitate 
evaluation and corrective action concerning these deviations 
(including, where necessary, whether associated batches of product 
should be recalled from the marketplace), and enable a manufacturer to 
assure that the corrective action was effective. Written procedures 
also will help ensure that personnel follow hygienic practices; permit 
evaluation of whether equipment, including software that may run the 
equipment, performs as it is intended; and help ensure that the

[[Page 34784]]

equipment is properly maintained and adequately cleaned.
    The CGMP final rule establishes the parameters for the production 
and process control system in which dietary supplements are to be 
manufactured. The dietary supplement manufacturer establishes the 
identity, strength, purity, and composition of the supplement it 
manufactures (final Sec.  111.70); determines whether the established 
specifications are met (final Sec.  111,73); uses the tests it needs to 
ensure that those characteristics are consistently met (final 
Sec. Sec.  111.75 and 111.315); and identifies the steps necessary to 
ensure that any necessary tests or examinations are completed, 
reviewed, and recorded in a timely fashion before the dietary 
supplement is released for distribution to the public (final Sec. Sec.  
111.110 and 111.325(b)(2)). The CGMP final rule also requires that the 
manufacturer establish written procedures for its quality control 
operations to ensure the personnel performing this function provide 
proper review and oversight of the production and process control 
system, have the knowledge and experience to identify and anticipate 
possible problems in the manufacturing of the dietary supplement, and 
ensure corrective measures are taken promptly when problems occur 
(final Sec. Sec.  111.103 through 111.140). The final rule also 
requires that the manufacturer establish the ``master recipe(s)'' for 
the dietary supplement(s) it manufactures so that such recipe(s) can be 
followed for each batch produced (final Sec. Sec.  111.205 through 
111.210). In sum, manufacturers cannot operate without records because 
critical elements in a manufacturing process are entirely dependent on 
information written or captured in the form of a record.\6\ Such 
records are also necessary to protect consumers by enabling 
manufacturers to identify and recall problematic products as necessary 
and make necessary corrections to deviations in their processes.
---------------------------------------------------------------------------

    \6\It is also worth noting that standard references used in many 
industries establish clear expectations for documentation and 
recordkeeping practices for assuring quality control in 
manufacturing operations (Refs. 9 and 13).
---------------------------------------------------------------------------

    The authority granted us under sections 402(g) and 701(a) of the 
act not only includes the authority to establish record requirements, 
but also includes access to such records. Without such authority, the 
dietary supplement CGMP requirements are, practically speaking, not 
enforceable. Under section 402(g)(1) of the act, the failure to meet 
any CGMP requirements, including the failure to have a record that is 
required by this final rule, renders a dietary supplement so 
manufactured to be adulterated as a matter of law. The introduction or 
delivery for introduction into interstate commerce of an adulterated 
dietary supplement is a prohibited act under section 301(a) of the act 
(21 U.S.C. 331(a)), and acts done to an ingredient in a dietary 
supplement, or to a dietary supplement, while held for sale after 
shipment in interstate commerce that result in the ingredient or 
dietary supplement being adulterated violates section 301(k) of the act 
(21 U.S.C. 331(k)). Thus, in order for us to determine whether the 
dietary supplement product is adulterated and whether a manufacturer 
has committed a prohibited act, we must have access to the 
manufacturer's records that we are requiring to be kept under section 
402(g) of the act.
    In light of the foregoing, without access to such records, we would 
not know whether a manufacturer was complying with the procedures and 
processes required in this final rule. For example, our investigator 
must have access to the test results for the identity of a dietary 
ingredient to determine whether such ingredient meets the 
manufacturer's specification for identity. The investigator needs to 
understand, by reviewing a record, what the software that runs a 
production operation is set up to do and whether it performs those 
functions to achieve the desired product characteristics. Observation 
of these processes alone, by an investigator, would not allow that 
investigator to evaluate compliance with this final rule. Moreover, 
records often cannot be thoroughly evaluated by the investigator on 
site. In such cases, records must be readily available to food experts 
at the Center for Food Safety and Applied Nutrition (CFSAN) and agency 
consultants. We must have accurate, reliable, and objective data about 
the manufacturing specifications to be able to achieve an enforceable 
rule.
    We also disagree with comments stating our records inspection 
authority is limited to that provided by section 306(a) of the 
Bioterrorism Act. There is no basis to conclude that Congress intended 
to limit our authority to inspect records, to enforce section 402(g) of 
the act, to the records inspection authority under the Bioterrorism 
Act. The Bioterrorism Act, enacted almost 8 years after section 402(g), 
to address credible threats of serious adverse health consequences or 
death to humans and animals, required recordkeeping to identify the 
immediate previous sources and the immediate subsequent recipients of 
food (21 U.S.C. 350c).
    There is nothing in the Bioterrorism Act that reflects any 
Congressional intent to modify section 402(g) of the act. In fact, 
section 414(d)(1) of the act (21 U.S.C. 350c(d)(1)), added by section 
306(a) of the Bioterrorism Act, shows a contrary intent. Section 
414(d)(1) provides that ``This section shall not be construed--(1) to 
limit the authority of the Secretary to inspect records or to require 
establishment and maintenance of records under any other provision of 
this Act.'' Moreover, Congress, in the legislative history to the 
Bioterrorism Act, supported our general approach of requiring 
recordkeeping pursuant to authority in section 701(a) of the act in 
combination with other provisions.\7\ We are not relying on section 704 
of the act for its underlying authority to require recordkeeping and 
records access in this final rule. Those comments asserting that we do 
not have such authority and the underlying references, for example, to 
past hearings on records inspection authority under section 704 of the 
act, are not controlling with regard to the action we are taking under 
sections 402(g) and 701(a) of the act. When there are other bases for 
jurisdiction and tools to protect the public interest, we may use what 
``will be the most effective in advancing the Congressional objective'' 
(U.S. v. Midwest Video Corp., 406 U.S. 649, 656 (1972)).
---------------------------------------------------------------------------

    \7\In discussing section 306 of the Bioterrorism Act 
(Maintenance and Inspection of Records for Foods), Congress stated, 
``The managers did not adopt a Senate proposal to authorize the 
Secretary to require the maintenance and retention of other records 
for inspection relating to food safety, because the Secretary has 
authority under section 701(a) of the [act] to issue regulations for 
the `efficient enforcement of this Act' and this authority, in 
combination with other provisions (such as section 402 [of the 
act]), gives the Secretary the authority to require appropriate 
record keeping in food safety regulations.'' (H.R. Conf. Rep. No. 
107-481, at 135 (2002), (Ref. 14)).
---------------------------------------------------------------------------

    Some comments stated that our access to dietary supplement records 
is not consistent with constitutional jurisprudence. We disagree. The 
comment which expressed concern about ``constitutional issues'' in the 
context of an FDA inspection of records during a warrantless FDA 
inspection expressed concern about the criminal liability that could be 
imposed on a manufacturer under the act (citing United States v. 
Dotterweich, 320 U.S. 277 (1944) and United States v. Park, 421 U.S. 
658 (1975)). To the extent that the comment asserts that the records 
access established in this final rule constitutes an improper search 
and seizure under the Fourth Amendment, we disagree.
    The dietary supplement industry, as the food industry as a whole, 
is a

[[Page 34785]]

pervasively regulated industry that is subject to warrantless 
inspections (see, e.g., United States v. Biswell, 406 U.S. 311, 315 
(1972) (``In the context of a regulatory inspection system of business 
premises * * * the legality of the search depends not on consent but on 
the authority of a valid statute.''); United States v. New England 
Grocers Supply Co., 488 F. Supp. 230, 238 (D. Mass. 1980) (holding that 
a warrantless inspection under 21 U.S.C. 374 is ``fully consistent with 
the Fourth Amendment''); United States v. Acri Wholesale Grocery Co., 
409 F. Supp. 529, 533 (S.D. Iowa 1976) (holding that a warrantless 
inspection, which includes photographic activities, conducted under 21 
U.S.C. 374 does not violate the Fourth Amendment); United States v. 
Business Builders, Inc., 354 F. Supp. 141, 143 (N.D. Okla. 1973) (``the 
statute takes the place of a valid search warrant''); United States v. 
Del Campo Baking Mfg. Co., 345 F. Supp. 1371 (D. Del 1972) (finding 
warrantless inspection of food establishment lawful under 21 U.S.C. 
374)).
    As explained earlier in this section, we have ample authority, 
under sections 402(g) and 701(a) of the act, to require that certain 
records be kept and accessible to us upon inspection. Records access is 
imperative to the efficient enforcement of the dietary supplement CGMP 
final rule, and we are not prohibited from requiring access to these 
records under sections 402(g) and 701(a) of the act (See Permian Basin 
Area Rate Cases, 390 U.S. 747, 780 (1968) (``in the absence of 
compelling evidence that such was Congress' intention * * * [the court 
should not] prohibit administrative action imperative for the 
achievement of an agency's ultimate purposes.'')).
    We also disagree with the comment suggesting that voluntary records 
access is sufficient. In our experience, many manufacturers are not 
willing, as the comments suggest, to provide records voluntarily to us 
(Ref. 15). Moreover, it is often the case that the most uncooperative 
manufacturers are the very ones whose records and processes are 
deficient. Without mandatory requirements for agency access to records 
required by the final rule, we could not enforce and there would be 
minimal incentives for manufacturers to comply with the rule, which 
would frustrate Congressional intent in enacting section 402(g) of the 
act.
    We also disagree with the comment that cited In the Matter of 
Establishment Inspection of Medtronic, Inc., 500 F. Supp. 536 (D. Minn. 
1980), to suggest that our proposed recordkeeping requirements exceed 
our statutory inspection authority. As already discussed, we are not 
relying on section 704 of the act for our authority to require access 
to dietary supplement CGMP records. Thus, to the extent the comment 
cited to Medtronic as an example of the statutory authority for 
inspection of device records under section 704 of the act, Medtronic is 
not pertinent to our authority for records access in this final rule.
    Finally, we disagree that the records access in this final rule 
will violate any protection a manufacturer has with respect to 
protection of confidential commercial or financial information or trade 
secrets. Trade secrets and commercial or financial information that is 
privileged or confidential are protected from disclosure under FOIA and 
other laws (see, e.g., 21 U.S.C. 331(j), 18 U.S.C. 1905). Further, our 
FOIA regulations set forth the specific procedures for assuring such 
protection.
    It was not clear from the comments what was meant by ``rights to 
privacy of corporate manpower.'' We note that Sec. Sec.  20.63 and 
20.64 contain provisions for the protection of personal privacy.

C. Public Health Service Act Authority

    (Comment 20) One comment acknowledges that we have authority under 
the PHS Act to regulate intrastate activities that may cause the spread 
of communicable diseases. The comment states that, in any situation in 
which we need to exercise our authority over any disease-causing 
substance within the State where a component or dietary supplement is 
manufactured, packed, or held, we can and should exercise our authority 
under the PHS Act. However, the comment asserts that nothing in the 
preamble clearly states whether we believe that the final rule will be, 
in its entirety, binding on manufacturers, packers, and holders of 
dietary supplements who are engaged solely in intrastate commerce, and 
that we have not requested comment on this specific issue. The comment 
requests that we clearly state that the final rule applies only to 
interstate commerce, except for activities that may spread communicable 
diseases.
    (Response) We address each of these issues in turn.
1. The Communicable Disease Risk Posed by Dietary Supplements
    There are communicable disease risks related to the manufacture of 
dietary supplements that are appropriately addressed not only under the 
act, but, as the comment acknowledges, also under the PHS Act. 
Microorganisms, including Salmonella enterica (Salmonella), 
Campylobacter jejuni, and enterohemorrhagic Escherichia coli 0157:H7 
(EHEC), are well-known causes of communicable diseases, and may be 
present in dietary supplements and their components. There are a number 
of microorganisms that cause communicable diseases and that may be 
found in components or dietary supplements. These microorganisms cause 
serious effects and symptoms. For example, Salmonella causes 
salmonellosis, which affects the gastrointestinal (GI) tract and is 
characterized by diarrhea, fever, abdominal cramps, headache, nausea, 
and vomiting (Ref. 16). In a small portion of healthy people (1 to 4 
percent), infection spreads from the GI tract into the blood stream, 
which can be life-threatening. Persons with immune compromising 
conditions (such as cancer, Acquired Immunodeficiency Syndrome (AIDS), 
autoimmune disorders) are at greater risk of blood stream infection 
(Ref. 16).
    Campylobacteriosis, often due to infection with Campylobacter 
jejuni, is characterized by diarrhea, fever, and abdominal cramps, 
which can be severe (Ref. 17). These symptoms frequently relapse, and 
the disease may become chronic in immune compromised persons. People 
with campylobacteriosis are also at increased risk of developing 
certain post-infectious complications, which will prolong their 
recovery.
    EHEC may cause infections with a very low infectious dose (as low 
as 2 to 45 organisms), and may result in non-bloody and bloody 
diarrhea, hemolytic-uremic syndrome (a cause of red blood cell 
destruction, damage of blood vessel walls, and, in severe cases, kidney 
failure (especially in young children)), thrombotic thrombocytopenic 
purpura (i.e., a blood disorder characterized by low platelets, low red 
blood cell count, abnormalities in kidney function, and neurological 
abnormalities (especially in adults)), and death (Ref. 18).
    Animal tissues (e.g., organs from livestock), as well as 
botanicals, used as components in dietary supplements may contain EHEC, 
Salmonella, and Campylobacter jejuni. In addition, because the same 
microorganisms are also present in the environment, they may 
contaminate components during manufacturing activities. Moreover, 
people who harbor those pathogens could transmit them to components and 
dietary supplements during processing. Therefore, components and 
dietary supplements, as potential sources of communicable diseases, may 
be regulated under the PHS Act.
    For these microorganisms (e.g., EHEC, Salmonella, and Campylobacter 
jejuni)

[[Page 34786]]

humans carry and transmit infections through their feces or by direct 
contact with other persons. For other microorganisms, domestic and wild 
animals serve as the reservoir, and humans become infected when 
contaminated tissues of infected animals are used in dietary 
supplements. For both categories of microorganisms, dietary supplements 
can also become contaminated indirectly by human and animal fecal 
contamination of water or through the production or processing 
environment.
    Dietary supplements may contain a variety of components derived 
from domestic and wild animals, such as powders prepared from whole or 
partial gecko, deer antler velvet, and organs, such as cow liver and 
brain, pork stomach, or sheep spleen from common domestic livestock. 
Each of these tissues may be contaminated with microorganisms such as 
Salmonella, Campylobacter jejuni, and EHEC. Even clinically normal 
animals obtained from safe sources may harbor these communicable 
pathogens and result in contaminated products (Ref. 19). (Information 
on these animals and potential pathogens can be accessed at http://www.fsis.usda.gov/Science/Microbiology/index.asp). Dietary supplements 
also may contain crustacean or molluscan shellfish or components 
prepared from them, such as glucosamine from shrimp exoskeletons and 
oyster extract, that may be contaminated with Vibrio species, including 
V. parahaemolyticus. Vibrio species are natural inhabitants of 
shellfish harvest waters, and shellfish are commonly naturally 
contaminated, especially during times of the year when harvest waters 
are warm (Refs. 20 through 23). V. parahaemolyticus most often causes 
gastroenteritis characterized by diarrhea, abdominal cramps, nausea, 
vomiting, and fever (Ref. 24).
    Dietary supplements may also contain botanicals (plants) that may 
harbor microorganisms, including organisms from animal feces 
(Salmonella and Shigella spp., Escherichia coli), and organisms arising 
from handling (Staphylococcus aureus), harvesting, processing, and 
transportation.
    Components contaminated with microorganisms must be treated to 
prevent the finished dietary supplements from being contaminated. The 
processes used to manufacture dietary supplements do not, by 
themselves, always eliminate the microorganisms. Studies show, for 
example, that microorganisms, such as EHEC and Salmonella, can even 
survive the tablet production process and thereby expose consumers 
(Ref. 25).
    The industry is aware of the dangers of using components 
contaminated with Salmonella and other microorganisms. For example, in 
2001, a component manufacturer recalled 2,400 pounds of pepsin 
contaminated with Salmonella. As a result, a number of dietary 
supplement manufacturers issued recalls for their dietary supplements 
that contained the pepsin. In the press releases accompanying the 
recalls, the dietary supplement manufacturers warned consumers of the 
possible dangers of Salmonella contamination, and encouraged consumers 
to either destroy or return the supplements (Ref. 26).
    Therefore, because of the communicable disease concerns associated 
with dietary supplements, we are asserting legal authority under the 
PHS Act in support of the final rule. As discussed in the following 
section of this document, our authority under the PHS Act is not 
limited to interstate activities. It also covers intrastate activities.
2. Activities For Which We Are Asserting Legal Authority Under the PHS 
Act
    There are many opportunities for components and dietary supplements 
to become contaminated with microorganisms that spread communicable 
diseases. The final rule requires firms to take all the necessary 
precautions during the manufacture of a dietary supplement to prevent 
such contamination.
    These precautions, for example, include: Performing manufacturing 
operations under conditions and controls that protect against potential 
microorganism growth; washing or cleaning components that contain soil 
or other contaminants; performing microbiological testing, as 
necessary, to prevent the use of contaminated components; 
sterilization, pasteurization, freezing, refrigeration, and controlling 
pH, humidity, and water activity (a<INF>w</INF>), or using other 
effective means to remove, destroy, or prevent the growth of 
microorganisms and decomposition; and holding components and dietary 
supplements that can support the growth of infectious microorganisms of 
public health significance in a manner that prevents them from becoming 
adulterated.
    Failure to properly clean components, or take any other appropriate 
steps, such as those listed in the previous paragraph, could lead to 
pathogen growth and the spread of communicable diseases. If, for 
example, a dietary supplement manufacturer purchased an animal-derived 
ingredient that harbored Salmonella enterica, but failed to take the 
steps necessary to inactivate the pathogen, the consumption of the 
dietary supplement could lead to the spread of salmonellosis.
    The final rule also requires firms to take measures to exclude from 
certain operations any sick persons who might contaminate material, 
including components, dietary supplements, and contact surfaces used to 
manufacture, package, label, or hold a dietary supplement.

D. The Interstate Commerce Nexus for the Final Rule

1. The PHS Act
    (Comment 21) Several comments assert that, although the PHS Act may 
extend to some intrastate activities, its reach is very limited. The 
comments appear to conclude that the reach of the PHS Act and the act 
extends only to situations in which the finished dietary supplement is 
shipped in interstate commerce.
    (Response) We do not agree that this view is correct. The PHS Act 
extends to intrastate commerce. Under section 361 of the PHS Act (42 
U.S.C. 264), we may ``make and enforce such regulations as in [our] 
judgment are necessary to prevent the introduction, transmission, or 
spread of communicable diseases from foreign countries into the States 
or possessions, or from one State or possession into any other State or 
possession.''
    In Louisiana v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977), the 
court upheld FDA's regulation that banned the sale of small turtles to 
prevent the spread of disease caused by turtles harboring Salmonella 
and Arizona microorganisms. The ban covered both interstate and 
intrastate sales. The court held that the intrastate ban is not only 
authorized by the law, but, under modern conditions of transportation 
and commerce ``is clearly reasonable to prevent the interstate spread 
of disease'' (id.).
    We are authorized under the PHS Act to regulate conduct that occurs 
within a State to the extent necessary to prevent the interstate spread 
of communicable diseases. Such is the present case with respect to the 
provisions of the dietary supplement CGMP final rule for which section 
361 of the PHS Act provides authority.
2. The Act
    The act extends to the sale of a dietary supplement that was 
manufactured and

[[Page 34787]]

distributed entirely in one State, if the supplement contains any 
ingredient or uses any component that came from outside of that State. 
Such a dietary supplement is subject to section 301(k) of the act, 
which prohibits ``[t]he alteration, mutilation, destruction, 
obliteration, or removal of the whole or any part of the labeling of, 
or the doing of any other act with respect to, a food, drug, device, or 
cosmetic, if such act is done while such article is held for sale 
(whether or not the first sale) after shipment in interstate commerce 
and results in such article being adulterated or misbranded.'' 
(emphasis added). See also 21 U.S.C. 321(b)(3) (defining food to 
include articles used as components of food).
    The interstate commerce prerequisite under section 301(k) or 
section 304(a) (21 U.S.C. 334(a)) of the act is established when one or 
more components used in the manufacture of the product have crossed 
State lines. This principle is known as ``component jurisdiction'' 
(See, e.g., Baker v. United States, 932 F.2d 813, 814-15 (9th Cir. 
1991); United States v. Article of Food * * * Coco Rico, Inc., 752 F.2d 
11, 14 (1st Cir. 1985); United States v. Dianovin Pharmaceuticals, 
Inc., 475 F.2d 100, 103 (1st Cir.), cert. denied, 414 U.S. 830 (1973) 
(``appellants' use of components shipped in interstate commerce to make 
vitamin K for injection brought their activities within Sec.  
331(k)''); United States v. Cassaro, Inc., 443 F.2d 153, 155-56 (1st 
Cir. 1971); United Statesv. Detroit Vital Foods, Inc., 330 F.2d 78, 81-
82 (6th Cir.), cert. denied, 379 U.S. 832 (1964); United States v. 
Allbrook Freezing & Cold Storage, Inc., 194 F.2d 937, 939 (5th Cir. 
1952); United States v. Varela-Cruz, 66 F.Supp.2d 274, 277-281 (D. P.R. 
1999)).
    Nor does it matter that the interstate product component comprises 
only a minute part of the article, United States v. Miami Serpentarium 
Laboratories, [1981--1982 Transfer Binder] Food Drug Cosm. L.Rep. (CCH) 
paragraph 38,164 at 38,930 (S.D. Fla. 1982); United States v. 14 Cases 
* * * Naremco, 374 F.Supp. 922, 925 (W.D. Mo. 1974), or if the 
interstate ingredient combines with others to form a different product. 
Detroit Vital Foods, 330 F.2d at 81; United States v. 40 Cases * * * 
Pinocchio Brand * * * Oil, 289 F.2d 343, 346 (2d Cir.), cert. denied, 
368 U.S. 831 (1961).
    Finally, we note that section 709 of the act creates a presumption 
of interstate commerce (see 21 U.S.C. 379a (``In any action to enforce 
the requirements of this Act respecting a device, food, drug, or 
cosmetic the connection with interstate commerce required for 
jurisdiction in such action shall be presumed to exist.'')).
    In conclusion, the final rule covers not only finished products 
that have moved in interstate commerce but also products made from 
ingredients or components that have moved in interstate commerce. This 
is true regardless of the amount of the ingredient or component in the 
product and regardless of whether the finished dietary supplement has 
itself moved in interstate commerce. The final rule also covers 
products, components, and ingredients that may contribute to the spread 
of communicable disease, regardless of whether the component, 
ingredient, or product has itself moved in interstate commerce.
3. Commerce Clause
    (Comment 22) One comment states that we must be ``mindful of the 
limits'' imposed on the regulation of intrastate commerce by the 
Supreme Court in United States v. Lopez, 514 U.S. 549 (1995). The 
comment asserts that we may only regulate intrastate activity that has 
a ``substantial effect'' on interstate commerce and activity that 
``exerts a substantial economic effect on interstate commerce.''
    (Response) The final rule is consistent with the Lopez decision. 
Among the cases cited by the Court in Lopez as support for its decision 
is Wickard v. Filburn, 317 U.S. 111 (1942), which involved the 
production and consumption of homegrown wheat. In that case, the Court 
explained: ``although Filburn's own contribution to the demand for 
wheat may have been trivial by itself, that was not enough to remove 
him from the scope of federal regulation where, as here, his 
contribution, taken together with that of many others similarly 
situated, is far from trivial'' (Lopez, 514 U.S. at 556). The same is 
true for dietary supplement manufacturers. Therefore, the requirements 
of the final rule are consistent with the Commerce Clause of the 
Constitution.

E. Fifth Amendment

    (Comment 23) Several comments allege a number of the sections of 
the proposed regulation are unconstitutionally vague and violate the 
Administrative Procedure Act (APA) because the rule would be ``contrary 
to constitutional right, power, privilege, or immunity.'' The comments 
express concern that if such terms are not defined or deleted, there 
would be no fair notice on what conduct is prohibited and would result 
in ``unbridled discretion'' in how the rule will be enforced. The 
comments focus on provisions containing words such as ``adequate,'' 
``qualified,'' ``readily accessible,'' ``convenient,'' ``suitable,'' 
``appropriate,'' and ``necessary.'' For example, one comment notes that 
proposed Sec.  111.15(e) would require physical plant plumbing to be of 
an adequate size and design and to be adequately installed and 
maintained. The comment objects to the section on the ground that 
``what constitutes `adequate' in those contexts is left undefined.''
    (Response) We disagree these terms are vague or that the identified 
terms should be deleted from the final rule. The qualifying terms 
objected to in the comments have been in use since the umbrella food 
CGMP rule (part 110) was first promulgated in 1969. For example, this 
regulation included requirements that: ``[p]lant buildings and 
structures shall be suitable in size;'' there must be ``sufficient 
space'' for equipment and storage materials; there must be ``adequate 
lighting;'' and protection against pests must be provided ``where 
necessary'' (see 34 FR 6977 at 6978, April 26, 1969). The court in 
National Association of Pharmaceutical Manufacturers. v. Department of 
Health & Human Services, 586 F.Supp. 704 (S.D.N.Y 1986), addressed the 
very question of whether terms such as ``adequate,'' ``appropriate,'' 
``proper,'' ``sufficient,'' and ``suitable,'' in the drug CGMP 
regulation were vague. The court found that the drug CGMP regulation 
containing such terms was ``sufficiently definite to give notice of the 
required conduct to one who would avoid [their] penalties, and to guide 
the judge in [their] application * * *'' (Id. at 753). The court so 
held, in part, in light of the fact that the drug CGMP statute was 
upheld against a constitutional vagueness attack in United States v. 
Bel-Mar Laboratories, Inc., 284 F. Supp. 875, 883 (E.D.N.Y. 1968) 
(``the phrase `current good manufacturing practice' is not strange to 
those in the trade to whom the subject section is directed.''). 
Furthermore, the use of such ``ordinary terms to express ideas which 
find adequate interpretation in common usage and understanding'' are 
not the types of terms that have been held to be unconstitutionally 
vague (Boyce Motor Lines v. United States, 342 U.S. 337, 342 (1952)). 
Some of these very terms have been in use for over 30 years in food 
CGMP regulations.
    No comments were submitted objecting to the use of such terms, when 
the umbrella food CGMP rule was revised in 1986 (see 51 FR 22458, June 
19, 1986). Also, when we began work on the dietary supplement CGMP 
rule, we

[[Page 34788]]

received and published for comment an industry draft of a CGMP 
regulation for dietary supplements. The industry draft used many of the 
same terms. For example, it provides in part: ``Plumbing shall be of 
adequate size and design and adequately installed and maintained'' (62 
FR 5700 at 5703, February 6, 1997). Thus, there has been sufficient 
common usage of these terms in the food industry and, in particular, 
the dietary supplement industry to enable manufacturers, and those who 
enforce the requirements, to comprehend and apply such terms ``with a 
reasonable degree of certainty'' to their particular operations (Boyce 
Motor Lines v. United States, 342 U.S. at 340 (``[F]ew words possess 
the precision of mathematical symbols, most statutes must deal with 
untold and unforeseen variations in factual situations, and the 
practical necessities of discharging the business of government 
inevitably limit the specificity with which legislators can spell out 
prohibitions [and therefore] no more than a reasonable degree of 
certainty can be demanded.'')). The same reasoning applies here. It 
addresses ``untold and unforeseen variations in factual situations'' 
and, as such, ``no more than a reasonable degree of certainty can be 
demanded.''
    Agencies are permitted to, and indeed must, use such qualifying 
terms to address the variety of conditions that exist at different 
companies. We do not need to, nor could we, predict with mathematical 
precision how many inches or feet, for example, would be ``adequate 
space'' to allow for cleaning a particular piece of equipment that 
could be applied to every size of facility and every operation (id.). 
Moreover, defining such terms too precisely would unduly restrict the 
application of the regulation to a very narrow, limited set of 
circumstances and not provide industry with the needed flexibility to 
address the number and variety of types of manufacturing operations 
that Congress intended for this rule to cover (see Freeman United Coal 
Mining Company v. Federal Mine Safety and Health Review Commission, 108 
F.3d 358, 363 (D.C. Cir. 1997) (citations omitted) (upholding a 
regulation that required equipment to be ``maintained in good repair,'' 
the court rejected the vagueness challenge: ``specific regulations 
cannot begin to cover all of the infinite variety of [conditions at 
firms and that] * * * [b]y requiring regulations to be too specific 
[courts] would be opening up large loopholes allowing conduct which 
should be regulated to escape regulation.''); United States v. Bel-Mar 
Laboratories, Inc., 284 F. Supp. at 883 (rejecting a vagueness 
challenge to the CGMP requirements for drugs, noting that ``[a]s a 
matter of fact, there are responsible segments of opinion within the 
industry itself which oppose a greater degree of specificity in this 
area.'').
    Finally, it is important to understand that rules are not 
unconstitutionally vague simply because they require interpretation by 
regulated persons. For example, courts have held that the term 
``insanitary conditions'' in the act is not unconstitutionally vague 
(See Golden Grain Macaroni Co. v. United States, 209 F.2d 166, 168 (9th 
Cir. 1953) (citing Boyce Motor Lines, supra); Berger v. United States, 
200 F.2d 818 (8th Cir. 1952)). In Berger, the court rejected the claim 
that the term ``insanitary condition'' is unconstitutionally vague on 
the ground that it does not specify the ``degree of insanitation'' 
required for a violation (id. at 822). A law may require a person to 
make ``estimates of the degree of dirtiness and lack of sanitation'' 
which may result in a violation (id., see alsoBoyce Motor Lines v. 
United States, 342 U.S. at 340 (It is not ``unfair to require that one 
who deliberately goes close to an area of proscribed conduct shall take 
the risk that he may cross the line'')). There are sufficient 
protections under the act to overcome any concerns related to how it 
will be criminally enforced. We disagree that such terms will lead to 
``unbridled discretion'' on how the rule is enforced.
    In short, we find that the rule is not unconstitutionally vague, 
and does not violate section 706(2)(B) of the APA (5 U.S.C. 706(2)(B)).

F. Miscellaneous

    (Comment 24) One comment states that the proposed rule violates 
section 402(f)(1)(A)(i) and (f)(1)(A)(ii) of the act (21 U.S.C. 342 
(f)(1)(A)(i) and (f)(1)(A)(ii)), which deems a dietary supplement 
adulterated if it contains a dietary ingredient that presents an 
unreasonable risk of illness or injury under conditions of use in 
labeling or ordinary conditions of use, if none are suggested or 
recommended in labeling. Under section 402(f) of the act, the 
Government bears the burden of proof to show that a dietary supplement 
is adulterated. The comment states that the proposed rule reversed the 
presumption under section 402(f) of the act, and would revise the rule 
to require us to first show a violation under section 402(f) of the act 
before we could take any enforcement action under section 402(g). 
Another comment states that, because the rule was intended to enable 
manufacturers to be able to detect and avoid adulteration through CGMP, 
the proposed rule created a presumption that dietary supplements are 
adulterated until proven otherwise.
    (Response) The final rule does not violate section 402(f) of the 
act. Section 402(f) and (g) of the act provide two independent bases 
under which we may take enforcement action against dietary supplements. 
A dietary supplement may be adulterated either because a manufacturer 
has failed to follow a CGMP requirement, or because a dietary 
supplement presents an unreasonable risk of illness or injury, or both. 
There would be no reason to assert a second basis for adulteration 
under section 402(g) of the act if one always had to demonstrate 
adulteration under section 402(f) of the act as a prerequisite.
    We also disagree with the comment that the proposed rule creates a 
presumption that the dietary supplement is adulterated simply because 
the proposed requirements would enable a manufacturer to detect and 
avoid adulteration. The requirements for CGMP are prophylactic and are 
designed in part to ensure that all aspects of manufacturing, from 
receipt through distribution, provide the necessary controls and 
monitoring to ensure the quality of the dietary supplement, including 
that it is manufactured, packaged, labeled, and held in a manner to 
prevent adulteration.
    (Comment 25) One comment states that, if there is reduced 
competition through the enforcement of the rule, there will be a 
secondary effect of elimination of speech on dietary supplement 
innovative uses.
    (Response) The comment seems to conclude that, if a dietary 
supplement manufacturer is not able to stay in business due to adverse 
enforcement actions against it by us, or elects to not go into business 
based on the possibility of enforcement action by us, there will be 
reduced competition due to fewer products, less labeling, and 
``elimination of speech on innovative uses.'' To the extent that the 
comment is suggesting that the dietary supplement CGMP requirements are 
unconstitutionally overbroad, this argument is wholly without merit 
(Cf. Wisconsin v. Mitchell, 508 U.S. 476, 488-89 (1993) (finding no 
merit to an overbreadth argument that the possibility of enhanced 
sentences based on prior racially motivated speech or associations 
constitutes an impermissible chill on free speech)). Manufacturing a 
dietary supplement in a manner that violates the CGMP requirements 
causes the product to be adulterated, and therefore, unlawful.

[[Page 34789]]

 The fact that a manufacturer may not stay in business, or elects not 
to enter business, due to: (1) Our implementation of CGMP requirements 
or (2) our enforcement against a product that violates CGMP 
requirements, does not mean that we are somehow prohibiting speech. In 
any event, there is no First Amendment protection for speech that 
concerns unlawful activity under the first prong of the test set out in 
Central Hudson Gas & Electric Corp. v. Public Service Commission, 447 
U.S. 557 (1980). Therefore, the comment's suggestion that there is 
elimination of speech based on the rulemaking is not supportable. The 
requirements in the final rule do not infringe on a manufacturer's 
right to lawfully label and market a dietary supplement.

VI. What Comments Did We Receive on the General Provisions? (Subpart A)

A. Organization of Final Subpart A

    Proposed subpart A contained five provisions regarding the scope of 
the proposed rule, definitions, and exclusions. Table 2 of this 
document lists the sections in final subpart A and identifies the 
proposed sections that form the basis of the final rule.

           Table 2.--Derivation of Sections in Final Subpart A
------------------------------------------------------------------------
                  Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.1 Who is subject to this part?      Sec.   111.1
------------------------------------------------------------------------
Sec.   111.3 what definitions apply to this    Sec.   111.3
 part?
------------------------------------------------------------------------
Sec.   111.5 Do other statutory provisions     Sec.   111.5
 and regulations apply?
------------------------------------------------------------------------

B. Who Is Subject to This Part? (Final Sec.  111.1)

    Section 111.1 explains who is subject to the dietary supplement 
CGMP requirements. In brief, final Sec.  111.1(a) states that you are 
subject to the dietary supplement CGMP requirements if you manufacture, 
package, label, or hold a dietary supplement. This requirement includes 
a dietary supplement you manufacture but that is packaged or labeled by 
another person, and a dietary supplement that is imported, offered for 
import in any State or Territory of the United States, the District of 
Columbia, or the Commonwealth of Puerto Rico. Final Sec.  111.1(b), 
however, excludes certain persons from the rule. Specifically, Sec.  
111.1(b) states that the requirements pertaining to holding dietary 
supplements do not apply to you if you are holding those dietary 
supplements at a retail establishment for the sole purpose of direct 
retail sale to individual consumers. This section also states that a 
retail establishment does not include a warehouse or other storage 
facility for a retailer or a warehouse or other storage facility that 
sells directly to individual consumers.
    This exclusion represents specific changes sought by the comments. 
We provide detail on the comments and our reasons for revising final 
Sec.  111.1 in the following paragraphs.
    (Comment 26) Some comments interpret the proposal as not applying 
to persons who perform labeling operations. For example, one comment 
claims that proposed Sec.  111.35(e), which would require 
manufacturers, packagers, and persons who hold dietary supplements to 
establish specifications, did not apply to ``labelers'' because the 
proposed definition of ``you'' did not expressly mention persons who 
label dietary supplements.
    (Response) We disagree with the comments. Various provisions in the 
proposal expressly mentioned or pertained to labels and labeling 
operations (see, e.g., proposed Sec. Sec.  111.20(c)(6) (which would 
require your physical plant to have separate or defined areas for 
packaging and label operations), 111.30(a) (which would impose certain 
requirements on automatic, mechanical, or electronic equipment used to 
``manufacture, package, label, and hold'' a dietary supplement), 
111.35(a) (which would require you to implement a system of production 
and process controls that cover, among other things, all stages of 
labeling dietary supplements), 111.37(a) (which would require you to 
use a quality control unit to ensure, among other things, your label 
operations are performed in a manner that prevents adulteration and 
misbranding), 111.40(b) and (c) (which would impose certain 
requirements on packaging and labels you receive and on persons who 
perform label requirements), and 111.70 (which would impose various 
requirements on packaging and label operations)). Although the proposed 
definition of ``you'' and proposed Sec.  111.1 did not include the word 
``label'' or ``labeling,'' we considered label operations to be part of 
a broader manufacturing process, and it would be illogical to interpret 
the proposal's specific references to label operations as somehow being 
inapplicable to labelers simply because a proposed definition of 
``you'' or a general ``scope'' provision did not mention labels or 
otherwise distinguish label operations from the broader context of 
manufacturing.
    In any case, to correct such misinterpretation, we have revised 
Sec.  111.1 to include the word ``label.'' Thus, under final Sec.  
111.1(a), you are subject to the dietary supplement CGMP requirements 
if you ``manufacture, package, label, or hold a dietary supplement.'' 
We also have made corresponding changes to other sections in this final 
rule; for example, we have revised the definition of ``you'' in final 
Sec.  111.3 to state that ``you'' means ``a person who manufactures, 
packages, labels, or holds'' a dietary supplement, and we also have 
inserted the word ``labeling'' in the title to this final rule. We have 
not explained this change in the preamble each time it is made in the 
codified provision.
    In addition, we refer to ``label'' and ``labeling'' in the context 
of CGMP requirements related to operations for ensuring the correct 
label is on the product. To help clarify that we are referring to 
labeling requirements in this final rule for labeling operations and 
not, for example, to the labeling requirements in part 101, we inserted 
the word ``operations'' in the title of part 111 to read ``Current Good 
Manufacturing Practice in Manufacturing, Packaging, Labeling, or 
Holding Operations for Dietary Supplements.''
    (Comment 27) Several comments ask for clarification about the 
rule's applicability to different types of businesses and practices. 
Some comments ask for a clear listing of who is subject to the rule, 
stating that it is difficult to apply the rule's specific provisions. 
According to these comments, the rule's level of detail and 
inflexibility does not account for variations in manufacturing needs 
within the entire industry.
    Several comments on various proposed sections ask who would be 
responsible for complying with CGMP requirements if more than one party 
was involved in the manufacturing, packaging, labeling, or holding of 
the dietary supplement. For example, some comments ask whether 
consultants are subject to a specific proposed section; others ask who 
would be responsible if a firm employed another firm to handle 
packaging or labeling operations.
    Other comments request clarification regarding the rule's 
applicability to distributors. Some comments claim that a person who 
holds and sells packaged products should not be subject to dietary 
supplement CGMP requirements. Other comments state that dietary 
supplement CGMPs should apply to distributors as well as

[[Page 34790]]

manufacturers. These comments assert many supplement distributors are 
merely marketers who employ contract manufacturers. The comments said 
that, because marketers are the parties providing supplements to 
consumers, we should hold marketers responsible for their products and 
require marketers to ensure that their contract manufacturers adhere to 
CGMP requirements. These comments argue we should not permit marketers 
to transfer their responsibilities in delivering safe supplements. 
Other comments assert questions about the rule's applicability are 
underscored by typical dietary supplement labeling practices where the 
contact information listed on the product label pertains to the 
distributor/marketer instead of the actual manufacturer.
    Collectively, these comments raise a basic question as to which 
party or parties are responsible for complying with the dietary 
supplement CGMP requirements where more than one party is involved in 
the manufacture, packaging, labeling, or holding of that dietary 
supplement.
    (Response) In the 2003 CGMP Proposal, we stated that it would apply 
to a wide variety of activities associated with the manufacture, 
packaging, and holding of a dietary supplement, including labeling, 
testing, quality control, holding, and distribution (68 FR 12157 at 
12175). We stated under proposed part 111 you would need to comply with 
those regulations directly applicable to the operations that you 
perform and provided examples (id.). All activities may not be 
performed by the same person. For example, a manufacturer may contract 
with another firm to package and label the dietary supplement in the 
containers used for distribution to consumers. Alternatively, a 
distributor may contract with one firm to manufacture a dietary 
supplement, and another firm to package and label the dietary 
supplement that the distributor ultimately distributes under its own 
name.
    Under this final rule, you must comply with the CGMP requirements 
that apply to your operations related to the manufacture, packaging, 
labeling, and holding of dietary supplements. It is not practical to 
list all possible contractual relationships that persons may enter into 
in the manufacture of a dietary supplement, or to list all businesses 
or practices that may be subject to the requirements of this final rule 
in order for persons to know whether they are subject to requirements 
of this final rule. To provide additional clarity about how this rule 
may apply to various persons, we provide some examples in the following 
paragraphs.
    A manufacturer that manufactures a dietary supplement, and then 
packages and labels and distributes the dietary supplement, is subject 
to all the requirements in this final rule. If that manufacturer 
contracts with another person to package and label the dietary 
supplement, then the packager/labeler is responsible for complying with 
the requirements for packaging and labeling operations, in addition to 
other relevant requirements. The packager/labeler, in this example, 
would need to comply, not only with the specific requirements related 
to packaging and labeling operations in subpart L, but also with the 
general requirements related to personnel, physical plant, quality 
control, and other requirements that apply to that firm's operations. 
However the packager/labeler would not need to comply with requirements 
that do not apply to it; for example, the packager/relabeler would not 
have to conduct testing on the finished batch of dietary supplement 
since it does not manufacture the finished batch of dietary supplement.
    A manufacturer who contracts with a person to do packaging and 
labeling, but who later distributes the packaged and labeled product, 
is ultimately responsible for the dietary supplement it releases for 
distribution. The manufacturer would be responsible for the CGMP 
requirements for the operations that it performs, including those 
related to the release of the product for distribution. For example, 
the manufacturer must determine whether the packaged and labeled 
dietary supplement it receives from the packager/labeler conforms to 
applicable specifications (final Sec.  111.127(d)), and must approve 
the release of the packaged and labeled dietary supplement for 
distribution (final Sec.  111.127(h)). Although the manufacturer is not 
performing the specific activities related to the packaging and 
labeling operations done by another person, the manufacturer has an 
obligation to know what and how such activities are performed so that 
it can make decisions related to whether the packaged and labeled 
product conforms to applicable specifications and whether to approve 
and release the product for distribution.
    Some manufacturers may sell their finished batch of dietary 
supplement to a packager/labeler that the packager/labeler may package, 
label, and then hold and distribute. The manufacturer and packager/
labeler would each be responsible for complying with the applicable 
CGMP requirements related to the operations that they perform. The 
manufacturer would not be responsible for the oversight of the 
packager/labeler, since the packager/labeler is not under the control 
of the manufacturer and has control over the release of the packaged 
and labeled dietary supplement.
    A manufacturer may decide to hire a contractor or a consultant for 
specific operations within the scope of the manufacturer's 
responsibilities under the final rule. For example, a manufacturer may 
hire a person to calibrate its equipment. The manufacturer is 
responsible for complying with the requirements related to its 
responsibilities, e.g., calibration requirements in this example, even 
though the manufacturer has hired another person to perform that job 
task.
    In another example, a distributor who purchases a packaged and 
labeled dietary supplement and who then holds the product in a 
warehouse for distribution to another physical location is subject to 
the requirements related to its operations. The codified uses the word 
``hold'' since it is a broad term which encompasses the activities of a 
distributor. Thus, the distributor would be responsible for complying 
with requirements in subpart M, Holding and Distributing, in addition 
to other requirements related to its operations (e.g., Personnel, 
Physical Plant and Grounds).
    In cases where a distributor contracts with a manufacturer to 
manufacture a dietary supplement that the distributor then distributes 
under its own label, the distributor has an obligation to know what and 
how manufacturing activities are performed so that the distributor can 
make decisions related to whether the packaged and labeled product 
conforms to its established specifications and whether to approve and 
release the product for distribution.
    (Comment 28) Some comments state that the proposed rule 
requirements would require the manufacturer to report adverse events to 
us, but would not require those who distribute the product and whose 
name is likely to be on the product label, to report adverse events to 
us. The comments state that reports of adverse events submitted by 
consumers to those who distribute, but do not make, dietary supplements 
could be hidden from the public if such persons are not required to 
submit those reports to us.
    (Response) The comments may have misinterpreted the proposed rule. 
The requirement to review and investigate a product complaint is 
distinct from any report about the product complaint to

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us. Reporting a complaint to us is not covered by these CGMP 
requirements and would be voluntary, unless the complaint is subject to 
the statutorily mandated reporting requirements for ``significant 
adverse events'' pursuant to the ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462), 
signed into law on December 22, 2006 (see discussion in section XX of 
this document).
    Under the procedures that are set forth in subpart O, Product 
Complaints (see section XX of this document), a distributor and a 
manufacturer are both subject to the requirements related to the review 
and investigation of a product complaint that they receive.
    (Comment 29) Some comments argue against including minimum CGMPs 
necessary for activities related to manufacturing, packaging, labeling, 
or holding dietary ingredients in the final rule. Several comments 
argue the proposed rule is overly broad and inconsistent with 
congressional intent. These comments question whether Congress intended 
that CGMP apply to persons involved in the manufacture, packaging, 
labeling, and holding of dietary ingredients. The comments also argue 
that, if the rule applies to dietary ingredient manufacturers, we would 
be establishing precedent and that we lack legal authority to regulate 
ingredients rather than the finished products themselves. The comments 
state that neither food CGMP nor drug CGMP offers precedent or guidance 
on regulating ingredients. The comments argue those who provide dietary 
ingredients should be subject to the existing general food CGMP 
requirements in part 110 rather than to the dietary supplement CGMP 
requirements.
    Several comments argue that many dietary ingredients are used in 
regular foods and in drugs as well as in dietary supplements. The 
comments argue, for some dietary ingredients, their use in dietary 
supplements represents a very small percentage of the dietary 
ingredient's worldwide usage. The comments say we should allow those 
who deal only with dietary ingredients to operate under one set of 
regulations, such as the general food CGMP requirements in part 110. 
According to these comments, we have not demonstrated either a failure 
of the current system or a compelling need to create different 
regulations for raw materials common to both the food and dietary 
supplement industries. The comments would revise the title of part 111 
and proposed Sec.  111.1 and make conforming revisions throughout the 
proposed rule to limit the rule's applicability to dietary supplements.
    In contrast, other comments say the rule should apply to dietary 
ingredient manufacturers as well as to dietary supplement 
manufacturers. The comments state that excluding those who provide or 
supply dietary ingredients would mean those who have the greatest 
expertise in these goods would not be subject to dietary supplement 
CGMP requirements and thus fail to cover a crucial step in preventing 
the adulteration or contamination of dietary supplements. The comments 
argue that, for some dietary ingredients (especially raw botanical and 
agricultural goods), the most critical point in ensuring an 
ingredient's quality and purity is at time of harvest or creation, and 
that this is particularly true with new or original ingredients.
    The comments state problems with dietary supplements often arise 
from substandard ingredients, and the difficulty in testing the 
properties of some botanical and other dietary ingredients at the in-
process or finished product stage makes it necessary to include dietary 
ingredient manufacturers in the final rule. Furthermore, these comments 
assert a flexible testing scheme that they recommend (which emphasizes 
establishing specifications for components, relying on certificates of 
analysis from qualified suppliers, qualifying component suppliers, and 
establishing written procedures, with testing of finished batches 
serving as a check on the overall manufacturing process) makes it 
important to regulate dietary ingredient manufacturers.
    Other comments suggest we issue a separate or modified set of CGMP 
requirements that would apply to persons who manufacture, package, 
label, or hold dietary ingredients. These comments say the proposed 
rule does not work for all dietary ingredients, especially those 
converted from non-food grade to food grade during the manufacturing 
process. These comments said the rule should be modified for dietary 
ingredients.
    (Response) Two issues seem to be raised by these comments: (1) 
Whether dietary ingredients are within the scope of this final rule and 
(2) whether dietary ingredient manufacturers are subject to this final 
rule. Dietary ingredients are included within the scope of this final 
rule but dietary ingredient manufacturers are not necessarily subject 
to this rule. The definition of ``component'' in this final rule 
includes ``any substance intended for use in the manufacture of a 
dietary supplement including those that may not appear in the finished 
batch of the dietary supplement. Component includes dietary ingredients 
(as described in section 201(ff) of the act) and other ingredients'' 
(final Sec.  111.3). The proposed rule, Sec.  111.3, recognized that 
``dietary ingredients'' are ``components'' (68 FR 12157 at 12176) 
(describing how dietary ingredients would fall within the proposed 
definition of ``component'').
    There are specific requirements in this final rule that relate to 
components, and thus dietary ingredients, that are used in the 
manufacture of a dietary supplement. For example, final Sec.  111.70(b) 
requires you to establish certain component specifications. Such 
requirements would include specifications for dietary ingredients as 
``components.'' It is important to control the components used in the 
manufacture of dietary supplements to ensure consistency and to ensure 
the quality of the dietary supplement. Since dietary ingredients are 
considered components, the various requirements apply to dietary 
ingredients as part of the production and process control. Therefore, 
we disagree to the extent comments were suggesting that there should be 
no CGMP requirements related to the dietary ingredients used by a 
manufacturer in the manufacture of dietary supplements.
    Dietary ingredients are included within the meaning of 
``component.'' In those requirements in the proposed rule where 
``component'' encompasses ``dietary ingredient'' we are, in the final 
rule, removing ``dietary ingredient'' in those requirements and only 
refer to ``component.'' Given the scope of the final rule, it is 
redundant to refer to both ``component'' and ``dietary ingredient'' 
where the latter is subsumed in the former.
    In response to comments that questioned the need to include 
manufacturers of dietary ingredients within the scope of part 111, we 
have made changes to the scope of the rule, as applied to dietary 
ingredient manufacturers. As we explain more fully in our discussion of 
final Sec. Sec.  111.70, 111.73, 111.75, and 111.77 (see section X of 
this document), after considering comments about the overall production 
and process control system, we revised the final rule's approach to 
ensuring product quality. This approach emphasizes that it is important 
to ensure the quality of the dietary supplement throughout the 
production and process control system. This approach emphasizes 
establishing specifications for components and ensuring those 
specifications are met.

[[Page 34792]]

 You may rely on a certificate of analysis for specifications (except 
for the identity of the dietary ingredient) only if you satisfy certain 
criteria, which include qualifying the supplier of the components. With 
this approach, the goal of ensuring the quality of dietary supplements 
can be achieved without applying the rule specifically to persons who 
manufacture, package, label, or hold dietary ingredients that will be 
further processed as a dietary supplement by other persons.
    Consequently, we revised Sec.  111.1 by deleting ``dietary 
ingredient.'' Therefore, those who manufacture, package, label, or hold 
dietary ingredients are not subject to the final rule. To illustrate, 
assume you manufacture a dietary ingredient and sell that bulk dietary 
ingredient to Company X. Company X then utilizes the bulk dietary 
ingredient in a dietary supplement. Under final Sec.  111.1(a), you 
would not be subject to these dietary supplement CGMP requirements 
because you are not manufacturing a dietary supplement, rather you are 
manufacturing a dietary ingredient for further incorporation into a 
dietary supplement by Company X. If, however, you sell herbs in bulk to 
Company X, and Company X simply packages the herbs into smaller units 
for sale as a dietary supplement, you would be subject to the dietary 
supplement CGMP requirements because you are manufacturing a dietary 
supplement that Company X is simply packaging and labeling, and not 
further processing into a dietary supplement. In other words, in the 
latter example, you would have acted as a manufacturer whose finished 
product is simply repackaged or relabeled.
    Under final Sec.  111.1(a) persons engaged solely in activities 
relating to the harvesting, storage, or distribution of raw 
agricultural commodities that will be incorporated into a dietary 
supplement by others are not included within the scope of the rule as a 
dietary supplement manufacturer. This is because those persons simply 
``supply'' a component (i.e., the raw agricultural commodity) that 
another person will process into a dietary supplement; thus you do not 
manufacture, package, label, or hold a dietary supplement.
    Note, too, that if you manufacture and supply a component directly 
to consumers as a dietary supplement, you would be considered a dietary 
supplement manufacturer within the scope of final Sec.  111.1(a). 
Likewise, if you manufacture a component and sell part of the batch to 
another person who, in turn, will further process the component as a 
dietary supplement and sell the remainder of the batch to consumers as 
a dietary supplement, you would be subject to the dietary supplement 
CGMP requirements, as a manufacturer, for the product sold to consumers 
and not subject to an exclusion under final Sec.  111.1(b), discussed 
in this section. In other words, final Sec.  111.1(a) refers to the 
nature of your activity, and simply engaging in some activities that do 
not bring you within the scope of the final rule does not necessarily 
mean that all your activities are outside the scope of the final rule.
    We do not agree, as some comments suggested, that we need to issue 
a separate or modified set of CGMP requirements for dietary 
ingredients. That is because there are adequate controls established in 
this final rule for the use of dietary ingredients used by the 
manufacturer of a dietary supplement. However, if you manufacture, 
package, label, or hold dietary ingredients that will be further 
processed as a dietary supplement by another person, you must comply 
with food CGMP requirements in part 110. A dietary ingredient is a food 
under section 201(f) of the act, as a food, or as a component of food. 
Because the final rule gives manufacturers an incentive to qualify 
suppliers of dietary ingredients, persons who manufacture, package, 
label, or hold dietary ingredients may wish to familiarize themselves 
with these dietary supplement CGMP requirements and use them in 
manufacturing, packing, labeling, or holding operations for dietary 
ingredients.
    (Comment 30) Some comments argue if the final rule ultimately 
covers dietary ingredient suppliers then we should clarify what 
constitutes a ``consumer.'' According to these comments, dietary 
ingredient suppliers do not typically supply their products directly to 
those individuals who will ultimately consume or ingest them. Thus, 
``consumers'' of dietary ingredients are other companies, not 
individuals. The comments express concern about the possible 
application of proposed Sec.  111.95 which would require procedures for 
handling complaints.
    (Response) The final rule applies only to persons who manufacture, 
package, label, or hold dietary supplements and are not subject to an 
exclusion in final Sec.  111.1. However, as explained in the previous 
response to comment 29, if a dietary ingredient manufacturer also 
supplies or sells a dietary ingredient as a dietary supplement, such a 
manufacturer would be subject to final Sec.  111.1(a) and subject to 
all relevant dietary supplement CGMP requirements.
    Some comments expressed concern about dietary ingredient 
manufacturers having to comply with proposed Sec.  111.95 on product 
complaints. If a dietary ingredient manufacturer receives a product 
complaint, we encourage the manufacturer to evaluate the complaint to 
determine if it may involve a problem with the manufacture of the 
dietary ingredient. In addition, we encourage the dietary ingredient 
manufacturer to notify the dietary supplement manufacturer so that it 
can review the complaint and investigate, as needed.
    (Comment 31) Several comments question the proposal's applicability 
to persons who sell packaged products or seek clarification as to 
whether the rule applies to dietary supplement manufacturers that 
operate from homes and those that distribute product to other 
distributors.
    (Response) To the extent that the comments question whether 
retailers or individuals who sell dietary supplements directly to 
individual consumers are subject to the dietary supplement CGMP 
requirements, we have revised the final rule by creating a new Sec.  
111.1(b) which states that: ``The requirements pertaining to holding 
dietary supplements do not apply to you if you are holding those 
dietary supplements at a retail establishment for the sole purpose of 
direct retail sale to individual consumers. A retail establishment does 
not include a warehouse or other storage facility for a retailer or a 
warehouse or other storage facility that sells directly to individual 
consumers. '' This means, for example, if you operate a storefront 
retail establishment where you stock dietary supplements on your 
shelves for purchase by individual consumers, we do not consider you to 
be ``holding'' those dietary supplements in a manner that would require 
you to comply with the holding provisions in this final rule. Sale to 
individual consumers, where you are not storing bulk dietary 
supplements as one would in a warehouse or storage facility, does not 
fall within the manufacturing, packaging, labeling, or holding 
activities that would subject you to dietary supplement CGMP 
requirements.
    However, if you operate storefront retail establishments, and those 
retail establishments obtain their stocks from your warehouse, we would 
consider your warehouse operations to be ``holding'' dietary 
supplements and expect your warehouse operations to comply with the 
rule's holding requirements. Such distribution is no different than 
other warehouse operations that are normally subject to CGMP 
requirements. Consequently, to

[[Page 34793]]

distinguish between ``holding'' dietary supplements for retail sale to 
consumers and ``holding'' dietary supplements in a warehouse for 
further distribution, final Sec.  111.1(b) limits the exclusion to 
persons holding dietary supplements ``at a retail establishment for the 
sole purpose of direct retail sale to individual consumers.'' Final 
Sec.  111.1(b) also makes it clear that a retail establishment does not 
include a warehouse or other storage facility that a retailer uses to 
hold the dietary supplements or an operation that sells directly to 
consumers, but that itself distributes the product to the consumer from 
a warehouse or storage facility and not from a storefront retail 
establishment.
    (Comment 32) Many comments question the rule's applicability to 
various practitioners such as herbalists, acupuncturists, naturopaths, 
and other health care providers who prepare individualized herbal 
formulas for specific individuals on a case-by-case basis. Most 
comments say such practitioners should not be covered by the rule. 
These comments give various reasons to justify their position, 
including:
    <bullet> These practitioners do not broadly sell products;
    <bullet> These practitioners make very small quantities of 
individualized formulas, and can therefore be very selective as to the 
quality of ingredients used;
    <bullet> The testing and storage requirements of each finished 
batch cannot apply to a small dispensary where several different 
modified herbal formulas are prepared each day;
    <bullet> Based on the projected costs to implement CGMPs, it would 
be virtually impossible for an individual practitioner or university 
clinic to develop the necessary quality control unit, maintain reserve 
samples, maintain the required paperwork, or retrofit clinics to comply 
with the rule;
    <bullet> Many States regulate or license these practitioners, so 
further Federal regulation is unnecessary;
    <bullet> Some practitioners do not consider themselves to be 
manufacturers;
    <bullet> In an analogous situation, compounding pharmacists are not 
required to comply with drug CGMPs; and
    <bullet> Despite the growing number of such practitioners, there is 
no proof that greater harm has occurred to the general public from the 
herbs these practitioners sell.
    (Response) We stated in the 2003 CGMP Proposal (68 FR 12157 at 
12175) that we declined to exempt herbalist practitioners from the 
proposed rule. We continue to believe that the risks of adulteration 
are not eliminated just because the practitioner is an herbalist, and 
therefore, such an exemption should not be included in this final rule. 
However, after further consideration, we have determined that it would 
be appropriate for us to consider the exercise of our enforcement 
discretion in deciding whether to apply the requirements of this final 
rule to certain health care practitioners, such as herbalists, 
acupuncturists, naturopaths, and other related health care providers.
    We find it noteworthy that the comments identified two potential 
safeguards that could support the exercise of our enforcement 
discretion on whether to apply the requirements of the final rule to 
certain practitioners: (1) Adequate training in the professional 
practice and (2) an individual client and practitioner relationship. 
For example, comments claimed that the practitioners receive adequate 
training to formulate dietary supplements and that they provide the 
dietary supplements to individuals in the course of a one-on-one 
consultation on the premises of the practitioner. One comment from a 
practitioner states that she received her training from an accredited 
4-year university and it included didactic and clinical training in 
acupuncture and Chinese herbs. Another comment from an organization 
provides detailed training guidelines for practitioners, including 
1,600 hours of training, 400 hours of which should include clinical 
work. Moreover, many comments also assert that the practitioners are 
different from dietary supplement manufacturers because they formulate 
the dietary supplements in the course of a one-on-one consultation at 
their premises. That enables them to ensure the formulations are made 
to meet the specific needs of the individuals.
    We believe that a one-on-one consultation by a practitioner who is 
adequately trained in their profession may not necessitate the same 
types of controls as we are establishing in this final rule for 
manufacturing activities that are on a larger scale. Such a 
practitioner may make some formulations in advance of the consultation 
and still make the formulations in very limited quantities for the 
individual client. We believe that it would be appropriate to consider 
the exercise of our enforcement discretion, on a case-by-case basis, to 
determine whether to apply the requirements of this final rule to such 
persons.
    We do not expect the number of those subject to the consideration 
of our enforcement discretion to be very large. Many products that are 
manufactured by practitioners would not necessarily be considered to be 
dietary supplements (e.g., certain products used by traditional Asian 
medicine practitioners). Further, we are not considering exercising our 
enforcement discretion with respect to practitioners who prepare 
batches of herbs and sell them to individual consumers without 
determining whether the dietary supplement is appropriate for each 
consumer's needs in a one-on-one personal consultation, or those that 
prepare batches of a dietary supplement for which there is a known or 
suspected safety concern.
    (Comment 33) Several comments asked us to exempt academic 
institutions that provide training for therapeutic disciplines that 
use, for example, herbal formulas in their practice regardless of 
whether the dietary supplements they produce enter into interstate 
commerce. Specifically, these comments would revise the final rule to 
state that it does not apply ``to academic institutions that provide 
training in dispensing of nutritional or herbal products and formulas 
related to courses in therapeutic disciplines that provide such 
products and formulas as a part of their therapy, for example, 
naturopathy, herbalism, traditional Chinese medicine, and 
acupuncture.''
    (Response) Similar to what we stated in response to comment 32, we 
believe that it may be appropriate to consider the exercise of our 
enforcement discretion in circumstances where an academic institution's 
actions are similar to those of a practitioner who is adequately 
trained in their profession and who provides dietary supplements within 
the context of an individual client and practitioner relationship. In 
general, it is not our policy to inspect an academic institution that 
provides training for therapeutic disciplines that use, for example, 
dietary supplements in their practice. We intend to consider the 
exercise of our enforcement discretion in those situations where there 
is a one-on-one consultation that includes a practitioner with adequate 
training. We intend to issue guidance to further clarify how the agency 
intends to exercise its enforcement discretion on the application of 
this final rule to certain academic institutions.
    (Comment 34) Several comments discuss the position taken by certain 
nations, notably Australia and Canada, that have developed CGMP 
requirements and related guidance for botanicals. According to these 
comments, these nations recognize that there are various types of 
practitioners who sell herbs and herbal preparations in a clinical 
setting, and do not consider such persons to be manufacturers. The

[[Page 34794]]

comments ask us to follow the example of these nations.
    (Response) We intend to consider the positions taken by other 
nations to inform us in our decisionmaking in any future guidance on 
how we intend to exercise our enforcement discretion on the application 
of this final rule to certain practitioners.
    (Comment 35) Many comments say we should define when a dietary 
supplement will be said to have entered interstate commerce. The 
comments state herbal practitioners (and academic institutions) often 
purchase source herbs from outside their State, even if they prepare 
these herbs for their specific customers within the State. These 
comments request we clarify that the rule does not apply to herbs 
purchased out of State if prepared for local use. Other comments 
request clarification regarding clients who have moved across State 
lines, yet maintain a relationship with an herbalist practitioner.
    (Response) In section V of this document we explain the interstate 
and intrastate issue related to the final rule.
    (Comment 36) A few comments assert individual practitioners and 
practitioner organizations often are unaware of the opportunity to 
comment on CGMP or regulatory issues. Therefore, the comments say these 
practitioners and organizations often fail to provide comment or 
otherwise participate in rulemaking and say we should give these 
practitioners and practitioner organizations a chance to comment.
    (Response) We provided many opportunities for comment and, 
therefore, we decline to adopt the comments' suggestion. As we discuss 
in section I of this document, we published an ANPRM concerning dietary 
supplement CGMPs on February 6, 1997 (62 FR 5700); the 1997 ANPRM 
provided an opportunity for public comment. On March 7, 2003, we issued 
a Talk Paper, along with other background documents, announcing the 
issuance of a proposed dietary supplement CGMP rule. We made the 
proposed rule available when it went on display (before it published) 
in the Federal Register on March 13, 2003 (68 FR 12157), and, again, 
provided an opportunity for public comment. We also held public 
meetings on April 29, 2003, in College Park, MD and on May 6, 2003, in 
Oakland, CA. We also held a public meeting (via satellite downlink) on 
May 9, 2003, with viewing sites at our district and regional offices 
throughout the country. Thus, we provided numerous opportunities for 
interested persons to learn about the rule and to submit comments or 
otherwise participate in the rulemaking process. Consequently, we 
decline to provide yet another opportunity for comment.
    (Comment 37) The preamble to the 2003 CGMP Proposal noted that 
comments submitted in response to our 1997 ANPRM state we should not 
distinguish between dietary supplements made in the United States and 
those made in a foreign country (68 FR 12157 at 12174). Although we 
agreed with the comments and made no distinction between foreign and 
domestic firms in the proposed rule, we invited comment on how we might 
ensure dietary ingredients and dietary supplements exported to the 
United States have been manufactured, packaged, labeled, and held 
consistent with part 111 (68 FR 12157 at 12175).
    Several comments argue the rule should apply to foreign firms as 
well as domestic manufacturers to ensure a ``level playing field'' and 
to protect American consumers. Some comments say we should work with 
foreign countries to harmonize our requirements and thus avoid 
potential trade disputes under international trade agreements such as 
the General Agreement on Tariffs and Trade. Other comments suggest 
compliance by foreign firms could be achieved through the use of third 
party certification programs, such as the dietary supplement 
verification program administered by USP, or the adoption of importer 
verification provisions similar to those used in our HACCP requirements 
for seafood (see Sec.  123.12).
    In contrast, another comment says we should inspect foreign firms 
to ensure compliance, whereas other comments claim we lack jurisdiction 
over foreign firms.
    (Response) We are amending proposed Sec.  111.1 to clarify the 
regulation's applicability to foreign firms. We explain in this section 
how we may enforce the rule against foreign firms. We, however, are not 
making any changes in response to the comments calling for the 
harmonization of the rule with foreign rules because this request is 
beyond the scope of the final rule.
    In response to comments, and for clarification, we have revised 
final Sec.  111.1(a) to clarify that the regulation applies to the 
extent that you manufacture, package, label, or hold a dietary 
supplement, including a dietary supplement imported or offered for 
import in any State or Territory of the United States, the District of 
Columbia, or the Commonwealth of Puerto Rico.
    With respect to the comments requesting that we make clear our 
position for enforcing the rule against foreign firms, we explain our 
position as follows. Section 801(a) of the act (21 U.S.C. 381a) 
authorizes us to refuse admission of an imported food if it appears 
from the examination of such samples or otherwise that such article is, 
among other things, adulterated. A foreign firm's refusal to allow us 
to obtain records via an inspection for CGMP purposes, as required by 
final Sec.  111.610 (for the dietary supplements the foreign firm 
offers for import into the United States), would create the appearance 
that such imported dietary supplements are adulterated under section 
402(g) of the act, and thus, could lead to a refusal of admission under 
section 801(a) of the act.
    Foreign firms who ship to the United States must operate under 
conditions that satisfy our regulations, including the requirement that 
records be made available during the course of an FDA inspection. We 
note that except in circumstances where there is a public health 
emergency or we receive information that would indicate the appearance 
of adulteration of products shipped to the United States, foreign 
inspections are generally scheduled well, e.g., weeks, in advance. 
Thus, we believe that taking action under section 801 of the act is 
appropriate if companies do not accommodate our inspectional request.

C. What Definitions Apply to This Part? (Final Sec.  111.3)

    Section 111.3 defines various terms that we use in the final rule 
and notes that definitions or interpretations of terms in section 201 
of the act also apply. In general, we adopted the definitions that we 
proposed, although, in some cases, we deleted words or concepts as a 
result of other changes we made to the final rule. We have added a 
definition of ``quality'' for purposes only of this final rule.
    A recurring change we made is the deletion of the words ``dietary 
ingredient'' in several definitions. In some cases, the use of the 
words ``dietary ingredient'' was redundant to the use of ``component'' 
and thus not necessary in the final rule. Because a ``dietary 
ingredient'' is subsumed within the definition of ``component,'' as 
explained in our response to comment 29, we deleted ``dietary 
ingredient'' in those definitions where ``component'' was used to avoid 
redundancy.
    In other provisions, we deleted ``dietary ingredient'' from the 
definition because the use of those words was no longer necessary given 
the narrowing of the scope of the rule as it applies to dietary 
ingredient manufacturers (explained in the response to comments

[[Page 34795]]

29 and 30). For example, we deleted ``dietary ingredient'' from the 
proposed definition of ``ingredient'' that referred to the 
``manufacture of a dietary ingredient or dietary supplement'' and the 
``finished batch of the dietary ingredient or dietary supplement.'' We 
did not need to state ``manufacture of the dietary ingredient'' or 
refer to ``finished batch of dietary ingredient'' because dietary 
ingredient manufacturers that only supply such ingredients to other 
persons for processing into a dietary supplement are not subject to the 
final rule.
    We discuss changes to the definitions, other than the changes we 
have made globally such as the deletion of ``dietary ingredients,'' the 
change from ``include, but not limited to'' to ``includes'' or 
``include,'' the addition of labels and labeling, and the deletion of 
the word ``quality'' from the phrase ``identity, purity, quality, 
strength, and composition,'' as well as comments asking us to define 
more terms or to delete certain definitions, in more detail in the 
following paragraphs.
1. Actual Yield
    The final rule defines ``actual yield'' as ``the quantity that is 
actually produced at any appropriate step of manufacture or packaging 
of a particular dietary supplement.''
    We received no substantive comments to the proposed definition.
2. Batch
    The final rule defines ``batch'' as ``a specific quantity of a 
dietary supplement that is uniform, that is intended to meet 
specifications for identity, purity, strength, and composition, and 
that is produced during a specified time period according to a single 
manufacturing record during the same cycle of manufacture.''
    This definition differs from the proposed definition of ``batch'' 
by stating that a batch is a specific quantity of a dietary supplement 
that is ``uniform.''
    We inserted the word ``uniform'' in response to comments asking 
that we define ``lot'' to be consistent with ``batch.'' We explain our 
reasons for harmonizing the definitions and for inserting ``uniform'' 
into the definition of ``batch'' in the response to comment 42 of this 
document.
    We discuss the comments on our proposed definition of ``batch'' and 
our changes to the definition in our responses to the following 
comments.
    (Comment 38) Several comments ask us to clarify what the ``same 
cycle of manufacture'' is in the definition of ``batch.'' One comment 
asks if it meant the same product made with the same lot(s) of raw 
materials regardless of how many days it took to produce the batch, or 
if it meant a quantity produced in 1 day. The comment also asks whether 
batches produced on consecutive days, using the same formula, can be 
considered to be the same batch with respect to the proposed testing 
requirements if the quality control unit determined that different lots 
of raw materials are equivalent (e.g., by meeting all specifications).
    (Response) The ``same cycle of manufacture'' refers to a process 
during which equipment remains dedicated to the manufacture of the 
batch. The terms do not limit you to any particular time period or 
require you to operate equipment continuously until you have completed 
the ``same cycle of manufacture.'' The ``same cycle of manufacture'' 
also does not limit the number of lots of components you use.
    You may consider, as one batch, a product produced using different 
lots of raw materials where the production of the batch is a continuous 
process on a dedicated line. However, for each component that you use 
in the manufacture of the batch of dietary supplement, you would need 
to establish specifications under final Sec.  111.70, determine whether 
these specifications are met under final Sec.  111.73, and ensure that 
these component specifications are met using the criteria under final 
Sec.  111.75. Further, you may not consider different batches of 
product produced on consecutive days using the same formula to be the 
same batch for purposes of testing requirements. The term ``different 
batches'' suggests that the production is not a continuous process on a 
dedicated line.
3. Batch Number, Lot Number, or Control Number
    The final rule defines these terms as ``any distinctive group of 
letters, numbers, or symbols, or any combination of them, from which 
the complete history of the manufacturing, packaging, labeling, and/or 
holding of a batch or lot of dietary supplements can be determined.''
    We received no substantive comments on the definition. We added the 
word ``and'' before ``or'' to emphasize that the history of each 
activity must be able to be determined.
4. Component
    The final rule defines ``component'' as ``any substance intended 
for use in the manufacture of a dietary supplement, including those 
that may not appear in the finished batch of the dietary supplement. 
Component includes dietary ingredients (as defined in section 201(ff) 
of the act) and other ingredients.''
    The definition of component now refers only to the manufacture of a 
dietary supplement (whereas the proposal also referred to the 
manufacture of dietary ingredients). We also made a nonsubstantive, 
editorial revision in the last sentence to put parentheses around the 
reference to section 201(ff) of the act and to change the word order so 
that ``component'' includes ``dietary ingredients * * * and other 
ingredients.'' (The proposed definition had ``components'' including 
``ingredients and dietary ingredients.'')
    (Comment 39) Some comments would distinguish among ``raw 
material,'' ``components,'' and ``starting material'' because the 
comments said that defining ``component'' to include all these 
materials is confusing. One comment adds that many starting materials 
are not food grade or approved food ingredients until they have been 
processed. One comment states the term ``raw material'' is typically 
used to describe the materials (such as dietary ingredients, fillers, 
and processing aids) that will be used to make the final product. The 
comment further states ``component'' is typically used to describe the 
specific items used to assemble the finished product for the end user. 
The components would include packaging components such as bottles, 
caps, and labels, as well as the bulk dietary supplement. This comment 
also suggests that we use the term ``starting material'' to distinguish 
substances used in the manufacture of dietary ingredients from 
substances used in the manufacture of dietary supplements.
    (Response) We decline to revise the rule as suggested by the 
comments. There may be differences in how components are referred to by 
certain manufacturers and how we refer to it in this final rule. 
However, for purposes of this final rule we refer to all substances 
used in the manufacture of dietary supplements as ``components,'' 
whether or not those substances appear in the finished product.
    Please note that, although ingredients are ``components'' under our 
definition, not all components are ingredients. For example, a solvent 
used to make an herbal extract is not an ingredient when it is removed 
from the extract by a process such as drying, because the solvent was 
not intended to be present in the finished dietary supplement. However, 
the solvent would be a ``component'' because it was used in the 
manufacture of the dietary supplement.

[[Page 34796]]

    As for materials that might not be food grade or approved food 
ingredients until processing, see the discussion in response to comment 
240 in section XII of this document.
    (Comment 40) Several comments express concern that ``component'' 
could be interpreted to mean any constituent present in a botanical 
extract or other natural product. The comments say a single botanical 
can contain tens of thousands of constituents or metabolites and that 
chemists have not identified all constituents of a single botanical. 
According to the comments, the cost of testing for all constituents 
would exceed a product's total annual revenues.
    (Response) In general, we would consider the botanical extract or 
the other natural product to be the ``component'' as defined in this 
final rule rather than consider that all the various chemical 
substances contained in the botanical extract or other natural product 
are components. Thus, if you are manufacturing a dietary supplement 
that is intended to provide a certain substance (e.g., vitamin C ) and 
you add a natural product which is intended to supply the vitamin C 
(e.g., vitamin C in the form of rosehips), we would consider the 
natural product (e.g. rosehips that contain a certain amount of vitamin 
C) to be a component which must be listed in the master manufacturing 
record. The component specifications for the rosehips must include a 
specification for the strength of the substance (e.g., vitamin C) in 
whatever amount you determine is necessary to meet the specification 
for the strength of the vitamin C in the finished batch of dietary 
supplement. Under final Sec.  111.70, we expect you to establish 
specifications for the natural product and ensure that the 
specifications are met. As an example relevant to an extract, if you 
are manufacturing a dietary supplement that is intended to provide a 
certain amount of vitamin C that derives from the natural product 
rosehips, and the substance that you purchase from a supplier to add as 
a component is a purified extract of rosehips (rather than rosehips 
themselves), we would consider the purified extract to be a component 
(as an ingredient). The component specifications for the purified 
extract must include a specification for the strength of the substance 
(i.e., vitamin C) in whatever amount you determine is necessary to meet 
the specification for the strength of the vitamin C in the finished 
batch of dietary supplement. However, in this example ``rosehips'' 
would not be considered a component, because ``rosehips'' is not what 
you added.
5. Contact Surface
    The final rule defines ``contact surface'' as ``any surface that 
contacts a component or dietary supplement, and those surfaces from 
which drainage onto the component or dietary supplement, or onto 
surfaces that contact the component or dietary supplement, occurs 
during the normal course of operations.'' The final rule lists 
containers, utensils, tables, contact surfaces of equipment, and 
packaging as examples of ``contact surfaces.''
    We did not receive any substantive comments on the proposed 
definition. We deleted ``ordinarily'' from ``ordinarily occurs during 
the normal course of operations'' because ``ordinarily'' is redundant 
to ``normal.''
6. Ingredient
    The final rule defines ``ingredient'' as ``any substance that is 
used in the manufacture of a dietary supplement and that is intended to 
be present in the finished batch of the dietary supplement. An 
ingredient includes, but is not necessarily limited to, a dietary 
ingredient as defined in section 201(ff) of the act.'' We did not 
receive any substantive comments on this definition. We made a 
nonsubstantive, editorial change to replace ``finished dietary 
supplement'' with ``finished batch of the dietary supplement.''
    (Comment 41) One comment says we should define ``ingredient'' 
better to ensure consistent interpretation of CGMP at all levels 
throughout the dietary supplement industry.
    (Response) We disagree with the comment. We believe the definition 
is adequate, including as it does both dietary ingredients as described 
in section 201(ff) of the act and other ingredients that do not fit 
that description, such as an emulsifier used to establish a uniform 
dispersion in a liquid dietary supplement or a color additive used to 
color a capsule. Moreover, the comment did not explain or specify which 
aspects of the proposed definition should be revised or explain why the 
proposed definition would lead to inconsistent interpretations of CGMP.
7. In-Process Material
    The final rule defines ``in-process material'' as ``any material 
that is fabricated, compounded, blended, ground, extracted, sifted, 
sterilized, derived by chemical reaction, or processed in any other way 
for use in the manufacture of a dietary supplement.''
    We did not receive any substantive comments on the proposed 
definition.
8. Lot
    The final rule defines ``lot'' as ``a batch, or a specific 
identified portion of a batch, that is uniform and that is intended to 
meet specifications for identity, purity, strength, and composition; 
or, in the case of a dietary supplement produced by continuous process, 
a specific identified amount produced in a specified unit of time or 
quantity in a manner that is uniform and that is intended to meet 
specifications for identity, purity, strength, and composition.''
    The final rule differs from the proposed definition in that the 
proposed definition of ``lot'' would have the batch or specific 
identified portion of a batch be intended to have ``uniform identity, 
purity, quality, strength, and composition.''
    (Comment 42) One comment agrees with the proposed definition for 
``lot,'' but several other comments would revise the definition to be 
more consistent with the proposed definition of ``batch.'' 
Specifically, the comments note the proposed definition of ``batch'' 
would refer to a quantity of dietary supplement that is ``intended to 
meet specifications for identity, purity, quality, strength and 
composition,'' whereas the proposed definition of ``lot'' would refer 
to a batch or specific identified portion of a batch that is ``intended 
to have uniform identity, purity, quality, strength, and composition.'' 
The comments would revise the definition of ``lot'' by deleting the 
phrase ``intended to have uniform'' and inserting the phrase ``intended 
to meet specifications for'' in order to make the definitions of 
``batch'' and ``lot'' consistent.
    (Response) We agree that the definitions for ``batch'' and ``lot'' 
should be consistent, but we disagree with the comments' suggestion to 
delete the term ``uniform'' from the definition of ``lot.'' The 
attributes of a lot or batch should be uniform throughout the lot or 
batch and meet established specifications for those attributes. If 
samples from a lot or batch were tested for appropriate specifications 
of identity, purity, strength, and composition, the attributes should 
be consistent throughout the sample and be uniform from sample to 
sample regardless of whether the test samples are taken from the 
beginning, middle, or end of the lot or batch. Consequently, we revised 
the definition of ``lot'' to state, in relevant part, that a ``lot'' is 
a batch or specific identified portion of a batch that ``is uniform and 
that is intended to meet specifications

[[Page 34797]]

for identity, purity, strength, and composition'' or, for dietary 
supplements produced by a continuous process, a specific identified 
amount produced in a specified unit of time or quantity in a manner 
that is uniform and that is intended to meet specifications for 
identity, purity, strength, and composition.''
    Similarly, we revised the definition of ``batch'' so that it 
states, in relevant part, that a ``batch'' is a specific quantity of a 
dietary supplement ``that is intended to meet specifications for 
identity, purity, strength, and composition.''
    These revisions make the definitions of ``batch'' and ``lot'' 
consistent.
9. Microorganisms
    The final rule defines ``microorganisms'' as ``yeasts, molds, 
bacteria, viruses, and other similar microscopic organisms having 
public health or sanitary concern.'' It adds that the definition 
includes species that: (1) May have public health significance; (2) may 
cause a component or dietary supplement to decompose; (3) indicate that 
the component or dietary supplement is contaminated with filth; or (4) 
otherwise may cause the component or dietary supplement to be 
adulterated.
    (Comment 43) One comment would revise the definition to identify 
specific microorganisms that have public health or sanitary concern 
(i.e., Salmonella species, Escherichia coli, Pseudomonas aeruginosa, 
and Staphylococcus aureus). The comment says this would be consistent 
with USP requirements.
    (Response) We disagree with the comment. A list of specific 
microorganisms could easily become outdated as new pathogens emerge, 
and constantly issuing new rules to revise the list would be both 
inefficient and impractical.
    (Comment 44) One comment expresses concern that the proposed 
definition for microorganisms would include microorganisms that are a 
natural part of the ecology of all natural products. The comment says 
certain levels of microorganisms are expected on botanical raw 
materials (i.e., those naturally occurring or introduced through 
organic cultivation techniques) and that many do not present a public 
health risk. The comment expresses concern that nonpathogenic 
microorganisms that are not a public health risk would be a 
``sanitary'' concern that would render a product adulterated. The 
comment argues there should be little concern about the presence of 
microorganisms that present no public health consequence, and so we 
should revise the definition accordingly. The comment further discusses 
the difficulties in ``sterilizing'' botanicals to render them free of 
microorganisms associated with insanitary conditions. The comment notes 
that some international organizations have established ``upper limits'' 
for these organisms for botanical supplements, which, in the comment's 
opinion, represent more realistic standards than trying to attain a 
``sterile'' botanical supplement.
    (Response) We disagree with the comment. We do not interpret the 
definition of ``microorganism'' as making the presence of nonpathogenic 
microorganisms that are not a public health risk a ``sanitary concern'' 
that would render a product adulterated. Instead, we interpret the 
definition as saying that microorganisms of public health significance 
and microorganisms presenting sanitary concerns are ``microorganisms'' 
under this rule. These are the types of microorganisms that may cause a 
component or dietary supplement to become adulterated.
    As for upper limits on microbial contamination, the comment offered 
no suggested limits, and we decline to establish such limits in this 
rule. The final rule requires manufacturers to establish limits for 
those types of contamination that may adulterate or lead to 
adulteration of components or dietary supplements. Thus, for example, a 
manufacturer of a botanical dietary supplement would have to determine 
what, if any, microorganisms are likely or certain to be present and 
establish limits, as appropriate to prevent adulteration of the 
finished batch of the dietary supplement.
    We have modified the word ``have'' with the word ``may'' to 
indicate that the determination or evaluation of whether there is a 
``public health significance'' is not made after the fact. There does 
not have to be a factually established determination of public health 
significance for you to conclude that the microorganisms ``may 
adulterate'' the dietary supplement. The change from ``could cause'' to 
``may cause'' is to be consistent with the previous change to ``may 
have.''
10. Must
    The final rule explains that the word ``must'' is ``used to state a 
requirement.''
    (Comment 45) One comment would revise the definition to say that 
the term ``must'' be used to state mandatory requirements ``unless 
shown to be inapplicable or replaced by an alternative demonstrated to 
provide at least an equivalent level of quality assurance.''
    (Response) We decline to revise the rule as suggested by the 
comment. The comment's revision would undermine the reasons for issuing 
a rule. Rules create enforceable requirements. It is not clear, nor did 
the comment discuss, how we could enforce the requirements in this 
final rule if firms were able to avoid a particular requirement by 
declaring them to be ``inapplicable'' or substituting alternatives 
which they felt they had demonstrated were ``at least an equivalent 
level of quality assurance.'' There would be inconsistency in the 
general CGMP practices used within the dietary supplement industry and 
uncertainty as to whether the process and production controls ensure 
the quality of the dietary supplement. Consequently, we decline to 
revise the rule as suggested by the comment.
    We have, however, made a nonsubstantive, editorial change to the 
definition so that ``must'' is used to state ``a requirement.'' The 
proposed definition had referred to ``mandatory requirements.'' Since a 
requirement by its nature is mandatory, the word ``mandatory'' is 
unnecessary.
11. Pest
    The final rule defines ``pest'' as ``any objectionable insect or 
other animal, including birds, rodents, flies, mites, and larvae.''
    We did not receive any substantive comments on this definition. 
However, on our own initiative, we made nonsubstantive, editorial 
changes to delete the words, ``but not limited to'' after ``including'' 
and to place the word ``animals'' in the singular.
12. Physical Plant
    The final rule defines ``physical plant'' as ``all or any part of a 
building or facility used for or in connection with manufacturing, 
packaging, labeling, or holding a dietary supplement.''
    We received no substantive comments on this definition. The final 
rule is substantially similar to the proposed rule's definition of 
``physical plant.'' We added ``any'' and placed ``part'' in the 
singular to clarify that individual parts of a building or facility are 
subject to the CGMP requirements.
13. Product Complaint
    The final rule defines ``product complaint'' as ``any communication 
that contains any allegation, written, electronic, or oral, expressing 
concern, for any reason, with the quality of a dietary supplement, that 
could be related to current good manufacturing practice. Examples of 
product complaints are: Foul odor, off taste, illness or injury, 
disintegration time,

[[Page 34798]]

color variation, tablet size or size variation, under-filled container, 
foreign material in a dietary supplement container, improper packaging, 
mislabeling, or dietary supplements that are superpotent, subpotent, or 
contain the wrong ingredient, or contain a drug or other contaminant 
(e.g., bacteria, pesticide, mycotoxin, glass, lead).''
    This definition modifies the proposed rule's definition of 
``consumer complaint,'' which would define such a complaint as any 
``communication that contains any allegation, written or oral, 
expressing dissatisfaction with the quality of a dietary supplement 
related to good manufacturing practices. Examples of product quality 
related to good manufacturing practices are: Foul odor, off taste, 
superpotent, subpotent, wrong ingredient, drug contaminant, other 
contaminant (e.g., bacteria, pesticide, mycotoxin, glass, lead), 
disintegration time, color variation, tablet size or size variation, 
under-filled container, foreign material in a dietary supplement 
container, improper packaging, or mislabeling. For the purposes of this 
regulation, a consumer complaint about product quality may or may not 
include concerns about a possible hazard to health. However, a consumer 
complaint does not include an adverse event, illness, or injury related 
to the safety of a particular dietary ingredient independent of whether 
the product is produced under good manufacturing practices.''
    We explain the reasons for revising the proposed definition in our 
response to the following comments.
    (Comment 46) Some comments would broaden the definition of consumer 
complaint to include complaints from dietary ingredient suppliers. One 
comment would change ``consumer complaint'' to ``customer complaint.''
    (Response) As discussed in section VI of this document, the final 
rule does not apply to those who only manufacture dietary ingredients. 
However, we encourage such firms that receive complaints about a 
dietary supplement to share those complaints with those in the 
manufacturing chain associated with that dietary supplement's 
manufacture so others may take corrective action as needed. Those who 
engage in the manufacture of a dietary supplement, including 
manufacturing, packaging, labeling, and holding operations, are 
responsible for complying with this final rule's product complaint 
requirements.
    Furthermore, we encourage packagers, labelers, and distributors who 
receive a product complaint to notify those in a dietary supplement's 
manufacturing chain about product complaints they receive or they, 
themselves, generate that may relate to operations outside the 
packagers', labelers', or distributors' control. For example, a 
distributor who purchases a dietary supplement in bulk for packaging 
and labeling may complain about product quality to the dietary 
supplement manufacturer. The manufacturer who receives the complaint 
must then take appropriate action to determine whether the complaint 
involves a possible failure of a dietary supplement to meet any CGMP 
requirements. Thus, the final rule revises the term ``consumer 
complaint'' to ``product complaint'' to emphasize that the complaint is 
about the product regardless of the complaint's source.
    (Comment 47) One comment disagrees that ``disintegration time'' and 
``tablet size'' are appropriate examples of complaints about product 
quality specifications.
    (Response) We disagree with this comment. Complaints about 
disintegration time or tablet size could indicate a problem with the 
production and process control system that may affect the quality of 
the dietary supplement.
    (Comment 48) Some comments disagree with the proposed definition of 
``consumer complaint'' because it excluded an adverse event, illness, 
or injury related to the safety of a particular dietary ingredient. The 
comments say there should be a consistent approach for handling all 
complaints, including adverse events. One comment states consumers will 
not be able to determine whether a product quality issue related to 
CGMP caused an adverse event. This comment expresses concern that not 
classifying adverse events as consumer complaints could lead 
manufacturers to avoid investigating certain adverse events and, 
therefore, prevent them from determining the appropriate cause and 
implementing the associated corrective action. The comments stress we 
should not treat complaints related to CGMP issues differently from 
other complaints and urged us to classify all adverse events as 
consumer complaints, whether or not they might have been caused by a 
particular dietary ingredient.
    A few comments state the proposal, which did not specifically 
address adverse event reporting, but did address the broader category 
of consumer complaints and would require companies to investigate 
``adverse event reports,'' may simply create more confusion and may 
contradict the overall objective of a comprehensive adverse event 
reporting system. The comments also state neither the food CGMP 
regulations nor the 1997 ANPRM defined ``consumer complaints.'' The 
comments say we should delete this definition and deal with consumer 
complaints separately as part of the new CFSAN Adverse Event Reporting 
System (CAERS).
    One comment states we should define the term ``serious adverse 
dietary supplement experience.'' The comment would define a ``serious 
adverse dietary supplement experience'' as ``any adverse dietary 
supplement experience occurring at any dose that results in any of the 
following outcomes: death, a life-threatening adverse dietary 
supplement experience, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/
incapacity, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse dietary supplement 
experience and, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this 
definition.''
    (Response) We decline to include in the definition of ``product 
complaint'' an adverse event related to the safety of a particular 
dietary ingredient. The final rule establishes CGMP requirements for 
dietary supplements and does not focus on whether dietary ingredients 
that manufacturers may use in their dietary supplements are inherently 
safe. Nevertheless, we encourage firms to investigate all complaints, 
regardless of whether the complaints relate to CGMP. Furthermore, 
mandatory reporting to FDA of serious adverse events is now required as 
a result of the enactment of the ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462), 
signed into law on December 22, 2006. In any event, consistent with 
these CGMP requirements, manufacturers must establish limits on 
contamination, as needed, for all ingredients or any component they use 
in manufacturing a dietary supplement.
    We agree it may be unclear whether a particular product complaint 
is related to CGMP. Final Sec.  111.560, relating to product 
complaints, applies in situations where the product complaint involves 
a ``possible failure of a dietary supplement to meet any of its 
specifications or any other requirements of this part.'' Thus, if a 
firm is unclear whether a particular complaint it receives relates to a 
CGMP issue, we would consider that complaint to be related to a 
``possible failure'' to meet CGMP. Consequently, the firm must

[[Page 34799]]

comply with the requirements in subpart O, unless the firm 
affirmatively determines that the complaint is not related to a 
``possible failure'' to meet CGMP, and therefore, is not a ``product 
complaint.'' To make this clear, we revised the definition so that it 
applies to any ``communication * * * that could be related to good 
manufacturing practice'' rather than to be any ``communication * * * 
that is related to good manufacturing practice.''
    We disagree with comments that suggested that the requirements for 
product complaints would somehow contradict the overall objective of 
the CAERS. This final rule has no effect on the mandatory or voluntary 
reporting of adverse events. We agree some adverse events may be 
related to a failure to ensure the quality of the dietary supplement as 
required by the final rule. To the extent that an adverse event is 
associated with CGMP, it would be considered a ``product complaint'' 
under the final rule. The fact that it is considered a product 
complaint does not mean that such complaint could not be voluntarily 
reported as an adverse event through CAERS. Such a complaint may be 
required to be reported under the mandatory reporting requirements of 
the ``Dietary Supplement and Non-Prescription Drug Consumer Protection 
Act'' (Public Law 109-462), signed into law on December 22, 2006. We 
have added ``illness or injury'' to the final rule's definition of 
``product complaint'' as an example of a product problem relating to 
CGMP to help clarify that there may be some overlap in the type of 
complaints related to product quality that may also be considered an 
adverse event.
    As for defining ``serious adverse dietary supplement experience,'' 
we decline to add such a definition to the final rule. We define 
certain terms in a rule to give those terms a clear and consistent 
meaning. None of the provisions in this rule addresses or even mentions 
``serious adverse dietary supplement experiences,'' so there would be 
no advantage in codifying a definition for the term in this final rule. 
If, however, the comment meant to narrow the definition of ``consumer 
complaint'' to ``serious'' illness, or injury, we decline to do so. If 
a consumer reports an illness or injury, which he or she attributes to 
consuming a dietary supplement, the report may indicate a problem with 
the production and process control system for that dietary supplement, 
even if the injury or illness is not ``serious'' or severe.
    We have, however, decided to delete the last two sentences in the 
proposed definition of ``consumer complaint'' (now ``product 
complaint'' in the final rule). These sentences explained, in part, 
that a consumer complaint does not include an adverse event, illness, 
or injury related to the safety of a particular dietary ingredient 
independent of whether the product is produced under CGMP. We deleted 
those sentences because they are unnecessary to include in the 
definition and can be included as further explanation of what the 
definition of ``product complaint'' means in the preamble discussion.
    The proposed definition of ``consumer complaint'' used the phrase 
``expressing dissatisfaction with the quality of a dietary * * * 
supplement;'' the final rule uses the phrase ``expressing concern, for 
any reason, with the quality of a dietary supplement.'' This change is 
to ensure that even if the consumer is not actually dissatisfied with 
the product, but has a concern with the product, this is still handled 
as a product complaint.
    We made several editorial or grammatical changes to the definition 
of product complaint in this final rule for simplicity and revised the 
order of the listed examples of product complaints. For example, the 
proposed definition of ``consumer complaint'' states the term ``means 
communication that contains any allegation * * *.'' The final rule 
defines ``product complaint'' as meaning ``any communication that 
contains any allegation * * *.'' Another nonsubstantive change was to 
insert the words ``dietary supplements that are'' before ``superpotent, 
subpotent'' to give the reader a clear understanding as to the article 
that is superpotent or subpotent.
    Finally, we added ``electronic'' as an example of how a product 
complaint could be communicated to ensure that all forms of 
communication are included and added ``current'' to modify ``good 
manufacturing practice'' for consistency.
    We discuss in section V of this document, our general response to 
the comment that stated that neither the food CGMP regulations nor the 
1997 ANPRM contains a definition of ``consumer complaint,'' is in our 
discussion of whether this final rule exceeds our authority or it has 
to be identical to the food CGMP regulations. More specifically, we 
acknowledge that the industry draft that we published in the 1997 ANPRM 
did not define ``consumer complaint.'' The industry draft did contain 
provisions that would be directed to ``complaint files.'' The 
provisions for complaint files would require the use of written 
procedures to handle complaints, retention of records of complaints for 
a certain time period, and the inclusion of specific information in the 
record of a complaint.
14. Quality
    For purposes solely of this final rule we have decided to define 
``quality.'' Quality means that the dietary supplement consistently 
meets the established specifications for identity, purity, strength, 
and composition and limits on contaminants and has been manufactured, 
packaged, labeled, and held under conditions to prevent adulteration 
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
    (Comment 49) Some comments asked that we define ``quality.'' Some 
comments claimed the proposal described ``quality'' in terms of 
``identity,'' ``purity,'' and ``composition.'' One comment would define 
``quality'' as ``the total characteristics of a product that bear on 
its ability to satisfy stated (i.e., labeled) or implied needs of 
identity, purity, strength and composition.'' Another comment would 
define ``quality'' as ``having the appropriate identity, purity, and 
strength for the intended purpose.'' Another comment would define 
quality using all the other attributes of identity, purity, strength 
and composition.
    (Response) For purposes only of this final rule, we have added a 
definition of quality. This definition is not intended to apply to CGMP 
requirements other than those that apply to dietary supplements. In 
section III of this document, in the overview discussion, we discuss 
the concept of ``quality'' as it applies to these dietary supplement 
CGMP requirements and the distinction between the use of the term in 
the final rule and in the proposed rule.
    Because we have defined ``quality'' as encompassing identity, 
purity, strength, and composition, we have revised each section with 
requirements for the ``identity, purity, quality, strength, and 
composition'' to remove the word ``quality.'' The affected sections in 
this final rule are: Sec.  111.3 (definition of batch); Sec.  111.3 
(definition of lot); Sec.  111.65 (``What are the requirements for 
quality control operations?''); Sec.  111.70 (``What specifications 
must you establish?''); Sec.  111.75 (``What must you do to determine 
whether specifications are met?''); Sec.  111.80 (``What representative 
samples must you collect?''); Sec.  111.95 (``Under this subpart E, 
what records must you make and keep?''); Sec.  111.105 (``What must 
quality control personnel do?''); Sec.  111.455 (``What requirements 
apply to holding components, dietary supplements, packaging, and 
labels?''); and Sec.  111.515

[[Page 34800]]

(``When must a returned dietary supplement be bestroyed, or otherwise 
suitably disposed of?'').
15. Quality Control
    The final rule defines ``quality control'' as ``a planned and 
systematic operation or procedure for ensuring the quality of a dietary 
supplement.'' The proposed rule defined ``quality control'' as ``a 
planned or systematic operation for preventing a dietary ingredient or 
dietary supplement from being adulterated.''
    (Comment 50) One comment suggests revising the definition to use 
more positive language. Specifically, the comment would define 
``quality control'' as ``a planned and systematic operation or 
procedure for ensuring the quality of dietary supplement products.''
    (Response) We agree that the comment's suggested language conveys a 
positive concept about quality control's role and value and adopt the 
language in part. The final rule's quality control requirements will 
help ensure compliance with other CGMP requirements and, therefore, 
will help ensure the quality of the dietary supplement and that the 
dietary supplement is packaged and labeled as specified in the master 
manufacturing record. We have defined the term ``quality'' in this 
final rule as including preventing a dietary supplement from being 
adulterated. Consequently, we revised the definition of ``quality 
control'' to state that ``quality control'' means a planned and 
systematic operation or procedure ``for ensuring the quality of a 
dietary supplement.'' We deleted ``for preventing a dietary ingredient 
or dietary supplement from being adulterated'' in the proposed 
definition since the concept of quality includes preventing 
adulteration.
16. Quality Control Personnel
    The final rule defines ``quality control personnel'' as ``any 
person, persons, or group, within or outside your organization, who you 
designate to be responsible for your quality control operations.''
    (Comment 51) Some comments seem to suggest that the reference in 
the 2003 CGMP Proposal to a ``quality control unit'' mandates a 
separate unit or department with responsibility for all quality control 
operations. One comment explains many companies do not have one quality 
control unit with oversight of all operations within the facility. This 
comment states companies commonly have each separate section of an 
operation perform both its function and its own quality control. A few 
comments would clarify the definition by indicating that a distinct or 
separate unit need not perform the quality control function. These 
comments say the quality control function is best performed by a person 
or persons qualified by training, education, or experience in the 
different processing areas.
    Many comments say we should consider any individual carrying out a 
quality control function to be part of the quality control unit for 
purposes of this rule.
    (Response) We agree that the quality control function is best 
performed by a person or persons qualified by training, education, or 
experience in relevant areas. To the extent that the comments 
interpreted the proposed definition as requiring firms to have a 
separate person or group whose sole function in the company is to 
perform quality control operations or that the quality control 
functions are limited to those who are employed within the firm, we 
disagree. As discussed in the preamble to the proposal, the quality 
control unit should consist of as many people as necessary to perform 
the quality control operations (68 FR 12157 at 12252). We have 
reconsidered the use of the term ``unit.'' In order to clarify that we 
do not intend to require a separate division or office be created, we 
instead use the term ``personnel.'' Although we have eliminated 
references to ``unit,'' we still agree that personnel can be a person, 
persons, or a group, and as many persons as necessary, who perform the 
quality control operations. The manufacturer must identify the 
appropriate person or persons to be responsible for the quality control 
operations associated with a particular manufacturing operation. For 
example, the manufacturer may designate one individual as a packaging 
expert who is responsible for the quality control operations related to 
packaging, designate a second individual as an expert in deciding 
whether to accept or reject incoming components, and designate a third 
individual as an expert in deciding whether in-process specifications 
are met at certain control points. The definition does not limit the 
other activities that these designated individuals may perform within 
the manufacturing operations; thus, for example, the packaging expert 
who performs the quality control function for packaged dietary 
supplements could also have responsibilities in the actual packaging 
operation. Quality control responsibilities and specific activities are 
distinct and separate from any other responsibilities and specific 
activities that an employee might perform for any other operation. In 
addition, the quality control operations may be performed by someone 
outside the organization (such as a contractor).
    To clarify these points and to prevent potential misinterpretation 
of quality control operations, we revised the definition of ``quality 
control unit.'' Instead of a unit, quality control personnel who 
perform quality control operations may be a person, persons, or group 
and may be ``within or outside of your organization.'' We also added a 
new Sec.  111.12(b) to require you to identify who is responsible for 
your quality control operations. Under final Sec.  111.12(b) each 
person who is identified to perform quality control operations must be 
qualified to do so and have distinct and separate responsibilities 
related to performing such operations from those responsibilities that 
the person otherwise has when not performing such operations. 
Throughout the codified, we use the term ``quality control personnel'' 
when referring to the performance of specific quality control 
operations. The term ``quality control personnel'' refers to the person 
or persons designated to perform the particular quality control 
operation.
17. Representative Sample
    The final rule defines ``representative sample'' as ``a sample that 
consists of an adequate number of units that are drawn based on 
rational criteria, such as random sampling, and that are intended to 
ensure that the sample accurately portrays the material being 
sampled.'' This definition is similar to the proposed definition of 
``representative sample.'' We have added ``an adequate'' before 
``number'' to emphasize that the sample must be sufficient for its 
purpose. We also made nonsubstantive grammatical changes to insert 
``that are'' between ``and'' and ``intended.''
    (Comment 52) Some comments note the proposed rule would use the 
terms ``representative sample,'' ``reserve sample,'' and 
``representative reserve sample'' but would only define 
``representative sample.'' The comments ask us to clarify the 
distinction, if any, between these terms.
    (Response) A ``reserve sample'' is a sample that is to be held or 
kept for a designated time. It differs from a ``representative sample'' 
in the sense that a representative sample is not always kept; for 
example, one might take a representative sample to test product 
quality, but one would not necessarily keep every tested sample.
    To clarify this distinction, the final rule now defines a ``reserve 
sample'' as ``a representative sample of product that

[[Page 34801]]

is held for a designated period of time.'' We also revised the rule to 
refer solely to a ``reserve sample'' rather than use both ``reserve 
sample'' and ``representative reserve sample.''
18. Reprocessing
    The final rule defines ``reprocessing'' as ``using, in the 
manufacture of a dietary supplement, clean, uncontaminated components 
or dietary supplements that have been previously removed from 
manufacturing and that have been made suitable for use in the 
manufacture of a dietary supplement.'' We modified the definition that, 
in part, read ``* * * dietary supplements that have been previously 
removed from manufacturing for reasons other than insanitary 
conditions'' by removing ``for reasons other than insanitary 
conditions'' to expand the scope of what may be reprocessed. We explain 
the reason for the latter change in our response to the following 
comments. We also changed ``unadulterated'' to ``uncontaminated'' to be 
consistent with the revisions we have made in other sections, including 
the definition of quality.
    (Comment 53) Some comments ask us to clarify whether components or 
dietary supplements that have been successfully treated to reduce 
microbial levels to acceptable levels can be reprocessed. Some comments 
object to the proposed definition of ``reprocessing'' because it did 
not include components or dietary supplements removed for insanitary 
conditions, and several comments object to the restrictions to 
reprocessing described in proposed Sec. Sec.  111.35(i)(4)(iii) and 
111.50(f), because, they argue, the definition and sections associated 
with reprocessing would not permit the reprocessing of previously 
insanitary ingredients even if there are processes available that are 
safe and effective in removing foreign matter, microorganisms, or 
chemicals that may have rendered the ingredient ``insanitary.'' One 
comment would revise the definition as follows: ``Reprocessing means 
using, in the manufacture of a dietary supplement, clean, unadulterated 
components * * * or dietary supplements that have been previously 
removed from manufacturing for reasons other than insanitary conditions 
or that have been successfully reconditioned so that they are suitable 
for use.''
    (Response) We agree that materials can be treated, subjected to in-
process adjustments, or reprocessed when there are suitable processes 
available, and we revised the definition of ``reprocessing'' to reflect 
this. However, there must be appropriate oversight of the treatment, 
in-process adjustments, and reprocessing so the dietary supplement will 
still meet required specifications. Therefore, we added a conforming 
requirement to final Sec. Sec.  111.90(b) and 111.140(b)(3)(vi) to 
require oversight by quality control personnel for any reprocessing, 
treatment, or in-process adjustment of a dietary supplement that have 
been previously removed from manufacturing and that have been made 
suitable for use in the manufacture of a dietary supplement (see 
sections X and XI of this document).
19. Reserve Sample
    The final rule contains a new definition of ``reserve sample.'' 
``Reserve sample'' is defined as ``a representative sample of product 
that is held for a designated period of time.'' We explain our reasons 
for creating this definition in this section under the definition of 
``representative sample.''
20. Sanitize
    The final rule defines ``sanitize'' as ``to adequately treat 
cleaned equipment, containers, utensils, or any other cleaned contact 
surface by a process that is effective in destroying vegetative cells 
of microorganisms of public health significance, and in substantially 
reducing numbers of other microorganisms, but without adversely 
affecting the product or its safety for the consumer.''
    The final rule's definition of ``sanitize'' differs from the 
proposal in that the proposed definition would have specified a 
reduction of 5 logs or 99.999 percent reduction of ``representative 
disease microorganisms of public health significance'' and ``other 
undesirable microorganisms'' and would have specified the use of heat 
or chemicals. The preamble to the 2003 CGMP Proposal explained that we 
based the proposed definition of ``sanitize'' on the definition of 
``sanitization'' in the ``Food Code'' (which is a model that gives food 
control authorities a scientifically sound technical and legal basis 
for regulating the retail and food service segment of the industry) 
because dietary supplements are often consumed without further 
processing, similar to foods consumed in retail outlets (68 FR 12157 at 
12179). The preamble to the 2003 CGMP Proposal also explained that, to 
achieve the reduction levels in the proposed definition, one would need 
to validate control measures to ensure they are both appropriate to 
their operation and scientifically sound. The preamble explained that 
in many cases, manufacturers may rely on a written certification from 
the equipment manufacturer or may obtain a written scientific 
evaluation of a process, especially in cases where two or more control 
measures are used to accomplish the 99.999 percent reduction in the 
target pathogen, to ensure the process is adequate to destroy 
microorganisms of public health significance or to prevent their 
growth.
    (Comment 54) Many comments object to the proposed text concerning 
the application of heat or chemicals to a food contact surface to yield 
a reduction of 5 logs or 99.999 percent of representative disease 
organisms of public health significance. The comments state the aspect 
of the proposed definition is overly prescriptive, beyond our legal 
authority, and would not provide additional public health benefits. 
Many comments say it is inappropriate to use the definition of 
sanitization from our Food Code because retail and manufacturing 
operations are distinct. A few comments assert the process of 
manufacturing dietary supplements shares more in common with food or 
drug manufacturing than with retail operations. Most comments recommend 
that we define ``sanitize'' in the manner that was presented in the 
1997 ANPRM and consistent with the current food CGMP definition at 
Sec.  110.3 so that ``sanitize'' means ``to adequately treat dietary 
product contact surfaces by a process that is effective in destroying 
vegetative cells of microorganisms of public health significance, and 
in substantially reducing numbers of other undesirable microorganisms, 
but without adversely affecting the product or its safety for the 
consumer.''
    One comment states that consistently validating the effectiveness 
of the sanitizing procedure is impractical and recommended we state 
instead that equipment, utensils, etc., should be cleaned and sanitized 
in a manner that keeps undesirable microorganisms and other adulterants 
from contaminating all components, ingredients, in-process materials, 
and finished product. The comment claims that, by this approach, the 
microbial and analytical test results of product produced on a 
facility's equipment, coupled with random testing of final rinse water 
after cleaning and sanitizing equipment and utensils, would provide 
sufficient and continuous evidence of a proper and effective cleaning 
and sanitizing plan.
    Two comments claim that the proposed definition for sanitize 
denotes ``validation methodology'' found in drug CGMP, and that we must 
base dietary supplement CGMP on food rather than on drug standards.

[[Page 34802]]

    Other comments express concern about validating control measures to 
ensure that they are scientifically sound and appropriate to operations 
and the economic burden to do the testing. A few comments state it 
would be difficult to show a 100,000-fold reduction on an already 
cleaned surface, particularly if the pre-sanitization level is at or 
near the lower limit of the test method employed.
    One comment states the definition required the manufacturer to 
demonstrate a 100,000-fold reduction in microbial count every time a 
food contact surface is sanitized. A few comments express concern that 
processing lines would have to be closed down each time they are 
sanitized in order to test them, creating a financial hardship 
especially on smaller operations. Other comments ask us to give 
companies the flexibility necessary to monitor sanitation needs based 
on individual products and manufacturing operations to be consistent 
with existing industry practices and food and drug CGMPs.
    One comment requests we clarify that a sanitizing agent for use on 
food processing equipment must be approved in accordance with part 178, 
Indirect Food Additives: Adjuvants, Production Aids, and Sanitizers (21 
CFR part 178) and our expectations with respect to what documentation 
would be necessary to prove the effectiveness of the sanitizer used. 
Two comments say the proposed definition of sanitize means that 
manufacturers must perform validation studies to demonstrate that the 
sanitizers they are using reduce the microbial load on equipment by 
100,000-fold, a requirement for a ``sanitizer'' under regulations 
issued by the Environmental Protection Agency. The comments say a 
sanitizer should not be held to this standard for the purpose of 
reducing microbial loads on food product contact surfaces, and that 
manufacturers of a solid dosage form may not need to ``sanitize'' their 
equipment because the processing environment is not suitable for 
microbial growth due to the low water activity. One comment recommended 
using the approach in the Food Code, which specifies conditions under 
which chemical sanitizers listed in Sec.  178.1010 may be used, 
including the requirement that they be used in accordance with the 
Environmental Protection Agency-approved manufacturer's label use 
instructions, and be used for dietary supplements rather than imposing 
a validation requirement on manufacturers.
    Some comments would divide the definition of ``sanitize'' by 
creating separate definitions for ``sanitize'' and ``sanitizing 
agent.'' The comments would define ``sanitize'' as meaning ``to 
adequately treat equipment, containers, utensils, or any other dietary 
product contact surface by applying a sanitizing agent on cleaned food 
contact surfaces.'' One comment would define ``sanitizing agent'' as 
``cumulative heat or chemicals that, when evaluated for efficacy, yield 
a reduction of 5 logs, which is equal to 99.999 percent reduction, of 
representative disease microorganisms of public health significance and 
substantially reduce the numbers of other undesirable microorganisms, 
but without adversely affecting the product or its safety for the 
consumer.'' Another comment would define ``sanitizing agent'' in a 
similar manner, except it would omit references to a 5-log reduction.
    (Response) The proposed definition of ``sanitize'' was intended to 
give firms the flexibility to monitor sanitation needs based on their 
products and operations. We did not intend to suggest that 
manufacturers had to demonstrate a 100,000-fold reduction in microbial 
count every time they sanitized a contact surface, nor did we intend, 
as some comments claimed, to have firms close down processing lines 
every time they were sanitized to test them for microbial reduction. 
Rather, the language of the proposed rule was intended to make it clear 
that processes used to sanitize contact surfaces should be effective. 
However, we recognize that the proposed definition caused confusion as 
to our intent. The proposed definition may have been interpreted as 
proposing validation to ensure an area was sanitized; however our 
intent was simply to require that effective sanitizers and sanitizing 
processes be used, just as in food establishments. Therefore, in order 
to clarify the provision, we have revised the definition of 
``sanitize'' to be consistent with Sec.  110.3(o). The final rule 
defines ``sanitize'' as adequately treating ``cleaned equipment, 
containers, utensils, or any other cleaned contact surface by a process 
that is effective in destroying vegetative cells of microorganisms of 
public health significance, and in substantially reducing numbers of 
other microorganisms, but without adversely affecting the product or 
its safety for the consumer.'' The final definition of sanitize does 
not include any statements about mechanisms that you may use to achieve 
compliance because including such nonbinding information is 
inconsistent with our current practices for establishing regulations.
    We note that the Environmental Protection Agency has regulatory 
authority over certain uses of sanitizers as pesticide chemicals and we 
have regulatory authority over certain uses of sanitizers as food 
additives. Under section 201(q)(1)(B) of the act, as amended by the 
Food Quality Protection Act (FQPA) (Public Law 104-170) and the 
Antimicrobial Regulation Technical Corrections Act (ARTCA) (Public Law 
105-324), certain substances used as food contact surface sanitizing 
solutions are subject to the Environmental Protection Agency's 
regulatory authority as pesticide chemicals. The Environmental 
Protection Agency recently codified tolerance exemptions under section 
408 of the act (21 U.S.C. 346a) for those food contact surface 
sanitizing solutions that were previously subject to our authority at 
Sec.  178.1010 and transferred to the Environmental Protection Agency's 
authority under FQPA and ARTCA (see 40 CFR 180.940 (69 FR 23113, April 
28, 2004). Such pesticide chemicals must comply with the Pesticide 
Tolerance regulations in 40 CFR 180.940. Sanitizers used on food 
packaging must comply with our regulations at Sec.  178.1010. For an in 
depth discussion of appropriate sanitizers for food contact surface 
use, see the Environmental Protection Agency's Pesticides; Tolerance 
Exemptions for Active and Inert Ingredients for Use in Antimicrobial 
Formulations (Food Contact Surface Sanitizing Solutions) (69 FR 23113, 
April 28, 2004) and DIS/TSS-4 Efficacy Data Requirements Sanitizing 
Rinses (for previously cleaned food-contact surfaces) (January 30, 
1979) (Ref. 27) (available on the Internet at http://www.epa.gov/oppad001/dis_tss_docs/dis-04.htm).
21. Theoretical Yield
    The final rule defines ``theoretical yield'' as ``the quantity that 
would be produced at any appropriate step of manufacture or packaging 
of a particular dietary supplement, based upon the quantity of 
components or packaging to be used, in the absence of any loss or error 
in actual production.''
    We received no substantive comments on the proposed definition.
22. Water Activity
    The final rule defines ``water activity'' as ``a measure of the 
free moisture in a component or dietary supplement and is the quotient 
of the water vapor pressure of the substance divided by the vapor 
pressure of pure water at the same temperature.''
    We received no substantive comments on the proposed definition.

[[Page 34803]]

23. We
    The final rule explains that ``we'' means the United States Food 
and Drug Administration.
    The final rule's definition is identical to the proposed 
definition. We received no substantive comments on the proposed 
definition.
24. You
    The final rule defines ``you'' as a ``person who manufactures, 
packages, labels, or holds dietary supplements.''
25. What Other Terms Did the Comments Want Defined?
    (Comment 55) Some comments ask us to define ``adulteration'' (based 
on the provisions of section 402 of the act), ``dietary ingredient,'' 
and ``dietary supplement'' (based on the definition in section 201(ff) 
of the act).
    (Response) We decline to revise the rule as suggested by the 
comments. The terms have meaning within the context of the act and case 
law. Further, under final Sec.  111.3 the act's definitions and 
interpretations ``apply to such terms when used in this part.'' Thus, 
there is no need for us to define the terms as requested by the 
comments.
    (Comment 56) Proposed Sec.  111.35(e)(2) would require a person to 
establish a specification for any point, step, or stage in the 
manufacturing process where control is necessary to prevent 
adulteration, and proposed Sec.  111.35(f) would require monitoring of 
the in-process control points, steps, or stages to ensure these 
established specifications are met and to detect any unanticipated 
occurrence that may result in adulteration. Some comments ask us to 
define the term ``control point'' as ``any point, step or stage in the 
manufacturing process where control is necessary to prevent 
adulteration.''
    (Response) We decline to add a definition of ``control point'' as 
requested by the comments. Instead, we revised final Sec.  111.75(b) 
(formerly proposed Sec.  111.35(f)) to state that you must monitor the 
in-process points, steps, or stages where control is necessary to 
ensure the quality of the finished batch of dietary supplement; this 
revision eliminates the need to define ``control point.''
    (Comment 57) Several comments would have us define one or more of 
the following terms: Identity, purity, strength, and composition. Some 
comments suggest specific text for the definitions.
    Similarly, some comments suggest codifying the preamble description 
that we used for these terms, i.e., the phrase ``identity, purity, 
quality, strength, and composition'' means that the production on a 
batch-by-batch basis is consistent with the master manufacturing record 
and is what it is represented on the label to be (identity); is without 
impurities and is the desired product (purity); is the identity, 
purity, and strength for its intended purpose (quality); is the 
concentration, that is, the amount per unit of use intended (strength); 
and is the intended mix of product and product-related substances 
(composition) (68 FR 12157 at 12176). One comment says ``identity'' 
should mean ``a substance or product is what it is represented on the 
label to be.''
    One comment says that it does not seem appropriate to define the 
term ``purity'' to mean ``without impurities.'' The comment states it 
would be difficult to consider an herbal extract as being ``pure'' 
because it is a mixture of naturally occurring compounds in a solvent. 
Another comment suggests the term ``purity'' be defined to mean ``free 
from objectionable and/or deleterious levels of impurities including, 
but not limited to, heavy metals, pesticides, mycotoxins, 
radioactivity, filth, extraneous material, molds, yeasts and 
bacteria.'' Another comment suggests defining the term ``purity'' as 
``having the intended identity and composition and being without 
significant impurities.'' However, the comment does not explain what is 
meant by ``without significant impurities.''
    One comment suggests defining the term ``strength'' as ``having the 
intended concentration, that is, the amount of the dietary ingredient 
per unit of use (tablet, capsule, soft gel, teaspoon, or other unit).'' 
Another comment expresses concern about the use of the term 
``strength'' in relationship to nonstandardized herbals because there 
are no current industry standards for these products. This comment 
suggests we clarify the term ``strength'' so it refers to having the 
correct amount of a stated ingredient. One comment notes St. Johns wort 
has a composition of approximately 40 different constituents in 
addition to the essential oil that contains numerous constituents. The 
comment asks which constituent it should use to determine ``strength.'' 
Another comment would use the term ``quantity'' instead of 
``strength.''
    One comment would define ``composition'' as ``having the intended 
mix of components or ingredients, including dietary ingredients.'' 
Another comment would delete ``composition'' from the rule because, the 
comment claimed, an FDA investigator might conclude that 
``composition'' refers to every constituent of every botanical. 
According to this comment, there are many tests that could be used to 
identify the botanical constituents, but that it would be economically 
exhausting considering the number of botanical constituents, and it 
would not contribute to quality or safety.
    (Response) We decline to revise the rule to define identity, 
purity, strength, or composition. The exact way in which the dietary 
supplement industry uses these terms may vary, and defining these terms 
could limit the flexibility that is needed to accommodate such 
variations.
    Nevertheless, to elaborate on our interpretation of identity, 
purity, strength, and composition, and to respond to the particular 
concerns raised by some comments, we provide the following information.
    a. Identity. The ``identity'' of a dietary supplement refers to the 
dietary supplement's consistency with the master manufacturing record 
and/or that it is the same as described in the master manufacturing 
record.
    b. Purity. The ``purity'' of a dietary supplement refers to that 
portion or percentage of a dietary supplement that represents the 
intended product. For example, amino acids generally can exist in two 
forms (i.e., dextro (D-, or right) and levo (L-, or left) forms) called 
enantiomers. Enantiomers have the same chemical formula and the same 
chemical structure, but differ in their three-dimensional orientation. 
If you manufacture a dietary supplement to provide the amino acid L-
arginine, and you determine that 90 percent of the manufactured product 
is L-arginine and 10 percent of the manufactured product is D-arginine, 
you could describe your L-arginine product as ``90 percent pure.'' As 
another example, if you manufacture a mixture of triglycerides that 
provides polyunsaturated fatty acids in the diet, the manufactured 
triglycerides may contain small amounts of free fatty acids and 
sterols. The free fatty acids and sterols could derive, for example, 
from the source of the triglycerides or could be byproducts of the 
manufacturing process. If you determine that 95 percent of the 
manufactured product is the mixture of the triglycerides that provides 
the polyunsaturated fatty acids, and 5 percent of the product is free 
fatty acids and sterols, you could describe the purity of your product 
as ``95 percent pure.''
    Just as we use the term ``purity'' to refer to the identity and 
amount of a dietary supplement that is the desired product, we use 
``impurity'' to refer to the identity and amount of a dietary 
supplement that is not the desired product. In the previous examples, 
we

[[Page 34804]]

view the D-arginine that is present in the product that is intended to 
be L-arginine as an ``impurity,'' and we view the free fatty acids and 
sterols that are present in the product that is intended to be a 
mixture of triglycerides that provide polyunsaturated fatty acids in 
the diet as ``impurities.'' For the purposes of these examples, we do 
not view these ``impurities'' as ``contaminants.''
    If the comments were concerned that the dietary supplement CGMP 
requirements regarding a dietary supplement's ``purity'' mean that we 
expect you to characterize each constituent of a natural product to 
determine whether each constituent is present in a certain pre-
established quantity (i.e., purity specification) to determine whether 
it contributes to the ``purity'' of the dietary supplement or would be 
considered as an ``impurity,'' we do not consider such constituents to 
be ``components'' of a dietary supplement (see discussion of the 
definition of component in this section). For example, if you 
manufacture a dietary supplement containing fish oil, we would not 
consider the triglycerides, which are constituents of the fish oil, to 
be components. Likewise, we would not consider particular fatty acids 
(such as the polyunsaturated fatty acids docosahexaenoic acid (DHA) and 
eicosapentaenoic acid (EPA)), which are constituents of the 
triglycerides, to be components of the dietary supplement. In this 
example, you would be required to establish a purity specification for 
the amount of triglycerides in the fish oil. (Note that if you are 
manufacturing fish oil to provide the fatty acids DHA and EPA in the 
dietary supplement, the component specifications for the fish oil must 
include a strength specification for DHA and EPA in whatever amount you 
determine is necessary to meet the specification for strength of DHA 
and EPA in the dietary supplement.) We do, however, expect you to set 
appropriate limits on contaminants (e.g., toxic substances) that are 
known to be constituents of botanical extracts or other natural 
products that are likely or certain to contain constituents that are 
harmful.
    c. Strength. The strength of a dietary supplement relates to its 
concentration. By concentration, we mean the quantitative amount per 
serving (for example, weight/weight, weight/volume, or volume/volume). 
Therefore, for purposes of this final rule, strength does not refer 
simply to the quantity of an ingredient, rather it refers to the amount 
of a stated ingredient per a specified unit of measure.
    If the comments were concerned that the ``strength'' of a dietary 
supplement meant that you need to establish the quantitative amount per 
unit of measure of each constituent in a dietary ingredient, such as a 
botanical extract or natural product, we do not consider such 
constituents to be ``components'' of a dietary supplement, unless you 
add such constituents as components (as in an extract) (see discussion 
of the definition of component in this section).
    We do not consider the rule's requirements on dietary supplement 
strength as necessarily relating to the individual constituents of such 
products. Whether the requirements regarding dietary supplement 
strength apply to one or more constituents of dietary ingredients in a 
dietary supplement depends on what you are manufacturing. For example, 
if you are manufacturing vitamin C, and your source of vitamin C is 
rosehips, you would establish a strength specification for vitamin C in 
the finished batch of the dietary supplement (e.g., ``x milligrams (mg) 
of vitamin C per tablet''). You are required to ensure that the dietary 
supplement does in fact contain ``x mg of vitamin C per tablet.'' 
Alternatively, if you are manufacturing rosehips and not vitamin C from 
rosehips, the strength specification that you establish for the 
finished batch of the dietary supplement is the strength of the 
rosehips themselves (i.e., the concentration of rosehips in the final 
product, such as ``x mg of rosehips per tablet''). You are required to 
ensure that the product does in fact contain ``x mg of rosehips per 
tablet.''
    We discuss the requirements to establish and meet specifications in 
our discussion of subpart E (see section X of this document).
    d. Composition. A dietary supplement's ``composition'' refers to 
the specified mix of product and product-related substances in a 
dietary supplement. For example, a dietary supplement manufactured to 
provide vitamin C may contain, in addition to vitamin C, a tablet 
coating agent and substances used as binders. The composition could be 
described as the percent of the dietary supplement that is vitamin C, 
the tablet-coating agent, and each binder.
    e. Other terms.
    (Comment 58) Several comments would revise the rule to define 
``manufacturer.'' Many comments ask whether the rule applies to certain 
types of companies or professionals and said a definition of 
``manufacturer'' would clarify the rule's applicability.
    Some comments suggest specific text for a definition. For example, 
one comment would define ``manufacturer'' as ``a person who formulates 
or changes the composition or physical characteristics of a dietary 
supplement or who packages or labels the product in a container for 
distribution'' to clarify that a company that does not manufacture a 
specific dietary supplement, but purchases a dietary supplement in bulk 
and then packages or labels the bulk dietary supplement for sale to 
consumers, is still subject to dietary supplement CGMP requirements. 
The comment cites our proposed definition of ``manufacturer'' in our 
infant formula CGMP proposal (see 61 FR 36154 at 36209, July 9, 1996 
(proposing to define a ``manufacturer'' as ``a person who prepares, re-
constitutes or otherwise changes the physical or chemical 
characteristics of an infant formula or packages or labels the product 
in a container for distribution'')).
    Other comments would define ``manufacturer'' to exclude a health 
care practitioner or herbalist and noted the Canadian Natural Health 
Product regulations do not apply to health care practitioners.
    (Response) We decline to define ``manufacturer'' in the final rule. 
In section III, footnote 1 of this document, we explain that 
``manufacture'' is a broad term and is not limited to production, 
packaging, or labeling activities. Consequently, we prefer to explain 
our interpretation of the final rule in this preamble and to have the 
codified provisions state general principles rather than attempt to 
capture subtleties in a definition of ``manufacturer.''
    (Comment 59) Proposed Sec.  111.35(e)(1) through (e)(3) would 
require you to establish specifications for identity, purity, quality, 
strength, and composition at receipt, in-process, and finished batch 
stages, while proposed Sec.  111.35(g)(1) would require you to test 
each dietary supplement at the finished batch stage before release for 
distribution to confirm that specifications are met, provided that 
there are scientifically valid analytical methods available to perform 
such testing. If your quality control unit determined that finished 
batch testing could not be completed for any specification because a 
scientifically valid analytical method was not available, proposed 
Sec.  111.35(g)(2) and (g)(3) would require you to perform testing on 
components and at the in-process stage to determine whether that 
specification is met. The preamble to the 2003 CGMP Proposal explained 
that a scientifically valid analytical method is one that is based on 
scientific data or

[[Page 34805]]

results published in, for example, scientific journals, references, 
text books, or proprietary research (68 FR 12157 at 12198).
    Several comments agree that scientifically valid analytical methods 
are those that are based on scientific data or results published in 
scientific journals, references, textbooks, or proprietary research. 
However, several comments ask us to define or better explain the terms 
``test'' or ``scientifically valid analytical method'' as used in the 
dietary supplement CGMP final rule. One comment argues that, because of 
the evolving nature of methodology for ingredients used in dietary 
supplements, we should give the industry more guidance as to what can 
be considered authoritative for the purpose of compliance with CGMP. 
Some comments state we should acknowledge methods from the Institute 
for Nutraceutical Advancement (INA), American Herbal Pharmacopoeia 
(AHP), European Pharmacopoeia, and the World Health Organization (WHO) 
as scientifically valid analytical methods. One comment notes the USP 
establishes scientifically valid procedures in its compendia and 
encouraged us to designate compendial procedures as ``scientifically 
valid'' by defining ``scientifically valid'' to include compendial 
procedures. The comment further argues that failure to acknowledge 
compendial procedures as scientifically valid would be inconsistent 
with section 403(s)(2)(D) of the act, which acknowledges the role of 
compendia, by considering a dietary supplement misbranded if the 
supplement is covered by the specifications of an official compendium, 
is represented as conforming to the specifications of an official 
compendium, and fails to so conform.
    Other comments would define ``validation'' and ``verification'' and 
directed us to ``ANSI Standard A8402-1994'' (a description of 
validation and verification standards).
    (Response) We decline to define ``test,'' ``scientifically valid 
analytical method,'' or ``scientifically valid method'' in this final 
rule. As the comments recognized, the analytical methods for components 
are evolving. A regulatory definition for ``test,'' ``scientifically 
valid analytical method,'' or ``scientifically valid method'' could 
become obsolete if we based it on specific sources such as INA, AHP, or 
USP that may or may not themselves stay current or that may be modified 
in a manner that did not enjoy widespread support.
    The preamble to the 2003 CGMP Proposal acknowledged that compendia 
can have a role in establishing tests used to determine whether 
specifications are met. For example, we noted that compendial standards 
may be appropriate reference materials for use in conducting tests or 
examinations (68 FR 12157 at 12208). However, we did not list specific 
compendia that would be suitable sources or scientifically valid 
analytical tests, and are not listing such compendia in this final 
rule. The compendia identified in the comments, i.e., INA, ANSI, AHP, 
and USP, may include some methods that are based on scientific data or 
results published in scientific journals, references, textbooks, or 
proprietary research, but also contain some methods that are not based 
on such data or results. Thus, whether or not a method is 
scientifically valid is not determined solely by its inclusion in a 
compendium. Rather, it is the responsibility of quality control 
personnel to approve the use of those scientifically valid tests that 
will ensure a product's identity, purity, strength, and composition 
whether or not such tests are contained in a particular compendium.
    We also decline to define ``validation'' and ``verification'' 
because the final rule does not establish any requirements that use 
these terms.
    (Comment 60) One comment asks us to define the terms ``adequate,'' 
``sufficient,'' and ``qualified'' and argues that, without these 
definitions, an FDA investigator may assert that something or someone 
is not adequate, sufficient, or qualified.
    (Response) We decline to define ``adequate,'' ``sufficient,'' or 
``qualified'' in this final rule. Deciding what is ``adequate'' or 
``sufficient,'' or who is ``qualified'' must be done on a case-by-case 
basis, depending on the operations and the particular facts. As 
explained in section V of this document, we do not need to, nor could 
we, predict with mathematical precision how many inches or feet, for 
example, would be ``adequate space'' to allow for cleaning a particular 
piece of equipment that could be applied to every size of facility and 
every operation. Furthermore, defining ``adequate,'' as defined in part 
110, as ``that which is needed to accomplish the intended purpose in 
keeping with good public health practice'' would still require context 
to determine whether, in a particular operation and based on a 
particular set of facts the particular practice was ``adequate.'' 
Moreover, for terms such as ``adequate,'' ``sufficient,'' and 
``qualified,'' where there has been common usage in the food industry 
to enable manufacturers and FDA investigators to comprehend and apply 
such terms to a particular operation, we do not believe a definition 
for these terms is necessary.
    (Comment 61) Several comments would define the terms ``certificate 
of analysis,'' ``certificate of compliance/conformance,'' and 
``continuing product guarantee.'' Most comments include these terms in 
a list of terms that they want us to define to ensure consistent 
interpretation of the rule throughout the industry. One comment says a 
standard for documentation, such as a certificate of analysis, would 
put greater emphasis on the firm's responsibility to comply with CGMP.
    (Response) We decline to define these terms as suggested by the 
comments. We have included, in the codified, the use of a certificate 
of analysis as an option to determine whether certain specifications 
have been met. The final Sec.  111.75(a)(2)(ii)(B) requires that 
certain information be provided in a ``certificate of analysis.'' This 
provision states that the certificate of analysis must include a 
description of the test or examination method(s) used, limits of the 
test or examinations, and actual results of the tests or examinations, 
provided you satisfy certain other criteria.
    As for the claim that a standard for documentation, such as a 
certificate of analysis, would emphasize a firm's responsibility to 
comply with CGMP, we encourage firms who are excepted from the scope of 
the rule in final Sec.  111.1 and who supply dietary ingredients and 
other components to follow dietary supplement CGMP requirements.
    We decline to define ``certificate of compliance/conformance'' or 
``continuing product guarantee'' because the final rule does not 
establish any requirements that use these terms.
26. What Definitions Did the Comments Want Us to Delete?
    (Comment 62) Some comments would delete certain definitions (e.g., 
``component'' and ``ingredient'') because these terms do not appear in 
the food CGMP, the 1997 ANPRM, or both.
    (Response) We decline to delete any definition for the reasons 
stated by the comments. As discussed in section V of this document, 
Congress did not require dietary supplement CGMP requirements to be 
identical to the food CGMP requirements, so the mere fact that a 
definition may not appear in a food CGMP regulation does not mean we 
must delete that definition from this final rule, especially when the 
comments offered no other justification for deleting the definition. 
Definitions

[[Page 34806]]

provide clarity and consistency in interpreting various terms in a 
rule.

D. Do Other Statutory Provisions and Regulations Apply? (Final Sec.  
111.5)

    Final Sec.  111.5 states: ``In addition to this part, you must 
comply with other applicable statutory provisions and regulations under 
the act related to dietary supplements.'' Proposed Sec.  111.5 stated 
that, in addition to the dietary supplement CGMP requirements, ``you 
must comply with other applicable statutory provisions and regulations 
under the act related to the manufacturing, packaging or holding of 
dietary ingredients or dietary supplements.''
    Section 111.5 reminds you that other statutory or regulatory 
requirements, not included in the dietary supplement CGMP requirements, 
may apply to your particular products, operations, or activities. In 
our further review of this provision, we determined that we do not need 
to elaborate on the individual operations and have shortened the 
provision to eliminate the references to particular operations. You are 
required to comply with other applicable statutory and regulatory 
requirements, and we have retained this provision to ensure you 
understand that this final rule does not relieve you of your 
responsibilities to comply with other applicable statutory and 
regulatory requirements related to dietary supplements.

E. What Sections Did We Remove From the Rule, and Why?

    The final rule omits sections that were in the proposed rule. 
Proposed Sec.  111.2, ``What Are These Regulations Intended to 
Accomplish,'' would have described the rule's purpose as establishing 
the minimum CGMP you must use to the extent that you manufacture, 
package, or hold a dietary supplement. Proposed Sec.  111.6, 
``Exclusions,'' would have excluded ``persons engaged solely in 
activities related to the harvesting, storage, or distribution of raw 
agricultural commodities that will be incorporated into a dietary 
supplement by other persons'' from the dietary supplement CGMP 
requirements.
1. ``What Are These Regulations Intended to Accomplish?'' (Proposed 
Sec.  111.2)
    We elected to remove proposed Sec.  111.2 from the final rule 
because we realized that it created no enforceable obligations and 
provided little, if any, helpful information. The few comments that 
address proposed Sec.  111.2 either disagreed with its general 
statement or sought to weaken the provision; the comments' arguments 
prompted us to reconsider whether proposed Sec.  111.2 was necessary at 
all, and, in the end, we decided to delete the proposed section. We 
describe the comments on proposed Sec.  111.2 in the following 
paragraphs.
    (Comment 63) Several comments argue the proposed rule went beyond 
the ``minimum standards'' mentioned in proposed Sec.  111.2. These 
comments also assert the proposed rule lacked flexibility.
    (Response) We disagree with the comments. In several instances, the 
proposed requirement is practically identical to requirements in the 
umbrella food CGMP regulations. For example, most of the proposed 
requirements for personnel, physical plants, and equipment and utensils 
correspond to long-established, similar requirements in the umbrella 
food CGMP regulations in part 110. In other instances, the proposed 
rule would require a particular action or result (such as establishing 
specifications for components, in-process controls, manufactured 
dietary supplements, and packaged and labeled dietary supplements under 
proposed Sec.  111.35(e)), but gave firms the flexibility and the 
responsibility to decide what those specifications will be. We have 
included flexibility where it is appropriate to do so, and, after we 
revised parts of the rule in response to the comments, the final rule 
provides more flexibility than the proposal. For example, final Sec.  
111.75 sets forth criteria for relying on a certificate of analysis to 
ensure that certain specifications for components are met and for when 
you can test a subset of finished batches for a select number of 
specifications; this differs considerably from the proposal which would 
have required testing all batches for all specifications.
    (Comment 64) One comment would revise proposed Sec.  111.2 to read 
as follows: ``These regulations recommend general minimum current good 
manufacturing practices that, when modified by manufacturer product 
specifications, will extend to the manufacture, package, or holding of 
dietary ingredients or dietary supplements for that manufacturer.''
    (Response) We decline to revise the rule as suggested by the 
comment. Section 402(g) of the act states that ``The Secretary may by 
regulation prescribe good manufacturing practices for dietary 
supplements.'' If a dietary supplement has been prepared, packaged, 
labeled, or held under conditions that do not meet the final rule's 
requirements, the dietary supplement is deemed to be adulterated under 
section 402(g)(1) of the act. Here, the comment's suggestion that 
dietary supplement CGMP requirements could be ``modified by 
manufacturer product specifications'' would create uncertainty over 
whether manufacturers could unilaterally ``modify'' their product 
specifications to fit a batch that failed to meet specifications or 
claim that a violation was ``cured'' by a manufacturer's new product 
specification. In any event, given that we decided to omit proposed 
Sec.  111.2 altogether, the change sought by the comment is moot.
2. ``Exclusions'' (Proposed Sec.  111.6)
    As we stated earlier in this section, proposed Sec.  111.6 would 
exclude from the dietary supplement CGMP requirements persons who 
engage solely in activities related to the harvesting, storage, or 
distribution of raw agricultural commodities that would be incorporated 
into a dietary supplement by other persons. However, as we explained in 
our response to comment 27 of this document, we decided that the 
exclusion was not necessary, given the changes that we made to final 
Sec.  111.1(a).
    Nevertheless, we received several comments on proposed Sec.  111.6, 
and we address those comments here.
    (Comment 65) One comment would revise the rule to exclude or use 
different requirements for small businesses. The comment suggested we 
categorize small businesses by employment levels or dollar sales and 
adopt a tiered enforcement strategy similar that used in other 
government programs, such as those under the Occupational Safety and 
Health Act, the Americans with Disabilities Act, and the Family Leave 
Act. Another comment would exempt small businesses from the specific 
requirements for testing if those businesses produce annual batch runs 
of 25,000 capsules and tablets.
    (Response) We decline to exclude small businesses from the final 
rule or to have different criteria for such businesses. As we stated in 
our response to comments 1, 3, and 16, there is no reason to assume 
that Congress meant to apply different or lesser CGMP requirements, or 
no CGMP requirements at all, to dietary supplements made by small 
businesses. Dietary supplement CGMP requirements help to ensure the 
quality of the dietary supplement and, among other things, that a 
dietary supplement meets its specifications, that it contains the 
ingredients specified in its master manufacturing record, and that it 
is not contaminated. Consumers should be able to expect that the 
dietary supplements they purchase meet CGMP requirements regardless of 
the manufacturer's size. However, to help

[[Page 34807]]

businesses comply with dietary supplement CGMPs, we are giving 
businesses with fewer than 500 employees but 20 or more employees a 
compliance date of 24 months after the date of publication of this 
final rule, and we are giving businesses with fewer than 20 employees a 
compliance date of 36 months after the date of publication of this 
final rule.
    We carefully considered the size of a business when developing 
these regulations. The most common Small Business Association size 
standard applicable to manufacturers covered by this final rule is 500 
employees. Based on comments and our knowledge of the dietary 
supplement industry, we know that there are a number of dietary 
supplement manufacturers who fall significantly below the standard of 
500 employees. To accommodate these manufacturers, we have established 
different compliance dates as noted.
    (Comment 66) One comment would exempt ``consolidators'' (whom it 
described as individuals who purchase raw agricultural commodities for 
sale to raw ingredient manufacturers) from the rule. Some comments 
suggest expanding the exclusion pertaining to harvesting, storage, and 
distribution of raw agricultural commodities to include other common 
and basic raw botanical processing activities, such as drying, 
chopping, cutting, size reduction, sifting, grinding, and storage. One 
comment would delete the word ``solely'' to make the rule more flexible 
and make it possible to exclude producers, who do not manufacture a 
distinct product, from the CGMP rule. Another comment expresses concern 
about potential safety issues that can arise from the early stages of 
manufacturing, such as the use of improper handling of agricultural 
commodities and the risk of adulteration; the comment says businesses 
involved in producing or distributing raw agricultural commodities 
should be subject to some requirements under the rule. A few comments 
ask us to draft guidance documents to address activities such as 
wildcrafting, plant identification, good agricultural practices, and 
good hygienic practices for wildcrafters (persons who harvest plants 
grown in the wild), and growers and brokers and specific service 
providers (millers, extractors). Some comments would exempt individual 
wildcrafters because wildcrafters deal in relatively small amounts of 
material at a time and sell their material to larger brokers who 
combine materials from different pickers together.
    (Response) As explained in our responses to comments 29 and 30, 
persons who only manufacture or supply a component that will be further 
processed as a dietary supplement by another person are not within the 
scope of this final rule. Thus, a ``consolidator'' who simply buys raw 
agricultural commodities and then sells them to dietary ingredient 
manufacturers would not be subject to this final rule. Similarly, 
persons engaged in drying, chopping, cutting, size reduction, sifting, 
and grinding of raw agricultural commodities which they then sell to 
others for processing into a dietary supplement would not be subject to 
this final rule. We note, however, that such persons are not exempt 
from other regulatory requirements. We remind readers that a dietary 
ingredient is a food under section 201(f)(3) of the act. Consequently, 
a raw agricultural commodity that is a dietary ingredient is still 
subject to the umbrella food CGMP requirements in part 110, and 
activities such as drying, chopping, and cutting are what we have long 
considered to be types of food processing.
    As for ``wildcrafters,'' if they package and label raw agricultural 
commodities as dietary supplements or sell them to consumers for use as 
a dietary supplement, we would consider them to be manufacturers of a 
dietary supplement and subject to the rule. If, however, the 
wildcrafter simply sells the raw agricultural commodity to another for 
incorporation into a dietary supplement, it would not be subject to 
this final rule, but might be subject to the CGMP requirements in part 
110. Persons engaged in the harvesting, storage, or distribution of raw 
agricultural commodities, whether for distribution as a dietary 
supplement or for distribution as a dietary ingredient to a dietary 
supplement manufacturer, may want to read our guidance entitled ``Guide 
to Minimize Microbial Food Safety Hazards for Fresh Fruits and 
Vegetables'' available at http://www.cfsan.fda.gov/~dms/prodguid.html 
(Ref. 28). This guidance addresses common areas of food safety concern 
in the growing, harvesting, sorting, packing, and distribution of fresh 
produce, and contains principles that would apply to raw agricultural 
commodities, such as herbs and botanicals.
    As for the comment that would delete the word ``solely'' from 
proposed Sec.  111.6, we note that such a change is no longer necessary 
since we are deleting Sec.  111.6. However, we caution that only those 
persons or entities that manufacture or supply components that will be 
further processed as a dietary supplement by others are not subject to 
the final rule. If you manufacture and sell dietary supplements, in 
addition to supplying components to others, you would be subject to 
this final rule under Sec.  111.1(a).
    As for potential safety issues arising from the early stages of 
manufacturing, such as the use of improper handling of agricultural 
commodities and the risk of adulteration, the final rule, at Sec.  
111.75, describes criteria that enable a manufacturer of a dietary 
supplement to rely on a certificate of analysis. One criterion is that 
the manufacturer must first qualify the firm providing the component by 
establishing the reliability of the firm's certificate of analysis 
through confirmation of the results of the firm's tests or 
examinations. Firms that improperly handle raw agricultural 
commodities, such that the commodities that they provide are 
adulterated, are not likely to be qualified as suppliers of those 
commodities.
    In the future, we will consider the requests to develop guidance 
for subsets of agricultural and post-harvest activities (such as for 
hygienic practice for wildcrafters, identifying botanicals) associated 
with dietary supplement manufacturing, along with other guidance we may 
find useful as they relate to certain CGMP requirements for dietary 
supplements.

VII. Comments on Personnel (Final Subpart B)

A. Organization of Final Subpart B

    Proposed subpart B contained three provisions regarding personnel. 
Table 3 of this document lists the sections in final subpart B and 
identifies the proposed sections that form the basis of the final rule.

           Table 3.--Derivation of Sections in Final Subpart B
------------------------------------------------------------------------
                  Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.8 What are the requirements under   N/A
 this subpart B for written procedures?
------------------------------------------------------------------------
Sec.   111.10 What requirements apply for      Sec.   111.10
 preventing microbial contamination from sick
 or infected personnel and for hygienic
 practices?
------------------------------------------------------------------------

[[Page 34808]]

 
Sec.   111.12 What personnel qualification     Sec.   111.12
 requirements apply?
------------------------------------------------------------------------
Sec.   111.13 What supervisor requirements     Sec.   111.13
 apply?
------------------------------------------------------------------------
Sec.   111.14 Under this subpart B, what       N/A
 records must you make and keep?
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Personnel

1. Revisions
    The final provisions in subpart B include revisions that clarify 
that the final rule applies only to persons who manufacture, package, 
label, or hold dietary supplements unless subject to an exclusion in 
Sec.  111.1.
    The final provisions also include revisions that clarify the 
applicability of the rule to persons who perform labeling operations 
for dietary supplements.
2. Changes After Considering Comments
    The final rule:
    <bullet> Requires you to establish and follow written procedures to 
fulfill the requirements of subpart B;
    <bullet> Provides flexibility regarding the requirement to exclude 
personnel who might be a source of microbial contamination (e.g., due 
to illness or open lesions) so that such personnel must be excluded 
only from operations where such contamination may occur;
    <bullet> Clarifies that the qualification of personnel and 
supervisors may be done through education, training, or experience;
    <bullet> Sets forth a new requirement that you identify qualified 
personnel to perform quality control operations and requires that such 
personnel have distinct and separate responsibilities related to 
performing quality control operations from those responsibilities that 
the person otherwise has when not performing quality control 
operations; and
    <bullet> Sets forth a new requirement to make and keep records that 
document training of personnel.

C. General Comments on Proposed Subpart B

    (Comment 67) Some comments assert one or more proposed requirements 
are unconstitutionally vague under the Fifth Amendment and arbitrary 
and capricious under section 706(2)(B) of the Administrative Procedure 
Act (APA) and therefore should be deleted. The comments focus on:
    <bullet> Proposed Sec.  111.12(a) which would require ``qualified 
employees'' and
    <bullet> Proposed Sec.  111.13(a) which would require ``qualified 
personnel to supervise.''
    In general, these comments say the proposal's failure to define the 
term ``qualified'' means that persons who are subject to the rule could 
not discern the meaning of the term. These comments also say the 
proposal imposes no limits on enforcement officers as to what would 
satisfy the requirements and, thus would represent an exercise of 
unbridled discretion and disparate decisionmaking. These comments argue 
proposed Sec.  111.12(b), which would require employees to have ``the 
training and experience to perform the person's duties,'' and proposed 
Sec.  111.13(b), which would require supervisors to be ``qualified by 
training and experience to supervise,'' would suffice.
    (Response) We are not deleting Sec. Sec.  111.12(a) and 111.13(a) 
as requested by these comments. As discussed in section V of this 
document, we disagree that the terms in question are unconstitutionally 
vague, need to be defined, or may result in discriminatory enforcement. 
There has been sufficient common usage of these terms in the food 
industry to enable manufacturers, and those who enforce the 
requirements, to comprehend and apply such terms ``with a reasonable 
degree of certainty'' to their particular operations (see Boyce Motor 
Lines v. United States 342 U.S. at 340). Further, agencies are 
permitted to use qualifying terms to enable them to address a wide 
variety of conditions at companies. For these reasons, we have retained 
the use of the terms in the final rule. The provisions at issue also 
give firms the flexibility to determine how to comply with the 
regulations. We also explain in section V of this document that the 
final rule does not violate the APA.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.8)

    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV. We also respond to individual comments on 
specific provisions in the same section. Final Sec.  111.8 requires you 
to establish and follow written procedures to fulfill the requirements 
of subpart B. Additionally, to ensure that we can evaluate firms' 
compliance with their written procedures, final Sec.  111.14 requires 
that a person who manufactures, packages, labels, or holds dietary 
supplements make and keep records of such procedures. Such records 
would be available to us under subpart P.

E. What Requirements Apply for Preventing Microbial Contamination From 
Sick or Infected Personnel and for Hygienic Practices? (Final Sec.  
111.10)

    The title of this provision has been changed from proposed Sec.  
111.10 to clarify that the requirements are related to the prevention 
of microbial contamination due to the health condition of personnel and 
not other sources.
1. Final Sec.  111.10(a)
    Final Sec.  111.10(a) requires you to take measures to exclude from 
any operations any person who might be a source of microbial 
contamination, due to a health condition, where such contamination may 
occur, of any material including components, dietary supplements, and 
contact surfaces used in the manufacture, packaging, labeling, or 
holding of a dietary supplement. This provision is similar to proposed 
Sec.  111.10. We added ``due to a health condition'' for clarity.
    (Comment 68) Several comments suggest that employees who are sick 
should be allowed to work in areas where they will not come into 
contact with components, dietary supplements, or contact surfaces, and 
that the requirements of proposed Sec.  111.10 are too strict. These 
comments say proposed Sec.  111.10(a) is too broad in stating that such 
persons be excluded ``from working in any operation.'' These comments 
explain that such persons may be suitable for performing other tasks, 
such as warehouse functions or administrative work. These comments 
would revise proposed Sec.  111.10(a) so that it is acceptable for such 
persons to work so long as they will not be a vessel for microbial 
contamination.
    Other comments agree with proposed Sec.  111.10(a), and state that 
employees who are sick should be excluded from the plant, even from 
areas where products are not processed. These comments state excluding 
such personnel should be mandatory as the microbes from an open sore, 
wound, or other source of contamination could contaminate the 
surrounding air, personnel, etc. For example, if the production area is 
a closed loop air handling system, then contamination could spread to 
the other areas through the common air handling units/ducts.

[[Page 34809]]

    (Response) We agree that some tasks may be suitable for a person 
who might be a source of microbial contamination. Certain warehouse 
functions or administrative tasks may be appropriate for such a person 
to do, provided that these functions or tasks do not expose components, 
dietary supplements, or contact surfaces to microbial contamination 
from the person, and provided that the person would not infect others 
who would then expose components, dietary supplements, or contact 
surfaces to microbial contamination.
    A requirement to exclude employees from being present at work would 
limit potential microbial contamination, which is the basis of the 
point made by some comments that employees who are sick should be 
excluded from the plant. However, the comments do not persuade us to 
deny firms the flexibility to determine whether it would be appropriate 
for an employee who may be a source of microbial contamination to work 
in some areas of the physical plant that are sufficiently separated 
from areas where product contamination could occur. When considering 
whether an employee may be permitted to work and whether he/she 
represents a potential source of microbial contamination, one should 
look beyond the obvious potential sources of contamination, and 
consider possibilities such as the forms of indirect contamination 
discussed by the comments. Therefore, we are revising proposed Sec.  
111.10(a) to require you to take measures to exclude ``from any 
operations any person who might be a source of microbial contamination, 
due to a health condition, where such contamination may occur, of any 
material including components, dietary supplements, and contact 
surfaces used in the manufacture, packaging, labeling, or holding of a 
dietary supplement.''
    As one measure to reduce potential microbial contamination, final 
Sec.  111.10(a)(1) requires you to exclude, from working in any 
operations that may result in contamination, any person who, by medical 
examination, the person's acknowledgement, or supervisory observation, 
is shown to have, or appears to have an illness, infection, open 
lesion, or any other abnormal source of microbial contamination, that 
may result in microbial contamination of components, dietary 
supplements, or contact surfaces, until the health condition no longer 
exists. Final Sec.  111.10(a)(1) is similar to proposed Sec.  
111.10(a)(1). We have added that the person can acknowledge that he or 
she may be a source of microbial contamination. We are moving and 
modifying the prepositional phrase concerning ``working in any 
operation.'' We also have added the word ``infection'' to clarify the 
sources of potential abnormal contamination.
    (Comment 69) Several comments suggest employees who may be the 
source of microbial contamination should be permitted to work in areas 
of the plant where they pose no risk of contamination, and therefore 
should not be excluded unless they pose such a risk.
    (Response) We agree with the comments and are revising proposed 
Sec.  111.10(a)(1) accordingly. Therefore, you may allow persons with 
certain health conditions to work in areas of a plant where they pose 
no risk of contamination even though they must be excluded from other 
areas where they would pose such a risk.
    Final Sec.  111.10(a)(2) requires you to instruct your employees to 
notify their supervisor(s) if they have, or if there is a reasonable 
possibility that they have, a health condition stated in Sec.  
111.10(a)(1) that could contaminate any components, dietary 
supplements, or any contact surface.
    We did not receive comments specific to proposed Sec.  
111.10(a)(2).
2. Final Sec.  111.10(b)
    Final Sec.  111.10(b) requires, if you work in an operation during 
which adulteration of the component, dietary supplement, or contact 
surface may occur, you to use hygienic practices to the extent 
necessary to protect against contamination of components, dietary 
supplements, or contact surfaces. Final Sec.  111.10(b) lists nine 
hygienic practices, such as wearing outer garments in a manner that 
protects against contamination, washing hands thoroughly, and wearing, 
where appropriate, hair nets, caps, beard covers, or other effective 
hair restraints.
    We did not receive any comments concerning proposed Sec.  
111.10(b)(1) (wearing outer garments in a manner that protects against 
contamination), Sec.  111.10(b)(2) (maintaining adequate personal 
cleanliness), Sec.  111.10(b)(3) (washing hands thoroughly), Sec.  
111.10(b)(4) (removing all unsecured jewelry and other objects that 
might fall into components, dietary supplements, equipment, or 
packaging and removing hand jewelry that cannot be adequately 
sanitized), Sec.  111.10(b)(6) (wearing, where appropriate, hair nets, 
caps, beard covers, and other effective hair restraints), Sec.  
111.10(b)(7) (not storing clothing or other personal belongings where 
components, dietary supplements, or contact surfaces are exposed or 
where contact surfaces are washed), and Sec.  111.10(b)(9) (taking any 
other precautions necessary to protect against contamination).
    Proposed Sec.  111.10(b)(5) would require the hygienic practices 
that you use to include maintaining gloves used in handling components, 
dietary ingredients, or dietary supplements in an intact, clean, and 
sanitary condition and ensuring that gloves be of an impermeable 
material.
    (Comment 70) One comment asks us to clarify the requirements for 
the use of gloves in proposed Sec.  111.10(b)(5). The comment says 
there are situations in which gloves are ineffective or cumbersome. The 
comment provides as an example, if a person is packaging a bulk 
material in fiber packs with metal ring lids, bulky gloves can 
interfere with the finer work such as attaching security tabs, and 
thin, flexible gloves can be easily damaged by the sharp edges of the 
metal rings on the lid.
    (Response) Final Sec.  111.10(b)(5) requires you to maintain gloves 
in an intact, clean, and sanitary condition; it does not require you to 
use gloves in any specific situation. Although there is no requirement 
for wearing gloves while performing specific operations, you must wear 
gloves when they are necessary to protect against contamination of any 
components, dietary supplements, or contact surfaces.
    (Comment 71) Proposed Sec.  111.10(b)(8) would require that the 
hygienic practices that you use, to the extent necessary to protect 
against contamination, include not eating food, chewing gum, drinking 
beverages, or using tobacco products in areas where components, dietary 
ingredients, dietary supplements, or any contact surfaces are exposed, 
or where contact surfaces are washed.
    One comment would substitute the word ``processed'' for the word 
``exposed'' in proposed Sec.  111.10(b)(8). The comment says, although 
areas where components, dietary supplements, and contact surfaces are 
exposed pose the greatest risk, adulteration is also possible where 
these items are held (i.e., stored in containers and, thus, not 
exposed). Furthermore, the comment explains the use of the word 
``processed,'' rather than ``exposed,'' would cover all areas intended 
to be covered by CGMPs and would alleviate the need to specify that the 
requirement applies to areas where contact surfaces are washed.
    (Response) We decline to revise the rule as suggested by the 
comment. We believe the word ``exposed'' covers all areas intended to 
be covered by the

[[Page 34810]]

requirement, including areas where contact surfaces are washed. We 
consider an area where contact surfaces are washed to ``expose'' the 
contact surface. To avoid any confusion, we are modifying Sec.  
111.10(b)(8) to say ``* * * any contact surfaces are exposed, or where 
contact surfaces are washed.'' As written, the requirement to not eat, 
chew gum, drink, or use tobacco products in areas where components, 
dietary supplements, and contact surfaces are exposed gives firms 
appropriate flexibility to determine areas where employees may or may 
not eat, chew gum, drink, or use tobacco products.

F. What Personnel Qualification Requirements Apply? (Final Sec.  
111.12)

    Final Sec.  111.12(a) requires you to have qualified employees who 
manufacture, package, label, or hold dietary supplements. Final Sec.  
111.12(a) is similar to proposed Sec.  111.12(a), except that the final 
rule includes an editorial change to clarify that the requirement is to 
have the qualified employees do the work rather than merely to have 
qualified employees.
    (Comment 72) The 2003 CGMP Proposal invited comment on whether 
there is a minimum number of employees needed to manufacture dietary 
supplements (68 FR 12157 at 12183). Several comments state the final 
rule should not include such a minimum number because firms should be 
able to decide for themselves how many qualified personnel they need.
    (Response) The final rule does not stipulate a minimum number of 
employees. However, there should be enough employees to manufacture, 
package, label, and hold dietary supplements to ensure compliance with 
the final rule. In general, CGMP suggests the need for a minimum of two 
persons: One to perform the work, and a second to check the work 
performed to ensure that a manufacturing deviation or an unanticipated 
occurrence is not overlooked.
    (Comment 73) Some comments about the proposed definition of 
``quality control unit'' say the quality control function need not be 
performed by a distinct or separate unit. These comments say the 
quality control function is best performed by a person or persons 
qualified by training, education, or experience in the different 
processing areas.
    (Response) As discussed, we have revised the proposed definition 
and substituted the term ``personnel'' for ``unit.'' (For the 
definition of quality control personnel, see section VI of this 
document.) We agree the quality control functions do not need to be 
performed by a distinct or separate unit or person and that a person 
who is qualified by training, education, or experience can serve a 
quality control function. Therefore, we are adding a new Sec.  
111.12(b) to clarify that you must identify who is responsible for 
quality control operations. Under final Sec.  111.12(b) each person 
identified must be qualified to perform such operations, and must have 
distinct and separate responsibilities related to performing such 
operations from those responsibilities that the person otherwise has 
when not performing such operations. The quality control personnel can 
have dual functions within the facility but should separately perform 
the different responsibilities.
    Final Sec.  111.12(c) requires that each person engaged in 
manufacturing, packaging, labeling, or holding, or in performing any 
quality control operations, have the education, training, or experience 
to perform the person's assigned functions. Final Sec.  111.12(c) 
includes a revision associated with final Sec.  111.12(b) by including 
persons who perform quality control operations as persons who also need 
to have the education, training, or experience for the assigned 
functions.
    (Comment 74) Several comments state we should revise the rule to 
allow for any combination of ``training or experience.'' These comments 
explain it is not always possible for an employee to have both 
``training and experience.'' These comments would revise proposed Sec.  
111.12(b) to read, ``each person engaged in the manufacture of a 
dietary product should have the proper education, training, and 
experience (or any combination thereof) needed to perform the assigned 
functions. Training should be in the particular operations(s) that the 
employee performs as they relate to the employee's functions.'' Another 
comment asks for guidance as to what type of education, training, or 
experience is required for an employee to be considered qualified.
    (Response) We agree with the point made by the comments. We 
acknowledge that some positions will require an appropriate educational 
background in addition to any on-the-job training. In the preamble to 
the 2003 CGMP Proposal (68 FR 12157 at 12183) we noted ``training'' may 
be considered a form of ``education'' and elected to require that 
employees be qualified by ``training and experience'' rather than 
``education, training, and experience.'' The 2003 CGMP Proposal used 
the conjunction ``and'' because we considered ``experience'' to be 
different from training, in that ``experience'' is knowledge that a 
person gains over time, e.g., as he or she becomes increasingly 
familiar with a particular action or piece of equipment.
    These comments persuade us that the rule would be clearer if we 
added ``education'' to the list of attributes that are used to qualify 
an employee. We also agree there are some employees who could be 
qualified based solely on their education or experience and other 
employees who would become qualified through, for example, on-the-job 
training before they are left on their own to perform their assigned 
duties. Rather than revise the rule to list all three attributes and 
then explain that an employee can be qualified by any combination of 
the attributes, we have changed the conjunction from ``and'' to ``or.'' 
Additionally, on our own initiative, we have replaced ``person's 
duties'' with ``person's assigned functions.'' This change reinforces 
the principle that the employee's training relates to the functions 
that he or she is assigned to perform.
    We will consider whether it would be useful to provide guidance on 
what type of education, training, or experience would be sufficient for 
an employee to be properly qualified. We believe that such education, 
training, or experience may vary by job function and that it would be 
difficult to provide generic guidance that would be sufficient for all 
specific job tasks. We decline to suggest that training should be 
limited, as the comments suggest, to the particular operation(s) that 
the employee performs as they relate to the person's functions. These 
CGMP requirements apply to many types of manufacturing operations of 
various size and complexity, so the training may vary depending on the 
circumstances and may include more than the employee's assigned 
functions.
    (Comment 75) One comment states we should provide training 
materials such as texts, videos, Internet training, or seminars, to 
help companies properly train their employees.
    (Response) We have no plans at this time to provide companies with 
training materials for their employees. We expect that most companies 
already have trained or will train their employees and that where 
additional training is needed to comply with these regulations, 
companies will develop the training materials that are appropriate for 
the functions their employees perform. We may consider providing 
guidance in the future if circumstances warrant such guidance.

[[Page 34811]]

G. What Supervisor Requirements Apply? (Final Sec.  111.13)

    Final Sec.  111.13(a) requires you to assign qualified personnel to 
supervise the manufacturing, packaging, labeling, or holding of dietary 
supplements. Final Sec.  111.13(a) derives from proposed Sec.  
111.13(a).
    We did not receive comments specific to proposed Sec.  111.13(a).
    Final Sec.  111.13(b) requires each supervisor you use to be 
qualified by education, training, or experience to supervise. Final 
111.13(b) derives from proposed Sec.  111.13(b) which would require you 
and your supervisors to be qualified by training and experience to 
supervise.
    (Comment 76) Several comments ask us to revise the rule so that 
supervisors may be qualified by any combination of training or 
experience. These comments would revise proposed Sec.  111.13(b) to 
read, ``supervisors must be qualified by education, training, and 
experience (or any combination thereof) to supervise the manufacturing, 
packaging, or holding of dietary ingredients and dietary supplements in 
compliance with this rule.'' One comment, however, would make an 
exception for quality control and sanitation supervisors, stating we 
should require these supervisors to have both training and experience.
    (Response) Consistent with the change we made to proposed Sec.  
111.12(c), we are revising proposed Sec.  111.13(b) to require the 
supervisors you use to be qualified by ``education, training, or 
experience.'' We acknowledge that some supervisory personnel may need a 
different range of education, training, or experience than others, and 
expect firms to determine the appropriate balance of education, 
training, and experience.
    (Comment 77) Several comments say our use of the phrase ``you and 
the supervisors you use'' in proposed Sec.  111.13(b) was unclear. 
According to these comments, the term ``you'' as defined in the 
proposal, is quite expansive and could be read so broadly as to require 
the Chief Executive Officer (CEO) of a company be ``qualified'' to 
supervise.
    (Response) We agree that the phrase ``you and the supervisors you 
use'' could be clearer. Therefore, we are revising proposed Sec.  
111.13(b) to say that ``each supervisor whom you use'' must be 
qualified to supervise. Section 111.13(b) applies to any person who 
supervises the manufacturing, packaging, labeling, or holding of 
dietary supplements, even if that person also is an executive such as 
the CEO. Thus, final Sec.  111.13(b) states, ``Each supervisor whom you 
use must be qualified by education, training, or experience to 
supervise.''
    (Comment 78) Several comments say the term ``to supervise'' is 
ambiguous and would revise the rule to clarify what a supervisor must 
be qualified to supervise: The manufacture, packaging, or holding of 
dietary ingredients and dietary supplements. Another comment would 
revise proposed Sec.  111.13(b) to clarify what type of training and 
experience are required so that firms would have more guidance as to 
what is expected to confirm that personnel are qualified.
    (Response) We decline to revise the rule as suggested by the 
comments. We disagree that the term ``to supervise,'' which is commonly 
used in the industry, is ambiguous. These CGMP requirements apply to 
many types of manufacturing operations of various size and complexity, 
and the training must be suited to the circumstances.

H. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.14)

    As discussed in this section, the final rule contains a new Sec.  
111.8 requiring you to establish and follow written procedures to 
fulfill the requirements of subpart B. Those written procedures are 
records. Therefore, we are adding a new Sec.  111.14(a) requiring you 
to make and keep records in accordance with subpart P. Final Sec.  
111.14(b)(1) requires you to make and keep a record of the written 
procedures for fulfilling the requirements of subpart B.
    The preamble to the 2003 CGMP Proposal invited comment on whether 
we should require documentation and records regarding each employee's 
training (68 FR 12157 at 12183). After considering comments and for the 
reasons discussed in the following paragraphs, Sec.  111.14(b)(2) 
requires you to make and keep documentation of training, including the 
date of training, the type of training, and the person(s) trained.
    We also invited comment on whether the final rule should contain 
requirements for documentation about consultants that you use (68 FR 
12157 at 12183). We specifically suggested any such requirement include 
the consultant's name, address, qualifications, and a description of 
services provided. After considering the comments and for the reasons 
discussed in the following paragraphs, the final rule does not include 
any requirements to make and keep records regarding consultants.
    (Comment 79) Several comments state employee training records are 
critical and should be required under the final rule. The comments 
explain that these records should show the content of the training, the 
date of the training, and the signature of the employee trained. These 
comments assert that a formal (written) GMP training program is 
necessary to track which employees have been trained in the CGMP 
requirements. These comments add, without a written and documented 
training program, it is likely that some employees may not receive 
sufficient training, or in some cases, any CGMP training at all. These 
comments say successful quality control programs are inextricably 
connected to appropriate training programs, and written documentation 
of employee training is an important safeguard to ensuring safe and 
accurately labeled dietary supplements. These comments also state it is 
already an industry standard to document training.
    Other comments question our ability to evaluate whether a firm's 
employees have been adequately trained without written documentation of 
the training.
    (Response) As discussed more fully in the discussion of subpart E 
in section X of this document, the final rule focuses on ensuring the 
quality of the dietary supplement at every stage of the production and 
process control system. Such a system begins with the proper training. 
We agree that documentation of employee training is necessary to track 
which employees have been trained in which operations. Therefore, final 
Sec.  111.14(b)(2) requires you to keep documentation of training, 
including the date of the training, the type of training, and the 
person(s) trained.
    (Comment 80) One comment says we should not require manufacturers 
to document and keep records regarding each employee's training. The 
comment says the rule should focus on end results and not on process.
    (Response) We disagree with the comment. As we have explained in 
this section, each person engaged in an activity covered by these CGMP 
regulations must have the education, training, or experience to perform 
the person's assigned functions. Some employees will be considered 
qualified based in part on training taken as company employees. To show 
that such training is appropriate to the employee's functions and has 
in fact occurred, the training must be properly documented. This 
documentation is an important aspect of ensuring adequate training and, 
therefore, helping to ensure the result of having qualified employees 
who perform their functions properly.

[[Page 34812]]

    (Comment 81) Several comments state the documentation of the 
training program should include the title of the person doing the 
training, an evaluation of the employee's understanding of the 
training, and recommendations for the frequency of refresher training. 
One comment describes a specific method for training and for tracking 
training. The comments state an evaluation of the employee's 
understanding of the training would ensure that employees who receive 
training understand what they have been taught.
    (Response) We decline to require specific additional documentation 
of employee training. We believe a firm should have some flexibility in 
how it wants to document training.
    (Comment 82) Several comments respond to our question as to whether 
the final rule should require documentation about consultants, 
including each consultant's name, address, qualifications, and a 
description of services provided. Several comments say that documenting 
this information is useful and could be done on a voluntary basis, but 
that such information is not necessary to ensure safe and accurately 
labeled supplements and, thus, should not be required. One comment 
notes that recommendations from consultants may or may not be used, and 
that a company should not have to explain at a later date why such 
decisions were made. Another comment asserts that we and the company 
may have different opinions on whether a consultant is qualified and 
that the consultant's qualification is not our concern if a product is 
not adulterated. One comment says documenting the name and services of 
the GMP consultants should be required to facilitate contact in case of 
need.
    (Response) The proposal noted documentation of the name, address, 
qualifications, and services rendered for each consultant may help you 
know whom to contact and if questions arise concerning the advice that 
the consultant has given. Thus, our intent in suggesting such 
documentation was to help you rather than to make the information 
available for us to determine whether we agreed with you that a 
particular individual was qualified to be a consultant. However, the 
comments persuade us that such information is not necessary to help 
ensure dietary supplement quality. Therefore, the final rule does not 
require documentation regarding consultants.

VIII. Comments on Physical Plant and Grounds (Final Subpart C)

A. Organization of Final Subpart C

    Proposed subpart C contained two provisions regarding physical 
plants. Table 4 of this document lists the sections in final subpart C 
and identifies the corresponding proposed sections that form the basis 
of the final rule.

           Table 4.--Derivation of Sections in Final Subpart C
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.15 What sanitation requirements  Sec.   111.15
 apply to your physical plant and grounds?
------------------------------------------------------------------------
Sec.   111.16 What are the requirements     N/A
 under this subpart C for written
 procedures?
------------------------------------------------------------------------
Sec.   111.20 What design and construction  Sec.   111.20
 requirements apply to your physical
 plant?
------------------------------------------------------------------------
Sec.   111.23 Under this subpart C, what    Sec.   111.15(d)(3) and
 records must you make and keep?             (e)(2)
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Physical 
Plant and Grounds

1. Revisions
    The final rule:
    <bullet> Reflects that the rule applies to persons who manufacture, 
package, label, or hold dietary supplements unless subject to an 
exclusion in Sec.  111.1.
    <bullet> Requires you to have documentation or otherwise be able to 
show that water that is used in a manner such that the water may become 
a component of the dietary supplement, e.g., when such water contacts 
components, dietary supplements, or any contact surface, meets 
applicable Federal, State, and local requirements and does not 
contaminate the dietary supplement.
2. Changes After Considering Comments
    The final rule:
    <bullet> Includes requirements similar to the food CGMP 
requirements in Sec.  110.20(a) for keeping the grounds bordering your 
physical plant in a condition that protects against contamination.
    <bullet> Clarifies that sanitation supervisors can be qualified by 
education, training, or experience.
    <bullet> Modifies the minimum requirements for water that is used 
in a manner such that the water may become a component of the dietary 
supplement, e.g., when such water contacts components, dietary 
supplements, or any contact surface. Such water must, at a minimum, 
comply with applicable Federal, State, and local requirements and not 
contaminate the dietary supplement.
    <bullet> Simplifies the sanitation requirements for toxic 
materials, bathroom facilities, and hand-washing facilities.
    <bullet> Simplifies and clarifies the design requirements for 
floors, walls, and ceilings; fans and other air-blowing equipment; 
equipment that controls temperature and humidity; and the use of 
safety-type glass or glass-like materials.
    <bullet> Requires written procedures for cleaning the physical 
plant and for pest control.
    <bullet> Requires that you make and keep records of the written 
procedures.

C. General Comments on Proposed Subpart C

    (Comment 83) Several comments say we should have different 
sanitation requirements for dietary ingredient manufacturers than for 
dietary supplement manufacturers. These comments state that the 
manufacture of synthetic or highly processed dietary ingredients 
includes extensive purification steps, especially toward the end of the 
manufacturing process, and that these steps remove contaminants that 
may have been introduced at earlier stages in the manufacturing 
process. These comments consider some stages of the dietary ingredient 
manufacturing process to not be subject to the same strict controls as 
those used for manufacturing finished dietary supplements.
    (Response) As discussed in section VI of this document (subpart A), 
the final rule applies to persons who manufacture, package, label, or 
hold dietary supplements and who are not subject to an exclusion in 
Sec.  111.1, and does not apply to establishments that only manufacture 
dietary ingredients. We addressed this comment in the response to 
comment 29.
    (Comment 84) Some comments assert that one or more proposed 
requirements are unconstitutionally vague under the Fifth Amendment and 
are arbitrary and capricious under section 706(2)(B) of the APA. The 
comments would delete the following proposed requirements:
    <bullet> Sec.  111.15(e), which would require plumbing to be ``of 
an adequate size and

[[Page 34813]]

design and be adequately installed and maintained;''
    <bullet> Sec.  111.15(g), which would require bathrooms to be 
``adequate'' and ``readily accessible; ''
    <bullet> Sec.  111.15(h), which would require hand-washing 
facilities ``to be adequate, convenient, and furnish running water at a 
suitable temperature;''
    <bullet> Sec.  111.15(h)(i), which would require hand-washing and, 
where appropriate, hand-sanitizing facilities ``at each location in 
your physical plant'' where good hygienic practices require employees 
to wash or to sanitize or both wash and sanitize their hands;
    <bullet> Sec.  111.20(a), which would require your physical plant 
to ``be suitable in size, construction, and design to facilitate 
maintenance, cleaning, and sanitizing operations;'' and
    <bullet> Sec.  111.20(d)(6), which would require aisles or working 
spaces between equipment and walls to be adequately unobstructed and of 
adequate width.
    In general, these comments assert the 2003 CGMP Proposal did not 
define terms or phrases (such as ``adequately'' or ``at each 
location'') in a way that persons who are subject to the rule can 
discern the meaning of the term or phrase. These comments argue that 
the proposed rule imposes no limitations on enforcement officers on the 
exercise of their discretion and, thus, invites exercise of unbridled 
discretion and disparate decisionmaking.
    (Response) As discussed in section V of this document, we disagree 
that the terms that the comments objected to in the 2003 CGMP Proposal 
are unconstitutionally vague, need to be defined, or may result in 
discriminatory enforcement. We are retaining the terms in the final 
rule.

D. What Sanitation Requirements Apply to Your Physical Plant and 
Grounds? (Final Sec.  111.15)

1. Final Sec.  111.15(a)
    The preamble to the 2003 CGMP Proposal (68 FR 12157 at 12184) 
stated that we were not proposing requirements similar to the food CGMP 
requirements found in Sec.  110.20(a) for keeping the grounds bordering 
your physical plant in a condition that protects against contamination 
of components or dietary supplements in order to limit the burden to 
manufacturers. However, we invited comment on whether we should include 
such requirements in a final rule. After considering the comments, we 
have drafted final Sec.  111.15(a) to require you to keep the grounds 
of your physical plant in a condition that protects against the 
contamination of components, dietary supplements, or contact surfaces. 
The methods for adequate ground maintenance include:
    <bullet> Properly storing equipment, removing litter and waste, and 
cutting weeds or grass within the immediate vicinity of the physical 
plant so that it does not attract pests, harbor pests, or provide pests 
a place for breeding;
    <bullet> Maintaining roads, yards, and parking lots so that they do 
not constitute a source of contamination in areas where components, 
dietary supplements, or contact surfaces are exposed;
    <bullet> Adequately draining areas that may contribute to the 
contamination of components, dietary supplements, or contact surfaces 
by seepage, filth or any other extraneous materials, or by providing a 
breeding place for pests;
    <bullet> Adequately operating systems for waste treatment and 
disposal so that they do not constitute a source of contamination in 
areas where components, dietary supplements, or contact surfaces are 
exposed; and
    <bullet> If your plant grounds are bordered by grounds not under 
your control, and if those other grounds are not maintained in the 
manner described in this section, you must exercise care in the plant 
by inspection, extermination, or other means to exclude pests, dirt, 
and filth or any other extraneous material that may be a source of 
contamination.
    (Comment 85) Several comments say the final rule should require the 
maintenance of external areas similar to the food CGMP requirement at 
Sec.  110.20(a) for keeping the grounds outside the facility adequately 
maintained. These comments state that such a requirement is basic, is 
equally important to facilities that manufacture conventional foods and 
to facilities that manufacture dietary supplements, and that there is 
no reason why this requirement should differ from food CGMPs. One 
comment asserts such a requirement is basic to the industry and it 
should not be dismissed as a burden to the industry. Some comments also 
assert that a provision similar to Sec.  110.20(a) would help train 
staff and would explain to plant maintenance personnel what is required 
and why.
    One comment says there should be some minimum requirement for 
sanitation and cleanliness in the area surrounding the plant and that 
requirements for drainage and trash removal should be adequate.
    (Response) We agree that a requirement to maintain grounds is 
equally important for facilities that manufacture conventional foods 
and for facilities that manufacture dietary supplements. Although some 
requirements in Sec.  110.20(a) are not strictly limited to drainage 
and trash disposal, the comment suggesting the requirements to maintain 
grounds be limited to drainage and trash disposal did not explain why, 
for example, it would not be as important for a facility that 
manufactures dietary supplements to maintain roads, yards, and parking 
lots so that they do not become a source of contamination as it already 
is for facilities that manufacture conventional foods. Therefore, the 
final rule is adding Sec.  111.15(a), which is similar to Sec.  
110.20(a) with editorial revisions consistent with the rest of this 
final rule.
2. Final Sec.  111.15(b)(1)
    Final Sec.  111.15(b)(1) (proposed Sec.  111.15(a)) requires you to 
maintain your physical plant in a clean and sanitary condition. Final 
Sec.  111.15(b)(2) requires you to maintain your physical plant in 
repair sufficient to prevent components, dietary supplements, or 
contact surfaces from becoming contaminated.
    We did not receive comments specific to proposed Sec.  111.15(a).
3. Final Sec.  111.15(c)
    Final Sec.  111.15(c) (proposed Sec.  111.15(b)) sets forth 
requirements for cleaning compounds, sanitizing agents, pesticides, and 
other toxic materials.
    Final Sec.  111.15(c) includes changes that we are making for 
clarity and consistency. We added other ``toxic'' materials because 
some paragraphs within final Sec.  111.15(c) simply refer to the 
cleaning compounds, sanitizing agents, and pesticides as ``toxic 
materials,'' and because proposed Sec.  111.15(b)(2) addressed the use 
and storage of toxic materials that are not within the general category 
of cleaning compounds, sanitizing agents, or pesticides.
    Final Sec.  111.15(c)(1) requires you to use cleaning compounds and 
sanitizing agents that are free from microorganisms of public health 
significance and that are safe and adequate under the conditions of 
use. Final Sec.  111.15(c)(1) is similar to proposed Sec.  
111.15(b)(1), except that we inserted ``that are'' before ``safe and 
adequate.'' We consider this to be a nonsubstantive, editorial change. 
Proposed Sec.  111.15(b)(1) was, itself, patterned after Sec.  
110.35(b)(1), which: (1) Requires cleaning compounds and sanitizing 
agents used in cleaning and sanitizing procedures to be free from 
undesirable microorganisms and safe and adequate under the conditions 
of use and (2) provides that compliance may be verified by any 
effective means including purchase of these substances

[[Page 34814]]

under a supplier's guarantee or certification or examination of these 
substances for contamination.
    (Comment 86) Several comments ask us to clarify our expectations 
with respect to substantiating that a cleaning compound or sanitizing 
agent is free from microorganisms of public health significance and is 
safe and adequate under conditions of use. Some comments suggest 
proposed Sec.  111.15(b)(1) provide for the use of certifications or 
guarantees from a supplier because our investigators otherwise may not 
recognize such documents as evidence of compliance. Several comments 
say it is not necessary for a manufacturer to test these types of 
products, and that a continuing product guarantee, combined with a 
statement of intended use from the manufacturer of the cleaning 
compound or sanitizing agent, should satisfy the requirements.
    (Response) When assessing compliance with final Sec.  111.15(c)(1), 
we would not treat a firm that manufactures, packages, labels, or holds 
a dietary supplement differently than we would treat a facility that 
manufactures, packages, labels, or holds conventional foods. Therefore, 
we intend to accept, as the comments request, a supplier's guarantee or 
certification that a cleaning compound or sanitizing agent is free from 
microorganisms of public health significance and is safe and adequate 
under the conditions of use for the purpose of determining compliance 
with final Sec.  111.15(c)(1).
    Final Sec.  111.15(c)(2) requires you to not use or hold toxic 
materials in a physical plant in which components, dietary supplements, 
or contact surfaces are manufactured or exposed, unless those materials 
are necessary: (1) To maintain clean and sanitary conditions, (2) for 
use in laboratory testing procedures, (3) for maintaining or operating 
the physical plant or equipment, or (4) for use in the plant's 
operations.
    We did not receive comments specific to proposed Sec.  
111.15(b)(2). We have made a nonsubstantive edit to Sec.  111.15(c)(2) 
by moving ``contact surfaces'' to be the last item on the list.
    Final Sec.  111.15(c)(3) requires you to identify and hold cleaning 
compounds, sanitizing agents, pesticides, pesticide chemicals, and 
other toxic materials in a manner that protects against contamination 
of components, dietary supplements, or contact surfaces. Final Sec.  
111.15(c)(3) is similar to proposed Sec.  111.15(b)(3).
    We did not receive comments specific to proposed Sec.  
111.15(b)(3), but replaced ``toxic cleaning compounds'' with ``cleaning 
compounds,'' and added ``other toxic materials.''
4. Final Sec.  111.15(d)
    Final Sec.  111.15(d) (proposed Sec.  111.15(c)) sets forth 
requirements for pest control. Section Sec.  111.15(d) is almost 
identical to proposed Sec.  111.15(c).
    Final Sec.  111.15(d)(1) requires you to not allow animals or pests 
in any area of your physical plant. Final Sec.  111.15(d)(1) allows 
guard or guide dogs in some areas of your physical plant if the 
presence of the dogs will not result in contamination of components, 
dietary supplements, or contact surfaces. Final Sec.  111.15(d)(2) 
requires that you take effective measures to exclude pests from your 
physical plant and to protect against the contamination of components, 
dietary supplements, and contact surfaces on the premises by pests. 
Final Sec.  111.15(d)(3) requires that you not use insecticides, 
fumigants, fungicides, or rodenticides unless you take precautions to 
protect against the contamination of your components, dietary 
supplements, or contact surfaces.
    (Comment 87) Several comments claim proposed Sec.  111.15(c) would 
require that sealed equipment outside of the plant (e.g. storage tanks, 
vessels, piping) be enclosed to prevent pests from roaming around these 
areas. The comments say there is no need to shelter outdoor equipment 
if it is properly sealed. These comments state that dietary supplements 
are sometimes manufactured in extensive, highly automated facilities in 
which large tanks and vessels are interconnected via piping, and that 
in these cases ``the physical plant'' and ``the equipment in the 
plant'' converge so that some or much of the equipment is effectively 
located outdoors. Thus, the comments ask us to revise proposed Sec.  
111.15(c) to clarify that it applies only to interior areas of the 
physical plant.
    (Response) Equipment such as that described by the comments, if 
properly sealed, should protect components, dietary supplements, and 
contact surfaces from contamination with pests. Final Sec.  111.15(d) 
does not require that sealed equipment outside of the plant, such as 
storage tanks, vessels, or piping, be enclosed, e.g., inside a 
building. Final Sec.  111.15(d)(2) requires that you take effective 
measures to exclude pests from your physical plant and to protect 
against the contamination of components, dietary supplements, or 
contact surfaces on the premises by pests. Moreover, final Sec.  
111.15(a) includes several requirements designed to limit or exclude 
pests around all parts of the exterior of your physical plant. 
Therefore, although you do not have to enclose your outside equipment, 
you must take measures to exclude pests from areas outside of the 
plant.
5. Final Sec.  111.15(e)
    Final Sec.  111.15(e) (proposed Sec.  111.15(d)) sets forth 
requirements for the water supply of your physical plant.
    Final Sec.  111.15(e)(1) requires that you must provide water that 
is safe and sanitary at suitable temperatures and under pressure as 
needed for all uses where water does not become a component of the 
dietary supplement.
    We did not receive comments specific to proposed Sec.  
111.15(d)(1). We have modified the phrase ``safe and of adequate 
sanitary quality'' to read ``safe and sanitary.'' To avoid confusion 
with the definition of ``quality'' we have adopted solely for purposes 
of this final rule, we deleted the references to ``quality'' as it 
applies to water standards. We consider this change to be 
nonsubstantive and still require water that is not a component of a 
dietary supplement to meet a safe and sanitary standard.
    Final Sec.  111.15(e)(2) requires that water used in a manner such 
that the water may become a component of the dietary supplement, e.g., 
when such water contacts components, dietary supplements, or any 
contact surface, must, at a minimum, comply with applicable Federal, 
State, and local requirements and not contaminate the dietary 
supplement. Final Sec.  111.15(e)(2) derives from proposed Sec.  
111.15(d)(2) which would require that water that contacts components, 
dietary supplements, or any contact surfaces must, at a minimum, comply 
with the applicable National Primary Drinking Water (NPDW) regulations 
and any State and local government requirements. Final Sec.  
111.15(e)(2) includes changes we are making after considering comments 
discussed in the following paragraphs.
    (Comment 88) Several comments state the water quality that is 
required for conventional foods is sufficient for dietary supplements. 
The comments argue that no additional water standards are listed in the 
CGMPs for low-acid canned foods in part 113 or in the CGMPs for 
acidified foods in part 114. These comments argue that, if ``safe and 
of adequate sanitary quality'' is sufficient to ensure the quality of 
the water used in most food products, then it is also adequate to 
ensure the quality of the water used in dietary supplements.
    Other comments would revise the final rule to allow different 
standards and requirements for water that contacts or is used in 
dietary supplements

[[Page 34815]]

compared to water that contacts components, including dietary 
ingredients. These comments state current food CGMP regulations require 
only that water supplies that contact food (defined to include 
ingredients and raw materials) be ``safe and of adequate sanitary 
quality.'' These comments say that this would be consistent with the 
act's basis for CGMP requirements for foods, i.e., that food is not 
prepared ``under unsanitary conditions whereby it may have become 
contaminated with filth, or whereby it may have been rendered injurious 
to health'' (section 402(a)(4) of the act). Several comments state the 
final rule should adopt a similar rationale for components, including 
dietary ingredients. These comments explain that components, including 
dietary ingredients, are not in a form in which they will be consumed 
and are subject to further processing prior to consumption.
    Several comments say that requiring water used for cleaning contact 
surfaces to meet Environmental Protection Agency regulations is an 
unnecessary burden for companies that do not have access to municipal 
water. According to these comments, potable water should be sufficient.
    (Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157 
at 12185), we stated that water should, at a minimum, be potable and 
that water that is ``safe and of adequate sanitary quality'' should be 
potable. We also said water that contacts components, dietary 
supplements, or contact surfaces should, at a minimum, meet the 
Environmental Protection Agency's NPDW regulations and State, and local 
requirements. We proposed to require that water used in operations 
where water contacts components, dietary supplements, or any contact 
surfaces meet the NPDW regulations because of the potential for 
contamination if water were used that did not adhere to the microbial 
standards, for example, in the NPDW regulations. Finally, we stated 
these requirements were minimum requirements and that water that is 
more pure than that required under the NPDW regulations may be desired.
    The comments stated some manufacturers may not have access to 
municipal water, and therefore, that meeting the NPDW regulations for 
cleaning contact surfaces would be too burdensome. These comments 
asserted that potable water would be sufficient. The comments do not 
provide a definition of ``potable water.'' We have defined ``potable 
water,'' in the regulations on interstate conveyance sanitation in 21 
CFR part 1250 to be, in part, water that meets the standards prescribed 
in the Environmental Protection Agency's NPDW regulations in 40 CFR 
part 141.
    We would consider it to be a rare situation where a dietary 
supplement manufacturer uses well water and has no access to municipal 
water. Nonetheless, to the extent that a manufacturer uses water that 
is not subject to Federal oversight, the manufacturer would have to 
comply with any State or local regulations that apply to food 
manufacturing facilities using such water in food processing.
    Manufacturers that use water from a municipal source, which is 
subject to the Environmental Protection Agency NPDW regulations, should 
not be subject to a lesser standard in this final rule than what is 
already required of them by the Environmental Protection Agency. Thus, 
to accommodate manufacturers subject to the Environmental Protection 
Agency's NPDW regulations for the water that they use in the 
manufacture of dietary supplements, as well as those dietary supplement 
manufacturers who are not subject to the Environmental Protection 
Agency's NPDW regulations, we are modifying the rule to state water 
that is used in a manner such that the water may become a component of 
the dietary supplement, e.g., when such water contacts components, 
dietary supplements, or any contact surface, must, at a minimum, comply 
with applicable Federal, State, and local requirements and not 
contaminate the dietary supplement. We decline to use ``safe and of 
adequate safety'' that some comments state is sufficient because it is 
for conventional foods. We believe that requiring that water comply 
with Federal, State and local requirements and not contaminate dietary 
supplements provides a clear standard as to what is required.
    (Comment 89) Some comments assert that water that is used to 
manufacture components or dietary ingredients where such components or 
dietary ingredients are subject to further processing prior to 
consumption, should be subject to the ``safe and of adequate sanitary 
quality'' standard in Sec.  110.37.
    (Response) We acknowledge that such components and dietary 
ingredients are subject to the requirement in Sec.  110.37. If the 
manufacturers do not fall within the scope of final Sec.  111.1, such 
manufacturers would be subject to the CGMP requirements in part 110.
    To the extent that such comments request the ``safe and of adequate 
sanitary quality'' language apply to water used in the manufacture of a 
dietary supplement, we decline to make that change. Water that is safe 
and sanitary would not necessarily comply with, for example, the NPDW 
regulations. A requirement stating ``safe and of adequate sanitary 
quality'' or, as stated in the final rule, the requirement of ``safe 
and sanitary'' could be seen as a lesser standard than water that 
complies with ``applicable Federal, State, and local requirements.'' We 
want to make clear that you must comply with applicable Federal, State, 
and local requirements related to the water that you use for food 
processing that would otherwise be required of you, and not to some 
lesser standard that you may consider is ``safe and sanitary'' when 
water is used in a manner such that the water may become a component of 
the dietary supplement, e.g., when such water contacts a component, 
dietary supplement, or any contact surface. Foreign manufacturers would 
need to comply with the water standard required in this final rule and 
achieve the same level of performance as is required of domestic 
manufacturers. The water used in domestic or foreign manufacturing must 
not contaminate the dietary supplement. To clarify that the water used, 
whether by a domestic or foreign manufacturer, must not be a source of 
contamination, we are adding the words ``and not contaminate the 
dietary supplement'' in final Sec.  111.15(e)(2). We also want to make 
it clear that water includes what is in the water, e.g., any of its 
contaminants in addition to H<INF>2</INF>O. For example, when we speak 
of drinking water, we do not just mean the H<INF>2</INF>O, we mean the 
iron, lead, sulfur, and any other contaminants contained in the water.
    (Comment 90) Several comments suggest water should meet some or all 
standards of the USP monograph for sterile, purified water and say that 
the standard in the USP monograph is a higher, and presumably safer, 
standard than the NPDW standard. The comments state the USP's water 
deionization and purification systems requirements are already common 
in the industry.
    (Response) We do not discourage firms from using water in dietary 
supplement manufacturing that meets USP standards, including deionized 
or purified water, but we do not require, as a CGMP, the use of USP 
standards. This final rule sets forth minimum requirements for persons 
who manufacture, package, label, or hold a dietary supplement. Thus, 
firms may use water that exceeds our minimum requirements.
    (Comment 91) The preamble to the 2003 CGMP Proposal recognized that 
foreign firms might not be subject to Environmental Protection Agency 
water

[[Page 34816]]

requirements or adhere to such requirements, but also stated that water 
quality is an important part of CGMP (68 FR 12157 at 12185). Thus, in 
the preamble to the 2003 CGMP Proposal, we invited comment on how we 
might ensure that foreign firms meet the same water quality 
requirements as domestic firms. Several comments respond to our request 
for comments specific to the applicability of the water standards to 
foreign firms. Several comments recommend we not distinguish between 
domestic and foreign firms with regard to water quality. The comments 
claim all firms must compete on a ``level playing field.'' These 
comments state water quality standards vary from country to country, 
and many countries do not have requirements that are comparable to 
those in the United States. The comments say foreign manufacturers 
should not be permitted to import products into the United States that 
do not meet the same safety standards as domestic goods.
    Other comments ask us to consider the water quality requirement to 
be met if the water complies with the NPDW standard or any equivalent 
water quality standard that is ensured by a foreign public agency.
    (Response) We agree that foreign firms should be required to meet 
the water safety and sanitary requirements required of domestic firms 
and achieve the same level of performance of domestic firms. As 
discussed in this section, foreign firms are required to meet all 
requirements and would need to comply with their own national or local 
water safety requirements and not contaminate the dietary supplement.
    (Comment 92) One comment would combine proposed Sec.  111.15(d)(1) 
and (d)(2) into a single paragraph. The comment says the two proposed 
paragraphs are redundant. Proposed Sec.  111.15(d)(1) would require 
that you provide water that is safe and of adequate sanitary quality, 
at suitable temperatures, and under pressure as needed, in all areas 
where water is necessary for: (1) Manufacturing dietary ingredients or 
dietary supplements; (2) making ice that comes in contact with 
components, dietary ingredients, dietary supplements, or contact 
surfaces; (3) cleaning any surface; and (4) employee bathrooms and 
hand-washing facilities. Proposed Sec.  111.15(d)(2) would require that 
water that contacts components, dietary ingredients, dietary 
supplements, or any contact surface must at a minimum comply with the 
NPDW regulations prescribed by the Environmental Protection Agency 
under 40 CFR part 141 and any State and local government requirements.
    (Response) We disagree that proposed Sec.  111.15(d)(1) and (d)(2) 
were redundant. For example, as described in the proposed sections, 
nonpotable water that would have been ``safe and of adequate sanitary 
quality'' for use in flushing toilets may not have been ``safe and of 
adequate sanitary quality'' for use in the manufacture of a liquid 
dietary supplement.
    Final Sec.  111.15(e)(1) requires that you provide water that is 
safe and sanitary, at suitable temperatures, and under pressure as 
needed, for all uses where water does not become a component of the 
dietary supplement. Final Sec.  111.15(e)(2) requires that water that 
is used in a manner such that the water may become a component of the 
dietary supplement, e.g., when such water contacts components, dietary 
supplements, or any contact surface, must, at a minimum, comply with 
applicable Federal, State, and local requirements and not contaminate 
the dietary supplement. As an example of how the requirements would 
apply, water that contains lead at a level that is 20 times higher than 
the maximum accepted level in the Environmental Protection Agency's 
NPDW standards for lead may not be safe for use in the manufacture of 
dietary supplement that is consumed in four 2-ounce portions per day, 
but may be safe for use in cleaning the floors of the physical plant. 
Therefore, to emphasize that water that is ``safe and sanitary'' may be 
different depending on its use, the final rule continues to separate 
Sec.  111.15(e)(1) and (e)(2) (formerly proposed Sec.  111.15(d)(1) and 
(d)(2)).
    Additionally, to emphasize the importance of the water that is used 
in the manufacture of a dietary supplement, where the water is used in 
a manner such that the water may become a component of the dietary 
supplement, final Sec.  111.23(c) (proposed Sec.  111.15(d)(3)) 
requires you to have documentation and keep records that such water 
meets the requirements of final Sec.  111.15(e)(2). In contrast, there 
is no corresponding requirement for documentation in final Sec.  111.23 
that other water, such as water that is used to clean floors or used in 
employee bathrooms, meets requirements of final Sec.  111.15(e)(1).
    (Comment 93) Several comments state, if we retain a water standard 
requirement based on the Environmental Protection Agency NPDW standard, 
then it is important to include provisions recognizing the 
acceptability of municipal water sources and the frequency of testing 
required for other water sources. Some comments recommend water should 
meet the USP standard for purified water and point out that the USP 
standard provides an assurance of the water's consistency and provides 
a system that can be monitored.
    Several comments suggest we include timetables for water testing or 
describe water testing frequency requirements. These comments state we 
should apply something analogous to the proposed requirements for 
infant formula which would require manufacturers to conduct the tests 
with sufficient frequency to ensure that the water meets the 
Environmental Protection Agency's NPDW standard, but not less 
frequently than annually for chemical contaminants, every 4 years for 
radiological contaminants, and weekly for bacteriological contaminants. 
Other comments refer to the amendments to the bottled water regulations 
at Sec.  165.110 which require a minimum yearly monitoring of source 
water and finished bottled water products for chemical contaminants for 
which allowable levels have been established in the bottled water 
quality standard.
    (Response) Final Sec.  111.23(c) requires you to have documentation 
that water, when used in a manner such that the water may become a 
component of the dietary supplement, e.g., when such water contacts a 
component, dietary supplement, or contact surface, meets the 
requirements of final Sec.  111.15(e)(2). You must meet the requirement 
for final Sec.  111.15(e)(2) at the point of use, rather than at the 
point of delivery, i.e., at the point the water may become a component 
of the dietary supplement, such as when the water contacts components, 
dietary supplements, or any contact surface (such as when the water 
comes out of the faucet or comes out of a spigot from a holding tank 
where you store water). Thus, you must ensure that the water used in a 
manner such that the water may become a component of the dietary 
supplement, not the water source before it enters your facility, meets 
the NPDW regulations, or if not subject to the NPDW regulations, that 
it meets any other applicable Federal, State, and local requirements 
and does not contaminate the dietary supplement.
    For example, if the water that enters your facility is subject to 
the Environmental Protection Agency NPDW regulations, then the water 
must comply with such requirements at the point of use, i.e., when it 
contacts the components, dietary supplement, or any contact surface 
(such as when the water comes out of the faucet or out of a spigot from 
a holding tank where you store water). You could rely on a certificate 
of analysis under final Sec.  111.75(a)(2)(ii)

[[Page 34817]]

from the supplier of the water (e.g., the municipality) to ensure that 
the water entering your facility complies the applicable Federal, 
State, and local requirements. However, you must ensure that nothing 
happens to the water that may contaminate the water once it enters your 
facility and before the water may become a component of the dietary 
supplement at the point of use. Certain contaminants or microorganisms 
may be introduced into the water from the facility. Thus, you may need 
to establish specifications and procedures to prevent contamination 
from pipes through which the water travels in the facility or from 
vessels in which the water is held in the facility prior to use. You 
may need to test for certain contaminants, e.g., lead or 
microorganisms, at point of use to ensure there is no contamination of 
the water within your facility. Such tests may not need to include all 
of the chemical, microbiological, or contaminant testing already 
certified by the supplier to determine whether the water entering your 
facility complies with Federal, State and local requirements. Rather, 
you would need to evaluate what, if any, introductions of contaminants 
are likely to occur within your facility and determine whether 
additional tests are needed to verify that the water, at point of use, 
will comply with Federal, State, and local requirements and not 
contaminate the dietary supplement. Alternatively, you may decide not 
to rely on a certificate of analysis and instead conduct your own 
testing at point of use to determine if the water complies with 
applicable Federal, State, and local requirements. We decline to set 
out testing requirements or frequency of testing in this final rule in 
lieu of giving manufacturers the flexibility to decide on the 
appropriate testing and frequency of such testing to ensure that the 
water meets the requirements in final Sec.  111.15(e)(2). We may 
consider issuing guidance, as needed, on our recommendation for testing 
based on water sources and the purposes for which the water is used. If 
you rely on a certificate of analysis from the supplier of the water, 
we recommend that you qualify your facility by conducting appropriate 
tests at the point of use to verify that no other tests are necessary 
or that any additional tests you have chosen are sufficient to 
establish that the water that is used in a manner such that the water 
may become a component of the dietary supplement, e.g., when such water 
contacts components, dietary supplements or any contact surface, meets 
the requirements of final Sec.  111.15(e)(2). We also recommend that 
you requalify your facility at the point of use at appropriate 
intervals.
    If you use water from a private source, you must use water that 
complies with any State and local requirement and does not contaminate 
the dietary supplement. You may need to perform appropriate water 
treatment procedures, including filtration, sedimentation, and 
chlorination to satisfy final Sec.  111.15(e)(2).
    (Comment 94) Several comments would delete proposed Sec.  
111.15(d)(2), arguing that it is unnecessary to state a requirement 
that water meet the Environmental Protection Agency's NPDW standards. 
These comments state that if water is used in processing or at critical 
points in the cleaning process, then a manufacturer will already have 
established specifications for its appropriate use.
    (Response) We agree that a manufacturer will need to establish 
specifications, under final Sec.  111.70(a), for any point, step, or 
stage in the manufacturing process where control is necessary to ensure 
the quality of the dietary supplement, and for water that is used in a 
manner such that the water may become a component of the dietary 
supplement. For reasons set forth in response to comment 88, final 
Sec.  111.15(e)(2) establishes the minimum standards for water that 
will be used in a manner such that the water may become a component the 
dietary supplement, e.g., when such water contacts components, dietary 
supplements, or any contact surface. Thus, we disagree that proposed 
Sec.  111.15(e)(2) be eliminated.
6. Final Sec.  111.15(f)
    Final Sec.  111.15(f) (proposed Sec. 111.15(e)) sets forth 
requirements for the plumbing of your physical plant.
    Final Sec.  111.15(f) requires your plumbing to be of an adequate 
size and design and be adequately installed and maintained to: (1) 
Carry sufficient amounts of water to required locations throughout the 
physical plant; (2) properly convey sewage and liquid disposable waste 
from your physical plant; (3) avoid being a source of contamination to 
components, dietary supplements, water supplies, or any contact 
surface, or creating an unsanitary condition; (4) provide adequate 
floor drainage in all areas where floors are subject to flooding-type 
cleaning or where normal operations release or discharge water or other 
liquid waste on the floor; and (5) not allow backflow from, or cross-
connection between, piping systems that discharge waste water or sewage 
and piping systems that carry water used for manufacturing dietary 
supplements, for cleaning contact surfaces, or for use in bathrooms and 
hand-washing facilities.
    We did not receive comments specific to proposed Sec.  111.15(e), 
other than comments arguing that certain text was unconstitutionally 
vague and arbitrary and capricious. We address those comments in 
section V of this document.
7. Final Sec.  111.15(g)
    Final Sec.  111.15(g) (proposed Sec.  111.15(f)) sets forth 
requirements for sewage disposal and requires you to dispose of sewage 
into an adequate sewage system or through other adequate means.
    We did not receive comments specific to proposed Sec.  111.15(f).
8. Final Sec.  111.15(h)
    Final Sec.  111.15(h) (proposed Sec.  111.15(g)(1)) sets forth 
requirements for the bathrooms of your physical plant. Final Sec.  
111.15(h) requires you to provide your employees with adequate, readily 
accessible bathrooms, and that the bathrooms be kept clean and not be a 
potential source of contamination to your components, dietary 
supplements, or contact surfaces.
    (Comment 95) Several comments state companies should be given 
flexibility in designing their bathrooms. These comments assert the 
food CGMP requirements allow flexibility in bathroom design, so the 
dietary supplement CGMP rule should do the same. The comments would 
delete proposed Sec.  111.15(g)(1) through (g)(3), which pertained to: 
(1) Keeping the bathrooms in good repair at all times; (2) providing 
self-closing doors; and (3) providing doors that do not open into areas 
where components, dietary ingredients, dietary supplements, or contact 
surfaces are exposed to airborne contamination, except where alternate 
means have been taken to protect against contamination.
    (Response) We agree that it is unnecessary to require specific 
bathroom features such as those in proposed Sec.  111.15(g)(1) through 
(g)(3) because you may be able to achieve compliance through other 
means better suited to your operations. Accordingly, we are revising 
the rule by deleting proposed Sec.  111.15(g)(1) through (g)(3) as 
requested by the comments. However, we continue to believe that 
mechanisms such as self-closing doors and doors that do not open onto 
areas where components, dietary supplements, or contact surfaces are 
exposed to

[[Page 34818]]

contamination will help protect against contamination.
9. Final Sec.  111.15(i)
    Final Sec.  111.15(i) (proposed Sec.  111.5(h)) sets forth 
requirements for the hand-washing facilities of your physical plant. 
Final Sec.  111.15(i) requires you to provide hand-washing facilities 
that are designed to ensure that an employee's hands are not a source 
of contamination of components, dietary supplements, or any contact 
surface, by providing facilities that are adequate, convenient, and 
furnish running water at a suitable temperature.
    Final Sec.  111.15(i) differs from the proposal in that the 
proposal would list six specific features of a hand-washing facility, 
such as effective hand-cleaning and sanitizing preparations (proposed 
Sec.  111.15(h)(2)), air driers, sanitary towel service, or other 
suitable drying devices (proposed Sec.  111.15(h)(3)), and trash bins 
that are constructed to protect against recontamination (proposed Sec.  
111.15(h)(4)).
    (Comment 96) Several comments state we should give firms the 
flexibility to design their hand-washing facilities. According to these 
comments, substituting the word ``may'' for the word ``must'' would 
accomplish this. The comments argue that, as with bathrooms, an overall 
sanitation requirement should be sufficient, and that, as long as there 
is a strong and enforceable standard, firms should have the flexibility 
to adopt only those measures that are needed to meet the underlying 
requirement.
    (Response) We agree that it is unnecessary to require specific 
hand-washing mechanisms because you may be able to achieve compliance 
through other means better suited to your operations. However, we 
disagree that an overall sanitation requirement would be sufficient, 
because such a requirement would not clearly state the purpose of the 
requirement, which is to ensure that an employee's hands are not a 
source of contamination of components, dietary supplements, or any 
contact surface.
    We are revising proposed Sec.  111.15(h) (final Sec.  111.15(i)) in 
the final rule in two respects. First, the final rule states that the 
hand-washing facilities are to be designed to ensure that an employee's 
hands are not a source of contamination. Second, final Sec.  111.15(i) 
states that the hand-washing facilities are to be adequate, convenient, 
and furnish running water at suitable temperatures but does not provide 
the specific hand-washing mechanisms detailed in the 2003 CGMP 
Proposal.
10. Final Sec.  111.15(j)
    Final Sec.  111.15(j) (proposed Sec.  111.15(i)) sets forth 
requirements for trash disposal at your physical plant. Final Sec.  
111.15(j) requires that you convey, store, and dispose of trash to: (1) 
Minimize the development of odors; (2) minimize the potential for trash 
to attract, harbor, or become a breeding place for pests; (3) protect 
against contamination of components, dietary supplements, any contact 
surface, water supplies, and grounds surrounding your physical plant; 
and (4) control hazardous waste to prevent contamination of components, 
dietary supplements, and contact surfaces.
    (Comment 97) One comment suggests deleting proposed Sec.  
111.15(i)(1) concerning minimizing the development of odors, because, 
the comment claimed, minimizing odors is not a ``true'' CGMP 
requirement.
    (Response) We disagree that minimizing the development of odors is 
not part of CGMP. Odor from trash is often an indication of problems 
with microbial contamination, such as decomposition, decay, and the 
growth of harmful bacteria. In addition, odor from trash can attract 
pests. By conveying, storing, and disposing of trash to minimize the 
development of odors, you will help reduce the potential for problems 
with microbial contamination and pests.
11. Final Sec.  111.15(k)
    Final Sec.  111.15(k) (proposed Sec.  111.15(j)) sets forth 
requirements for sanitation supervisors at your physical plant. Final 
Sec.  111.15(k) requires that you assign one or more employees to 
supervise overall sanitation. Each supervisor must be qualified by 
education, training, or experience to develop and supervise sanitation 
procedures. Final Sec.  111.15(k) differs from proposed Sec.  111.15(j) 
in that the proposal would require that each supervisor be qualified by 
training and experience.
    (Comment 98) Several comments suggest revising proposed Sec.  
111.15(j) to state that sanitation supervisors may be qualified by 
education, training, or experience (or any combination thereof) to 
develop and supervise sanitation procedures. In contrast, several 
comments say that sanitation supervisors should be qualified by both 
training and experience.
    (Response) Consistent with our response to comment 76 in section 
VII of this document, final Sec.  111.15(k) provides that sanitation 
supervisors, like other supervisors, must be qualified by education, 
training, or experience to develop and supervise sanitation procedures. 
As we also stated in response to comment 76, we acknowledge that some 
supervisory personnel may need a different range of education, 
training, or experience than others. However, we have decided to give 
firms the flexibility to decide the appropriate amount of education, 
training, or experience for a given job function. If that includes a 
combination of attributes, the firm should select and train employees 
accordingly.

E. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.16)

    We received many comments that recommend written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to comments 
on specific provisions in the same section.
    We are adding a new final Sec.  111.16 entitled ``What Are the 
Requirements Under This Subpart for Written Procedures?,'' to require 
you to establish and follow written procedures for fulfilling certain 
requirements of subpart C. You must establish and follow written 
procedures for cleaning the physical plant and for pest control.

F. What Design and Construction Requirements Apply to Your Physical 
Plant? (Final Sec.  111.20)

    Final Sec.  111.20 addresses physical plant design and construction 
requirements.
1. Final Sec.  111.20(a) and (b)
    Final Sec.  111.20(a) and (b) require that any physical plant that 
you use in the manufacturing, packaging, labeling, or holding of 
dietary supplements: (1) Be suitable in size, construction, and design 
to facilitate maintenance, cleaning, and sanitizing operations and (2) 
have adequate space for the orderly placement of equipment and holding 
of materials as is necessary for maintenance, cleaning, and sanitizing 
operations and to prevent contamination and mixups of components and 
dietary supplements during manufacturing, packaging, labeling, or 
holding.
    We did not receive comments specific to proposed Sec.  111.20(a) or 
(b), other than comments arguing that certain text in proposed Sec.  
111.20(b) was unconstitutionally vague and arbitrary and capricious. We 
address those comments in this section and section V of this document.

[[Page 34819]]

2. Final Sec.  111.20(c)
    Final Sec.  111.20(c) requires that any physical plant you use in 
the manufacturing, packaging, labeling, or holding of dietary 
supplements provide for the use of proper precautions to reduce the 
potential for mixups or contamination of components, dietary 
supplements, or contact surfaces, with microorganisms, chemicals, 
filth, or other extraneous material.
    Under final Sec.  111.20(c) your physical plant must have, and you 
must use, separate or defined areas of adequate size or other control 
systems, such as computerized inventory controls or automated systems 
of separation, to prevent contamination and mixups of components and 
dietary supplements during the following operations: (1) Receiving, 
identifying, holding, and withholding from use, components, dietary 
supplements, packaging, and labels that will be used in or during the 
manufacturing, packaging, labeling, or holding of dietary supplements; 
(2) separating, as necessary, components, dietary supplements, 
packaging, and labels that are to be used in manufacturing from 
components, dietary supplements, packaging, or labels that are awaiting 
material review and disposition decision, reprocessing, or are awaiting 
disposal after rejection; (3) separating the manufacturing, packaging, 
labeling, and holding of different product types including different 
types of dietary supplements and other foods, cosmetics, and 
pharmaceutical products; (4) performing laboratory analyses and holding 
laboratory supplies and samples; (5) cleaning and sanitizing contact 
surfaces; (6) packaging and label operations; and (7) holding 
components or dietary supplements.
    (Comment 99) Several comments would change ``computerized inventory 
controls'' to ``adequate inventory controls'' in proposed Sec.  
111.20(c). The comments say that a requirement to use a computerized 
system is too prescriptive and that inventory controls that are not 
computerized may be equally effective in achieving compliance with 
proposed Sec.  111.20(c).
    (Response) These comments may have misinterpreted proposed Sec.  
111.20(c). Computerized inventory controls are an example of the type 
of system that may be appropriate; Sec.  111.20(c) does not require you 
to have a computerized system in the first instance. Thus, final Sec.  
111.20(c) continues to use computerized inventory controls as an 
example of a central system.
    (Comment 100) Several comments ask us to clarify the degree of 
separation that is intended under proposed Sec.  111.20(c) when it 
referred to ``separate or defined areas'' of a physical plant. These 
comments state that it is unclear if we expect a firm not to 
manufacture multiple products in a single room or area. The comments 
state that, if this is the case, this would be equivalent to the drug 
CGMP requirements and would be excessive. The comments argue that, if 
the proper controls are in place, manufacturing and packaging of 
multiple products is possible in a single room or area without 
compromising product identity, quality, strength, purity, and 
composition.
    (Response) Final Sec.  111.20(c) states that you must have and use 
separate or defined areas of adequate size or other control systems, 
such as computerized inventory controls or automated systems of 
separation. The preamble of the 2003 CGMP Proposal explained that if 
your physical plant does not allow for physically separate areas, you 
could develop an alternative approach for segregating components and 
dietary supplements at points when they are received, stored, and 
rejected (68 FR 12157 at 12188). We interpret the comments as asking 
whether alternative approaches for segregating products could be used, 
even if physically separate areas were available in a facility, so that 
different materials could be processed in the same area. Final Sec.  
111.20(c) allows you to use ``separate or defined areas of adequate 
size or other control systems;'' thus, you can comply with this 
requirement by manufacturing multiple products in the same room or area 
instead of using a physically separate location, as long as you have 
systems in place to prevent contamination and mixups of components and 
dietary supplements.
3. Final Sec.  111.20(d)
    Final Sec.  111.20(d) requires that any physical plant you use in 
the manufacturing, packaging, labeling, or holding of dietary 
supplements be designed and constructed in a manner that prevents 
contamination of components, dietary supplements, or contact surfaces.
    Final Sec.  111.20(d)(1) requires the design and construction to 
include: (1) Floors, walls, and ceilings that can be adequately cleaned 
and kept clean and in good repair; (2) fixtures, ducts, and pipes that 
do not contaminate components, dietary supplements, or contact surfaces 
by dripping or other leakage or condensate; (3) adequate ventilation or 
environmental control equipment, such as air flow systems, including 
filters, fans, and other air-blowing equipment, that minimize odors and 
vapors (including steam and noxious fumes) in areas where they may 
contaminate components, dietary supplements, or contact surfaces; (4) 
equipment that controls temperature and humidity, when such equipment 
is necessary to ensure the quality of the dietary supplement; and (5) 
aisles or working spaces between equipment and walls that are 
adequately unobstructed and of adequate width to permit all persons to 
perform their duties and to protect against contamination of 
components, dietary supplements, or contact surfaces with clothing or 
personal contact.
    Final Sec.  111.20(d)(1)(i) through (d)(1)(v) is similar to 
proposed Sec.  111.20(d)(1), (d)(2), (d)(3), (d)(5), and (d)(6), 
respectively. Additionally, as explained in the following paragraphs, 
we have made other changes to proposed Sec.  111.20(d)(1) (final Sec.  
111.20(d)(1)(i)) and proposed Sec.  111.20(d)(5) (final Sec.  
111.20(d)(1)(iv)).
    (Comment 101) Several comments argue that the requirement of 
proposed Sec.  111.20(d)(1) that floors, walls, and ceilings be made of 
``smooth and hard surfaces,'' if read literally, could be interpreted 
to prohibit the use of ceilings with drop-in tiles. These comments 
assert that, while there may be areas in a manufacturing plant where 
drop-in ceilings are inappropriate given the height of the ceiling, the 
nature of the product, or the type of operation conducted in that area, 
such ceilings are adequate in many areas of a manufacturing facility, 
and certainly are appropriate in places where product is labeled or 
stored. The comments argue that replacing such ceilings with surfaces 
that are ``smooth and hard'' is unnecessary. Several other comments 
argue that they could find no precedent in any food CGMP regulations 
for a provision specifying ``smooth and hard surfaces'' for ceilings, 
but did identify a precedent in the section of drug CGMP requirements 
relating to ``aseptic processing.'' The comments state that adopting 
such a drug CGMP requirement is inappropriate for dietary supplements.
    The comments say the overall purpose of proposed Sec.  111.20(d)(1) 
should be to ensure that facilities can be kept in a clean and sanitary 
condition. The comments would revise proposed Sec.  111.20(d)(1) to 
require physical plants to have surfaces that can be adequately 
cleaned, but would give manufacturers the flexibility to use 
appropriate surfaces in different parts of a plant.
    The comments also argue that the rule's specificity establishes a 
conundrum for certain manufacturers to conform to other Federal 
regulations,

[[Page 34820]]

e.g., Occupational Safety and Health Administration (OSHA) noise 
levels. The comments argue that firms should be allowed to 
simultaneously conform to both OSHA and FDA requirements.
    (Response) We agree that a smooth and hard surface may not be 
necessary in every case to prevent contamination of the dietary 
supplement. However, you may need floors, walls, and ceilings that are 
constructed of smooth and hard surfaces to prevent contamination of the 
dietary supplement when, for example, physical attributes of components 
(e.g., particle size or electrostatic charge) would make it difficult 
to keep floors, walls, and ceilings clean. Consequently, we conclude 
that a requirement that the physical plant have floors, walls, and 
ceilings that can be adequately cleaned and kept clean and in good 
repair to prevent contamination of the dietary supplement is 
sufficient. We are revising final Sec.  111.20(d)(1) to remove the 
language concerning smooth and hard surfaces. The final rule gives you 
the flexibility to determine how best to construct your facility in 
order to prevent contamination and to ensure the quality of the dietary 
supplements you manufacture, package, label, or hold.
    Section 111.20(d)(1)(ii) of the final rule (proposed Sec.  
111.20(d)(2)) requires your physical plant design and construction to 
have fixtures, ducts, and pipes that do not contaminate components, 
dietary supplements, or contact surfaces by dripping or other leakage, 
or condensate. Final Sec.  111.20(d)(1)(iii) (proposed Sec.  
111.20(d)(3)) pertains to adequate ventilation or environmental control 
equipment. We added ``or other leakage'' to clarify that the 
requirement relates to ``leakage'' regardless of whether the leakage is 
in the form of ``dripping.''
    (Comment 102) Proposed Sec.  111.20(d)(5) would require your 
physical plant design and construction to include equipment that 
controls temperature and humidity. Several comments suggest adding a 
qualifier to the temperature and humidity control requirements so that 
controls are only required as necessary to prevent adulteration. The 
comments state there is adequate evidence that temperature and humidity 
do not stimulate reproduction of microorganisms and pests in dietary 
supplements. The comments also argue that retesting older ingredients 
stored in an uncontrolled environment and subjected to heat, cold, and 
ambient humidity produced no evidence of reproduction of 
microorganisms. According to the comments, temperature and humidity may 
present issues with raw, unprocessed botanical ingredients or animal-
derived ingredients, but there is no proven issue with the powdered 
botanical and animal derived ingredients used by the dietary supplement 
industry.
    Several comments argue against requiring temperature and heat 
controls, asserting that most equipment used to manufacture dietary 
supplements is often cleaned with large amounts of hot water, and 
therefore temperature and humidity controls are not practical.
    (Response) We agree that controls for temperature and humidity 
should only be required when necessary to ensure the quality of the 
dietary supplement, and we are revising final Sec.  111.20(d) 
accordingly. However, we disagree that there is adequate evidence that 
temperature and humidity do not stimulate reproduction of 
microorganisms in dietary supplements. It is well-recognized that 
microorganisms such as bacteria will grow in a warm environment and 
that microorganisms, such as molds, will grow in a moist environment. 
In addition, if the comments are suggesting that this final rule should 
only include requirements that derive from specific, already known 
examples that the absence of a requirement directly led to a problem 
with a dietary supplement, we disagree. CGMP requirements can help 
prevent products from becoming adulterated during the manufacturing 
process, and, in certain cases, controlling temperature and humidity 
may be necessary to ensure the quality of the dietary supplement.
    With respect to the comments stating that using hot water to clean 
equipment makes control of temperature and humidity impractical, we 
advise that a firm unable to control temperature and humidity in those 
parts of its facility where control is necessary to ensure the quality 
of the dietary supplement because it uses hot water to clean equipment 
would not be in compliance with final Sec.  111.20(c). The provision 
requires that your physical plant have, and that you use, separate and 
defined areas of adequate size, or other control systems, to prevent 
contamination during operations such as cleaning contact surfaces 
(final Sec.  111.20(c)(5)).
    Final Sec.  111.20(d)(2) (proposed Sec.  111.20(d)(4)) requires 
that, when fans and other air-blowing equipment are used, such fans and 
equipment be located and operated in a manner that minimizes the 
potential for microorganisms and particulate matter to contaminate 
components, dietary supplements, or contact surfaces.
    (Comment 103) Several comments interpret proposed Sec.  
111.20(d)(4) as requiring fans and air-blowing equipment. These 
comments state this type of equipment is not always needed and may, in 
some instances, be more likely to cause adulteration than prevent it. 
The comments ask us to clarify that fans and other air-blowing 
equipment are only required when they are necessary to prevent 
adulteration.
    (Response) Proposed Sec.  111.20(d)(4) was intended to require that 
any fans and other air-blowing equipment you use be located and 
operated in a manner that minimizes the potential for microorganisms 
and particulate matter to contaminate components, dietary supplements, 
or contact surfaces.
    Nevertheless, given the comments' misinterpretation, we are 
revising proposed Sec.  111.20(d)(4) (final Sec.  111.20(d)(2)) to 
state that, ``When fans and other air-blowing equipment are used,'' 
those fans and equipment must be located and operated in a manner that 
minimizes the potential for contamination by microorganisms and 
particulate matter. This should clarify that the rule does not mandate 
the use of fans and air-blowing equipment.
    (Comment 104) Some comments state that exhaust and venting 
equipment can, under certain circumstances, be a source of microbial 
contamination. The comments would revise proposed Sec.  111.20(d)(4) to 
read: ``Fans and other air-blowing or exhaust and venting equipment 
located and operated in a manner that minimizes the potential for 
microorganisms and particulate matter to contaminate components, 
dietary ingredients, dietary supplements, or contact surfaces.''
    (Response) We decline to revise the rule as suggested by these 
comments as there is no need to do so. We consider exhaust equipment 
and venting equipment to be types of fans or air-blowing equipment and 
therefore covered by the term ``fans and other air-blowing equipment.''
4. Final Sec.  111.20(e)
    Final Sec.  111.20(e) (proposed Sec.  111.20(e)) requires that any 
physical plant that you use in the manufacturing, packaging, labeling, 
or holding of dietary supplements provide adequate light in: (1) All 
areas where components or dietary supplements are examined, processed, 
or held; (2) all areas where contact surfaces are cleaned; and (3) 
hand-washing areas, dressing and locker rooms, and bathrooms.
    We did not receive any comments specific to proposed Sec.  
111.20(e).
5. Final Sec.  111.20(f)
    Final Sec.  111.20(f) (proposed Sec.  111.20(f)) requires that any 
physical

[[Page 34821]]

plant you use in the manufacturing, packaging, labeling, or holding of 
dietary supplements use safety-type light bulbs, fixtures, skylights, 
or other glass or glass-like materials when the light bulbs, fixtures, 
skylights, or other glass or glass-like materials are suspended over 
exposed components or dietary supplements in any step of preparation, 
unless your physical plant is otherwise constructed in a manner that 
will protect against contamination of components or dietary supplements 
in case of breakage of glass or glass-like materials.
    We did not receive any comments specific to proposed Sec.  
111.20(f). On our own initiative, we are making clarifying changes to 
final Sec.  111.20(f) by:
    <bullet> Adding ``or glass-like materials'' after the word 
``glass.'' Although proposed Sec.  111.20(f) only specified glass, its 
intent was to cover any material that could shatter and contaminate 
components, dietary supplements, or contact surfaces. Therefore, we are 
adding glass-like material to final Sec.  111.20(f) to cover fixtures 
and skylights that use non-glass materials (such as acrylic and 
polycarbonate materials) but could still contaminate components, 
dietary supplements, or contact surfaces if shattered or broken.
    Further, we are stating that the requirement applies when the light 
bulbs, fixtures, skylights, or other glass or glass-like materials are 
suspended over exposed components or dietary supplements in any step of 
preparation. We made this change to prevent the rule from being 
misinterpreted as requiring firms to suspend light bulbs, fixtures, 
skylights, or other glass over components or dietary supplements in 
every step of preparation.
6. Final Sec.  111.20(g)
    Final Sec.  111.20(g) (proposed Sec.  111.20(g)) requires that any 
physical plant you use in the manufacturing, packaging, labeling, or 
holding of dietary supplements provide effective protection against 
contamination of components and dietary supplements in bulk 
fermentation vessels. Such protection includes: (1) Use of protective 
coverings; (2) placement in areas where you can eliminate harborages 
for pests over and around the vessels; (3) placement in areas where you 
can check regularly for pests, pest infestation, filth or any other 
extraneous materials; and (4) use of skimming equipment.
    We did not receive comments specific to proposed Sec.  111.20(g). 
We have made nonsubstantive, grammatical changes to the provision by 
replacing ``by any effective means'' with ``effective'' before the word 
protection and ``including consideration of'' with ``by, for 
example:''.
7. Final Sec.  111.20(h)
    Final Sec.  111.20(h) (proposed Sec.  111.20(h)) requires that any 
physical plant you use in the manufacturing, packaging, labeling, or 
holding of dietary supplements use adequate screening or other 
protection against pests, where necessary.
    (Comment 105) One comment argues that proposed Sec.  111.20(h) 
should be deleted because it is redundant when compared to proposed 
Sec.  111.15(c) which would require you to not allow animals or pests 
in any area of your physical plant, except for guard or guide dogs in 
certain circumstances.
    (Response) We disagree that final Sec.  111.20(h) is redundant to 
proposed Sec.  111.15(c) (final Sec.  111.15(d)). Although both 
paragraphs deal with pests, final Sec.  111.20(h) establishes a design 
requirement (i.e., a specific requirement to use adequate screening or 
other protection), while final Sec.  111.15(d) sets forth a sanitation 
requirement (i.e., to not allow animals or pests in your physical 
plant). Therefore, we are retaining Sec.  111.20(h) in the final rule.

G. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.23)

    Final Sec.  111.23(a) requires you to make and keep records 
required under this subpart in accordance with subpart P.
    Final Sec.  111.23(b) requires that you make and keep records of 
the written procedures for cleaning the physical plant and for pest 
control. This provision was added to ensure that the written procedures 
now required under final Sec.  111.16 are maintained as required under 
subpart P.
    Final Sec.  111.23(c)(1) (proposed Sec.  111.15(d)(3)) requires 
that you make and keep records that water, when used in a manner such 
that the water may become a component of the dietary supplement, meets 
the requirements of final Sec.  111.15(e)(2).
    (Comment 106) Several comments state there is no documentation 
requirement for water in the food or drug CGMPs. The comments, 
therefore, say there should be not be such a requirement in this final 
rule for dietary supplements.
    (Response) To the extent that the comments assert we cannot include 
such a requirement for documentation in the dietary supplement CGMP 
because there is no corollary requirement in part 110, we have 
responded to this issue in section V of this document. The absence of a 
provision in drug CGMP requirements does not preclude us from requiring 
it in this final rule establishing CGMP requirements for dietary 
supplements for which we have no pre-approval scheme for ingredients 
used in such a product.
    (Comment 107) Several comments ask us to clarify that, if a 
municipal water supply is used in a facility, the municipal water 
report is acceptable documentation of water quality. These comments say 
that a city's yearly report of its municipal water quality should be 
sufficient documentation, and that independent testing should not be 
required. Several comments claim that our officials made statements to 
this effect during a public meeting held on May 6, 2003.
    The comments also assert that water quality in a community is 
typically well known due to public notification that is required by the 
Environmental Protection Agency or due to other resources. These 
comments say that municipal water supplies are also well controlled as 
a result of Environmental Protection Agency regulations, and that, if 
water quality in a community or country is suspect, we can move 
aggressively to enforce the standards. The comments argue that, 
overall, our enforcement burden would be less than requiring every 
company in the industry to maintain and produce documentation related 
to water quality.
    (Response) A yearly municipal report is a good starting point for 
documenting water meets the requirements of final Sec.  111.15(e), 
however, such a report cannot stand on its own as the only assurance 
that the water of the regulated body (such as persons subject to this 
final rule) complies with these regulations. A municipal water report 
offers reasonable assurance that the water entering your plant 
satisfies the requirements of the Environmental Protection Agency's 
NPDW regulations. However, as discussed previously, the requirement to 
show that the water that is used in a manner such that the water may 
become a component of the dietary supplement, e.g., when such water 
contacts components, dietary supplements, or any contact surface, meets 
the requirements of Sec.  111.15(e)(2), applies to water at the point 
of use, i.e., after it has passed through your plumbing system.
    If you use a municipal water supply, you should take steps to 
ensure that you are at all times aware of problems, such as an acute 
problem with microbial contamination or a long-term problem associated 
with lead pipes that are present in some parts of the city water

[[Page 34822]]

supply, that may not be reflected in the municipal water report.

IX. Comments on Requirements Related to Equipment and Utensils (Subpart 
D)

A. Organization of Final Subpart D

    Proposed subpart D contained two provisions regarding equipment, 
utensils, and automatic, mechanical, or electronic equipment. Table 5 
of this document lists the sections in the final rule and identifies 
the corresponding sections in the 2003 CGMP Proposal that form the 
basis of the final rule.

              Table 5.--Derivation of Sections in Subpart D
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.25 What are the requirements    Sec.   111.25(c)(1)
 under this subpart D for written          Sec.   111.25(e)(1)
 procedures?
------------------------------------------------------------------------
Sec.   111.27 What requirements apply to   Sec.   111.25(a), (b), (d),
 the equipment and utensils that you use?   and (e)
------------------------------------------------------------------------
Sec.   111.30 What requirements apply to   Sec.   111.30
 automated, mechanical, or electronic
 equipment?
------------------------------------------------------------------------
Sec.   111.35 Under this subpart D, what   Sec.  Sec.   111.25(c)(1),
 records must you make and keep?            (c)(2), (d), and (f),
                                           Sec.   111.30(b)(2), (b)(5),
                                            and (c)
                                           Sec.   111.50(c)(4)
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Equipment and 
Utensils

1. Revisions
    The final rule includes revisions that reflect the final rule 
applies to persons who manufacture, package, label, or hold dietary 
supplements unless subject to an exclusion in Sec.  111.1.
2. Revisions Associated With the Reorganization
    The revisions associated with the reorganization include:
    <bullet> Renumbering proposed Sec.  111.25 as final Sec.  111.27 
and correcting the numbering of the sections misnumbered in the 2003 
CGMP Proposal;
    <bullet> Requiring documentation and backup files in a separate 
section for recordkeeping requirements; and
    <bullet> A nonsubstantive editorial change to refer to ``automated 
equipment'' rather than ``automatic equipment.'' Although there is no 
practical difference between these two terms, the term ``automated'' is 
the customary term.
3. Changes After Considering Comments
    The final rule:
    <bullet> Requires you to establish and follow written procedures to 
fulfill the requirements of subpart D, including written procedures 
for:
    [cir] Calibrating instruments and controls;
    [cir] Calibrating, inspecting, and checking automated, mechanical, 
and electronic equipment; and
    [cir] Maintaining, cleaning, and sanitizing, as necessary, 
equipment, utensils, and other contact surfaces;
    <bullet> Requires you to keep records of the maintenance, cleaning, 
and sanitizing of equipment either in equipment logs or in batch 
records;
    <bullet> Requires that quality control personnel periodically 
review records of calibrations, inspections, or checks of automated, 
mechanical, or electronic equipment rather than approve such records 
when they are made;
    <bullet> Specifies that software for a computer controlled process 
is included under automated, mechanical, or electronic equipment; and
    <bullet> Clarifies that the requirement to retain backup files of 
software programs and of data entered into computer systems is for 
computer systems that you use in the manufacture, packaging, labeling, 
or holding of dietary supplements.

C. General Comments on Proposed Subpart D

    (Comment 108) Some comments claim one or more proposed requirements 
are unconstitutionally vague under the Fifth Amendment and arbitrary 
and capricious under Sec.  706(2)(B) of the APA. These proposed 
requirements include:
    <bullet> Sec.  111.25(a)(1), which would require that equipment and 
utensils be ``of appropriate design, construction, and workmanship to 
enable them to be suitable for their intended use and to be adequately 
cleaned and properly maintained''; and
    <bullet> Sec.  111.25(a)(2), which would require you to ``use 
equipment and utensils of appropriate design and construction so that 
use will not result in the contamination of components, dietary 
ingredients, or dietary supplements.''
    In general, these comments assert the proposed sections did not 
define terms or phrases (such as ``suitable'' or ``appropriate 
design'') in a way that persons who are subject to the rule can discern 
the meaning of the term. These comments also assert the proposed 
sections do not limit enforcement officers' exercise of their 
discretion as to what will satisfy the requirements and, thus, invite 
exercise of unbridled discretion and disparate decisionmaking.
    (Response) As discussed in section V of this document, we disagree 
that the terms are unconstitutionally vague, need to be defined, may 
result in discriminatory enforcement, or violate the APA. There has 
been sufficient usage of these terms in the food industry to enable 
manufacturers, and those who enforce the requirements, to comprehend 
and apply such terms. Agencies are permitted to use qualifying terms to 
enable them to address a wide variety of conditions at companies.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.25)

    We received many comments that recommend written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to comments 
on specific provisions in the same section. We are adding final Sec.  
111.25 that requires you to establish and follow written procedures for 
certain requirements.

E. What Requirements Apply to the Equipment and Utensils That You Use? 
(Final Sec.  111.27)

    Final Sec.  111.27 (proposed Sec.  111.25) sets forth various 
requirements for equipment and utensils.
1. Final Sec.  111.27(a)
    a. Final Sec.  111.27(a). Final Sec.  111.27(a) (proposed Sec.  
111.25(a)(1)) requires you to use equipment and utensils that are of 
appropriate design, construction, and workmanship to enable them to be 
suitable for their intended use and to be adequately cleaned and 
properly maintained. In order to correct the misnumbering of this 
provision in the 2003 CGMP Proposal, this general requirement has been 
broken out from the remaining requirements of final Sec.  111.27(a).
    Final Sec.  111.27(a)(1)(i) through (a)(1)(v) provide examples of 
such equipment, such as equipment used to hold or convey (Sec.  
111.27(a)(1)(i)), equipment using compressed air or gas (Sec.  
111.27(a)(1)(iii)), and equipment used in automated, mechanical, or 
electronic systems (Sec.  111.27(a)(1)(v)).
    Final Sec.  111.27(a)(1) is similar to proposed Sec.  111.25(a)(1) 
except for two, nonsubstantive editorial changes. The first change 
replaces ``automatic equipment'' with ``automated equipment'' in what 
is now Sec.  111.27(a)(1)(v) (proposed Sec.  111.25(a)(1)(5)). Although 
there is no practical difference between

[[Page 34823]]

``automatic'' and ``automated,'' the latter is the customary term.
    (Comment 109) Some comments argue that the proposal's use of terms 
such as ``appropriate design, construction, and workmanship to enable 
them to be suitable for their intended use'' and ``adequately cleaned 
and properly maintained'' are unconstitutionally vague under the Fifth 
Amendment and arbitrary and capricious under the APA.
    (Response) We discuss those comments generally in section V of this 
document and, because we disagree that the final rule violates either 
the Fifth Amendment of the Constitution or the APA, we have not revised 
Sec.  111.27(a)(1) except for the changes mentioned in the previous 
paragraphs.
    b. Final Sec.  111.27(a)(2). Final Sec.  111.27(a)(2) (proposed 
Sec.  111.25(a)(2)) requires you to use equipment and utensils of 
appropriate design and construction so that use will not result in the 
contamination of components or dietary supplements with: (1) 
Lubricants, (2) fuel, (3) coolants, (4) metal or glass fragments, (5) 
filth or any other extraneous material, (6) contaminated water, or (7) 
any other contaminants.
    (Comment 110) Several comments state we should recognize that 
lubricants are an integral part of the encapsulation of gelatin-enrobed 
products and other dosage forms. These comments state lubricants are 
not potential contaminants, and in fact, help move gelatin ribbons 
through encapsulating machines. The comments would revise proposed 
Sec.  111.25(a)(2) to read, ``lubricants not intended for product 
contact,'' to clarify the rule's intent.
    (Response) We decline to revise the final rule as suggested by the 
comments. Final Sec.  111.27(a)(2) states that the use of equipment and 
utensils must not result in the contamination of components or dietary 
supplements with lubricants. If a lubricant used for encapsulation does 
not result in contamination of the components or dietary supplements 
then the encapsulating machine complies with final Sec.  111.27(a)(2).
    c. Final Sec.  111.27(a)(3). Final Sec.  111.27(a)(3) (proposed 
Sec.  111.25(a)(3)) requires all equipment and utensils you use to be: 
(1) Installed and maintained to facilitate cleaning the equipment, 
utensils, and all adjacent spaces; (2) corrosion-resistant if the 
equipment or utensils contact components or dietary supplements; (3) 
made of nontoxic materials; (4) designed and constructed to withstand 
the environment in which they are used, the action of components or 
dietary supplements, and, if applicable, cleaning compounds and 
sanitizing agents; and (5) maintained to protect components and dietary 
supplements from being contaminated by any source.
    We did not receive comments specific to proposed Sec.  
111.25(a)(3). We have substituted the phrase ``in which they are used'' 
for ``of their intended use'' to make clear the requirement applies to 
equipment actually used in the manufacture, packaging, labeling, or 
holding of dietary supplements.
    d. Final Sec.  111.27(a)(4). Final Sec.  111.27(a)(4) (proposed 
Sec.  111.25(a)(4)) requires that the equipment and utensils you use 
have seams that are smoothly bonded or maintained to minimize 
accumulation of dirt, filth, organic material, particles of components 
or dietary supplements, or any other extraneous materials or 
contaminants. Final Sec.  111.27(a)(4) is similar to proposed Sec.  
111.25(a)(4) and is analogous to Sec.  110.40(b) which requires that 
seams on food-contact surfaces be smoothly bonded or maintained so as 
to minimize accumulation of food particles, dirt, and organic matter 
and thus minimize the opportunity for growth of microorganisms. We have 
deleted the phrase ``to minimize the opportunity for growth of 
microorganisms'' as unnecessary in this context as the remaining 
wording of the provision encompasses this concept. In nonsubstantive 
editorial changes to final Sec.  111.27(a)(4) we substitute ``particles 
of components or dietary supplements'' for ``component or dietary 
supplement particles'' to improve clarity, and re-order the list of 
extraneous materials or contaminants.
    (Comment 111) Several comments argue that proposed Sec.  
111.25(a)(4) is overly restrictive by requiring equipment and utensils 
to ``have seams that are smoothly bonded or maintained'' to minimize 
contamination. The comments would revise the rule as follows: 
``Equipment and utensils you use must be of proper design and 
maintained to minimize accumulation * * *.''
    (Response) We disagree that proposed Sec.  111.25(a)(4) (final 
Sec.  111.27(a)(4)) is overly restrictive or that it requires a 
particular design. Final Sec.  111.27(a)(4) requires seams that are 
smoothly bonded or maintained to minimize accumulation of dirt and 
gives firms the flexibility to use any design they choose, provided 
that the seams, by design or maintenance, minimize accumulation of 
contaminants.
    e. Final Sec.  111.27(a)(5). Final Sec.  111.27(a)(5) (proposed 
Sec.  111.27(a)(5)) requires that each freezer, refrigerator, and other 
cold storage compartment you use to hold components or dietary 
supplements: (1) Be fitted with an indicating thermometer, temperature-
measuring device, or temperature-recording device that indicates, and 
records, or allows for recording by hand, the temperature accurately 
within the compartment and (2) have an automated device for regulating 
temperature or an automated alarm system to indicate a significant 
temperature change in a manual operation.
    (Comment 112) The preamble to the 2003 CGMP Proposal invited 
comment as to whether we should require specific target temperatures 
for dietary ingredients or dietary supplements held in freezers or cold 
storage (68 FR 12157 at 12190). Several comments assert there is no 
need for us to specify storage temperatures for dietary ingredients or 
dietary supplements. The comments state most dietary supplements and 
dietary ingredients are shelf stable based on their low water activity 
control, which limits and slows chemical degradation and 
microbiological growth. Other comments say target temperatures are not 
required where freezing is used only to enhance the milling properties 
(fracturing) of dried botanicals and not to prevent microbial 
contamination.
    (Response) We have not included any specific target temperature 
requirements in the final rule. Consequently, firms should determine 
for themselves what temperatures are needed to ensure that the their 
dietary supplements are not adulterated (see final Sec.  111.70 
regarding the specifications you must establish).
    f. Final Sec.  111.27(a)(6). Final Sec.  111.27(a)(6) (proposed 
Sec.  111.25(a)(6)) requires the instruments or controls you use in the 
manufacturing, packaging, labeling, or holding of a dietary supplement, 
and instruments or controls that you use to measure, regulate, or 
record temperatures, pH, a<INF>w</INF>, or other conditions, to control 
or prevent the growth of microorganisms or other contamination, be 
accurate and precise, adequately maintained, and adequate in number for 
their designated uses.
    (Comment 113) One comment states that proposed Sec.  
111.25(a)(6)(i)'s requirements that instruments and controls be 
``accurate and precise'' goes beyond ``typical'' calibration, and would 
require full validation of all instruments and controls. The comment 
argues that it is unnecessary to require both accuracy and precision 
for all instruments and controls, and would require precision only when 
necessary to prevent contamination. The comment states calibration to 
ensure accuracy of instruments and controls is usually sufficient to 
ensure control or prevention of the growth of

[[Page 34824]]

microorganisms or other contaminants in most situations. The comment 
gives an example where thermometers are used to monitor temperature in 
a warehouse where dietary supplements are stored.
    (Response) We disagree that proposed Sec.  111.27(a)(6) requires 
full validation of all equipment and controls. As discussed in the 
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12190), accuracy 
means that the recorded measurements are equal to the (true value) of 
the thing being measured and precision means that individual 
measurements should be close to each other when made under the same 
conditions.
    We also disagree that instruments need not be precise. An 
instrument that gives widely varying readings from one use to the next 
cannot ensure product quality over time. The degree of accuracy and 
precision is determined by the nature of the instrument or control and 
the process to which it relates. We have, however, made several 
nonsubstantive, editorial changes to Sec.  111.27(a)(6) as well as 
other edits to conform to changes made throughout the final rule. These 
are the nonsubstantive editorial changes:
    <bullet> Inserting a hyphen between ``hydrogen'' and ``ion'' and
    <bullet> Revising the end of the paragraph so that it discusses 
``instruments and controls that you use * * * to control or prevent the 
growth of microorganisms or other contamination * * *.'' The proposal 
stated ``instruments and controls that you use * * * that control or 
prevent the growth of microorganisms or other contamination * * *''. 
(In other words, the final rule replaces ``that'' with ``to''.)
    g. Final Sec.  111.27(a)(7). Final Sec.  111.27(a)(7) (proposed 
Sec.  111.25(a)(7)) requires that the compressed air or other gases you 
introduce mechanically into or onto a component, dietary supplement, or 
contact surface or you use to clean any contact surface be treated in 
such a way that the component, dietary supplement, or contact surface 
is not contaminated.
    We received no comments specific to proposed Sec.  111.25(a)(7).
2. Final Sec.  111.27(b)
    Final Sec.  111.27(b) (proposed Sec.  111.25(b)(1)) requires you to 
calibrate instruments and controls that you use in manufacturing or 
testing a component or dietary supplement. In order to correct the 
misnumbering of this provision in the 2003 CGMP Proposal, this general 
requirement has been broken out from the remaining requirements of 
final Sec.  111.27(b) and now has paragraphs (b) and (b)(1) through 
(b)(3).
    Final Sec.  111.27(b)(1) through (b)(3) (proposed Sec.  
111.25(b)(1) and (b)(2)) requires you to calibrate before first use, 
and at the frequency specified in writing by the manufacturer of the 
instrument or control, or at routine intervals, or as otherwise 
necessary to ensure the accuracy and precision of the instrument and 
control.
    (Comment 114) Several comments object to the level of detail 
regarding the proposed calibration. Specifically, the comments object 
to requiring that manufacturers calibrate instruments and controls ``as 
specified in writing by the manufacturer of the instrument and 
control.'' The comments say this requirement is more prescriptive than 
drug CGMP requirements. The comments acknowledge that following 
manufacturer specifications is likely to be part of the calibration 
procedure, but state that firms should have the flexibility to modify 
their procedures as necessary. These comments would couple proposed 
Sec.  111.25(b) with a requirement to establish and follow written 
procedures for calibrating instruments and controls and redraft 
proposed Sec.  111.25(b) to mirror the drug CGMP requirements, using 
language such as ``You must routinely calibrate instruments and 
controls that control or monitor critical parameters that you use in 
manufacturing or testing a component or dietary supplement.''
    (Response) We disagree that proposed Sec.  111.25(b) is overly 
prescriptive, exceeds drug CGMP requirements, or requires what is 
claimed by the comments. We discuss, generally, the issue of whether 
this final rule ``exceeds drug CGMPs'' in section V of this document. 
It is standard practice to calibrate an instrument before using it for 
the first time. A requirement that you calibrate as specified by the 
manufacturer of the equipment, or at routine intervals, or as otherwise 
necessary to ensure the accuracy and precision of the instrument and 
control, provides ample flexibility. Calibration, whether for 
instruments and controls used in manufacturing or testing drugs, 
devices, conventional foods, or dietary supplements, helps ensure the 
accuracy and precision of the instrument and control. We do not 
prescribe how frequently such calibration must be done, but it must be 
done often enough to ensure that instruments and controls are operating 
within the correct parameters. We are revising the 2003 CGMP Proposal 
(at Sec.  111.27(b)(2)) to clarify that the requirement relates to the 
frequency of calibration.
    (Comment 115) Several comments claim requirements relating to 
calibration of instruments and controls should be limited to those 
instruments and controls that directly affect the identity, purity, 
quality, strength, and composition of a dietary supplement. According 
to the comments, in most manufacturing facilities, there are many 
instruments and controls that do not directly affect identity, purity, 
quality, strength, and composition, and that calibrating all 
instruments and controls could easily become unduly burdensome. The 
comments also would limit the requirement for periodic calibration of 
instruments and controls to those instruments and controls directly 
involved in the critical control parameters of the process, i.e., those 
parameters needed to meet specifications or to ensure identity, purity, 
quality, strength, and composition. The comments suggest that critical 
control parameters would have to be established.
    (Response) We decline to revise the rule as suggested by the 
comments. The requirement to calibrate instruments and controls is 
limited to those instruments and controls that you use in testing a 
component or dietary supplement or in manufacturing a dietary 
supplement. Any such equipment has the potential to affect, directly or 
indirectly, the quality of the dietary supplement.
    (Comment 116) Some comments would revise proposed Sec.  
111.25(b)(1) to state that ``calibration should be done, where 
standards are available or where it is necessary to meet product 
specifications.''
    (Response) We decline to revise the rule as suggested by the 
comments. It would be customary for an equipment manufacturer to have 
standards that can be used to calibrate the equipment, irrespective of 
the specific composition of the dietary supplement that is manufactured 
using that equipment. Equipment that is not or cannot be calibrated is 
unlikely to be in compliance with the requirement of final Sec.  
111.27(a)(6)(i) which requires instruments used in the manufacturing, 
packaging, labeling, and holding of dietary supplements, and 
instruments and controls that you use to perform certain operations, be 
accurate and precise.
    (Comment 117) Some comments would revise proposed Sec.  111.25 from 
the active voice to the passive voice. These comments claim that the 
active voice--i.e., requiring that ``you'' calibrate instruments and 
controls--requires that the dietary supplement manufacturer perform the 
calibration,

[[Page 34825]]

when in fact such calibrations are often performed by an outside 
service.
    (Response) You may use an outside service. We would not consider 
that calibration done for you by an outside service is any different 
than calibration done by your employees, and it is you (rather than an 
outside service) whom we will hold responsible to ensure that the 
calibration is performed. Accordingly, we decline to revise the 
provisions as suggested.
    (Comment 118) Several comments say calibration before first use 
should not be required for certified, precalibrated instrumentation. 
The comments state precalibrated instrumentation is much more expensive 
than noncalibrated instrumentation, with the additional expense 
attributed to the precalibration. Several comments would revise 
proposed Sec.  111.25(b)(2) to read, ``you must calibrate, or be able 
to verify that the calibration has been completed, before first use,'' 
instead of ``you must calibrate before first use.'' The comments state 
that performance test results could be made available for this 
verification.
    (Response) As written, the requirement that equipment be calibrated 
before first use includes calibration performed by a third party as a 
precalibration because we would consider that calibration performed by 
a third party as no different from calibration performed by one of your 
own employees. Under final Sec.  111.35(b)(3) you must have 
documentation of the calibration.
    If you purchase a precalibrated instrument, we strongly recommend 
that the vendor conduct the certification onsite after installation. If 
not, we strongly recommend that you verify that the instrument remains 
calibrated after it has been installed.
    (Comment 119) Several comments ask whether the proposed requirement 
to calibrate ``before first use'' refers to the first use after 
installation or the first use after each start-up.
    (Response) Final Sec.  111.27(b)(1) refers to the first use after 
installation and does not require calibration after each start-up.
    (Comment 120) Some comments would require that instruments and 
controls be calibrated, but argue that the final rule should not 
include detailed procedures specifying calibration methods. The 
comments said the rule should stay focused on end results and not 
process.
    (Response) We disagree that the regulations should not focus on 
process. The essence of the CGMP requirements established by these 
regulations is a production and process control system, i.e., a 
process, that is designed to ensure the quality of the dietary 
supplement. The final rule gives firms the flexibility to use different 
calibration methods as long as the method used is established in a 
written procedure.
3. Final Sec.  111.27(c)
    Final Sec.  111.27(c) (proposed Sec.  111.25(d)) requires that you 
repair or replace instruments or controls that cannot be adjusted to 
agree with the reference standard.
    We received no comments specific to proposed Sec.  111.25(d).
4. Final Sec.  111.27(d)
    Final Sec.  111.27(d) (proposed Sec.  111.25(e)) requires you to 
maintain, clean, and sanitize, as necessary, all equipment, utensils, 
and any other contact surfaces used to manufacture, package, label, or 
hold components or dietary supplements. In order to correct the 
misnumbering of this provision in the 2003 CGMP Proposal, this general 
requirement has been broken out from the remaining requirements of 
final Sec.  111.27(d) and now has paragraphs (d) and (d)(1) through 
(d)(7).
    a. Final Sec.  111.27(d)(1). Final Sec.  111.27(d)(1) requires that 
the equipment and utensils be taken apart as necessary for thorough 
maintenance, cleaning, and sanitizing.
    (Comment 121) Some comments argue that individual manufacturing 
operations will determine when sanitizing agents are needed after 
cleaning because of the wide variety of processes in the industry. The 
comments also say widespread use of sanitizing agents is creating 
resistant microbial strains, and incorporating unnecessary sanitization 
processes would contribute to this health concern.
    Some comments recommend manufacturers calibrate sanitizing 
procedures to the particular process in a declared fashion depending 
upon the risk factors of their process and materials. The comments set 
out several standards for sanitation procedures.
    (Response) Final Sec.  111.27(d) requires you to maintain, clean, 
and sanitize, as necessary, equipment, utensils, and any other contact 
surfaces, used to manufacture, package, label, or hold dietary 
supplements. The final rule thus gives you discretion to decide when 
sanitizers or sanitizing treatments, such as heat, are necessary and 
does not mandate the incorporation of unnecessary sanitization 
processes.
    Additionally, under final Sec.  111.27(d) you have flexibility to 
determine when sanitizing is appropriate and to sanitize only as 
necessary. We note that this flexibility was also present in proposed 
Sec.  111.25(e)(1). Some comments suggested calibrating sanitation 
operations based on risk. The final rule largely leaves it up to firms 
to decide whether to sanitize or to just clean without sanitizing, 
based on the risks associated with the materials and process used. 
However, under final Sec.  111.27(d)(3), if you use wet processing, if 
you determine that it is necessary to clean a contact surface, you must 
also sanitize that surface.
    (Comment 122) Several comments state the final rule should include 
a requirement for validating cleaning procedures. The comments argue 
that testing requirements for finished dietary supplements might not 
test for certain contaminants that could arise as a result of cleaning. 
One comment asserts these potential contaminants would be discovered in 
a properly designed and executed cleaning validation protocol, and that 
including these written cleaning procedures in the final rule would 
help prevent adulteration and help ensure the identity, purity, 
quality, strength, and composition of dietary supplements.
    (Response) We decline to require specific cleaning validation 
procedures in the final rule. Final Sec.  111.27(d) and the 
requirements for written procedures under final Sec.  111.25(c) are 
sufficient to ensure the use of cleaning procedures to ensure the 
quality of the dietary supplement.
    b. Final Sec.  111.27(d)(2). Final Sec.  111.27(d)(2) (proposed 
Sec.  111.25(e)(2)) requires you to ensure that all contact surfaces, 
used for manufacturing or holding low-moisture components or dietary 
supplements, are in a dry and sanitary condition when in use. When the 
surfaces are wet-cleaned, you must sanitize them, when necessary, and 
allow them to dry thoroughly before you use them again.
    We received no comments specific to proposed Sec.  111.25(e)(2). We 
have substituted the phrase ``when in use'' for ``at the time of use'' 
for clarity.
    c. Final Sec.  111.27(d)(3). Final Sec.  111.27(d)(3) (proposed 
Sec.  111.25(e)(3)) requires you, if you use wet processing during 
manufacturing, to clean and sanitize all contact surfaces, as 
necessary, to protect against the introduction of microorganisms into 
components or dietary supplements. Final Sec.  111.27(d)(3) also 
requires that:
    <bullet> When cleaning and sanitizing is necessary, you clean and 
sanitize all contact surfaces before use and after any interruption 
during which the contact surface may become contaminated and
    <bullet> If you use contact surfaces in a continuous production 
operation or in consecutive operations involving

[[Page 34826]]

different batches of the same dietary supplement, you must adequately 
clean and sanitize the contact surfaces, as necessary. In this 
provision, we substituted ``consecutive'' for ``back-to-back,'' a 
nonsubstantive change. We also inserted ``adequately'' to make clear 
that cleaning and sanitizing must be adequate.
    (Comment 123) Several comments argue against using the term 
``sanitize'' in proposed Sec.  111.25(e)(3). The comments state that, 
based on the proposed definition of ``sanitize,'' Sec.  111.25(e)(3) 
would require evaluation of any sanitation steps to ensure that the 
level of log reduction is reached, for example, by taking ``before and 
after'' swab samples. The comments would revise proposed Sec.  
111.25(e)(3) to state that equipment, utensils, etc. shall be cleaned 
and sanitized in a manner that keeps microorganisms and other 
adulterants from contaminating all components, ingredients, in-process 
materials, and finished goods.
    (Response) The final rule now defines ``sanitize'' as ``to 
adequately treat cleaned equipment, containers, utensils, or any other 
cleaned product contact surface by a process that is effective in 
destroying vegetative cells of microorganisms of public health 
significance, and in substantially reducing numbers of other 
microorganisms, but without adversely affecting the product or its 
safety for the consumer.'' The definition no longer specifies a level 
of log reduction, so the revised definition should eliminate the 
comments' concern as to any possible need for ``before and after'' 
samples.
    d. Final Sec.  111.27(d)(4). Final Sec.  111.27(d)(4) (proposed 
Sec.  111.25(e)(4)) requires you to clean surfaces that do not come 
into direct contact with components or dietary supplements as 
frequently as necessary to protect against contamination. Final Sec.  
111.27(d)(4) relates to final Sec.  111.27(d)(2) and (d)(3). For 
example, you would not have to clean your ceilings as often as you 
clean your contact surfaces because your ceilings normally do not touch 
components or dietary supplements. However, you would have to clean 
your ceilings as frequently as necessary to prevent dust or other 
contaminants from falling onto your components, dietary supplements, 
and contact surfaces.
    We received no comments specific to proposed Sec.  111.25(e)(4). We 
substituted ``do not come into direct contact with'' for ``do not 
touch'' as a nonsubstantive editorial revision.
    e. Final Sec.  111.27(d)(5). Final Sec.  111.27(d)(5) (proposed 
Sec.  111.25(e)(5)) requires that single-service articles (such as 
utensils intended for one-time use, paper cups, and paper towels) be: 
(1) Stored in appropriate containers and (2) handled, dispensed, used, 
and disposed of in a manner that protects against contamination of 
components, dietary supplements, or any contact surface.
    We received no comments specific to proposed Sec.  111.25(e)(5).
    f. Final Sec.  111.27(d)(6). Final Sec.  111.27(d)(6) (proposed 
Sec.  111.25(e)(6)) requires your cleaning compounds and sanitizing 
agents to be adequate for their intended use and safe under their 
conditions of use.
    (Comment 124) One comment would delete proposed Sec.  111.25(e)(6), 
stating it is redundant to proposed Sec.  111.15(b), which would 
require you to use cleaning compounds and sanitizing agents that are 
free from microorganisms of public health significance and safe and 
adequate under the conditions of use.
    (Response) We disagree with this comment. Proposed Sec. Sec.  
111.15(b)(1) and 111.25(e)(6) (now final Sec. Sec.  111.15(b)(1) and 
111.27(d)(6), respectively) differed in their requirements and their 
applicability. Proposed Sec.  111.15(b)(1) would apply to cleaning 
compounds and sanitizing agents used in the physical plant and would 
require them to be ``safe and adequate under the conditions of use.'' 
In contrast, proposed Sec.  111.25(e)(6) would apply to cleaning 
compounds and sanitizing agents used on equipment, utensils, and 
contact surfaces used to manufacture, package, or hold components, 
dietary ingredients, or dietary supplements, and it would require such 
cleaning compounds or sanitizing agents to be ``adequate for intended 
use and safe under condition [sic] of use.'' By using the phrase 
``adequate for intended use,'' proposed Sec.  111.25(e)(6) would have 
you consider whether a particular cleaning compound or sanitizing agent 
was appropriate for the particular use to which it was being applied.
    Furthermore, depending on the situation, a cleaning compound or 
sanitizing agent that is appropriate for use on a physical plant may be 
inappropriate for use on equipment, utensils, and contact surfaces. For 
example, a powdered cleaning compound might be suitable for cleaning 
your physical plant's floors, but inappropriate for cleaning equipment 
that mixes components. In other words, the ``conditions of use'' can 
also vary between final Sec. Sec.  111.15(e)(1) and 111.27(d)(6) and 
lead to different conclusions regarding use of the same cleaning 
compound.
    Additionally, on our own initiative, we have made two editorial, 
nonsubstantive changes to final Sec.  111.27(d)(6). The final rule now 
states that the cleaning compounds and sanitizing agents must be 
adequate for ``their'' intended use and safe under ``their conditions'' 
of use.
    g. Final Sec.  111.27(d)(7). Final Sec.  111.27(d)(7) (proposed 
Sec.  111.25(e)(7)) requires you to store cleaned and sanitized 
portable equipment and utensils that have contact surfaces in a 
location and in a manner that protects them from contamination. We 
received no comments specific to proposed Sec.  111.25(e)(7).

F. Reorganization of Certain Paragraphs in Proposed Sec.  111.25

    Proposed Sec.  111.25 would impose certain requirements relating to 
written procedures for calibrating instruments and controls (proposed 
Sec.  111.25(c) and (d)) and keeping calibration records (proposed 
Sec.  111.25(f)). The final rule now contains a new recordkeeping 
section (Sec.  111.35) that combines elements of proposed Sec.  
111.25(c), (d), and (f), as well as other sections. We discuss comments 
on proposed Sec.  111.25(c), (d), and (f) and describe final Sec.  
111.35 in this section.

G. What Requirements Apply to Automated, Mechanical, or Electronic 
Equipment? (Final Sec.  111.30)

    Final Sec.  111.30 sets forth requirements for automated, 
mechanical, or electronic equipment that you use to manufacture, 
package, label, or hold a dietary supplement.
1. Comments on the Organization and Framework of Proposed Sec.  111.30
    (Comment 125) Some comments would revise proposed Sec.  111.30(a) 
to replace ``equipment to manufacture, package, label, and hold'' with 
``equipment to manufacture, package, label, or hold.'' The comments 
said that the same piece of equipment will not serve to manufacture, 
package, label, and hold components or dietary supplements.
    (Response) We agree, and have revised Sec.  111.30 accordingly. 
Final Sec.  111.30 also contains the following changes:
    <bullet> ``Automatic'' (as in ``automatic equipment'') is replaced 
with ``automated'' as an editorial, nonsubstantive change;
    <bullet> The phrase ``determine the suitability of your equipment'' 
has been revised to read ``determine the suitability of the equipment * 
* *'' in Sec.  111.30(b) and has no substantive impact; and

[[Page 34827]]

    <bullet> We have substituted the word ``met'' for ``achieved'' to 
comply with ``plain language'' initiatives and to be consistent with 
other provisions.
    We describe other changes to proposed Sec.  111.30 in the following 
paragraphs.
    (Comment 126) Several comments support proposed Sec.  111.30 
particularly with respect to computers. The comments state computers 
are susceptible to erroneous data input, are subject to malfunctions 
and software problems, and thus should be regulated under the final 
rule.
    One comment questions why we organized proposed Sec.  111.30 into 
two paragraphs (a) and (b). The comment claims there was no meaningful 
difference between the two paragraphs.
    Other comments say some proposed requirements for automatic, 
mechanical, and electronic equipment, such as the proposed requirement 
for maintaining backup files of data entered into computer systems, 
would apply to automatic, mechanical, and electronic equipment that are 
not related to CGMPs. The comments argue that proposed Sec.  111.30(b) 
would apply to computers on which payroll records are maintained, and 
that such a requirement does not belong in these CGMPs.
    (Response) We agree, in part, and disagree, in part, with the 
comments. We agree that computers used in the manufacture, packaging, 
labeling, or holding of dietary supplements should be, and are, subject 
to final Sec.  111.30.
    We disagree, however, with those comments that interpreted proposed 
Sec.  111.30(a) and (b) as being the same or interpreted proposed Sec.  
111.30 as applying to equipment that has no direct bearing on dietary 
supplements. Proposed Sec.  111.30(a) differed from proposed Sec.  
111.30(b) in that paragraph (a) would pertain to the operation and 
suitability of your equipment within your manufacturing process. In 
contrast, proposed Sec.  111.30(b) would apply to calibration of your 
equipment and controls you establish for your equipment.
    We disagree with those comments that would interpret proposed Sec.  
111.30(b) as applying to payroll computers or other equipment that has 
no CGMP function. To prevent misinterpretations of final Sec.  111.30, 
we have revised it to apply to equipment ``that you use to manufacture, 
package, label, or hold a dietary supplement'' and renumbered proposed 
Sec.  111.30(a)(1), (a)(2), (b)(1), (b)(3), and (b)(4) as Sec.  
111.30(a) through (e), respectively. Proposed Sec.  111.30(b)(2) which 
would require you to make and keep written records of equipment 
calibrations, inspections, and checks, and proposed Sec.  111.30(b)(5) 
which would require you to make and keep backup files of software 
programs and data, are now incorporated into final Sec.  111.35, and we 
discuss these provisions later in this section.
    (Comment 127) Several comments would limit proposed Sec.  111.30(a) 
and (b) to automatic, mechanical, or electronic equipment that actually 
affects product specifications. The comments argue that, in a modern 
manufacturing facility, most, if not all, equipment used to 
manufacture, package, label, or hold any food product is automatic, 
mechanical, or electronic. The comments say that equipment, such as 
forklifts, should not be required to be designed or selected in a 
manner that ensures that product specifications are met, as would be 
required in proposed Sec.  111.30(a)(1), or to be calibrated, as would 
be required in Sec.  111.30(b)(1).
    (Response) As we stated previously, we have revised Sec.  111.30 so 
that it applies to equipment ``that you use to manufacture, package, 
label, or hold a dietary supplement.'' This revision should prevent the 
rule from being interpreted as applying to forklifts or other equipment 
that have no bearing on the manufacture, packaging, labeling, or 
holding of dietary supplements.
    (Comment 128) Several comments argue that proposed Sec.  111.30 is 
redundant to proposed Sec.  111.25 and could be removed without 
meaningful effect. One comment argues that proposed Sec.  111.30(a) and 
(b) (i.e., that all automatic, mechanical, and electronic equipment be 
designed or selected to ensure that product specifications are 
consistently achieved and operate satisfactorily within operating 
limits required by the process) are redundant to proposed Sec.  
111.25(a)(1) (which would require that all equipment be of appropriate 
design, construction, and workmanship to enable them to be suitable for 
their intended use) and proposed Sec.  111.25(a)(1)(v) (which would 
state that ``equipment'' includes automatic, mechanical, or electronic 
systems). The comment states that, for equipment to be suitable for its 
intended use, the equipment must operate satisfactorily within 
operating limits and, by extension, ensure that product specifications 
are consistently achieved. The comment states the separate regulations 
for automatic equipment in the drug CGMPs is less detailed despite our 
efforts to present the 2003 CGMP Proposal in ``simplified language.''
    (Response) We disagree that proposed Sec.  111.30 is redundant to 
proposed Sec.  111.25 (final Sec.  111.27). Although both proposed 
Sec. Sec.  111.25 and 111.30 pertained to equipment, they differed in 
their focus. Proposed Sec.  111.25 would focus on equipment design, 
construction, maintenance, cleaning, sanitizing, and calibration. In 
contrast, proposed Sec.  111.30 would focus on the equipment's 
operation or suitability within your manufacturing process. For 
example, proposed Sec.  111.30(a)(2) would require you to determine the 
suitability of your equipment by ensuring that your equipment is 
capable of operating satisfactorily ``within the operating limits 
required by the process.'' In contrast, proposed Sec.  111.25 had no 
comparable suitability requirement insofar as your manufacturing 
processes were concerned. Thus, the proposed sections are not 
redundant, and the final rule retains both Sec.  111.27 (proposed Sec.  
111.25) and Sec.  111.30.
2. Comments Specific to Proposed Sec.  111.30
    a. Final Sec.  111.30(a) and (b). Final Sec.  111.30(a) (proposed 
Sec.  111.30(a)(1)) requires you, for any automated, mechanical, or 
electronic equipment you use to manufacture, package, label, or hold a 
dietary supplement, to design or select the equipment to ensure that 
dietary supplement specifications are consistently met.
    Final Sec.  111.30(b) (proposed Sec.  111.30 (a)(2)) requires you, 
for any automated, mechanical, or electronic equipment that you use to 
manufacture, package, label, or hold a dietary supplement, to determine 
the suitability of the equipment by ensuring that the equipment is 
capable of operating satisfactorily within the operating limits 
required by the process.
    (Comment 129) Some comments argue that the requirements of proposed 
Sec.  111.30(a) might be impossible to meet because, in many instances, 
dietary supplement manufacturers cannot predict, at the time of 
purchase, the entire range of ingredients and products for which a 
particular piece of equipment might be used. The comments argue that a 
particular piece of equipment's suitability for a particular ingredient 
or product must be evaluated at the time the need arises. The comments 
would revise proposed Sec.  111.30(a)(1). The words ``Design and select 
equipment to ensure'' would be replaced with the words ``Use equipment 
that ensures;'' and proposed Sec.  111.30(a)(2) would be revised to 
replace the words ``is capable of operating'' with the word, 
``operates.''
    (Response) We disagree with the comments. Although a company may 
not know the entire range of products that a machine may be used for,

[[Page 34828]]

proposed Sec.  111.30(a)(1) and (a)(2) would neither require you to 
determine all uses of equipment at the time of purchase nor prevent you 
from evaluating an old machine for a new use (these provisions are 
renumbered as final Sec.  111.30(a) and (b), respectively). Thus, even 
if you chose to use old equipment for a new use, you still must select 
that equipment to ensure that dietary supplement specifications are 
consistently met with the new equipment use and determine the 
suitability of the new equipment use by ensuring that the equipment is 
capable of operating satisfactorily within the operating limits 
required by the new process.
    (Comment 130) Several comments express concern that facilities and 
much equipment in the industry are old and lack historical 
documentation. These comments ask us to clarify whether manufacturers 
would have to establish baseline information for old facilities and 
equipment.
    (Response) All equipment that you use, regardless of whether it is 
old or new, must be capable of doing what you intend it to do. Just as 
you could evaluate old equipment for a new use, you can demonstrate 
that old equipment does, in fact, do what you intend it to do for uses 
that you developed before these CGMP requirements were established, and 
thereby comply with final Sec.  111.30(a) and (b).
    (Comment 131) Several comments argue that our statement in the 
preamble to the 2003 CGMP Proposal that ``systems need to be installed 
in a manner that takes into account the inherent limitations of the 
system, tested under conditions that reflect actual conditions of use'' 
(68 FR 12157 at 12193) is vague and subject to multiple 
interpretations.
    (Response) We disagree with the comment. The statement in question 
should be read in context because the preamble to the 2003 CGMP 
Proposal described several conditions for consideration. The preamble 
to the 2003 CGMP Proposal stated, in relevant part: ``Some systems may 
work properly only within a narrow range of environmental conditions, 
such as temperature and humidity, and some might be particularly 
sensitive to electromagnetic interference. The actual conditions of use 
of a system should be considered as early as possible in its design and 
development. Systems need to be installed in a manner that takes into 
account the inherent limitations of each system, tested under 
conditions of use, and properly maintained to ensure that they continue 
to function as expected during their lifetime'' (68 FR 12157 at 12193.) 
Thus, suitability under final Sec.  111.30(b) involves considerations 
of how the equipment would be affected by environmental conditions, 
whether the equipment is appropriate for its intended use, and whether 
the equipment can be maintained properly to ensure satisfactory 
operation.
    (Comment 132) Several comments argue that the requirement of 
proposed Sec.  111.30(a)(2) to ``determine the suitability of your 
equipment by ensuring that your equipment is capable of operating 
satisfactorily within the operating limits required by the process'' is 
vague and subject to many interpretations. These comments assert that 
this may cause an uneven playing field among companies as they apply 
differing standards to this requirement. The comments also argue that 
the vagueness of this requirement could potentially cause uneven 
enforcement, depending on the experience and understanding of 
individual inspectors.
    (Response) We disagree that proposed Sec.  111.30(a)(2) (final 
Sec.  111.30(b)) is vague or may result in uneven enforcement. There 
has been sufficient common usage of terms such as ``suitable,'' 
``capable,'' and ``satisfactorily'' in the industry to enable firms, 
and those who enforce the requirements, to comprehend and apply such 
terms to particular operations. Agencies may use qualifying terms to 
enable them to address a wide variety of conditions, and such terms 
provide the flexibility needed for various operations.
    (Comment 133) Several comments assert that proposed Sec.  
111.30(a)(2) is without justification and overly prescriptive when 
compared to conventional food CGMPs.
    (Response) As discussed in section V of this document, the mere 
fact that a dietary supplement CGMP requirement has no counterpart in 
the food CGMP regulations, or has more detail than a counterpart in 
such regulations, does not mean that it is overly prescriptive. Rather, 
what is important is whether proposed Sec.  111.30(a)(2) (final Sec.  
111.30(b)) is necessary to ensure the quality of the dietary 
supplements. For example, the preamble to the 2003 CGMP Proposal (68 FR 
12157 at 12193) discussed how the incorporation of software into the 
operation of automatic equipment has both increased the complexity of 
such equipment and resulted in a process that may operate differently 
for each execution, because a software-based control system can be 
configured at will by the operator or by the system itself. Therefore, 
it is essential that you ensure that automated equipment is capable of 
operating satisfactorily within the operating limits required by the 
process.
    (Comment 134) Several comments urge us to develop a separate 
guidance document with respect to determining the suitability and 
capability of equipment used in the manufacture of dietary supplements.
    (Response) We believe that firms have sufficient experience to 
determine whether equipment is suitable and capable of performing its 
intended function. However, if we find that guidance will be helpful, 
we will consider whether to issue guidance at a later date.
    b. Final Sec.  111.30(c). Final Sec.  111.30(c) (proposed Sec.  
111.30(b)(1)) requires you, for any automated, mechanical, or 
electronic equipment you use to manufacture, package, label, or hold a 
dietary supplement, to routinely calibrate, inspect, or check the 
equipment to ensure proper performance. Final Sec.  111.30(c) also 
requires quality control personnel to periodically review these 
calibrations, inspections, or checks.
    (Comment 135) Several comments claim the requirement for the 
quality control unit to approve calibrations, inspections, or checks of 
equipment is too prescriptive and that qualified persons outside of the 
quality control unit should be able to approve these calibrations, 
inspections, or checks. The comments also state the quality control 
unit should perform audits of the records generated to ensure the 
appropriate calibrations, inspections, or checks are being adequately 
performed at the required intervals.
    Other comments refer to related requirements in proposed Sec.  
111.37(b)(8) that the quality control unit review all records for 
equipment calibrations, inspections, or checks. The comments state the 
requirements for oversight by the quality control unit in proposed 
Sec.  111.37(b)(8) are excessive and go beyond requirements for both 
the drug CGMPs and food CGMPs. One comment would revise proposed Sec.  
111.37(b)(8) to require a review of all records when there is a 
negative impact on the dietary supplement due to a calibration failure.
    (Response) Final Sec.  111.12(b) requires that you identify who is 
responsible for your quality control operations, and each person who is 
designated to perform quality control operations must be qualified to 
do so and have distinct and separate responsibilities related to 
performing such operations from those responsibilities that the person 
otherwise has when not performing such operations. Thus, you may 
identify any person whom you believe is qualified to approve 
calibrations, equipments, or checks to perform quality control 
operations.

[[Page 34829]]

    We disagree that the review by quality control personnel should be 
limited to circumstances when there has been a calibration failure. One 
function of quality control personnel is to provide oversight to 
prevent problems with the product that you distribute by finding any 
problems with the equipment that you use to produce the product rather 
than to investigate the cause of a problem with a product that you 
already distributed. However, we agree that it is sufficient to 
periodically review the records of calibrations, inspections, or checks 
of automated, mechanical, or electronic equipment, for example, on an 
annual basis, rather than to approve each record when it is made. A 
periodic review can uncover trends in the performance of the equipment 
that have the potential to adversely affect the quality of the dietary 
supplement and that may not be obvious by merely approving each record 
when it is made. Seeing such trends would enable quality control 
personnel to recommend corrective actions. This periodic review is 
consistent with proposed Sec.  111.37(b)(8) which would require the 
quality control unit to ``review'' all records for equipment 
calibration, inspections, or checks rather than ``approve'' these 
records. Therefore, we have revised the requirement that the quality 
control unit approve calibrations, inspections, or checks of automatic, 
mechanical or electronic equipment so that final Sec.  111.30(c) 
requires that quality control personnel periodically review such 
operations rather than approve them when they are made.
    Additionally, we have made a minor change to Sec.  111.30(c). The 
change inserts the words ``the equipment'' after ``Routinely calibrate, 
inspect, or check * * *.'' This insertion simply reiterates that ``the 
equipment'' must be routinely calibrated, inspected, or checked.
    c. Final Sec.  111.30(d). Final Sec.  111.30(d) (proposed Sec.  
111.30(b)(3)) requires you, for any automated, mechanical, or 
electronic equipment you use to manufacture, package, label, or hold a 
dietary supplement, to establish and use appropriate controls for the 
equipment (including software for a computer-controlled process) to 
ensure that any changes to the manufacturing, packaging, labeling, 
holding, or other operations are approved by quality control personnel 
and instituted only by authorized personnel.
    (Comment 136) The preamble to the 2003 CGMP Proposal invited 
comment on whether we should regulate computerized systems separately 
from other automatic equipment, given the broad range in 
sophistication, complexity, and computerization in manufacturing 
equipment (68 FR 12157 at 12194).
    Several comments state that computers are susceptible to erroneous 
data input and subject to malfunctions and software problems and, thus, 
should be regulated under the final rule.
    (Response) We agree that computers used in the manufacturing 
processes should be regulated under the final rule. As the preamble to 
the 2003 CGMP Proposal stated the incorporation of software into the 
operation of automatic equipment has increased the complexity of such 
equipment and resulted in a process that may operate differently for 
each execution, because a software-based control system can be 
configured at will by the operator or by the system itself (68 FR 12157 
at 12193). Additionally, final Sec.  111.35(b)(5) requires you to make 
and keep backup files of software programs and data to keep them secure 
from alterations, inadvertent erasures, or loss. The issue in the 
preamble to the 2003 CGMP Proposal, however, was whether computerized 
systems should be regulated separately from other equipment; in the 
absence of comments supporting separate treatment for computerized 
systems, we have included computerized systems as ``equipment'' in 
final Sec.  111.30(d).
    We are, however, revising final Sec.  111.30(d) in the following 
manner:
    <bullet> We are inserting the words ``for automated, mechanical, 
and electronic equipment (including software for a computer controlled 
process)'' after ``Establish and use appropriate controls.'' This 
change simply reiterates the types of equipment for which appropriate 
controls must be established and used, and makes it clear that software 
is included under the rule and
    <bullet> We are rephrasing the purpose of Sec.  111.30(d). The 
proposal stated that you must establish and use appropriate controls 
``to ensure that your quality control unit approves changes in the 
master manufacturing record batch control records, packaging 
operations, and label operations, or changes to other operations 
related to the equipment that you use and that only authorized 
personnel institute the changes.'' The final rule states that you must 
establish and use appropriate controls for your equipment ``to ensure 
that any changes to the manufacturing, packaging, labeling, holding, or 
other operations are approved by quality control personnel and 
instituted only by authorized personnel.''
    As revised, final Sec.  111.30(d) shifts its emphasis from the 
person(s) who must approve or institute the changes to the types of 
changes that must be approved and instituted. This shift in emphasis is 
appropriate given that the final rule addresses responsibilities of the 
quality control personnel elsewhere.
    d. Final Sec.  111.30(e). Final Sec.  111.30(e) (proposed Sec.  
111.30(b)(4)) requires you, for any automated, mechanical, or 
electronic equipment you use to manufacture, package, label, or hold a 
dietary supplement, to establish and use appropriate controls to ensure 
that the equipment functions in accordance with its intended use. 
Quality control personnel must approve these controls.
    We did not receive comments specific to proposed Sec.  
111.30(b)(4).
3. Reorganization of Certain Paragraphs in Proposed Sec.  111.30
    As we explained earlier in this section, proposed Sec.  111.30 
would impose certain requirements relating to written records of 
equipment calibrations, inspections, or checks (proposed Sec.  
111.30(b)(2)) and making and keeping backup files of software programs 
and data (proposed Sec.  111.30(b)(5)). The final rule now contains a 
new recordkeeping section, final Sec.  111.35, that combines elements 
of proposed Sec.  111.30(b)(2) and (b)(5), as well as other sections.
    Additionally, proposed Sec.  111.30(c) would require you to keep 
records in accordance with the written procedure and recordkeeping 
requirements in proposed Sec.  111.125. Section 111.35 of the final 
rule now incorporates proposed Sec.  111.30(c) as well. We discuss 
final Sec.  111.35 in the following paragraphs.

H. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.35)

    Final Sec.  111.35 describes the recordkeeping requirements. It 
represents a combination of proposed Sec. Sec.  111.25(c)(1) through 
(c)(2), (d)(1) through (d)(7), and (f); 111.30(b)(2), (b)(5), and (c); 
and 111.50(c)(4).
1. Final Sec.  111.35(a)
    Final Sec.  111.35(a) states that you must make and keep records 
required under subpart D in accordance with subpart P. Subpart P deals 
with records and recordkeeping.
    Final Sec.  111.35(a) is broader than proposed Sec.  111.25(f), 
which stated that you ``must keep calibration records as required by 
this section in accordance with'' the 2003 CGMP Proposal's 
recordkeeping section, and compared to proposed Sec.  111.30(c), which 
stated that you must keep ``automatic, mechanical, or electronic 
equipment records required by this section in accordance

[[Page 34830]]

with'' the 2003 CGMP Proposal's recordkeeping section. However, final 
Sec.  111.35(a) has the same effect as proposed Sec. Sec.  111.25(f) 
and 111.30(c).
    We did not receive any substantive comments on proposed Sec. Sec.  
111.25(f) or 111.30(c).
2. Final 111.35(b)(1) and (b)(2)
    Final Sec.  111.35(b) combines the various recordkeeping 
requirements that were in proposed Sec. Sec.  111.25(c) (written 
procedures for calibrating instruments and controls and documentation 
that those procedures were followed and that the calibration was 
performed), 111.25(d) (written procedures or documentation for 
calibration, such as the instrument or control calibrated and the 
calibration date), 111.30(b)(2) and (b)(5) (written records of 
equipment calibrations, inspections, or checks, and backup files of 
software and data, respectively), and 111.50(b)(4) (inclusion of date 
and time of maintenance, cleaning, and sanitizing of equipment and 
processing lines in the batch record).
    Specifically, final Sec.  111.35(b)(1) states that you must make 
and keep records of ``written procedures for fulfilling the 
requirements of this subpart,'' including written procedures for:
    <bullet> Calibrating instruments and controls that you use in 
manufacturing or testing a component or dietary supplement. This 
paragraph is similar to proposed Sec.  111.25(c). Although we did not 
receive any substantive comment on proposed Sec.  111.25(c), we are 
rephrasing the paragraph due to its reorganization as part of final 
Sec.  111.35. Additionally, although proposed Sec.  111.25(c) would 
require you to document that the written procedures for calibration 
were followed each time a calibration is performed, we are moving the 
documentation requirement to final Sec.  111.35(b)(3) which we discuss 
later in this section.
    <bullet> Calibrating, inspecting, and checking automated, 
mechanical, and electronic equipment. This paragraph is similar to 
proposed Sec.  111.30(b)(2), although we are rephrasing the paragraph 
due to its reorganization as part of final Sec.  111.35.
    <bullet> Maintaining, cleaning, and sanitizing, as necessary, all 
equipment, utensils, and any other contact surfaces that are used to 
manufacture, package, label, or hold components or dietary supplements. 
This paragraph relates to final Sec.  111.25(c) which requires you to 
establish and follow written procedures for such activities.
    We did not receive any comments specific to proposed Sec. Sec.  
111.25(c) or 111.30(b)(2).
    Final Sec.  111.35(b)(2) (proposed Sec.  111.50(c)(4)) requires you 
to make and keep documentation, in individual equipment logs, of the 
date of the use, maintenance, cleaning, and sanitizing of equipment, 
unless such documentation is kept with the batch record.
    (Comment 137) Proposed Sec.  111.50(c)(4) would require that the 
batch record include the date and time of the maintenance, cleaning, 
and sanitizing of the equipment and processing lines used in producing 
the batch. The preamble to the 2003 CGMP Proposal also invited comment 
on whether the person performing the maintenance, cleaning, and 
sanitizing of portable equipment and utensils should document at the 
time of performance the maintenance, cleaning, and sanitizing (68 FR 
12157 at 12192\8\). Several comments argue that the final rule should 
require documentation at the time of performance of equipment, utensil, 
and contact surface maintenance, cleaning, and sanitation and should 
also require this documentation to be kept as records. The comments 
explain that such recordkeeping is common practice in the industry, is 
an important part of batch history, and omitting such a requirement 
would diminish the industry standard. In addition, the comments state 
that written records are an effective way to ensure that there is 
consistency in how employees are trained and to assess compliance.
---------------------------------------------------------------------------

    \8\Although the preamble to the 2003 CGMP Proposal discussed 
this issue in relation to proposed Sec.  111.25 (``What Requirements 
Apply to the Equipment and Utensils You Use?''), the same principle 
applies to proposed Sec.  111.50(c)(4).
---------------------------------------------------------------------------

    Several comments agree that equipment maintenance, cleaning, and 
sanitizing records should be kept and state that this information 
should be kept with individual pieces of equipment, rather than in the 
batch record as proposed Sec.  111.50(c)(4) would require. The comments 
say it is easier and more efficient for some companies to maintain 
equipment logs that can be referenced when necessary.
    Other comments say manufacturers should have flexibility to design 
a recordkeeping program suited to their operations, and should have the 
option of using an equipment log as it provides an efficient way to 
document, trace, and review equipment use, maintenance, cleaning, and 
sanitization of equipment. According to these comments, because the 
2003 CGMP Proposal would require batch production records to identify 
all equipment used during production, this will allow for cross-
referencing with the equipment log, should the need occur. The comments 
argue that the proposed approach will be awkward for some companies to 
comply with and would not result in collection of information in a 
logical order or location where it can be easily referenced and 
reviewed, such as on the production floor, or to provide data for trend 
analysis. The comments also contend requiring all information to be 
maintained in the batch record will be difficult in practice and place 
an enormous burden on companies.
    (Response) We agree that documenting the cleaning, sanitizing, and 
maintenance of equipment is important. However, we have revised the 
provision so that these records need not be part of the batch record. 
Instead, final Sec.  111.35(b)(2) requires you to make and keep 
documentation of the date of use, maintenance, cleaning, and sanitizing 
of equipment in individual equipment logs, unless such documentation is 
kept with the batch record. By ``equipment log,'' we mean a written 
record that includes information about the history of a piece of 
equipment. This history includes items such as date of installation, 
routine maintenance, repairs, and cleaning.
    Additionally, final Sec.  111.260 requires you to identify the 
equipment and processing lines used in producing the batch and either 
provide a cross-reference that will make it possible to find the 
applicable equipment log as needed or include documentation that 
equipment was cleaned, sanitized, or maintained (we discuss final Sec.  
111.260 in section XIV of this document). For example, you may keep 
records documenting that you cleaned containers you will use for 
holding a finished batch either in records associated with the 
equipment you use for cleaning, or with the applicable batch record, 
depending on what is most convenient and practical for your operations.
    (Comment 138) Several comments state documenting the cleaning of 
contact surfaces would be unnecessarily labor-intensive because the 
term is so broadly defined. Other comments argue that documenting the 
cleaning of utensils is unnecessary and inappropriate. These comments 
support requiring documentation for the cleaning of large equipment, 
but claim that requiring manufacturers to uniquely identify each spoon, 
spatula, container, and hose (or other general cleaning) in order to 
document each cleaning would be inappropriate and create an enormous 
burden on the manufacturer. According to these comments, such a 
requirement would slow and complicate the cleaning process, making 
proper cleaning more cumbersome. The comments assert that

[[Page 34831]]

contamination from these sources has not caused any recalls and is not 
justified.
    (Response) We disagree with these comments. The final rule requires 
you to document the work that was done, but gives you the flexibility 
to decide how to document that work was done. For contact surfaces such 
as containers you use to hold a finished batch, you could, for example, 
record the cleaning either on a single line that you provide in your 
batch record, or as a line entry in the log of the equipment that you 
use to clean the containers, or in some other way that suits your 
needs. These are not labor-intensive requirements.
    It is important that you have procedures in place to know that 
small items, such as spatulas, are clean when you use them. For 
example, if you have a log where you designate equipment that has been 
cleaned, your batch record could simply have a place to check that you 
used equipment designated as clean.
3. Final Sec.  111.35(b)(3)
    Final Sec.  111.35(b)(3) (proposed Sec.  111.25(d)(1) through 
(d)(7)) requires you to make and keep documentation of any calibration, 
each time the calibration is performed, for instruments and controls 
that you use in manufacturing or testing a component or dietary 
supplement. In the documentation you must: (1) Identify the instrument 
or control calibrated; (2) provide the calibration date; (3) identify 
the reference standard used, including the certification of accuracy of 
the known reference standard and a history of recertification of 
accuracy; (4) identify the calibration method used, including 
appropriate limits for accuracy and precision of instruments and 
controls when calibrating; (5) provide the calibration reading or 
readings found; (6) identify the recalibration method used, and reading 
or readings found, if accuracy or precision or both accuracy and 
precision limits for instruments and controls were not met; and (7) 
include the initials of the person who performed the calibration and 
any recalibration.
    (Comment 139) Some comments support proposed Sec.  111.25(d). 
However, other comments argue that the documentation requirements are 
unduly prescriptive. Some comments would revise proposed Sec.  
111.25(d) to more closely mirror the requirements in drug CGMPs. Some 
comments suggest the requirement to maintain written records of 
calibrations should simply state ``You must maintain written records of 
calibrations according to Sec. 111.125.'' Other comments suggest 
detailed calibration requirements would not be needed if the final rule 
included requirements to establish and follow written procedures.
    (Response) The information required under final Sec.  111.35(b)(3) 
(proposed Sec.  111.25(d)) is the minimum amount necessary to provide 
sufficient information concerning equipment calibration. For example, 
some firms may have more than one machine to perform a given function; 
in those situations, documentation that identified the exact machine 
that was calibrated would distinguish it from other, seemingly 
identical, but noncalibrated machines. Likewise, if the maintenance 
instructions for a machine called for calibration checks every month, 
documenting the date of calibration would show you whether calibrations 
were done on schedule. As another example, if a machine required 
calibration according to a particular standard, identifying the 
reference standard would help verify that the calibration was done 
correctly.
    Thus, we disagree with those comments claiming that proposed Sec.  
111.25(d) was too prescriptive. If, for example, the final rule simply 
directed you to document calibration, without specifying what 
information should be contained in that documentation, then the 
resulting documentation could have little or no value. For example, 
assume that you have two identical pieces of equipment, but only one 
had been calibrated. If the documentation simply said, ``machine was 
calibrated,'' you would not know which machine had been calibrated. As 
another example, if you had a machine that had to be recalibrated every 
year, and the documentation merely said, ``recalibration completed,'' 
you would not know whether the machine had been recalibrated yesterday, 
last month, last year, or 4 years ago.
    With respect to the argument that proposed Sec.  111.25(d) should 
be revised to resemble the drug CGMPs, we disagree. We recognize that 
the drug CGMPs are less detailed with respect to documentation; for 
example, 21 CFR 211.68(a), ``Automatic, mechanical, and electronic 
equipment,'' simply states, in relevant part, ``If such equipment is so 
used, it shall be routinely calibrated, inspected, or checked according 
to a written program designed to assure proper performance'' and 
``Written records of those calibration checks and inspections shall be 
maintained.'' However, the comments overlook the fact that, from 1993 
to 2003, the Center for Drug Evaluation and Research (CDER) issued 
periodic guidance, in the form of ``Human Drug CGMP Notes,'' and those 
guidances offered advice on various drug CGMP issues. With respect to 
calibration, for example, the December 1997 edition dealt with the 
question of whether the drug CGMP regulations require equipment to be 
labeled with calibration dates. The guidance identified various 
regulations that would be applicable and also said that: ``During an 
inspection a firm should be able to document when a specific piece of 
equipment was last calibrated/maintained, the results or action, and 
when its next calibration/maintenance is scheduled. The absence of such 
documentation is a CGMP deviation'' (see CDER, ``Human Drug CGMP 
Notes,'' December 1997, at page 3 (Ref. 29)).
    This advice is comparable, in several respects, to the information 
required by final Sec.  111.35(b)(3). For example, it refers to a 
``specific piece of equipment,'' which is similar to final Sec.  
111.35(b)(3)(i)'s requirement to identify the instrument or control 
calibrated. It refers to the time when calibration occurred; this is 
similar to final Sec.  111.35(b)(3)(ii)'s requirement to provide the 
calibration date. Although public distribution of ``Human Drug CGMP 
Notes'' ended in 2003, and the document was circulated only within FDA 
from 2001 to 2003 (but was available through FOIA), the guidances 
offered the drug industry advice on complying with the drug CGMPs, and 
we have retained the guidances on our Internet site. In other words, 
the drug CGMP regulations did not have to be as ``prescriptive'' 
because the drug industry learned about our interpretations or 
expectations of the drug CGMPs through guidance.
    Here, in contrast, there is no comparable history of issuing 
periodic guidance to inform the dietary supplement industry about 
specific CGMP issues.
    Yet, even if final Sec.  111.35 is more ``prescriptive'' than the 
drug CGMPs, that difference does not mean that we must revise the rule 
to ``mirror'' the drug CGMPs. The dietary supplement industry is more 
diverse compared to the drug industry, and so, at least with respect to 
documenting calibration, more--rather than less--detail is appropriate.
    We do note, however, that final Sec.  111.35(b)(3) differs from 
proposed Sec.  111.25(d) in the following respects:
    <bullet> Sec.  111.25(d) would require you to identify specific 
calibration-related information ``in any written procedure or at the 
time of performance,'' final Sec.  111.35(b)(3) requires documentation 
``each time the calibration is performed.'' Final section 111.35(b)(1)

[[Page 34832]]

requires you to have records of the written procedures for calibrating 
instruments and controls, but does not specify the contents of such 
written procedures;
    <bullet> Sec.  111.25(d) would refer to ``instruments and 
controls.'' Final Sec.  111.35(b)(3) now refers to ``instruments and 
controls that you use in manufacturing or testing a component or 
dietary supplement.'' This change clarifies the instruments and 
controls that are subject to final Sec.  111.35(b)(3) and is consistent 
with final Sec.  111.27(b), which requires you to calibrate instruments 
and controls;
    <bullet> The type of information that must be documented under 
Sec.  111.35(b)(3)(i) through (b)(3)(vii) is essentially identical to 
that in proposed Sec.  111.25(d)(1) through (d)(7), but we revised the 
sentence structure due to the manner in which we reorganized final 
Sec.  111.35;
    <bullet> Sec.  111.25(d)(6) would have you identify the 
recalibration method used. Final Sec.  111.35(b)(3)(vi) requires you to 
identify the recalibration method used ``and reading or readings 
found.'' The addition of ``reading or readings found'' is consistent 
with the remainder of proposed Sec.  111.25(d)(6) (final Sec.  
111.35(b)(3)(vi)) which is a simplification of the phrase ``accuracy or 
precision or both accuracy and precision limits for instruments and 
controls were not met.'' One would only know that limits were not met 
based on a reading or readings; and
    <bullet> Sec.  111.25(d)(7) would require the initials of the 
person who performed the calibration. Final Sec.  111.35(b)(3)(vii) 
requires the initials of the person who performed the calibration and 
any recalibration. Arguably, recalibration is a type of calibration, 
but we have added ``any recalibration'' to final Sec.  
111.35(b)(3)(vii) to ensure that recalibrations are included in the 
rule.
    (Comment 140) Several comments would revise proposed Sec.  
111.25(d) to read, ``The following must be identified * * *'', rather 
than ``you must identify.'' The comments explain that calibrations and 
recalibrations are often performed by the equipment manufacturer, 
vendor, or other outside service, rather than by the dietary supplement 
manufacturer. The comments argue that the proposal requires that the 
calibration or recalibration must be performed onsite (i.e., at the 
plant manufacturing the dietary ingredient or supplement) when in fact 
many calibrations can, or even must, be performed offsite.
    (Response) We decline to revise the paragraph as requested. As we 
discuss in section VI of this document, the term ``you'' can refer to 
someone with whom you contract, but you are responsible for ensuring 
that the calibration requirements are met, and to have documentation of 
the calibration, even though the steps may be performed offsite.
4. Final Sec.  111.35(b)(4)
    Final Sec.  111.35(b)(4) (proposed Sec.  111.30(b)(2)) requires you 
to make and keep written records of calibrations, inspections, and 
checks of automated, mechanical, and electronic equipment that is used 
to manufacture, package, label, or hold a dietary supplement.
    We did not receive comments specific to proposed Sec.  
111.30(b)(2). We have made nonsubstantive editorial changes to the 
rule. For example, proposed Sec.  111.30(b)(2) would require you to 
``make and keep'' written records; final Sec.  111.35(b)(4) omits the 
words `` make and keep'' because that requirement appears earlier in 
Sec.  111.35.
5. Final Sec.  111.35(b)(5)
    Final Sec.  111.35(b)(5) (proposed Sec.  111.30(b)(5)) requires you 
to make and keep backup file(s) of current software programs (and of 
outdated software that is necessary to retrieve records that you are 
required to keep in accordance with subpart P, when current software is 
not able to retrieve such records) and of data entered into computer 
systems that you use to manufacture, package, label, or hold dietary 
supplements. Under final Sec.  111.35(b)(5)(i), your backup file (e.g., 
a hard copy of data you have entered, diskettes, tapes, microfilm, or 
compact disks) must be an exact and complete record of the data you 
entered. Under final Sec.  111.35(b)(5)(ii), you must keep your backup 
software programs and data secure from alterations, inadvertent 
erasures, or loss.
    (Comment 141) Several comments would limit the requirement for 
maintaining backup files of data entered into computer systems to those 
data entered into computer systems that are relied upon for compliance 
with CGMPs. These comments argue that the paragraph, as written, calls 
for a firm to make and keep backup files of data entered into computers 
on which personnel payroll records are maintained, and state that no 
such requirement should be imposed. Therefore, these comments would 
replace the words ``your computer system'' with the words ``any of your 
computer systems that are relied upon for compliance with this part.''
    (Response) We have modified the provision to clarify that the 
requirement is for computer systems that you use to manufacture, 
package, label, or hold dietary supplements.
    (Comment 142) Several comments argue that many software programs 
are in a near constant state of revision and that it is not a common 
business practice for a firm in any industry to maintain records of 
outdated software programs, at least if the firm is still able to use a 
revised program to access data it entered using an outdated program. 
The comments assert that, although the drug CGMPs require the 
maintenance of certain backup files of data entered into computer 
systems, they do not require the maintenance of backup files of 
software programs.
    (Response) Keeping backup copies of software helps ensure that data 
can be retrieved if the primary software develops a problem. When we 
use the term ``backup,'' we mean a second copy of the software in 
question rather than a copy of previous versions of the software that 
are outdated, provided that data can be retrieved. However, if the data 
collected using outdated software cannot be retrieved by the newer 
software, there would still be a need to maintain a primary copy and a 
backup copy of the outdated software used to collect or manage the 
data.
    We have narrowed the requirement to retain backup files of software 
to current software and of outdated software that is necessary to 
retrieve records that you are required to keep in accordance with 
subpart P, when current software is not able to retrieve such records.
    (Comment 143) Some comments claim that, although the drug CGMPs 
require the maintenance of certain backup files of data entered into 
computer systems, they do not require the maintenance of backup files 
of software programs. Several comments also assert that it is not 
always possible to keep backup files of the software programs used in 
certain pieces of equipment, because the equipment manufacturer may be 
the only one having access to the programming of its equipment. The 
comments would delete the words ``software programs and'' from proposed 
Sec.  111.30(b)(5).
    (Response) In most cases, we anticipate that firms will have access 
to backup copies of their software programs. We acknowledge that in 
rare instances, backup copies may not be available and in these 
situations, we will take that into account in reviewing compliance with 
this provision. We decline to revise the provision as suggested.
6. Final Sec.  111.35(b)(6)
    Final Sec.  111.35(b)(6) states that you must make and keep 
``documentation of

[[Page 34833]]

the controls that you use to ensure that equipment functions in 
accordance with its intended use.''
    The preamble to the 2003 CGMP Proposal stated that we were not 
proposing verification requirements for automatic, mechanical, or 
electronic equipment (68 FR 12157 at 12194). However, we invited 
comment on whether the final rule should require such verification 
(id.). Verification would ensure that the processes using automatic, 
mechanical, and electronic equipment consistently produce an outcome 
that meets a predetermined specification and any predetermined quality 
characteristics. Verification would show whether your automatic, 
mechanical, or electronic processes will consistently operate as they 
should.
    (Comment 144) Several comments argue against including equipment 
verification requirements. The comments argue that the verification 
discussion in the preamble to the 2003 CGMP Proposal is difficult to 
distinguish from drug validation. The comments argue that validation 
should be allowed to evolve in the dietary supplement industry as it 
evolved in drug CGMPs. According to these comments, the dietary 
supplement industry, being largely self regulated in CGMPs to date and 
not generally practicing verification, would be more readily adaptable 
to, and better controlled by, strict operating controls and quality 
control checks including sufficient input and output checks on computer 
operated systems, than having to digest the concept of verification and 
implement verification processes. The comments state that, in the 
future, verification may be a means of offsetting some of the extensive 
testing of finished products.
    Other comments state we should not require verification of 
processes that use automatic, mechanical, or electronic equipment given 
the different processes that dietary supplement manufacturers use. The 
comments argue that although dietary supplement manufacturers, 
depending on the unique circumstances of a particular manufacturing 
process, may choose to verify processes using a sound verification 
system, we should not require verification.
    Several comments ask us to clarify whether we intended to require 
full validation of equipment used to process dietary supplements 
because terms such as ``suitability'' and ``capable,'' which we used in 
proposed Sec.  111.30(a)(1) and (a)(2), might be interpreted to require 
validation. These comments state validation is unnecessary and overly 
burdensome for equipment used in manufacturing dietary supplements.
    Several comments argue that proposed Sec.  111.30(a)(1) and (a)(2) 
have the effect of establishing unnecessarily formal, stringent, and 
expensive validation requirements on equipment design, selection, and 
capability. The comment states that this language represents a de facto 
``IQ/OQ/PQ'' (installation qualification/operational qualification/
performance qualification) requirement. According to these comments, 
emphasis should instead be directed to actual use and operation.
    In contrast, several comments argue we should require manufacturers 
to develop and maintain data that demonstrate that equipment is 
suitable and that the production process consistently delivers expected 
results. The comments argue that one key CGMP element is the 
requirement for systems to operate consistently and to produce an 
outcome that meets a predetermined specification. According to these 
comments, demonstration of system capability is best achieved through 
systems verification. The comments explain that, in an industry where 
the complexity of finished products often precludes finished product 
testing, the capability of the systems employed is of paramount 
importance. The comments state if the processes used fail to produce a 
product meeting predetermined specifications and quality 
characteristics, then the product should not be sold. The comments add 
that, although verification imposes additional costs on manufacturers, 
frequently rejected product, adequate rework procedures, and extensive 
in-process and finished product testing also would be costly.
    Several comments also claim the use of an appropriate verification 
system may, under certain circumstances, allow for lot testing as 
opposed to batch testing. These comments state that, with process 
verification and an appropriate testing scheme, a manufacturer could 
demonstrate that lot testing provides sufficient assurance of quality 
and lack of adulteration. The comments ask us to address these 
alternatives in the final rule. Many comments said written records of 
verification should be maintained. The comments offer several 
suggestions on how this could be accomplished, including using 
statistical process control techniques or other appropriate statistical 
tools.
    (Response) We used the term ``verification'' rather than 
``validation'' to signal that we did not expect that a final rule would 
include requirements for formal process validation requirements, such 
as an IQ/OQ/PQ requirement, for equipment. Regardless, several comments 
interpreted our request for comments as a suggestion that we were 
considering such formal validation requirements. At this time, we are 
not requiring formal process validation for equipment. However, we will 
monitor the development of systems that evolve within this diverse 
industry.
    We disagree that proposed Sec.  111.30(a)(1) and (a)(2) would have 
the effect of establishing unnecessarily formal, stringent, and 
expensive validation requirements on equipment design, selection, and 
capability, and that the language would represent a de facto ``IQ/OQ/
PQ'' requirement for equipment. Final Sec.  111.30(e) requires you to 
ensure equipment operates in accordance with its intended use. We agree 
with the comments that argued that data demonstrating that equipment is 
suitable, and that the production process consistently delivers 
expected results, are a key element of CGMP. Therefore, final Sec.  
111.35(b)(6) requires you to make and keep documentation of the 
controls that you use to ensure that the equipment functions in 
accordance with its intended use. Examples of such controls include 
temperature settings, fill rates, and blending times that must be set, 
checked, and adjusted as necessary.

X. Comments on Requirement to Establish a Production and Process 
Control System (Final Subpart E)

A. Reorganization of Proposed Sec.  111.35 Into Final Subpart E

    In the 2003 CGMP Proposal, the requirements for a production and 
process control system were set forth in Sec.  111.35. As shown in 
table 6 of this document, we are reorganizing proposed Sec.  111.35 
into subpart E. Table 6 lists the sections in final subpart E and 
identifies the sections in the 2003 CGMP Proposal that form the basis 
of the final rule.

           Table 6.--Derivation of Sections in Final Subpart E
------------------------------------------------------------------------
                Final Rule                      2003 CGMP  Proposal
------------------------------------------------------------------------
Sec.   111.55 What are the requirements    Sec.   111.35(a)
 to implement a production and process
 control system?
------------------------------------------------------------------------
Sec.   111.60 What are the design          Sec.   111.35(b)
 requirements for the production and
 process control system?
------------------------------------------------------------------------

[[Page 34834]]

 
Sec.   111.65 What are the requirements    Sec.   111.35(c)
 for quality control operations?
------------------------------------------------------------------------
Sec.   111.70 What specifications must     Sec.   111.35(e), (f), (g),
 you establish?                             and (k)
------------------------------------------------------------------------
Sec.   111.73 What is your responsibility  Sec.   111.35 (f), (g), and
 for determining whether established        (h)
 specifications are met?
------------------------------------------------------------------------
Sec.   111.75 What must you do to          Sec.   111.35(e), (f), (g),
 determine whether specifications are       (h), (i), (k), and (l)
 met?                                      Sec.   111.37 (b)(11)(iv)
                                           Sec.   111.40(a)(2)
------------------------------------------------------------------------
Sec.   111.77 What must you do if          Sec.   111.50(d)(2), (f), and
 established specifications are not met?    (g)
                                           Sec.   111.35(i)(4)(i) and
                                            (i)(4)(ii)
------------------------------------------------------------------------
Sec.  111.80 What representative samples   Sec.   111.37(b)(11)
 must you collect?
------------------------------------------------------------------------
Sec.   111.83 What are the requirements    Sec.   111.37(b)(12)
 for reserve samples?                      Sec.   111.50(h)
                                           Sec.   111.83(b)(2)
------------------------------------------------------------------------
Sec.   111.87 Who conducts a material      Sec.   111.35(i) and (n)
 review and makes a disposition decision?  Sec.   111.37(b)(5) and
                                            (b)(14)
                                           Sec.   111.40(a)(3)
                                           Sec.   111.50(d)(1)
                                           Sec.   111.85(a) and (c)
------------------------------------------------------------------------
Sec.   111.90 What requirements apply to   Sec.   111.35(i)(4)
 treatment, in-process adjustments, and    Sec.   111.50(d)(1), (f), and
 reprocessing when there is a deviation     (g)
 or unanticipated occurrence or when a     Sec.   111.65(d)
 specification established in accordance
 with Sec.   111.70 is not met?
------------------------------------------------------------------------
Sec.   111.95 under this subpart E, what   Sec.   111.35(m) and (o)
 records must you make and keep?
------------------------------------------------------------------------

B. General Comments on Proposed Sec.  111.35

    (Comment 145) Several comments emphasize the first step in ensuring 
safe, high quality products is to use high quality components that meet 
well-defined specifications. Some of these comments assert the 2003 
CGMP Proposal does not encourage development of such specifications.
    Several comments assert that a more appropriate balance is needed 
between an effective process control system and a reasonable testing 
scheme that is calculated to confirm the quality of dietary 
supplements, and that it is important to provide companies with more 
flexibility in developing a specific CGMP program that satisfies the 
requirements. The comments stress it is important to build quality into 
a product throughout the entire production process by relying on strong 
process controls rather than by testing at the finished batch stage. 
One comment asserts that, in an appropriate process control system, 
testing is a means to monitor and ensure that the control system is 
functioning as intended. Many comments recommend the final rule include 
rigorous in-process controls plus a requirement for one identity test 
of incoming components to ensure quality and safety.
    Many comments assert a certificate of analysis can be a key element 
of the manufacturing process provided that a manufacturer certifies 
that a vendor consistently supplies suitable product through a 
combination of vendor audits and product testing. (A certificate of 
analysis is a document, provided by the supplier of a component prior 
to or upon receipt of the component, that documents certain 
characteristics and attributes of the component.) Comments also assert 
that, with use of a certificate of analysis from a properly qualified 
supplier, the amount of required testing could be reduced. One comment 
notes that, although a certificate of analysis may not be relied upon 
completely to forgo testing of a received ingredient, the extent of 
testing could be reduced to take into account the history of the 
supplier in providing quality ingredients. This and other comments 
recommend the dietary supplement manufacturer conduct identity tests to 
ensure that the correct component has been received. A few comments 
note that the drug CGMP regulations permit the use of a supplier's 
certificate of analysis based upon certification of the supplier by a 
program of complete testing for conformance with the certificate of 
analysis.
    Several comments support the use of a qualified supplier's 
certificate of analysis in lieu of testing at the finished batch stage. 
One comment recommends testing be strategically employed to verify that 
other control procedures have accomplished their intended result; if 
other controls are adequate, a statistically-based testing program 
should be permitted for finished batches rather than the proposed 
requirement for testing every batch for every specification.
    Many comments note that section 402(g)(2) of the act directs us to 
develop dietary supplement CGMP requirements that are modeled after the 
CGMP regulations for food. These comments point out that, because the 
food CGMPs allow the use of a verified certificate of analysis, it is 
unfair and illogical to disallow a certificate of analysis in the 
dietary supplement CGMP final rule. One comment states the proposed 
requirements for production and process controls are more stringent 
than the requirements for drug products.
    Several comments stress that the most critical aspect of a 
successful CGMP system is effective process control, which includes a 
requirement for written procedures and documentation for all key 
processing operations. Many comments argue that effective process 
control, including extensive written procedures, should allow for a 
decreased testing burden with respect to the finished product. One 
comment suggests we exempt manufacturers from the requirement to test 
each batch of finished product if they have a qualified manufacturing 
process that meets certain basic criteria, including a requirement for 
written procedures for each stage of the process and a written plan for 
qualifying this process.
    Several comments urge us to build more flexibility into the testing 
requirements, in both the type and number of tests required and the 
point(s) in the supply chain at which they would be required. Some 
comments recommend that the frequency of testing be established under a 
statistically valid method to ensure that in-process controls are 
adequate to guarantee production of a safe and effective dietary 
supplement or ingredient. Several comments recommend we require 
manufacturers to test incoming ingredients and raw materials, in lieu 
of testing each finished batch of product. These comments state it is 
more prudent to test to ensure that the materials used in formulating a 
product are appropriate and safe than to risk making an adulterated 
product and, in so doing, contaminate manufacturing equipment.
    Several comments recommend we allow manufacturers to employ skip-
lot testing as an alternative to testing each finished batch of 
product. One comment states that, with adequate process controls in 
place, periodic or skip-lot testing is sufficient, and notes that skip-
lot testing is acceptable under the regulatory frameworks for herbal

[[Page 34835]]

products in other countries, including Canada and countries in the 
European Union.
    In summary, the comments suggest an approach that stresses the 
importance of establishing specifications for components, relying on a 
certificate of analysis from a qualified supplier for certain 
specifications with qualification of the suppliers, and establishing 
and following written procedures. This overall approach would focus on 
building quality into a dietary supplement throughout the production 
and process control system. The role of testing at the finished batch 
stage would become a check on whether the overall manufacturing process 
is, in fact, under control.
    (Response) Based upon a review of the comments, we have 
reconsidered the approach taken in the 2003 CGMP Proposal. The 2003 
CGMP Proposal would require that all finished batches of dietary 
supplements be tested at the finished batch stage to ensure that the 
products met specifications for identity, purity, strength, and 
composition. The 2003 CGMP proposal recommended, but would not require, 
testing of incoming components to ensure that component specifications, 
including identity, were met. However, if a specification (such as 
identity) could not be tested at the finished batch stage, the proposed 
rule would require a firm to test incoming components for that 
specification and to test for that specification at the in-process 
stage as necessary to ensure that products met specifications. We are 
persuaded that, as an alternative to testing each finished batch of 
product, we can allow for the use of a statistically sound sampling and 
testing program for finished batches of dietary supplements unless a 
manufacturer chooses to test every batch. Such a sampling and testing 
program is feasible when controls are implemented earlier than the 
final product stage in the manufacturing process. Controls include the 
use of a certificate of analysis from a qualified supplier for 
specifications other than the identity of a dietary ingredient, and the 
establishment and monitoring of in-process manufacturing controls. We 
agree with the comments that if we reduce the requirements for testing 
at the finished batch stage, then it is critical that you determine 
whether components meet specifications. We address this issue in the 
following two ways: (1) Each manufacturer must confirm the identity of 
each component prior to use (you must test or examine dietary 
ingredients to verify the identity, but may rely on a certificate of 
analysis to confirm the identify of components other than dietary 
ingredients) and (2) each company must confirm other required 
specifications for components prior to use, either by relying upon a 
certificate of analysis or by testing or examining the component.
    As the comments have suggested, specifications for the ``identity'' 
of components of dietary supplements are critically important. These 
comments included references to industry proposals that supported 
identity testing. The 1997 ANPRM (62 FR 5700) included an industry 
proposed outline of CGMP provisions which contained a provision that 
required identity testing as follows: ``(iv) Each lot of raw material 
shall undergo at least one test by the manufacturer to verify its 
identity. Such tests may include any appropriate test with sufficient 
specificity to determine identity, including chemical and laboratory 
tests, gross organoleptic analysis, microscopic identification, or 
analysis of constituent markers.'' (60 FR 5700 at 5705).
    In January 2004, a group of trade associations representing dietary 
supplement manufacturers and others submitted text of proposed CGMP 
requirements to the docket as an alternative to the 2003 CGMP Proposal. 
This submission also included a provision which required identity 
testing as follows:
    (1) For components, dietary ingredients, or dietary supplements 
that you receive, you must:
    (i) conduct at least one test or examination to verify that the 
specifications for identity are met; * * *
(1996N-0417, EMC000261-02 at 20).
    Both the 1997 ANPRM industry outline and the January 2004 industry 
docket submission included provisions that allowed certificates of 
analysis to establish specifications other than for identity for 
ingredients and components.
    In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12162) we 
discussed a case in which Digitalis lanata was labeled as plantain and, 
as a result, a young woman experienced a life-threatening abnormal 
heart function after consuming a dietary supplement containing D. 
lanata in lieu of plantain. The problem occurred notwithstanding the 
fact that certificates of analysis furnished by the supplier provided 
assurances that the component was indeed plantain.
    Because of the critical importance of ensuring the proper identity 
of dietary ingredients--they are the central defining ingredients of a 
dietary supplement--we are requiring each firm that uses a dietary 
ingredient to perform its own testing or examination for identity of 
each dietary ingredient prior to use. This requirement is similar to 
the proposed requirement set forth by industry in both the 1997 ANPRM 
and in the January 2004 industry comment to the proposed rule. Firms 
may not rely upon a certificate of analysis provided by suppliers to 
determine the identity of a dietary ingredient before use. We 
recognize, however, that it may be possible for a manufacturer to 
demonstrate, through various methods and processes in use over time for 
its particular operation, that a system of less than 100 percent 
identity testing would provide no material diminution of assurance of 
the identity of the dietary ingredient as compared to the assurance 
provided by 100 percent identity testing. To provide an opportunity for 
a manufacturer to make such a showing and reduce the frequency of 
identity testing of components that are dietary ingredients from 100 
percent to some lower frequency, we decided to provide, in an interim 
final rule published elsewhere in this issue of the Federal Register, a 
procedure that allows for submission to, and review by, FDA of an 
alternative to the required 100 percent identity testing of components 
that are dietary ingredients, provided certain conditions are met.
    In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12198), 
we explained that we would not permit firms to rely upon supplier 
certifications. The decision was based, in large part, on problems that 
have occurred with faulty certificates in the past. We have, however, 
reconsidered our position on certificates for specifications, other 
than for the identity of the dietary ingredients, based on comments 
discussing how firms have taken steps to ensure that their certificates 
are reliable. We believe that the minimum criteria that we are 
establishing for a certificate of analysis, together with the 
requirement that a firm relying on a certificate of analysis must 
qualify a supplier and periodically repeat that qualification process, 
can prevent the problems that have occurred with faulty certificates in 
the past. Therefore, for component specifications, other than the 
identity of a dietary ingredient, including confirming the identity of 
components that are not dietary ingredients, we are permitting firms to 
rely upon certificates of analysis provided by suppliers, if the 
certificates meet the requirements of the final rule. Under final Sec.  
111.75(a), a firm may rely upon a certificate of analysis from its 
supplier of a component, provided that certain criteria are met which 
include the following: (1) The

[[Page 34836]]

firm first qualifies the supplier by establishing the reliability of 
the supplier's certificate of analysis through confirmation of the 
results of the supplier's tests or examinations; (2) the certificate of 
analysis includes a description of the test or examination method(s) 
used, limits of the test or examinations, and actual results of the 
tests or examinations; (3) the firm maintains documentation of how it 
qualified the supplier; (4) the firm periodically reconfirms the 
supplier's certificate of analysis; and (5) the firm's quality control 
personnel review and approve the documentation setting forth the basis 
for qualification (and requalification) of any supplier.
    As we discussed in the preamble to the 2003 CGMP Proposal, in-
process controls are necessary to ensure that dietary supplements are 
manufactured in accordance with their specifications (68 FR 12157 at 
12197). Under final Sec.  111.75(b), firms must monitor the in-process 
points, steps, or stages where control is necessary to ensure the 
quality of the finished batch of the dietary supplement to: (1) 
Determine whether the in-process specifications are met and (2) detect 
any deviation or unanticipated occurrence that may result in a failure 
to meet specifications. In addition, we have strengthened the 
requirements for in-process controls by requiring that quality control 
personnel conduct all required material reviews and make all required 
disposition decisions using written procedures to ensure that 
deviations or unanticipated occurrences that occur are consistently 
handled.
    Because of the strengthened requirements regarding component and 
in-process specifications, the final rule permits testing of a subset 
of finished batches rather than requiring testing of each finished 
batch. Consistent with several suggestions in the comments, we built 
more flexibility into the testing requirements so that a firm may test 
a subset of finished dietary supplement batches that the firm 
identifies through a sound statistical sampling plan for selected 
specifications rather than test every batch of the finished dietary 
supplement for every specification. Finally, quality control personnel 
must review and approve any exceptions from testing requirements that 
are allowed under the rule and the basis for such exceptions. This 
approach is consistent with the comments that we received and will 
achieve a high degree of integrity in the manufacturing process, while 
at the same time provide flexibility to the industry.
    Additional discussion on the requirements for identity testing of 
dietary ingredients and the appropriate reliance on a certificate of 
analysis for components other than dietary ingredients is found in this 
section in response to comment 174.

C. Final Subpart E and Highlights of Changes to the Proposed 
Regulations

    The provisions in final subpart E reflect that the final rule 
applies only to persons who manufacture, package, label, or hold a 
dietary supplement unless subject to an exclusion in final Sec.  111.1. 
The approach that we are incorporating into the final rule requires 
changes in most of the individual paragraphs of proposed Sec.  111.35.

D. What Are the Requirements to Implement a Production and Process 
Control System? (Final Sec.  111.55)

    Final Sec.  111.55 requires you to implement a system of production 
and process controls that covers all stages of manufacturing, 
packaging, labeling, and holding of the dietary supplement to ensure 
the quality of the dietary supplement and that the dietary supplement 
is packaged and labeled as specified in the master manufacturing 
record. Final Sec.  111.55 derives from proposed Sec.  111.35(a).
    (Comment 146) A few comments say the production and process 
controls outlined in proposed Sec.  111.35 are critical in ensuring 
that dietary supplements meet specifications for identity, purity, 
quality, strength, and composition. One comment recommends proposed 
Sec.  111.35(a) be revised to state ``* * * that covers all stages of 
manufacturing, packaging, labeling, and holding of * * * dietary 
supplements that occur in your facility or for which you otherwise have 
responsibility.'' This comment explains that the production of dietary 
supplements is often broken up into several stages which are under the 
control of different entities. The comment gives the following 
examples: A marketing company may manufacture and package a product 
itself; or it may contract with one company to manufacture and package 
the product; or it may contract with one company to manufacture the 
product and another company to package the product; and contract 
manufacturers and packagers may subcontract portions of the 
manufacturing or packaging.
    (Response) We decline to revise the rule as suggested by the 
comments. As we discussed in response to comment 37 in section VI of 
this document, you must comply with the CGMP requirements that apply to 
your operations related to the manufacturing, packaging, labeling, and 
holding of dietary supplements. We decline to include codified language 
that may not capture all of the possible relationships that exist in a 
given operation.

E. What Are the Design Requirements for the Production and Process 
Control System? (Final Sec.  111.60)

    Final Sec.  111.60(a) requires that your production and in-process 
control system be designed to ensure that the dietary supplement is 
manufactured, packaged, labeled, and held in a manner that will ensure 
the quality of the dietary supplement and that the dietary supplement 
is packaged and labeled as specified in the master manufacturing 
record. Final Sec.  111.60(b) requires that the production and in-
process control system include all requirements of subparts E through L 
of part 111 and be reviewed and approved by quality control personnel. 
Final Sec.  111.60(a) and (b) derive from proposed Sec.  111.35(b).
    As discussed in section III of this document, we are clarifying a 
number of provisions that did not explicitly identify labeling as an 
operation that is covered by the rule. Final Sec.  111.60 is one such 
provision. Under proposed Sec.  111.35(a) we would require that you 
implement a system of production and process controls that covers all 
stages of manufacturing, packaging, labeling, and holding of the 
dietary supplements. In an oversight, proposed Sec.  111.35(b) would 
require your production and in-process control system to be designed to 
ensure that the dietary supplement is manufactured, packaged, and 
held--but not labeled--in a manner that would prevent adulteration of 
the dietary supplement. To correct this oversight, final Sec.  111.60 
explicitly identifies labeling as an operation that the design of your 
production and process control system must address.
    (Comment 147) A few comments recommend that the phrase ``designed 
to ensure'' in proposed Sec.  111.35(b) be deleted because it requires 
that formal, prospective studies (similar to a process validation) must 
be performed and such a requirement would be unduly burdensome.
    (Response) We disagree with the comments' interpretation of the 
proposed regulation and decline the request. Final Sec.  111.60(a) 
relates to the overall design of your production and process control 
system. It does not require validation based on scientific studies, but 
rather that your process contain all the controls necessary to ensure 
the quality of your dietary supplements and that the dietary supplement 
is packaged and labeled as specified in the master manufacturing 
record. The process, for example, must

[[Page 34837]]

ensure that the dietary supplement meets all specifications established 
under Sec.  111.70(e).

F. What Are the Requirements for Quality Control Operations? (Final 
Sec.  111.65)

    Final Sec.  111.65 requires that you implement quality control 
operations in your manufacturing, packaging, labeling, and holding 
operations for producing the dietary supplement to ensure that these 
operations are performed in a manner that ensures the quality of the 
dietary supplement and that the dietary supplement is packaged and 
labeled as specified in the master manufacturing record. Final Sec.  
111.65 derives from proposed Sec.  111.35(c).
    Proposed Sec.  111.35(c) referred to the role of the quality 
control unit in manufacturing, packaging, and label operations--but not 
in holding operations. This was an oversight. We, therefore, revised 
proposed Sec.  111.35(c) to include ``holding'' as an operation that is 
subject to the oversight of quality control personnel for consistency 
with final Sec.  111.105 (proposed Sec.  111.37(a)), which provides for 
the performance of quality control operations to ``ensure that your 
manufacturing, packaging, label, and holding operations ensure the 
quality of the dietary supplement and that the dietary supplement is 
packaged and labeled as specified in the master manufacturing record.''
    (Comment 148) One comment recommends proposed Sec.  111.35(c) be 
revised to state ``ensures that the * * * dietary supplement meets 
manufacturing specifications for identity, purity, quality, strength, 
and composition.''
    (Response) We are not making this change because it is unnecessary 
in the context of the provisions of final Sec.  111.65.
    (Comment 149) One comment argues that proposed Sec.  111.35(c) is 
too wordy and needs clarification. The comment recommends it be revised 
to state ``You must use a quality control unit to ensure that the 
dietary supplement meets specifications for identity, purity, quality, 
strength, and composition.''
    (Response) We disagree with this comment. The change requested by 
the comment would emphasize a single responsibility of quality control 
personnel (i.e., releasing final product) and would obscure the fact 
that quality control personnel have a role in the design and conduct of 
most of your operations.
    (Comment 150) One comment recommends proposed Sec.  111.35(c) be 
revised to state ``ensures that the * * * dietary supplement meets 
specifications for identity, purity, quality, strength, and composition 
as appropriate to protect the public health; and quality, strength, and 
composition as appropriate for the * * * product.'' This comment states 
it is confusing and unnecessary to require that all five of these 
attributes be addressed for all dietary supplements. The comment also 
states the term ``purity'' requires explanation because not all 
ingredients or supplements are subject to the same types of 
contamination.
    (Response) We are not making any changes in the provision as 
suggested by this comment. The comment provides no basis for the 
assertion that the proposed requirement to use a quality control unit 
to ensure that a dietary supplement meets specifications for identity, 
purity, strength, and composition is confusing and unnecessary. In 
section VI of this document, we explain that purity means that portion 
or percentage of a dietary supplement that represents the intended 
product.

G. What Specifications Must You Establish? (Final Sec.  111.70)

    Final Sec.  111.70 derives from proposed Sec. Sec.  111.35(e), (f), 
(g), and (k), 111.37(b)(11)(iv), and 111.70(c).
    (Comment 151) Some comments state proposed Sec.  111.35(k), which 
would require that you test or examine components and dietary 
supplements for those types of contamination that may adulterate or 
lead to adulteration, is more appropriate for, and should be 
incorporated into, proposed Sec.  111.35(e) which would require, in 
part, that you establish specifications for the identity, purity, 
quality, strength, and composition of components that you receive and 
of dietary supplements that you manufacture. The comments note this 
suggestion would help simplify and eliminate some redundancy in 
proposed Sec.  111.35. One comment would revise proposed Sec.  
111.35(k) to state ``Purity specifications for purchased or 
manufactured components and dietary supplements must be established for 
those types of contamination which can reasonably be expected to affect 
the component, ingredient, or supplement in question * * *.'' According 
to the comment not all ingredients or supplements are subject to the 
same types of contamination, and it would be unduly burdensome to 
require that all ingredients and supplements be tested for all possible 
contaminants (as opposed to all likely contaminants).
    (Response) We agree that not all ingredients or dietary supplements 
are subject to the same types of contamination. It would not be 
practicable or necessary to require testing for all possible 
contaminants for every dietary supplement, or for every component used 
to manufacture a dietary supplement. As we explained in the 2003 CGMP 
Proposal (68 FR 12157 at 12199 through 12200), the manufacturer has the 
responsibility to determine what types of contamination are likely or 
certain to contaminate a given product and to determine what types of 
tests to conduct and when to test for such contamination. We explained 
that botanicals are likely or certain to contain filth and 
microorganisms of public health significance based on the areas in 
which they are harvested (id.). As another example, fungal growth on a 
botanical component can provide the environment for mycotoxin 
production, especially aflatoxin (id.). If fungal growth is present, 
the manufacturer would need to perform an appropriate test that can 
detect the toxic substance. We stated that the manufacturer must be 
aware of potential contamination, regardless of whether due to filth, 
insects, microorganisms, or toxins and to test or examine, as 
appropriate, the components and dietary supplements for those types of 
contamination that may adulterate or that may lead to adulteration 
(id.). Thus, the types of contamination that we were referring to in 
proposed Sec.  111.35(k) are those that are likely or certain to be 
present in or on components received, based on the nature of the 
product, its source, handling prior to receipt by the facility, or 
other reason, and not due to poor manufacturing practices that resulted 
in their presence in the first instance.
    It is the responsibility of the manufacturer to identify those 
contaminants and to establish limits to prevent adulteration under 
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. For example, 
if you manufacture a polysaccharide that derives from seaweed, it is 
likely that you would include a limit on cadmium, because cadmium is a 
common contaminant that can be present in marine-derived ingredients. 
If you manufacture a polysaccharide that has a composition similar to 
seaweed-derived polysaccharide, but derives from a land-based plant, it 
is not likely that you would include a limit on cadmium, because 
cadmium is not a common contaminant of land-based plants. Likewise, if 
you manufacture a mineral that contains phosphates, it is likely that 
you would include a limit on arsenic, because phosphates are generally 
mined and arsenic is a common contaminant that can be present in 
ingredients that

[[Page 34838]]

are mined. If you manufacture a mineral that does not include 
ingredients that are mined, it is not likely that you would include a 
limit on arsenic.
    We agree that controlling contamination is critical to the quality 
of the dietary supplement. However, we do not agree that the types of 
contamination addressed by proposed Sec.  111.35(k) should be 
considered as a purity specification. We have described purity in this 
final rule to mean something that you intend to be present in the final 
product. As explained in section VI of this document, purity means that 
portion or percentage of a dietary supplement that represents the 
intended product. For example, you may manufacture a dietary supplement 
that uses a natural product such as fish oil to provide triglycerides 
that are a source of the polyunsaturated fatty acids DHA and EPA. The 
purity refers to the percent of the fish oil that is triglycerides. 
(Note that if you are manufacturing fish oil to provide the fatty acids 
DHA and EPA in the dietary supplement, the component specifications for 
the fish oil must include a strength specification for DHA and EPA in 
whatever amount you determine is necessary to meet the specification 
for strength of DHA and EPA in the dietary supplement.) If the natural 
product also contains lead, or other unwanted ingredients that may 
adulterate or may lead to adulteration, you would have to establish 
limits for such contaminants. Thus, to distinguish the proposed 
requirement in Sec.  111.35(k), which relates to contaminants that may 
be present on or in the components that you receive, from the 
requirements related to specifications for desired characteristics of 
identity, purity, strength, and composition, we are including a 
separate requirement on establishing limits on such contaminants for 
components that you receive (final Sec.  111.70(b)). We also include a 
requirement for establishing an in-process specification for any point, 
step, or stage in the master manufacturing record where control is 
necessary to help ensure that specifications are met, as necessary, for 
limits on contamination. In addition, we are including a requirement 
for such limits on contaminants in the finished batch of dietary 
supplement (or subset of finished batches) (final Sec.  111.70(e)) to 
ensure that the manufacturing process has not adversely affected such 
levels, e.g., has not contributed an additional source of such 
contaminant or failed to remove the contaminant, when necessary. Such 
limits would need to ensure the quality of the dietary supplement, 
i.e., to ensure that the dietary supplement has been manufactured, 
packaged, labeled, and held under conditions to prevent adulteration 
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
    Thus, in addition to the presence of contaminants that may be in or 
on components that you receive, there may be sources of contamination 
that you need to control for in your facility. As discussed in this 
section, you must establish specifications under final Sec.  111.70(a) 
and (c) to prevent adulteration from such sources. The specifications 
established under final Sec.  111.70(a) and (c) may or may not include 
limits on such contaminants. By ``limits on those types of 
contamination'' in final Sec.  111.70, we do not mean contamination 
from, for example, the presence of rodent pellets or other filth that 
would constitute an insanitary condition under section 402(a)(3) or 
(a)(4) of the act, if such filth was present in your facility. You are 
not allowed to establish specifications for limits on contaminants that 
would otherwise adulterate your product under the act if such 
contaminants were present.
    Further, in proposed Sec.  111.35(k), we included a listing of the 
types of contamination we considered to be applicable to dietary 
supplements (68 12157 FR at 12258). We stated that the types of 
contamination include: (1) Filth, insects, or other extraneous 
material; (2) microorganisms; and (3) toxic substances. We have deleted 
the listing of the types of contamination in the final rule because the 
listing is simply informative and establishes no independent 
requirement. We received several comments, discussed in the following 
paragraphs, on the types of contamination that may be present, some 
which were solicited by us in the 2003 CGMP Proposal (68 FR 12157 at 
12179 through 12181).
    In the 2003 CGMP Proposal, we solicited comment on whether we 
should include in the final rule specific requirements for 
manufacturing, packaging, or holding animal-derived dietary 
ingredients, because animal-derived dietary ingredients present 
important public health and safety issues.
    In the 2003 CGMP Proposal, the example we used was an animal-
derived dietary ingredient potentially contaminated with the agent that 
causes bovine spongiform encephalopathy (BSE), which is a type of 
transmissible spongiform encephalopathy (TSE). TSEs are fatal, 
neurodegenerative disorders, which have been identified in humans and a 
number of animal species (e.g., cattle, sheep, goats, elk, deer, cats, 
and mink), but primarily in ruminants (cattle, sheep, elk, deer) (69 FR 
42256, July 14, 2004). Most scientists believe that variant Creutzfeldt 
Jakob Disease (vCJD), a progressive neurological disease in humans, is 
caused by consumption of cattle products contaminated with the agent 
that causes BSE (69 FR 42256 at 42257).
    In the 2003 CGMP Proposal (68 FR 12157 at 12180), we stated that we 
had communicated with the public and manufacturers of FDA-regulated 
products about appropriate steps to increase product safety and 
minimize the risk of products contaminated with the BSE agent. We 
referenced a notice in the Federal Register of August 29, 1994 (59 FR 
44591), entitled ``Bovine-Derived Materials; Agency Letters to 
Manufacturers of FDA-Regulated Products.'' We sent letters to dietary 
supplements manufacturers to alert them to the developing concern about 
TSEs in animals and Creutzfeldt-Jakob Disease in humans. We recommended 
they investigate the source of any bovine and ovine material used in 
their products. We suggested that manufacturers develop plans to 
ensure, with a high degree of certainty, that bovine and ovine 
materials used in their products were not from BSE countries or from 
sheep flocks (foreign or domestic) infected with scrapie. We stated 
that our Center for Biologics Evaluation and Research (CBER) had 
developed guidances for industry that describe steps manufacturers 
should take to ensure the safety and suitability for human use of 
animal-derived biologics. We also stated that we were considering 
whether the procedures that CBER recommends for a product with animal-
derived materials, substances, or tissues would be appropriate for 
dietary ingredients and dietary supplements that contain animal-derived 
materials, substances, or tissues. We believed that the use of an 
animal-derived material, substance, or tissue in a dietary supplement 
may raise many of the same serious public health and safety issues as 
animal-derived materials, substances, or tissues, in a biologic. We 
invited comment on whether there is a scientific basis for us to treat 
animal-derived dietary ingredients in a manner different from, or that 
would offer less protection than, what is recommended for animal-
derived biologics when the same public health and safety risks may be 
present.
    (Comment 152) Several comments state there should not be specific 
requirements for manufacturing, packaging, or holding animal-derived 
dietary ingredients because BSE issues

[[Page 34839]]

are not specific to dietary supplements, and because other guidance and 
regulations, issued by FDA and by the U.S. Department of Agriculture 
(USDA), already address BSE and public health. Other comments state it 
would be appropriate to include specific CGMP requirements for BSE as 
long as the requirements reflect the thinking in currently existing 
regulations and guidance.
    Several comments do not support the need for additional provisions 
regarding the handling of imported animal-derived ingredients because 
the industry has already taken steps to comply with the requirements or 
recommendations issued by either USDA or FDA. The comments state that 
the regulations issued by USDA for meat related products in the food 
industry provide adequate control over the use of animal tissues that 
might contain microorganisms, specifically viruses, of public health 
concern.
    One comment argues that if purchases of domestic raw tissues have 
been inspected by USDA, it is unfair to impose additional regulations 
simply because these tissues are included in dietary supplements. This 
comment asserts it would be unfair to require testing of animal-derived 
products given the fact that there are no tests for BSE available, and 
that reliance on USDA and FDA is the best way to stop the spread of 
BSE.
    Another comment states that industry trade associations have been 
working actively with their member companies to ensure adherence to the 
requirements set forth in our various letters regarding the need to 
develop plans ``that ensure, with a high degree of certainty'' that 
animal-derived ingredients are used only in accordance with FDA and 
USDA policies designed to protect against BSE. The comment states that 
a summary of industry procurement and handling practices regarding 
animal-derived ingredients (submitted to us) contains lists of animal-
derived ingredients used by various companies, with examples of the 
certificates of origin and other documentation required for import of 
any animal-derived materials. One comment states that industry members 
who handle animal-derived ingredients already have implemented many of 
the controls that originated either from USDA or the dietary ingredient 
suppliers in response to demands by various governments or consumers, 
and that such matters should remain with USDA to avoid duplication of 
effort.
    Some comments oppose any recommendation that guidance issued by 
CBER for ensuring the safety and suitability for human use of animal-
derived biologics apply to dietary supplement products. One comment 
includes a review of literature on BSE and claims the review justifies 
not applying the CBER guidances on BSE to dietary supplement products 
under part 111.
    (Response) For cattle derived materials, you must comply with the 
requirements of the interim final rule on BSE set forth in Sec.  189.5 
(see 70 FR 53063, September 7, 2005) and any subsequent modifications. 
Under the interim final rule, no human food, including dietary 
supplements, shall be manufactured from, processed with, or otherwise 
contain, prohibited cattle materials as defined in the rule. In 
addition, manufacturers and processors of such food that is 
manufactured from, processed with, or otherwise contains, cattle 
material must make existing records relevant to compliance available to 
us for inspection and copying. For both cattle-derived and other 
animal-derived materials, you must comply with all applicable 
provisions of this final rule. For example, under final Sec.  111.70, 
you must establish specifications for any point, step, or stage in the 
manufacturing process where control is necessary to ensure the quality 
of the dietary supplement. Thus, you must establish specifications for 
your animal-derived materials that are necessary to ensure the quality 
of the dietary supplement. Ensuring quality includes preventing 
contamination that may adulterate the product under section 402(a)(1), 
(a)(2), (a)(3), or (a)(4) of the act. In addition, you must take 
actions to determine whether the specifications are met (final Sec.  
111.73). Therefore, if you used animal-derived materials other than 
prohibited cattle materials subject to the BSE interim final rule, you 
would need to establish specifications necessary to ensure the quality 
of the dietary supplement.
    The guidances issued by CBER are still in effect for animal-derived 
biologics, and we continue to recommend that you use them as 
appropriate for your products that contain animal-derived ingredients.
    (Comment 153) One comment agrees with the provisions of proposed 
Sec.  111.35(k) but requests that we provide guidance to the industry 
on allowable limits for the types of contamination listed. Another 
comment asks us to develop specific defect action levels (DALs) for 
dietary supplements as more information becomes available, rather than 
rely on existing DALs from the food industry.
    (Response) In the 2003 CGMP Proposal (68 FR 12157 at 12163), we 
stated that we were not identifying DALs for the types of contaminants 
for dietary ingredients because there are not enough data available to 
identify an appropriate DAL for most dietary ingredients. These 
comments do not provide data, or evidence that data are available, to 
enable us to issue guidance for DALs for specific contamination. 
Therefore, we are not taking the action requested by these comments. We 
discuss DALs in this section in response to comment 156.
    (Comment 154) Some comments suggest the provisions in proposed 
Sec.  111.35(k), testing for contamination that could adulterate a 
product, would be more appropriate to include in proposed Sec.  
111.35(e), which concerns the establishment of specifications.
    (Response) We agree with these comments and are including 
requirements to include limits on contamination in final Sec.  111.70. 
The requirements set forth in final Sec. Sec.  111.70 and 111.75 are 
consistent with this comment. Under final Sec.  111.70(b) you must 
establish limits on those types of contamination that may adulterate or 
may lead to adulteration of the finished batch of the dietary 
supplement to ensure the quality of the dietary supplement. Under final 
Sec.  111.70(c) you must establish in-process specifications for any 
point, step, or stage in the master manufacturing record where control 
is necessary to help ensure that specifications are met for the 
identity, purity, strength, and composition of the dietary supplements, 
and as necessary, limits on contamination for those types of 
contamination that may adulterate or may lead to adulteration of the 
finished batch of the dietary supplement. Under final Sec.  111.70(e), 
you must establish product specifications for the identity, purity, 
strength, and composition of the finished batch of the dietary 
supplement, and for limits on those types of contamination that may 
adulterate, or that may lead to adulteration of, the finished batch of 
the dietary supplement to ensure the quality of the dietary supplement. 
As we explained in the response to comment 151, by ``limits on those 
types of contamination'' in final Sec.  111.70, we do not mean 
contamination from, for example, the presence of rodent pellets or 
other filth that would constitute an insanitary condition under section 
402(a)(3) or (a)(4) of the act, if such filth was present in your 
facility. You are not allowed to establish specifications for limits on 
contaminants that would otherwise adulterate your product under the act 
if such contaminants were present.
    (Comment 155) Several comments object to proposed Sec.  111.35(k) 
because

[[Page 34840]]

the provision would be more stringent than the food or drug CGMP 
requirements. Some point out that the consumption levels for food are 
higher than for dietary supplements. A few comments argue that proposed 
Sec.  111.35(k) is too broad as it requires testing or examination for 
those contaminants that ``may'' adulterate or ``may lead to'' 
adulteration, which could be interpreted to mean testing for unknown 
contaminants of every description. The comments suggest that this 
provision be revised to require testing or examination for those types 
of contamination that ``may be present in an amount or at a level'' 
that may adulterate or lead to adulteration or that ``may reasonably be 
expected'' to adulterate or lead to adulteration. Other comments agree 
that to test for all possible contaminants would be burdensome.
    Several comments state that manufacturers should be allowed to rely 
on a supplier's certificate of analysis and that testing should not be 
required for every potential contaminant. One comment recommends that 
CGMPs should be specific to the source and that testing should depend 
on the nature of the material.
    Some comments note that for botanicals it is sometimes nearly 
impossible to identify and analyze all naturally occurring substances.
    (Response) The final rule does not include any specific 
requirements to test or examine components or dietary supplements for 
contamination. Rather, under final Sec.  111.70(b), (c), and (e), you 
are required to establish specifications for limits on those types of 
contamination that may adulterate or may lead to adulteration of the 
finished batch of the dietary supplement. Under final Sec.  111.73, you 
must determine whether the specifications established under Sec.  
111.70 are met. Final Sec.  111.75(a) through (d) sets forth the 
criteria you must use to determine whether the specifications that you 
establish under final Sec.  111.70(b), (c), and (e) are met. Consistent 
with these comments, under final Sec.  111.75(a) you may rely on a 
certificate of analysis (other than for the identity of a dietary 
ingredient) from a qualified supplier of components to ensure that 
specifications that include limits on contamination are met, provided 
you satisfy the criteria set forth in final Sec.  111.75(a). This would 
include, for example, relying on a certificate of analysis to ensure 
that the level of lead in each of your components would not adulterate 
the dietary supplement.
    In determining compliance with the requirements to set limits for 
those types of contamination that may adulterate the dietary supplement 
or lead to adulteration for received components, we would not expect 
you to set limits for every potential contaminant or for every 
naturally occurring constituent of a botanical. Rather, we agree with 
the comments that the substances you would consider when determining 
whether to set limits for particular types of contamination would vary 
depending on the source of a component, such as a plant source, an 
animal source, a microbial source, or a marine source.
    (Comment 156) Some comments point out that some compounds, such as 
mycotoxins, that are toxic at higher levels are detectable in nearly 
all plant ingredients and are found in the food supply. A few comments 
assert that dietary ingredients should not contain levels of certain 
toxic compounds that are higher than reasonable or higher than 
recognized maximum allowable limits as opposed to the zero tolerance 
for toxic compounds contained in the 2003 CGMP Proposal.
    One comment requests clarification of the term ``toxic 
substances.'' One comment points out that information for identifying 
potential adulterants is provided in monographs. Another comment 
requests clarification on whether dietary supplement manufacturers will 
be required to test for toxins while food manufacturers, who may use 
some of the same ingredients, will not.
    (Response) As the comments point out, the food supply does contain 
some degree of contaminants such as mycotoxins that can be found, for 
example, in certain grain. We do not have a ``zero tolerance'' policy 
for such unavoidable contaminants but we have issued some regulations 
and guidance to address certain common contaminants. We also have 
issued a booklet entitled ``Action Levels For Poisonous Or Deleterious 
Substances In Human Food And Animal Feed'' (Ref. 30; available at 
http://www.cfsan.fda.gov). The booklet is a useful resource for 
manufacturers who seek information about common contaminants that may 
adulterate a dietary supplement product or lead to adulteration. 
Another resource is the Foods Chemical Codex,\9\ which includes 
monographs on many substances, such as salts that are used as sources 
of minerals used in both dietary supplements and conventional food. 
These monographs include limits on common contaminants, such as lead or 
other heavy metals. In addition, the regulations in 21 CFR part 109 
provide information about certain contaminants.
---------------------------------------------------------------------------

    \9\The Food Chemicals Codex (FCC) project is an activity of the 
Food and Nutrition Board of the Institute of Medicine. The FCC was 
intended to provide standards for the purity of food chemicals and 
thus promote uniform quality and ensure safety in the use of such 
chemicals. The First Edition of the resulting FCC, published in 
1966, was limited to chemicals added directly to foods to achieve a 
desired technological function. Succeeding editions upgraded the 
specifications for these substances and added specifications for 
substances that come into contact with foods and some that are 
regarded as foods, rather than as additives. The FCC is available 
for purchase at 1-800-624-6242 or at http://www.nap.edu.
---------------------------------------------------------------------------

    (Comment 157) One comment recommends that all finished products be 
tested for microorganisms. Another comment contends the manufacturer 
should be allowed to restrict testing to the raw material if the 
facility and equipment are monitored for contamination. Some comments 
point out that contaminants may be detectable in raw materials but not 
in the finished product.
    (Response) We disagree that all finished products must, as a matter 
of course, be tested for contamination with microorganisms. Whether it 
is necessary to test the finished product for microorganisms would 
depend, for example, on the characteristics of your product, the nature 
and source of your components, the specifications you establish for 
microbial contaminants in your components and whether these 
specifications are addressed in a certificate of analysis, the in-
process specifications you establish, and the nature of your 
manufacturing process. However, these comments raise an important 
point--i.e., that microbial contamination could occur at your facility 
even if an incoming component is free of microorganisms. Final subpart 
K discussed in section XVI of this document, sets forth requirements 
for your manufacturing operations. Many of these requirements are 
designed to limit the potential for contamination with microorganisms.
    (Comment 158) Some comments would revise the requirements for 
establishment of specifications for in-process controls (proposed Sec.  
111.35(e)(2)) and the finished batch of dietary supplements (proposed 
Sec.  111.35(e)(3)), so that specifications for attributes of quality, 
strength, and composition are not required for a product that does not 
purport to possess such attributes.
    (Response) We decline to reword the provision as requested by these 
comments. The requirement to establish specifications for strength and 
composition relate to the manufacturers' responsibility to know what 
their finished dietary supplement is

[[Page 34841]]

composed of so that their products are consistently manufactured. 
Establishing specifications and following these CGMP requirements will 
help ensure the quality of the dietary supplement. The requirement to 
establish specifications is not limited to when a manufacturer purports 
that its product possesses attributes of strength and composition on 
the label. As discussed in the 2003 CGMP Proposal (68 FR 12157 at 
12162), the absence of minimum standards has contributed to the 
adulteration and misbranding of dietary supplements because of 
contaminants or because manufacturers do not set and meet 
specifications for their products, including specifications for 
identity, purity, strength, and composition and do not set and meet 
limits on contaminants, when necessary. The comment does not persuade 
us otherwise. We note, however, that the final rule's requirements to 
establish specifications for components do, in fact, provide 
flexibility so that you are not required to establish a component 
specification for certain attributes, such as the strength of a tablet 
coating agent (see the discussion of final Sec.  111.70(b) in this 
section).
    (Comment 159) One comment asks for guidance as to what constitutes 
an official or scientifically valid standard for specifications.
    (Response) We are not aware of any officially recognized standard 
for specifications. Specifications are critical standards that are 
proposed and justified by the manufacturer for each product that the 
manufacturer produces. The manufacturer establishes the set of criteria 
to which a product should conform to be considered acceptable for its 
intended use. In general, a specification may include a list of tests, 
references to analytical procedures, and appropriate acceptance 
criteria that are numerical limits, ranges, or other criteria for the 
tests described.
    (Comment 160) One comment asks that we clarify whether every 
specification sheet must include separate, specific qualitative or 
quantitative standards, and tests to be established for each attribute, 
or whether a specification sheet can be modeled after a compendial 
monograph. Some comments state that product specification sheets should 
be modeled after pharmacopoeia monographs other than those listed in 
the preamble to the 2003 CGMP Proposal.
    (Response) These CGMP requirements do not establish any 
requirements to have a ``specification sheet.'' Rather, the final rule 
(final Sec.  111.70(a)) requires you to establish a specification for 
any point, step, or stage in the manufacturing process where control is 
necessary to ensure the quality of the dietary supplement and that the 
dietary supplement is packaged and labeled as specified in the master 
manufacturing record. We require that you establish specifications for 
components (final Sec.  111.70(b)), in-process production (final Sec.  
111.70(c)), labels and packaging (final Sec.  111.70(d)), the finished 
batch of dietary supplement (final Sec.  111.70(e)), product that you 
receive from a supplier for packaging and labeling (final Sec.  
111.70(f)), and the packaging and labeling for the finished packaged 
and labeled dietary supplement (final Sec.  111.70(g)). The general 
requirement for establishing specifications in final Sec.  111.70(a) 
includes specifications, not otherwise required in final Sec.  
111.70(b) through (g), that the manufacturer determines are necessary 
to achieve quality, i.e., that are necessary to meet the identity, 
purity, strength, or composition of the dietary supplement or that are 
necessary to prevent adulteration under section 402(a)(1), (a)(2), 
(a)(3), and (a)(4) of the act.
    Requirements to establish specifications to control for 
contamination are included in final Sec.  111.70(a), (b), (c), and (e). 
As discussed earlier, the specifications for contaminants in final 
Sec.  111.70(b) refer to those types of contamination of a component or 
dietary supplement that may adulterate or that may lead to adulteration 
that are due to contaminants that may be present in or on the 
components that you receive, based on the nature of the product, its 
source, its handling prior to receipt, or other reason. Limits are 
established by the manufacturer for such contaminants at receipt.
    The requirement to establish specifications to control for 
contamination under final Sec.  111.70(a) and (c) include 
specifications necessary to prevent adulteration under section 
402(a)(1), (a)(2), (a)(3), and (a)(4) of the act as a result of what 
the manufacturer may do or fail to do in its manufacturing operation, 
and not as a result of contaminants that are in or on the components 
received. For example, it may be critical that a certain piece of 
equipment be cleaned and/or sanitized after handling certain raw 
materials to ensure that there is no microbial contamination from 
microorganisms of public health significance to components processed on 
the equipment. If the manufacturer failed to establish a specification 
for cleaning and/or sanitizing after handling those raw materials 
before processing components, the manufacturer would have failed to 
establish a specification required by final Sec.  111.70(a) or (c) 
necessary to prevent a type of contamination that may lead to 
adulteration under section 402(a)(4) of the act. We would consider it a 
failure to follow CGMP requirements if a manufacturer allowed 
conditions in the manufacture of a dietary supplement that would not 
ensure the quality of the dietary supplement.
    We have specified in final Sec.  111.70(b) that you must establish 
certain types of specifications that are critical to ensuring that you 
know what the components are that you use in manufacturing a dietary 
supplement and that are necessary to ensure that the dietary 
supplements you manufacture meet their specifications for identity, 
purity, strength, composition, and do not exceed their limits for 
contaminants. The identity, purity, strength, and composition, and the 
limits that you establish for contaminants, for a finished batch of 
dietary supplement are what we call ``product specifications'' in final 
Sec.  111.70(e). These product specifications must be met in order for 
you to ensure the quality of your finished batch of dietary supplement. 
A specification may include a list of tests, references to analytical 
procedures, and appropriate acceptance criteria that are numerical 
limits, ranges, or other criteria for the tests described. For example, 
a specification for a component may include information about the test 
used to verify the identity of the component and the range of test 
results that are acceptable. Under final Sec.  111.70(c), a 
specification for an in-process control may include information about 
the viscosity that must be achieved during a batch production of a 
liquid product and information about the test or equipment used to 
measure the viscosity. Under final Sec.  111.70(d), a specification for 
packaging may include the specific type or grade of plastic. Under 
final Sec.  111.70(e), a specification for the finished batch may 
include the quantitative amount of a dietary ingredient, such as 
vitamin C.
    Under this final rule, the manufacturer has the flexibility--and 
the responsibility--to develop specifications that are appropriate to 
the circumstances, including whether information in any particular 
monograph is an appropriate model for a given dietary supplement.
1. Final Sec.  111.70(a)
    Final Sec.  111.70(a) requires you to establish a specification for 
any point, step, or stage in the manufacturing process where control is 
necessary to

[[Page 34842]]

ensure the quality of the dietary supplement and that the dietary 
supplement is packaged and labeled as specified in the master 
manufacturing record. Final Sec.  111.70(a) derives from the opening 
statement in proposed Sec.  111.35(e).
    As we discussed in the preamble to the 2003 CGMP Proposal (68 FR 
12157 at 12196), the points, steps, or stages where specifications must 
be established may include heating steps, cooling steps, points where 
specific sanitation procedures are needed, product formulation control 
steps, points where cross-contamination may occur, and steps where 
employee and environmental hygiene are necessary to ensure the quality 
of the dietary supplement. These specifications are regulatory 
specifications addressed by these CGMP regulations. The final rule does 
not prevent you from establishing additional, nonregulatory 
specifications that are not at points, steps, or stages where control 
is necessary to ensure the quality of the dietary supplement. For 
example, you could establish specifications that largely address the 
appearance of the dietary supplement in an aesthetic sense. Such 
nonregulatory specifications are not addressed by the final rule.
    (Comment 161) One comment notes that labelers would not be subject 
to proposed Sec.  111.35(e).
    (Response) Consistent with final Sec.  111.1, persons who perform 
labeling operations are, in fact, subject to the final rule, including 
the requirements to establish specifications. As discussed in this 
section, the final rule includes an explicit requirement that, if you 
receive a product from a supplier for packaging or labeling as a 
dietary supplement (and for distribution rather than for return to the 
supplier), you must establish specifications to ensure that the product 
that you receive is adequately identified and is consistent with your 
purchase order (final Sec.  111.70(f)).
    (Comment 162) One comment asks whether the manufacturer determines 
where control is ``necessary'' to prevent adulteration.
    (Response) In accordance with the changes made to the section, the 
manufacturer does determine where control is necessary to ensure the 
quality of the dietary supplement.
    (Comment 163) Some comments express concern that manufacturers who 
must confirm the validity of subjective criteria established as 
specifications may set the specifications as low as possible or set 
meaningless specifications.
    (Response) The specifications you must establish under this final 
rule are designed to ensure the quality of the dietary supplement that 
you manufacture. It is not meaningless to establish requirements that 
will ensure, for example, the product meets the established 
specifications for identity, purity, strength, and composition, and is 
within specified limits on contaminants to prevent adulteration.
    (Comment 164) Some comments express concern that the language of 
proposed Sec.  111.35(e) may require specifications beyond those 
already required in the master manufacturing record, as stated in 
proposed Sec.  111.45(a)(1), to identify specifications for the points, 
steps, or stages in the manufacturing process where control is 
necessary to prevent adulteration, or may require specifications for 
attributes that are not present at all stages. These comments urge us 
to be flexible during inspections as to what specifications are 
appropriate.
    (Response) Final Sec.  111.70(a) provides the manufacturer with 
flexibility in determining what specifications may be necessary for its 
operation. Moreover, final Sec.  111.70(a) through (g) provide the 
manufacturer with flexibility to determine what the specifications 
require in order to ensure the quality of the dietary supplement.
2. Final Sec.  111.70(b)
    Final Sec.  111.70(b) requires you to establish component 
specifications for each component you use in the manufacture of a 
dietary supplement. Under final Sec.  111.70(b)(1), you must establish 
an identity specification for each component that you use in the 
manufacture of a dietary supplement. A specification for identity may 
include more than one attribute. For example, a specification for the 
identity of a salt used in the manufacture of a vitamin and mineral 
supplement may include the physical characteristics of the solid (e.g., 
as a crystal or as a powder), the color, and the state of hydration 
(e.g., with two or three molecules of water). A specification for the 
identity of a botanical may include the part of the plant (e.g., roots 
or leaves), the color, and whether the part of the plant is in a native 
state or has been ground. Under final Sec.  111.70(b)(2), you must 
establish component specifications that are necessary to ensure that 
specifications for the purity, strength, and composition of dietary 
supplements manufactured using the components are met. Under final 
Sec.  111.70(b)(3) you must establish limits on those types of 
contamination that may adulterate or may lead to adulteration of the 
finished batch of the dietary supplement to ensure the quality of the 
dietary supplement. Final Sec.  111.70(b) derives from proposed Sec.  
111.35(e)(1) and (k). Final Sec.  111.70(b) is consistent with 
comments, already discussed, that recommended the provisions of 
proposed Sec.  111.35(k), regarding contaminants that could adulterate 
a product, be incorporated into proposed Sec.  111.35(e). In addition, 
as discussed previously with respect to final Sec.  111.55, final Sec.  
111.70(b) provides that the required component specifications you must 
establish for a dietary supplement include identity, purity, strength, 
and composition.
    (Comment 165) A few comments state it is appropriate and acceptable 
to establish a requirement for a specification for the identity and 
purity of components, insofar as such specifications are necessary to 
ensure that components are not contaminated with substances having 
public health significance. However, these comments argue that 
specifications for quality, strength, and composition of components 
should only be required for the quality, strength, and composition that 
a component is purported to possess. One comment notes this would 
provide the same requirement that is currently established for drug 
products and processing. Some comments recommend that specifications 
should be established ``as appropriate'' or ``where control is 
necessary to assure production of a quality product.''
    (Response) After considering the comments that questioned the need 
to establish specifications for the identity, purity, quality, 
strength, and composition of components, as well as the general 
comments that led to the overall approach that focuses on building 
quality into a dietary supplement at every stage of the production and 
process control system (see discussion in section IV of this document), 
we are requiring in final Sec.  111.70(b)(1) that you establish an 
identity specification for components that you use. This identity 
specification is necessary to ensure that the finished dietary 
supplement meets its specification for identity because you could not 
know what your final product contains if you do not know what you put 
into it. In addition, final Sec.  111.70(b)(2) requires you to 
establish those component specifications for purity, strength, and 
composition that are necessary to ensure that specifications for the 
purity, strength, and composition of dietary supplements manufactured 
using the components are met.
    Final Sec.  111.70(b)(2) provides flexibility for you to determine 
which component specifications other than identity are, or are not, 
necessary to

[[Page 34843]]

ensure that the final dietary supplement meets its specifications. For 
example, it is likely that you will need to establish a specification 
for the strength of vitamin C added as a component, that you use to 
make a multivitamin supplement, so that you will know how much vitamin 
C to add to satisfy the specification for the strength of the vitamin C 
in the final product. Thus, if you are manufacturing a vitamin C tablet 
with a strength of 50 milligrams (mg) per tablet, you must determine 
how much vitamin C, of a given strength, you must add in order to 
produce tablets that will contain 50 mg, after accounting for the 
theoretical yield at each step in the manufacturing process. However, 
you may not need to establish a specification for the strength of the 
tablet coating agent for that multivitamin supplement, if your final 
specifications include the amount of the tablet coating agent as part 
of the specifications for the composition, but not the strength of the 
multivitamin supplement. In most cases, a specification for the 
composition of the dietary supplement would be sufficient to ensure 
that the tablet coating agent is used within the established level.
    (Comment 166) A few comments express concern about how to determine 
certain specifications for botanicals, such as the strength of 
peppermint leaf. The comments explain that a specification for strength 
of peppermint leaf could be based on a number of different attributes. 
One comment argues that establishing specifications for all dietary 
ingredients may not contribute to any assurance of product quality and 
will not protect public health. Some comments assert that ``quality, 
strength, and composition'' are subjective with respect to botanical 
ingredients for which no potency claim is made, and, thus, these 
attributes should not be included in the rule. Another comment asserts 
proposed Sec.  111.35(e)(1) goes beyond either food or drug CGMPs and 
that the composition of approximately 1,200 botanicals used in the 
industry will be impossible to determine in an economically feasible 
manner.
    (Response) To the extent that these comments assert that this final 
rule should not require you to establish specifications for the 
strength and composition of botanical ingredients, we disagree. As 
explained in response to comment 145, it is fundamental to CGMPs that 
you know what components are used to manufacture your dietary 
supplement and to ensure that the finished batch of dietary supplement 
contains the established identity, purity, strength, and composition. 
As explained in response to comment 40, this final rule does not 
require that you establish specifications for the identity, purity, 
strength, or composition of the various constituents that are 
inherently present in a natural product such as a botanical. However, 
as previously discussed in section VI of this document, depending on 
what you are manufacturing, the product specifications for the finished 
batch of a dietary supplement may include a specification, for example, 
of the strength of a substance that is present in the dietary 
supplement because it is a constituent of a natural product that you 
add as a component. For example, you may establish a specification for 
the amount of vitamin C in a dietary supplement that you manufacture by 
adding the component rose hips. If this is the case, then the component 
specifications for the natural product must include a specification for 
the strength of the constituent (e.g., vitamin C) in whatever amount 
you determine is necessary to meet the specification for the 
constituent (vitamin C) in the finished batch of dietary supplement.
    (Comment 167) One comment asserts it would be more appropriate for 
proposed Sec.  111.35(e)(1) to address components ``that you purchase'' 
than to address components ``that you receive,'' because customers 
sometimes provide the ingredient or product to be processed and the 
customer, rather than the manufacturer, establishes the specifications.
    (Response) Final Sec.  111.70(b) (derived from proposed Sec.  
111.35(e)(2)) requires that component specifications be established for 
each component that you use in the manufacture of a dietary supplement. 
Thus, the firm must establish specifications for the components it uses 
to manufacture a dietary supplement, regardless of whether it 
manufactures the components itself or contracts with another firm to 
manufacture the components. The firm that conducts the manufacturing 
operations, as explained in section VI of this document, would be 
responsible for complying with all relevant CGMP requirements in this 
final rule related to its operations.
    (Comment 168) One comment asserts that proposed Sec.  111.35(e)(1) 
is unnecessary because the requirements for testing to meet the 
manufacturer's specifications are described elsewhere.
    (Response) We disagree. The requirements to establish 
specifications are distinct from what you must do to determine whether 
specifications are met. Under the final rule (Sec.  111.73), you have a 
responsibility to determine whether the established specifications are 
met. What criteria you must use in order to determine whether 
specifications are met are set forth in final Sec.  111.75.
3. Final Sec.  111.70(c)
    Final Sec.  111.70(c)(1) requires you, for in-process production, 
to establish in-process specifications for any point, step, or stage in 
the master manufacturing record where control is necessary to help 
ensure that specifications are met for the identity, purity, strength, 
and composition of the dietary supplements and, as necessary, for 
limits on those types of contamination that may adulterate or may lead 
to adulteration of the finished batch of the dietary supplement. Final 
Sec.  111.70(c)(1) derives from proposed Sec.  111.35(e)(2). Final 
Sec.  111.70(c)(1) includes a nonsubstantive, editorial change that we 
are making for consistency with other regulations in part 111. This 
change is to refer to ``in-process specifications for any point, step, 
or stage in the master manufacturing record where control is 
necessary'' rather than ``in-process controls in the master 
manufacturing record where control is necessary.''
    We also have added that you must establish in-process 
specifications, as necessary, for limits on those types of 
contamination that may adulterate or may lead to adulteration of the 
finished batch of the dietary supplement. This clarifies that if it is 
necessary to establish limits on contaminants in-process, due to 
contamination that may occur in the facility you do so under final 
Sec.  111.70(c)(1). With a requirement to set, as necessary, limits on 
contamination in-process, aspects of the production and process system 
from receipt to finished product are covered with respect to 
contamination. For example, under final Sec.  111.70(e) you may 
determine that you need to establish a microbiological specification 
that the aerobic plate count of your finished batch of the dietary 
supplement will not exceed a certain number of colony forming units per 
gram of product. Under the written instructions in your master 
manufacturing record (final Sec.  111.210(h)) and your written 
procedures for manufacturing operations (final Sec.  111.353), you 
would establish controls to prevent microbial contamination at each 
point, step, or stage in the manufacturing process where control is 
necessary to prevent microbial contamination. To ensure that you will 
meet the microbiological specification that you set for the finished 
batch of the dietary supplement, you may determine that it is necessary 
to establish a specification

[[Page 34844]]

for the aerobic plate count at an intermediate stage of the in-process 
production.
    Final Sec.  111.70(c)(2) requires you, for in-process production, 
to provide adequate documentation of your basis for why meeting the in-
process specifications, in combination with meeting component 
specifications, will help ensure that the specifications are met for 
identity, purity, strength, and composition of the dietary supplements 
and for limits on those types of contamination that may adulterate or 
may lead to adulteration of the finished batch of the dietary 
supplement. Final Sec.  111.70(c)(3) requires that quality control 
personnel review and approve the documentation you provide under final 
Sec.  111.70(c)(2). Final Sec.  111.70(c)(3) also derives in part from 
proposed Sec.  111.37(b)(1) which would require the quality control 
unit to approve or reject all processes that may affect the identity, 
purity, strength, or composition of a dietary supplement.
    In final Sec.  111.70(c)(2), we are requiring documentation that 
includes the basis for why meeting the in-process specifications, in 
combination with meeting the component specifications will help ensure 
the specifications for the identity, purity, strength, and composition 
of the dietary supplement and limits on contamination are met. Meeting 
in-process specifications alone may not ensure the identity, purity, 
strength, or composition of the dietary supplement, but information 
about the component specification may be needed in order to put the 
results from the in-process specification in perspective. For example, 
if the manufacturer establishes a component specification for lead that 
it not be greater than ``x'' mg and establishes a specification that 
all piping that comes into contact with the component be lead free in 
the facility, and there are no other components or equipment that would 
be a source of lead, then there should be no added lead from 
processing, provided that the material only came in contact with the 
lead-free pipes and only the other lead-free components and equipment 
are used. Thus, we would not know by looking solely at the in-process 
specification whether the lead in the final product is not greater than 
``x'' mg. We would need to evaluate the component specification, in 
addition to the in-process specification, to ensure that the final 
product contains no greater than ``x'' mg lead. To emphasize the 
interplay of the specifications and component specifications in 
ensuring the specifications are met for the identity, purity, strength, 
and composition of dietary supplements, and, as necessary, for limits 
on contamination, final Sec.  111.70(c)(1) and (c)(2) state ``help 
ensure'' rather then ``ensure'' the identity, purity, strength, and 
composition of dietary supplements and for limits on contamination.
    (Comment 169) One comment asserts monitoring and process controls 
are more practical and effective than the proposed requirements for in-
process testing, which the comment asserts are overly broad and could 
impose an undue burden on small businesses.
    (Response) The comment's objection is unclear. The final rule 
requires that you establish in-process specifications for any point, 
step, or stage in the master manufacturing record where control is 
necessary in the manufacturing process to help ensure that 
specifications are met for the identity, purity, strength, and 
composition of the dietary supplement and, as necessary, for limits on 
contamination. You must monitor the in-process points, steps, or 
stages, where control is necessary to ensure the quality of the 
finished batch of dietary supplement, to determine whether the in-
process specifications are met and to detect any deviation or 
unanticipated occurrence that may result in a failure to meet 
specifications (see final Sec.  111.75(b)). The final rule does not 
establish specific requirements for in-process monitoring. The 
manufacturer must determine any in-process monitoring that is necessary 
to ensure that the specifications are met for the finished batch. 
Examples of such monitoring include measuring pH or viscosity.
4. Final Sec.  111.70(d)
    Final Sec.  111.70(d) requires you to establish specifications for 
dietary supplement labels (label specifications) and for packaging that 
may come in contact with dietary supplements (packaging 
specifications). Final Sec.  111.70(d) derives from proposed Sec.  
111.35(e)(4). Further, Sec.  111.70(d) requires that packaging that may 
come into contact with dietary supplements must be safe and suitable 
for its intended use and must not be reactive or absorptive or 
otherwise affect the safety or quality of the dietary supplements, 
consistent with proposed Sec.  111.35(e)(4). We deleted the phrase 
``comply with other statutory and regulatory provisions'' from proposed 
Sec.  111.35(e)(4) because the requirement was redundant to final Sec.  
111.5.
5. Final Sec.  111.70(e)
    Final Sec.  111.70(e) requires you, for each dietary supplement 
that you manufacture, to establish product specifications for the 
identity, purity, strength, and composition of the finished batch of 
the dietary supplement, and for limits on those types of contamination 
that may adulterate or may lead to adulteration of the finished batch 
of the dietary supplement, all to ensure the quality of the dietary 
supplement. Final Sec.  111.70(e) derives from proposed Sec.  
111.35(e)(3) and (k). Final Sec.  111.70(e) is consistent with 
comments, already discussed, recommending that the provisions of 
proposed Sec.  111.35(k) regarding contaminants that could adulterate a 
product be incorporated into proposed Sec.  111.35(e).
6. Final Sec.  111.70(f)
    Final Sec.  111.70(f) requires you, if you receive a product from a 
supplier for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier), to establish 
specifications to provide sufficient assurance that the product you 
receive is adequately identified and is consistent with your purchase 
order. Final Sec.  111.70(f) derives from proposed Sec.  111.35(e)(1) 
which would, in part, require you to establish specifications for 
dietary supplements that you receive. Final Sec.  111.70(f) includes 
changes we are making after considering comments.
    (Comment 170) One comment notes that labelers would not be subject 
to proposed Sec.  111.35(e). Other comments request we clarify the 
roles of the various parties in the ``pre-consumer supply chain'' for 
dietary supplements. One comment suggests that manufacturers and 
packagers be responsible for establishing specifications only for the 
operations occurring in their own facility or for which they are 
otherwise responsible (e.g., subcontracted operations), not for 
upstream or downstream operations over which they may not have any 
control. This comment states that we intended to relieve packagers from 
establishing specifications for the dietary supplements that they 
package, and also states that such requirements should not be in the 
CGMP regulations.
    (Response) We have discussed, in section VI of this document, who 
is subject to the final rule under Sec.  111.1 in what the comment 
describes as the ``pre-consumer supply chain'' and do not repeat that 
discussion. We agree that packagers and labelers must establish 
specifications for the dietary supplements that they package and did 
not intend to relieve them of complying with relevant CGMP 
requirements. We recognize that a firm that only packages and labels a 
product may rely on

[[Page 34845]]

information about the content of the product that it receives from the 
manufacturer. The information may consist of an invoice, certificate, 
guarantee, or other form of verification as to what the product 
consists of so that the packager or labeler has adequate information 
about the dietary supplement it receives to label the product and to 
ensure that the product is consistent with its purchase order. 
Therefore, we are setting forth certain requirements that distinguish a 
product you receive for packaging or labeling as a dietary supplement 
(and for distribution rather than for return to the supplier) from a 
product you manufacture. One such requirement is final Sec.  111.70(f) 
which requires you to establish specifications for a product you 
receive for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier).
    The inclusion of final Sec.  111.70(f), or any other provision that 
relates explicitly to a product you receive for packaging or labeling 
as a dietary supplement, does not alter the fact that such a product is 
no different from any other dietary supplement as far as the 
applicability of these CGMP requirements.
    Under final Sec.  111.70(f), the specifications you establish for a 
product you receive for packaging or labeling as a dietary supplement 
must provide sufficient assurance that the received product is 
adequately identified and is consistent with your purchase order. For 
example, you may be purchasing tablets that provide 500 mg (strength) 
(quantitative amount per serving) of vitamin C (identity). Therefore, 
your purchase order would need to include the identity and amount of 
vitamin C per tablet to distinguish it from other tablets of vitamin C 
that may contain only 60 mg, or from other vitamin tablets of 500 mg 
that you may also purchase.
    Final Sec.  111.70(f) sets forth a requirement for a product you 
receive for packaging or labeling as a dietary supplement that will be 
distributed by you, rather than returned to the firm from which you 
receive the product. Thus, Sec.  111.70(f) applies to product that has 
left the control of the person who manufactured the batch.
    If you are a packager or labeler who packages and labels for the 
manufacturer and you will return the packaged and labeled dietary 
supplement to the manufacturer, we would not consider that you are 
``receiving'' product within the meaning of final Sec.  111.70(f). 
Thus, you would not be subject to final Sec.  111.70(f).
    (Comment 171) Some comments assert that ``packaging'' should be 
included with ``manufacturing process,'' but that a firm involved only 
in ``holding'' a product should not have to set specifications.
    (Response) Under final Sec.  111.70(a), a person who holds packaged 
and labeled dietary supplements for distribution and who does no 
manufacturing, packaging, or labeling, would be required to establish a 
specification for any point, step, or stage in the manufacturing 
process where control is necessary to ensure the quality of the dietary 
supplement. For example, a person may need to establish a specification 
for the temperature at which the product will be held. However, a 
person who only holds packaged and labeled dietary supplements for 
distribution is not required to establish component specifications 
(final Sec.  111.70(b)), in-process specifications (final Sec.  
111.70(c)), specifications for labels and for packaging (final Sec.  
111.70(d)), product specifications (final Sec.  111.70(e)), 
specifications for product received from a supplier for packaging as a 
dietary supplement (and for distribution rather than for return to the 
supplier) (final Sec.  111.70(f)), or specifications for the packaging 
and labeling of the finished packaged and labeled dietary supplements 
(final Sec.  111.70(g)) because the person does not engage in any of 
those activities. This is consistent with the views expressed by the 
comments regarding the applicability of proposed Sec.  111.35(e) to 
persons who only hold packaged and labeled dietary supplements for 
distribution.
7. Final Sec.  111.70(g)
    Final Sec.  111.70(g) requires you to establish specifications for 
the packaging and labeling of the finished packaged and labeled dietary 
supplements, including specifications that ensure you used the 
specified packaging and you applied the specified label.
    Final Sec.  111.70(g) is a new provision we are adding for clarity 
and consistency. We had proposed to require that you conduct a material 
review and make a disposition decision of any packaged and labeled 
dietary supplements that do not meet specifications (proposed Sec.  
111.70(c)). We proposed minimum standards for packaged and labeled 
dietary supplements--i.e., we would require that the quality control 
unit collect representative samples of each batch of packaged and 
labeled dietary supplements to determine whether you used the packaging 
specified in the master manufacturing record and applied the label 
specified in the master manufacturing record (proposed Sec.  
111.37(b)(11)(iv)). Final Sec.  111.70(g) includes the minimum 
standards that we proposed to establish for packaged and labeled 
dietary supplements in proposed Sec.  111.37(b)(11)(iv).
    To make clear that the use of packaging and labels for a final 
packaged and labeled product must be that which is specified in the 
master manufacturing record, we have created a separate provision 
(under final Sec.  111.70(g)) requiring you to create the relevant 
specifications to be met.
    Final Sec.  111.70(g) requires you to establish specifications that 
ensure you use the ``specified packaging'' and to apply the ``specified 
label'' as we proposed under proposed Sec.  111.37(b)(11)(iv). We 
removed the words ``specified in the master manufacturing record'' as 
an editorial change that we are making to simplify the language of the 
requirement.
    As already explained (see discussion of final Sec.  111.70(a)), the 
specifications you establish under final Sec.  111.70 are regulatory 
specifications required by these final CGMP requirements. The final 
rule would not prevent you from establishing additional, nonregulatory 
specifications, such as specifications that largely address the 
appearance of the dietary supplement in an aesthetic sense.

H. What is Your Responsibility for Determining Whether Established 
Specifications Are Met? (Final Sec.  111.73)

    Final Sec.  111.73 requires you to determine whether all 
specifications you establish under final Sec.  111.70 are met. The 
criteria for determining whether the specifications that you establish 
under final Sec.  111.70 are met are set forth in final Sec.  111.75. 
The oversight by quality control personnel for determining whether 
specifications established under final Sec.  111.70 are met in 
accordance with the criteria established under final Sec.  111.75 and 
under what conditions quality control personnel can approve deviations 
from specifications are set forth in final Sec.  111.77 and final 
subpart F. Although final Sec.  111.73 requires you to determine 
whether specifications are met, it is the responsibility of quality 
control personnel to conduct a material review and make a disposition 
decision if a specification established in accordance with final Sec.  
111.70 is not met.
    Final Sec.  111.73 derives, in part, from proposed Sec.  111.35(f), 
(g), and (h). Final Sec.  111.73 includes changes associated with 
reorganization, and other revisions associated with final Sec.  111.70. 
Final Sec.  111.73 neither includes any finished

[[Page 34846]]

batch testing requirements that derive from proposed Sec.  111.35(g)(3) 
nor specifies what you must do to determine whether all specifications 
are met because the requirements for what means and methods you must 
use to determine whether specifications are met, including certain 
requirements for testing, are set forth in final Sec.  111.75.
    The comments relevant to final Sec.  111.73 are the general 
comments that recommend an overall approach that focuses on building 
quality into a dietary supplement throughout the production and process 
control system. Because the primary focus of the relevant comments is 
on the proposed requirements for testing, we discuss those comments 
when we describe the derivation of the testing requirements in final 
Sec.  111.75.

I. What Must You Do to Determine Whether Specifications Are Met? (Final 
Sec.  111.75)

    Final Sec.  111.75 derives from proposed Sec. Sec.  111.35(f), (g), 
(h), (k), and (l); 111.37(b)(11); and 111.40(a) and (b). Final Sec.  
111.75 describes the steps you must take to determine whether 
specifications are met.
    (Comment 172) Many comments assert that the CGMPs for dietary 
supplements should place greater emphasis on in-process controls and 
HACCP principles. The comments state FDA's narrow focus on finished 
product testing is not in line with the philosophy of HACCP, in which 
manufacturing steps are controlled and verified so as to result in end 
products that are safe, with minimal finished product testing. One 
comment cites a 1997 document entitled ``Hazard Analysis and Critical 
Control Point Principles and Application Guidelines'' in which we state 
that ``[A]n effective HACCP system requires little end-product testing, 
since sufficient validated safeguards are built-in early in the 
process.'' (Ref. 31).
    (Response) In the 1997 ANPRM, we asked for comments on whether 
certain, or all, of the requirements for manufacturing and handling 
dietary ingredients and dietary supplements may be more effectively 
addressed by a regulation based on the principles of HACCP, rather than 
the system outlined in the industry submission (62 FR 5700 at 5708). 
HACCP is a science-based, systematic approach to preventing food safety 
problems by anticipating how such problems are most likely to occur and 
by installing effective measures to prevent them from occurring. The 
HACCP concept is a systematic approach to the identification and the 
assessment of risk (likelihood of occurrence and severity), and control 
of the biological, chemical, and physical hazards associated with a 
particular food production process or practice. HACCP is a preventive 
strategy. It is based on development by the food producer of a plan 
that anticipates food safety hazards and identifies the points in the 
production process where a failure would likely result in a hazard 
being created or allowed to persist; these points are referred to as 
critical control points (CCPs).
    Under HACCP, identified CCPs are systematically monitored, and 
records kept of that monitoring. Corrective actions are taken when 
control of a CCP is lost, including proper disposition of the food 
produced during that period, and these actions are documented. Thus, 
the focus of a HACCP-based approach is to anticipate food safety 
hazards, take actions to prevent them, and keep records of both the 
actions taken to prevent problems and the actions taken if a problem 
nonetheless occurs.
    As discussed in the preamble to the 2003 CGMP Proposal (68 FR 12157 
at 12174), most of the comments that we received to the ANPRM opposed 
basing a CGMP regulation for dietary supplements on HACCP principles. 
Consistent with those comments, we proposed certain requirements that, 
although consistent with a HACCP-based approach, did not require a 
HACCP-based approach. For example, proposed Sec.  111.65 would 
establish requirements for manufacturing operations, including several 
proposed requirements to prevent contamination of components or dietary 
supplements, but would not require that you develop a specific plan for 
the precautions that you would take, or that you keep records of any 
monitoring that was directed solely at preventing specific types of 
contamination.
    In contrast to the specific focus of HACCP to anticipate food 
safety hazards, take actions to prevent them, and keep records of both 
the actions taken to prevent problems and the actions taken if a 
problem nonetheless occurs, CGMP requires that you take all necessary 
steps to both prevent hazards and ensure that the product that you 
manufacture is what you established in your specifications. The 
proposed testing requirements were directed at ensuring that a dietary 
supplement meets all of its established specifications, including 
specifications for the identity, purity, strength, and composition, 
rather than on ensuring only that specific food safety hazards that you 
take steps to prevent are not, in fact, present in the dietary 
supplement. The comments that assert that the CGMP requirements should 
place greater emphasis on HACCP principles and, in so doing, reduce the 
requirements to test product at the finished batch stage, did not 
explain how the preventive measures that are associated with a HACCP 
plan would be effective at ensuring that a dietary supplement is what 
you established it to be in your specifications. Therefore, we are not, 
as the comments request, including additional HACCP requirements as 
part of the overall approach set forth in this final rule.
    In the 2003 CGMP Proposal, we noted that you may voluntarily choose 
to implement a HACCP plan that meets the requirements of the National 
Advisory Committee on Microbiological Criteria for Foods, but that 
proposed part 111 would still apply to you (68 FR 12157 at 12174). We 
also noted that any HACCP plans that are intended to meet the records 
requirements under proposed part 111 would be treated as records under 
the CGMP regulations.
    (Comment 173) One comment states that it supports a requirement 
that a firm ensure that specifications have been met and asserts that 
the 2003 CGMP Proposal failed to do so. This comment asserts the 
specific testing requirements in proposed Sec.  111.35(g)(1) and (g)(2) 
must be significantly modified and suggests that a more effective 
approach would be to establish separate requirements for ensuring that 
specifications are met in each of the four categories addressed by 
proposed Sec.  111.35(e): Goods received (Sec.  111.35(e)(1)), in-
process controls (Sec.  111.35(e)(2)), manufactured goods (Sec.  
111.35(e)(3)), and labels and packaging (Sec.  111.35(e)(4)).
    (Response) The final rule is consistent with this comment. Final 
Sec.  111.70 requires you to establish certain specifications 
(including specifications for components, in-process controls, the 
finished batch and packaging and labels), and final Sec.  111.75 sets 
forth the requirements for what you must do to determine whether those 
specifications are met.
1. Final Sec.  111.75(a)
    Final Sec.  111.75(a)(1) requires you, before you use a component 
that is a dietary ingredient, to conduct at least one appropriate test 
or examination to verify the identity of the dietary ingredient. We 
recognize, however, that it may be possible for a manufacturer to 
demonstrate, through various methods and processes in use over time for 
its particular operation, that a system of less than 100 percent 
identity testing would provide no material diminution

[[Page 34847]]

of assurance of the identity of the dietary ingredient as compared to 
the assurance provided by 100 percent identity testing. To provide an 
opportunity for a manufacturer to make such a showing and reduce the 
frequency of identity testing of components that are dietary 
ingredients from 100 percent to some lower frequency, we decided to 
provide, in an interim final rule published elsewhere in this issue of 
the Federal Register, a procedure that allows for submission to, and 
review by, FDA of an alternative to the required 100 percent identity 
testing of components that are dietary ingredients, provided certain 
conditions are met.
    Final Sec.  111.75(a)(2) requires you, before you use a component, 
to confirm the identity of other components and determine whether other 
applicable component specifications established in accordance with 
Sec.  111.70(b) are met. To do so, final Sec.  111.75(a)(2) requires 
you to either conduct appropriate tests or examinations (final Sec.  
111.75(a)(2)(i)); or rely on a certificate of analysis from the suppler 
of the component that you receive (final Sec.  111.75(a)(2)(ii)). Final 
Sec.  111.75(a)(2)(ii) sets forth the criteria that you must satisfy in 
order to rely on a certificate of analysis from a supplier:
    <bullet> You must first qualify the supplier by establishing the 
reliability of the supplier's certificate of analysis through 
confirmation of the results of the supplier's tests or examinations;
    <bullet> The certificate of analysis must include a description of 
the test or examination method(s) used, limits of the test or 
examinations, and actual results of the tests or examinations;
    <bullet> You must maintain documentation of how you qualified the 
supplier;
    <bullet> You must periodically re-confirm the supplier's 
certificate of analysis; and
    <bullet> Quality control personnel must review and approve the 
documentation setting forth the basis for qualification (and re-
qualification) of any supplier.
    Final Sec.  111.75(a)(1) and (a)(2) derive, in part, from proposed 
Sec.  111.35(g) and (h) and proposed Sec.  111.40(a)(2) and (a)(3). 
Final Sec.  111.75(a)(1) and (a)(2) include changes that we are making 
after considering comments to proposed Sec. Sec.  111.35 and 111.40(a).
    (Comment 174) Many comments assert that a certificate of analysis 
from a properly certified supplier can be a key element of the 
manufacturing process, and reduce the need for testing at the finished 
batch stage. Some comments specifically recommend the dietary 
supplement manufacturer conduct identity tests to ensure that the 
correct component has been received (also, see comment 145 of this 
document).
    Some comments recommend an appropriate vendor qualification 
program, including a combination of vendor audits and product testing, 
to alleviate the need for complete testing of every lot of incoming 
components.
    Several comments stress that a meaningful certificate of analysis 
must be based on the results of actual analytical testing. One comment 
adds that reliance on a supplier's certificate of analysis should be 
conditioned on a qualification program whereby the recipient 
independently verifies the supplier's ability to conduct tests and 
verifies test results through confirmatory testing.
    Many comments provide suggestions for ways in which manufacturers 
could demonstrate the reliability of a certificate of analysis, which 
include the following: (1) Identity testing of ingredients and 
components, (2) maintenance of documentation of appropriate test 
results, (3) appropriate verification of the information provided 
initially and at appropriate intervals, and (4) documentation that any 
suppliers have adequate CGMP programs in place.
    Some comments recommend that vendor certification programs include 
plant visits and inspections, while other comments do not believe 
manufacturers should be required to conduct plant inspections. Other 
comments recommend that vendor certification programs include CGMP 
audits or process reviews at supplier facilities; verification of 
laboratory test results against a certificate of analysis; and 100 
percent inspection and testing of incoming materials for a specified 
period of time while reliability is being assessed.
    Some comments provide suggestions for the types of information that 
should be included on an acceptable certificate of analysis, such as 
moisture, sieve analysis, identity, and results of tests against 
established raw material specifications and specifications of any 
compendia referenced on the label. One comment suggests that a 
certificate of analysis could be converted into sworn affidavits to 
guarantee their reliability. Some comments suggest that a system of 
testing one batch for agreement with the certificate of analysis, and 
then relying on this information for future purchases, would work well 
if the suppliers are required to provide reliable and valid certificate 
of analysis documents. One comment suggests we issue guidelines as to 
what should be included in a properly verified certificate of analysis.
    Some comments address the requirement in proposed Sec.  
111.40(a)(2) to ``Visually examine the suppliers invoice, guarantee, or 
certification * * * and perform testing, as needed, to determine 
whether specifications are met.'' One comment agrees with this proposed 
requirement and asserts that the supplier's certification is not 
sufficient to ensure that appropriate standards are met. Other 
comments, however, disagree with this aspect of the proposed 
requirement or ask for further clarification. A few comments assert 
that manufacturers should not have to retest material already tested by 
a supplier. Some comments note that a certificate of analysis can be 
used for ensuring received materials are consistent with the purchase 
order, and assert the certificate of analysis can be an appropriate way 
to ensure specifications are met without requiring testing. One comment 
suggests the phrase ``perform testing, as needed'' be replaced with 
``perform testing, if necessary'' and that the CGMP regulations allow 
for the use of a certificate of analysis that has been verified through 
a vendor certification process. Another comment states that the 
provisions requiring testing in proposed Sec.  111.40(a)(2) are more 
burdensome than those required of food and pharmaceutical products and 
cites the drug CGMP provision that permits the use of certificates of 
analysis in lieu of testing for conformity with written specifications. 
One comment supports the idea of testing upon receipt in the specific 
circumstance when testing cannot be performed on the finished product.
    Several comments contend that there is a conflict between the 2003 
CGMP Proposal and our position during our stakeholder meetings. The 
comments assert that, at the meetings, FDA representatives recognized 
that a verified certificate of analysis is acceptable, provided it is 
based on appropriate testing from suppliers who are audited by their 
customers as to their testing and manufacturing practices.
    A few comments say the 2003 CGMP Proposal should allow more 
reliance on strict chain of custody and documentation requirements. 
Other comments recommend that manufacturers not be required to retest 
previously tested incoming ingredients if they arrive with the vendor's 
seal intact. Rather, the purchaser should be able to rely on the 
vendor's test results, as presented in a verified certificate of 
analysis, unless there has been a breach in quality control during 
distribution and subsequent manufacture. One

[[Page 34848]]

comment notes the Canadian regulations for Natural Health Products 
allow periodic testing of ingredients if a manufacturer has 
satisfactory evidence that the raw materials sold to him/her are 
consistently manufactured in compliance with established 
specifications.
    (Response) We agree that CGMP requires that a person who 
manufactures a dietary supplement conduct at least one appropriate test 
or examination to verify the identity of each dietary ingredient that 
will be used in the manufacture of the dietary supplement. For example, 
because some botanicals require microscopic examination and comparison 
to a reference to be distinguished, and because suppliers of such 
botanicals may manufacture several of these botanicals, it is important 
to verify that a botanical that you receive from a supplier is the 
correct botanical. In some cases, a single test or examination may be 
all that is needed to verify the identity of a dietary ingredient; in 
other cases, it may be necessary to conduct more than one test or 
examination. It is the responsibility of the manufacturer to determine 
the appropriate test(s) or examination(s) necessary to verify the 
identity of a dietary ingredient.
    The comments discussed the importance of testing all components for 
identity and did not appear to limit their recommendation for 
conducting identity tests to those components that are dietary 
ingredients. Based on the comments, we conclude that many firms would 
conduct an identity test for most ingredients and other components 
rather than limit identity testing to dietary ingredients. However, 
because dietary ingredients are the central defining ingredient of a 
dietary supplement, final Sec.  111.75(a) only requires you to conduct 
tests or examinations to verify the identity of any component that is a 
dietary ingredient. As discussed previously in this section, we 
recognize, however, that it may be possible for a manufacturer to 
demonstrate, through various methods and processes in use over time for 
its particular operation, that a system of less than 100 percent 
identity testing would provide no material diminution of assurance of 
the identity of the dietary ingredient as compared to the assurance 
provided by 100 percent identity testing. To provide an opportunity for 
a manufacturer to make such a showing and reduce the frequency of 
identity testing of components that are dietary ingredients from 100 
percent to some lower frequency, we decided to provide, in an interim 
final rule published elsewhere in this issue of the Federal Register, a 
procedure that allows for submission to, and review by, FDA of an 
alternative to the required 100 percent identity testing of components 
that are dietary ingredients, provided certain conditions are met. For 
components other than dietary ingredients you must confirm the identity 
of the component and you have the flexibility of relying on a 
certificate of analysis, in lieu of conducting a test or examination, 
to confirm identity. The preamble to the 2003 CGMP Proposal discussed 
why we were not proposing that you could rely on a certificate of 
analysis, but did not express a view as to whether the establishment of 
minimum criteria for how you would qualify the supplier, and for what 
must be included on the certificate of analysis, could alleviate our 
concerns about whether the certificate of analysis could ensure certain 
attributes of dietary supplements.
    After considering the comments, we also are persuaded that it is 
possible to rely on a certificate of analysis from the supplier, for 
attributes other than identity of the dietary ingredient, provided you 
satisfy certain minimum criteria set forth in final Sec.  
111.75(a)(2)(ii). These criteria include qualifying the supplier, 
maintaining documentation of how you qualified the supplier, 
periodically reconfirming the supplier's certificate of analysis, and 
having quality control personnel review and approve the documentation 
setting forth the basis for qualifying the supplier. These criteria 
also require that the certificate of analysis, at a minimum, includes a 
description of the test or examination method(s) used, limits of the 
tests or examinations, and the actual results of the tests or 
examinations. Under final Sec.  111.75(a)(2)(ii)(A), to qualify the 
supplier you must establish the reliability of the supplier's 
certificate of analysis through confirmation of the supplier's tests or 
examinations.
    Certain comments request that we provide guidance on what should be 
included in a certificate of analysis. As stated earlier in this 
section, a certificate of analysis is a document, provided by the 
supplier of a component prior to or upon receipt of the component, that 
documents certain characteristics and attributes of the component. 
Instead of guidance, we are establishing, in final Sec.  
111.75(a)(2)(ii)(B), minimum criteria that a certificate of analysis 
must meet to satisfy these CGMP requirements. As we gain experience in 
applying the CGMP regulations, we will consider whether it is 
appropriate to provide guidance on certificates of analysis.
    (Comment 175) One comment asks if a raw material contains an 
unknown amount of excipients, is it necessary to quantify the 
excipients or can a company simply assess the active material and rely 
on a vendor's specification for the excipient content?
    (Response) To the extent that this comment is asking whether it is 
necessary to set a component specification for the strength of 
excipients that are present in a dietary supplement, the final rule 
does not require you to do so provided that such a component 
specification is not necessary to ensure that the specifications for 
the purity, strength, composition, or contamination limit for the 
dietary supplement manufactured using the excipients are met (final 
Sec.  111.70(b)(2)). If such a strength specification for an excipient 
is necessary to ensure that the purity, strength, or composition 
specifications are met, or that a contamination limit is met for the 
dietary supplement, you could, as the comment suggested, rely on a 
certificate of analysis for that quantitative information provided that 
you satisfy the criteria set forth in final Sec.  111.75(a).
2. Final Sec.  111.75(b)
    Final Sec.  111.75(b) requires that you monitor the in-process 
points, steps, or stages where control is necessary to ensure the 
quality of the finished batch of dietary supplement, to determine 
whether the in-process specifications are met, and to detect any 
deviation or unanticipated occurrence that may result in a failure to 
meet specifications. Final Sec.  111.75(b) derives from proposed Sec.  
111.35(f) with revisions associated with final Sec.  111.70(c)(1).
    (Comment 176) A few comments argue that it is not possible to 
monitor in-process for those specifications required under proposed 
Sec.  111.35(e). One comment states that a specification such as 
identity is no longer identifiable at an in-process stage. This comment 
also notes any such requirement in proposed Sec.  111.35(e) would be 
redundant, because proposed Sec.  111.35(h) requires a firm to ensure, 
through testing or examination, that all established specifications are 
met. Another comment contends that some specifications are not met 
until processing is complete, such as with liquid extracts. A few 
comments recommend that the requirement for monitoring be limited to 
ensuring that specifications established for in-process controls under 
proposed Sec.  111.35(e)(2) and finished product under proposed Sec.  
111.35(e)(3) are met.

[[Page 34849]]

    One comment states it is not always possible for a manufacturer to 
monitor for strength and purity of raw materials during in-process 
steps. The comment suggests this proposed requirement be removed or 
revised.
    (Response) The comments may have misunderstood what we refer to as 
``in-process'' specifications. Under final Sec.  111.75(b), you must 
monitor the in-process points, steps, or stages where control is 
necessary to ensure the quality of the finished batch of dietary 
supplement, to determine whether the in-process specifications are met, 
and to detect any deviation or occurrence that may result in a failure 
to meet specifications. The in-process specifications that you 
establish ensure that, for example, the specification for strength is 
achieved. If you must deliver a certain amount of powdered vitamin C to 
a mixture at a certain point in the process in order to achieve a final 
product that contains 60 mg of vitamin C, a critical point in the 
process is where ``x'' mg of vitamin C is added to ensure that the 
final product contains 60 mg of vitamin C. You would monitor the 
operation to ensure that ``x'' mg of vitamin C is added. Your strength 
specification may be tested at the end of the process as a product 
specification, but your in-process specification to ensure the addition 
of ``x'' mg of vitamin C is a specification that is separate and 
distinct from the specification that you establish for strength, i.e., 
60 mg vitamin C. You may determine that in-process specifications are 
met through a test or examination. You could monitor for the vitamin C 
product by checking the equipment you use to mix the vitamin C-
containing product to ensure that the mixing process was carried out 
during the time period specified in the master manufacturing record to 
ensure uniformity in the finished batch. Other examples could include a 
measurement, such as checking pH during the course of a process, or 
removing samples during the course of a process to conduct a test for 
viscosity. There may be no need for certain in-process specifications 
to ensure that specifications for identity, purity, strength, and 
composition of the finished batch of dietary supplement are met. If 
there are no in-process points, steps, or stages at which any test or 
examination is needed to ensure that the identity specification for the 
finished batch of dietary supplement is met, then you would not need to 
establish an in-process specification to ensure identity in the 
finished batch, and, therefore, would not need to conduct in-process 
monitoring for identity.
    (Comment 177) One comment requests clarification on what would be 
considered ``in-process'' for materials that are simply blended 
together to form a final product. The comment asks how a firm would 
test the samples if a final material cannot be tested due to 
interferences or lack of an available method.
    (Response) Examples of in-process specifications when materials are 
simply blended together are the mixing time and speed.
    (Comment 178) One comment points out that in-process testing for 
``unanticipated occurrences'' required under proposed Sec.  111.35(f) 
would be difficult, because the manufacturer would not know what to 
test for.
    (Response) This comment may have misunderstood the provision, which 
did not propose to require that you test for an unanticipated 
occurrence. Rather, proposed Sec.  111.35(i)(2) would require you to 
review the results of any monitoring, and conduct a material review and 
make a disposition decision, if there is any unanticipated occurrence 
that adulterates or could result in adulteration of a component or 
dietary supplement. An example of such an occurrence is leakage of 
extraneous material from a pipe onto a component. Quality control 
personnel, under final Sec.  111.113(a)(3), must conduct a material 
review and make a disposition decision if there is such an 
unanticipated occurrence during the manufacturing operations.
    (Comment 179) One comment suggests that the provision is a HACCP 
requirement and is unnecessary for dietary supplements whose production 
generally does not involve bacterial contamination.
    (Response) We disagree. It is not a HACCP requirement because the 
provisions deal with unanticipated occurrences. Dietary supplement 
production can involve bacterial contamination as discussed in section 
V of this document. The purpose of final Sec.  111.75(b) is to ensure 
that the product meets all specifications, which include specifications 
associated with contamination, and, therefore, is a necessary 
provision.
3. Final Sec.  111.75(c) and (d)
    Final Sec.  111.75(c) requires you, for a subset of finished 
dietary supplement batches, which you identify through a sound 
statistical sampling plan (or for every finished batch), to verify that 
your finished batch of the dietary supplement meets product 
specifications for identity, purity, strength, composition, and limits 
on those types of contamination that may adulterate or that may lead to 
adulteration of the finished batch of the dietary supplement. Final 
Sec.  111.75(c) also sets forth the following verification 
requirements:
    <bullet> You must select one or more established specifications for 
identity, purity, strength, composition, and limits on those types of 
contamination that may adulterate or that may lead to adulteration of 
the dietary supplement that, if tested or examined on the finished 
batch of the dietary supplement, would verify that the production and 
process control system is producing a dietary supplement that meets all 
product specifications (or only those product specifications not 
otherwise exempted from this provision by quality control personnel 
under final Sec.  111.75(d));
    <bullet> You must conduct appropriate tests or examinations on the 
specifications selected in final Sec.  111.75(c)(1);
    <bullet> You must provide adequate documentation of your basis for 
why meeting the specification(s) selected under final Sec.  
111.75(c)(1), through the use of appropriate tests or examinations 
conducted under final Sec.  111.75(c)(2), will ensure that your 
finished batch of the dietary supplement meets all product 
specifications for identity, purity, strength, composition, and the 
limits on those types of contamination that may adulterate, or that may 
lead to the adulteration of, the dietary supplement; and
    <bullet> Quality control personnel must review and approve the 
documentation that you provide under final Sec.  111.75(c)(3).
    Final Sec.  111.75(c) requires you to verify that your finished 
batch of dietary supplement meets specifications for identity, purity, 
strength, composition, and limits that you established for those types 
of contamination that may adulterate or that may lead to adulteration 
of the finished batch. You may verify this by either testing or 
examining: (1) Every finished batch for each of these specifications or 
(2) a subset of finished batches for the dietary supplement. The subset 
of batches tested must be identified using a sound statistical sampling 
plan.
    If you choose to test or examine a subset of finished batches of 
dietary supplement, you may test or examine each subset of batches for 
identity, purity, strength, composition, and limits on contamination 
that you established. Alternatively, you may determine that you can 
select one, two, or three, or other number of these specifications 
that, if determined to be in compliance

[[Page 34850]]

with specifications, would be able to verify that the other untested 
specifications are met. For example, you may be able to substantiate 
that, if you determine compliance with the specification for the 
identity and composition of a product for which no contamination limits 
are needed, the system is adequately controlling for the purity and 
strength of the product, without the need to test for compliance with 
the specifications for purity and strength. If so, you must document, 
under final Sec.  111.75(c)(3) your basis for why this is so. Quality 
control personnel must review and approve such documentation under 
final Sec.  111.75(c)(4).
    Under final Sec.  111.75(d), you may determine, in the previous 
example, that you could not verify, by testing for compliance with the 
specifications for identity and composition, that the purity 
specification is met, and there may be no scientifically valid method 
for testing or examining the finished batch to evaluate the purity in 
the finished batch of dietary supplement. In that case, you could 
exempt the specification for purity from the requirement in final Sec.  
111.75(c)(1) if you can document why the purity specification is met 
without such testing or examination. You could do so through, for 
example, documentation that meeting component and specifications for 
strength is sufficient, or through documentation that in-process 
monitoring is sufficient. Quality control personnel must review and 
approve such documentation (final Sec.  111.75(d)).
    Final Sec.  111.75(c) and (d) derive from proposed Sec.  111.35(g) 
and (h) and include changes that we are making after considering 
comments.
    (Comment 180) Several comments assert that a more appropriate 
balance is needed between an effective process control system and a 
reasonable testing scheme calculated to confirm the quality of dietary 
supplements. The comments stress it is important to build quality into 
a product throughout the entire production process by relying on strong 
process controls rather than by testing at the finished batch stage. 
One comment asserts that in an appropriate process control system, 
testing is a means to monitor and ensure that the control system is 
functioning as intended. Several comments make a specific 
recommendation that the final rule include rigorous controls.
    Some comments support the requirement under proposed Sec.  
111.35(g) to test each batch of finished product when possible, and to 
perform testing of components and in-process testing when testing the 
finished product is not possible. Other comments object to the proposed 
requirements for finished product testing on the grounds that they are 
overly burdensome, duplicative, and unnecessary.
    Some comments suggest that a more practical approach to finished 
product testing would be to conduct identity testing of each component, 
combined with certification of the vendor by a program of complete 
testing for conformance with a certificate of analysis, as is allowed 
under the drug CGMP regulations. Some comments suggest manufacturers 
that have written procedures for each stage of their process, including 
raw material certification, production, and finished product analysis, 
and a written plan for qualifying the process, should be exempt from 
the proposed requirements to test each finished batch. Some comments 
urge us to give companies the flexibility to devise testing procedures.
    (Response) The approach in final Sec.  111.75(c) and (d) is 
consistent with these comments and is part of the overall approach of 
this final rule, which focuses on ensuring the quality of the dietary 
supplement throughout the production and process control system.
    The concept behind final Sec.  111.75(c) and (d) is analogous to 
the overall concept of proposed Sec.  111.35(g). Under proposed Sec.  
111.35(g) you could rely on a combination of meeting component 
specifications and in-process specifications when you are unable to 
test for a specification, provided you satisfied certain criteria. 
Under the final rule, you may rely on a combination of meeting 
component specifications and in-process specifications to verify that 
your product meets specifications, rather than test every batch to 
determine whether specifications are met, regardless of whether a test 
is available, provided you satisfy certain criteria. Thus, the final 
rule provides flexibility that is needed to build adequate controls 
early in the process to reduce the need for end product testing on 
every batch of finished dietary supplement.
    (Comment 181) One comment expresses concern that the requirement to 
use appropriate tests to determine compliance with specifications could 
be interpreted as requiring companies to test dietary supplements not 
only for compliance with company specifications, but also for 
compliance with any labeled specifications of the ingredient suppliers, 
such as for contaminants. The comment believes this would be redundant 
and overly burdensome.
    (Response) As we explain in section XXIV of this document, we have 
made changes to reduce the testing burden on companies while still 
requiring steps necessary to ensure the quality of dietary supplements. 
For example, under final Sec.  111.75(a), instead of testing or 
examination (other than for identity of the dietary ingredients), firms 
may rely upon supplier certificates of analysis in certain 
circumstances. Also, we recognize, however, that it may be possible for 
a manufacturer to demonstrate, through various methods and processes in 
use over time for its particular operation, that a system of less than 
100 percent identity testing would provide no material diminution of 
assurance of the identity of the dietary ingredient as compared to the 
assurance provided by 100 percent identity testing. To provide an 
opportunity for a manufacturer to make such a showing and reduce the 
frequency of identity testing of components that are dietary 
ingredients from 100 percent to some lower frequency, we decided to 
provide, in an interim final rule published elsewhere in this issue of 
the Federal Register, a procedure that allows for submission to, and 
review by, FDA of an alternative to the required 100 percent identity 
testing of components that are dietary ingredients, provided certain 
conditions are met. In addition, under final Sec.  111.75(c), testing 
or examination for a portion of the finished batches is an option, and 
exemptions are provided for in final Sec.  111.75(d).
    (Comment 182) One comment points out that, if a product cannot be 
tested for technical reasons at the final product stage, then it also 
cannot be tested at the final blending stage in the process, because 
the nature and composition of the product at both stages are virtually 
the same. Another comment asks whether a verification of content in the 
final product will suffice if there is no valid testing procedure.
    (Response) Under final Sec.  111.75(c), you have flexibility to 
select one or more established specifications for identity, purity, 
strength, composition, and limits on those types of contamination that 
may adulterate or that may lead to adulteration of the dietary 
supplement that, if tested or examined on the finished batch of the 
dietary supplement, would verify that the production and process 
control system is producing a dietary supplement that meets all product 
specifications. Under final Sec.  111.75(d), you have flexibility to 
exempt one or more product specifications from verification 
requirements, provided that

[[Page 34851]]

you satisfy the criteria established under final Sec.  111.75(d).
    (Comment 183) Some comments request that the rule include 
requirements for dissolution, disintegration, and bioavailability 
testing for dietary supplements. These comments note that, although a 
product may contain the labeled amount, it may not dissolve readily in 
the body or be available for absorption.
    (Response) We decline to revise the rule as suggested by the 
comments. As discussed in the preamble to the 2003 CGMP Proposal (68 FR 
12157 at 12163), tests for dissolution, disintegration, and 
bioavailability of dietary supplements are examples of areas where 
scientific study is still evolving; thus it is premature to impose 
requirements for such tests. The comments provide no specific 
information that would alter this view or support the technical 
feasibility of conducting such tests for all types of dietary 
supplement products. However, nothing in this final rule would preclude 
a manufacturer from establishing such requirements. A manufacturer 
should have data to support any specifications it establishes for 
parameters such as dissolution, disintegration, and bioavailability.
    (Comment 184) One comment questions the requirements in the 2003 
CGMP Proposal that all manufacturers quantify certain marker compounds 
in their products. The comment offers two reasons why such testing 
should not be required for botanical products: Their food-like 
composition and legal status, and the assertion that scientifically 
valid analytical methods may prove to be irrelevant or even hinder the 
development of superior products.
    (Response) The final rule does not require any specific testing 
requirements, such as testing for marker compounds. You would determine 
the specific testing requirements, and whether to use a marker compound 
in those tests, depending on your product and process. In the 2003 CGMP 
Proposal (68 FR 12157 at 12172), we merely discussed how a marker 
compound could help you identify whether you have a particular species 
of an herb to differentiate, for example, between a poisonous and 
nonpoisonous species.
4. Final Sec.  111.75(e)
    Final Sec.  111.75(e) requires you, before you package or label a 
product you receive for packaging or labeling as a dietary supplement 
(and for distribution rather than for return to the supplier), to 
visually examine the product and have documentation to determine 
whether the specifications that you established under final Sec.  
111.70(f) are met. Final Sec.  111.75(e) derives from proposed Sec.  
111.35(e)(1) and (g) and from proposed Sec.  111.40(a)(2).
    (Comment 185) Some comments request we clarify the roles and 
testing obligations of the various parties in the ``pre-consumer supply 
chain'' for dietary supplements. Some comments argue that redundant 
tests should not be required at every transaction point in the pre-
consumer supply chain. The comments contend that any testing already 
performed by a supplier, manufacturer, or packager should suffice, so 
long as other CGMP certification, and chain of custody standards, are 
met. Other comments urge us to give companies the flexibility to devise 
testing procedures and point out that different testing is needed for 
different roles in the supply chain.
    One comment requests clarification of the testing requirements 
applicable to packagers/labelers. The comment states it is unclear how 
a packager or labeler/distributor could conduct testing of component 
ingredients if all the firm receives is a finished product for which 
there is no scientifically valid testing method.
    (Response) As discussed in section VI of this document, you are 
responsible for the CGMP requirements that are applicable to your 
operations. We agree that redundant tests should not be required. 
Further, we agree that it is the responsibility of the manufacturer to 
do component testing. The packager or labeler does not need to do any 
required component testing because the packager or labeler does not 
receive components, rather it receives a finished dietary supplement. 
Under final Sec.  111.70(f) if you receive a product from a supplier 
for packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier), you must establish 
specifications to provide sufficient assurance that the product you 
receive is adequately identified and is consistent with your purchase 
order.
    Under final Sec.  111.75(e), before you package or label such a 
product, you must visually examine the product and have documentation 
to determine whether the specifications that you established under 
final Sec.  111.70(f) are met. Your documentation may consist of an 
invoice, certificate, guarantee, or other documentation from the 
supplier to ensure that the product is adequately identified and is the 
product that you ordered. Final Sec.  111.75(e) does not require that 
the documentation consist of the result of testing or examination by 
the packager or labeler of such a product.
    As with final Sec.  111.70(f), final Sec.  111.75(e) applies to 
``product that you receive for * * * for distribution rather than for 
return to the supplier'' and, thus, applies to product that has left 
the control of the person who manufactured the batch. If you are a 
packager or labeler who packages and labels a dietary supplement for 
the manufacturer, and you will return the packaged and labeled dietary 
supplement to the manufacturer, we would not consider that you are 
``receiving'' product within the meaning of final Sec.  111.75(e). 
Thus, you would not be subject to final Sec.  111.70(f).
5. Final Sec.  111.75(f)
    Before you use packaging, final Sec.  111.75(f)(1) requires you, at 
a minimum, to conduct a visual identification of the containers and 
closures and review the supplier's invoice, guarantee, or certification 
to determine whether packaging specifications are met. Before you use 
labels, final Sec.  111.75(f)(2) requires you, at a minimum, to conduct 
a visual examination of the label and review the supplier's invoice, 
guarantee, or certification to determine whether labeling 
specifications are met. Final Sec.  111.75(f)(1) and (f)(2) derive from 
proposed Sec.  111.40(b)(2) which, in part, would require you, for 
packaging and labels you receive, to conduct at least a visual 
identification on the containers and closures. Proposed Sec.  
111.40(b)(2) also would require you, in part, for packaging and labels 
you receive, to quarantine the packaging and labels until your quality 
control unit tests or examines a representative sample to determine 
whether specifications are met. Consistent with changes that we are 
making to the requirements for packaging and labels that you receive 
(see discussion of final Sec.  111.160 in section XII of this 
document), final Sec.  111.75(f)(1) and (f)(2) include a requirement 
analogous to proposed Sec.  111.40(a)(2) which would require you to 
visually examine the supplier's invoice, guarantee, or certification to 
determine whether the components, dietary ingredients, or dietary 
supplements you receive are consistent with your purchase order and to 
perform testing, as needed, to determine whether specifications are 
met.
6. Final Sec.  111.75(g)
    Final Sec.  111.75(g) requires you, at a minimum, to conduct a 
visual examination of the packaging and labeling of the finished 
packaged and labeled dietary supplements to determine whether you used 
the specified packaging and applied the specified label. Final Sec.  
111.75(g) derives from proposed Sec.  111.37(b)(11)(iv) which

[[Page 34852]]

would require the quality control unit to collect representative 
samples of each batch of packaged and labeled dietary ingredients or 
dietary supplements to determine whether you used the packaging 
specified in the master manufacturing record and applied the label 
specified in the master manufacturing record. Final Sec.  111.75(g) is 
associated with final Sec.  111.70(g) which requires you to establish 
specifications for the packaging and labeling for the finished packaged 
and labeled dietary supplements, including specifications that ensure 
you used the specified packaging and applied the specified label.
7. Final Sec.  111.75(h)
    Final Sec.  111.75(h)(1) requires you to ensure that the tests and 
examinations you use to determine whether the specifications are met 
are appropriate and scientifically valid methods. Final Sec.  
111.75(h)(1) derives from proposed Sec.  111.35(h). Final Sec.  
111.75(h)(1) includes editorial changes associated with the 
reorganization and changes that we are making after considering 
comments.
    Final Sec.  111.75(h)(2) requires that the tests and examinations 
you use include at least one of the following: Gross organoleptic 
analysis, macroscopic analysis, microscopic analysis, chemical 
analysis, or other scientifically valid methods. Final Sec.  
111.75(h)(2) derives from proposed Sec.  111.35(l).
    (Comment 186) Some comments suggest that the tests listed in 
proposed Sec.  111.35(l) be incorporated into proposed Sec.  111.35(h), 
relating to appropriate test methods.
    (Response) We agree with the comment, and final Sec.  111.75(h)(2) 
combines these requirements as requested.
    (Comment 187) One comment states that the list of tests should be 
deleted because it is not sufficient to cover the types of testing that 
will be required for compliance with proposed Sec.  111.35(g).
    (Response) The comment does not identify the types of tests that 
would not be covered. We believe that final Sec.  111.75(h)(2)(v)'s 
``catch-all'' provision, which requires that one of the tests that you 
use be an ``other scientifically valid method'' is sufficient to cover 
all other types of testing required under this final rule.
    (Comment 188) One comment states that the final rule should make 
clear that organolepsis is an acceptable method for identity testing. 
The comment contends it is imperative for the survival of small 
businesses that organolepsis be allowed, coupled as necessary with 
macroscopic and morphological examination and comparison with voucher 
specimens or photographs. Another comment requests clarification of 
whether gross organoleptic analysis alone can be a test for releasing 
finished products. Some comments assert that several organizations have 
published relevant methods that include macroscopic methods that can be 
used in identifying herbal ingredients.
    (Response) Organolpetic analysis would be an acceptable method 
under the 2003 CGMP Proposal and remains an acceptable method under the 
final rule, which clarifies that the method you use, including 
organoleptic analysis, must be appropriate. Organoleptic analysis may 
not be an appropriate method of testing for certain substances. This is 
particularly true when the nature of the substance decreases the 
reliability of organoleptic analysis. For example, while organoleptic 
analysis may be an appropriate identity test for whole or coarsely-cut 
botanical parts, it may not be an appropriate identity test for 
powdered or extracted botanicals because of decreased reliability, or 
in those instances where misidentification of botanicals is known to 
occur. Additionally, we recognize ``macroscopic analysis'' is one of 
the tests or examinations you may select to determine whether 
specifications are met.
    (Comment 189) One comment remarks that the appropriateness of the 
test depends on the material being tested, and the method selected by 
the manufacturer may be inappropriate. One comment believes the methods 
stated in proposed Sec.  111.35(l) (organoleptic, microscopy, chemical) 
for establishment of identity and purity would not be applicable to 
animal products. This comment suggests that a separate list of test 
methods should be identified for those materials.
    (Response) We agree that the appropriateness of the test depends on 
the material being tested. However, we are not revising the rule to 
identify methods that are, or are not, appropriate for specific 
circumstances (such as the case of animal-derived ingredients). There 
are so many distinct circumstances that such a list would be neither 
practical nor useful. Beyond that, the manufacturer is responsible for 
choosing the appropriate test.
    (Comment 190) One comment asks us to clarify in the final rule the 
requirement that methods be scientifically valid applies only to 
quantitative methods.
    (Response) In proposed Sec.  111.35(h), we did not intend that the 
proposed requirement that you use scientifically valid methods apply 
only to quantitative methods, because we also proposed that tests in 
accordance with proposed Sec.  111.35 must include at least one of the 
following: (1) Gross organoleptic analysis, (2) microscopic analysis, 
(3) chemical analysis, or (4) other appropriate test. To clarify that 
the requirement that methods be scientifically valid applies to all the 
tests and examinations you use, rather than to quantitative tests 
alone, final Sec.  111.75(h)(1) does not use the term ``analytical.''
    (Comment 191) One comment states that the proposed definition of 
``appropriate test'' (i.e., ``a scientifically valid analytical 
method'') is extremely onerous and violates congressional intent. The 
comment believes that mandating specific methods is inappropriate, and 
dietary supplement CGMPs should comply with Executive Order 12866 and 
not impose additional requirements on small businesses that are better 
left to normal business practices.
    Several comments take issue with our statement that we were not 
aware of a situation where an appropriate scientifically valid method 
is not available when, in fact, valid test methods are not always 
available for testing dietary ingredients or dietary supplements. One 
comment contends the 2003 CGMP Proposal contains conflicting 
information about available test methods. For example, the preamble to 
the 2003 CGMP Proposal states that we are ``not aware of a situation 
where an appropriate scientifically valid analytical method is not 
available,'' and our cost analysis does not address costs of method 
development. At the same time, however, we set out alternatives to 
finished product testing in cases where adequate methods are 
unavailable, and we decline to require expiration dating because there 
may not be adequate methods available for assessing the strength of a 
dietary ingredient. The comment cites numerous ongoing efforts in 
methods development by both industry and government that illustrate the 
lack of existing methods necessary to confirm compliance with all 
quality specifications.
    (Response) These comments appear to take our statements out of 
context. In the 2003 CGMP Proposal, we stated: ``If an AOAC or FDA 
method is not available, a scientifically valid analytical method is 
one that is based on scientific data or results published in, for 
example, scientific journals, references, text books, or proprietary 
research. Although there may not be an Association of Official 
Analytical

[[Page 34853]]

Chemist (AOAC) or FDA method available, we are not aware of a situation 
where an appropriate scientifically valid analytical method is not 
available'' (68 FR 12157 at 12198). We also stated: ``We recognize that 
certain tests for identity, purity, quality, strength, or composition 
for certain finished product may not be available due to complex 
finished matrices that would make such testing impracticable'' (68 FR 
12157 at 12197). We disagree that our statement acknowledging that the 
available tests may not be practicable in certain matrices is 
inherently inconsistent with our statement that we are not aware of a 
situation where an appropriate scientifically valid analytical method 
is not available. One statement relates to the availability of methods, 
the other relates to the practicality of using an available method in 
particular circumstances.
    In any case, under final Sec.  111.75(d)(1) you may exempt a 
product specification from the verification requirements of final Sec.  
111.75(c)(1) if you show that: (1) The specifications selected to 
verify that the product meets all product specifications are not able 
to verify that the control system is producing a dietary supplement 
that meets the exempted product specification and (2) there is no 
scientifically valid method for testing or examining the exempted 
product specification at the finished batch stage. Final Sec.  
111.75(c)(1) also requires you to document why other information, such 
as component and in-process testing, will determine whether the 
exempted product specification is met without finished batch testing. 
Although we agree that there may be some circumstances where there is 
not a scientifically valid method available for finished product 
testing, we believe that there would be some scientifically valid 
method available for component or in-process testing.
    (Comment 192) One comment encourages flexibility toward the 
development of a quality system that is based on a balance of 
prevention, appraisal, and process verification activities. Another 
comment asks whether the industry should use industry standards and 
tests now used.
    A few comments request that we clarify proposed Sec.  111.35(h) to 
make it clear whether the section recommends or requires the use of 
available USP, AOAC International (formerly Association of Official 
Analytical Chemists) or FDA methods. One comment recommends that the 
final rule give companies flexibility to use the method(s) most 
suitable to the ingredient they are testing and the specification they 
have set. The comment adds that companies should then be required to 
ensure, through appropriate rationale and data, that the method is 
indeed suitable and produces accurate and reproducible results.
    (Response) We agree that companies should have the flexibility to 
adopt the method most suitable to the ingredient they are testing. As 
discussed in the preamble to the proposal (68 FR 12157 at 12163 and 
12208), official methods, such as AOAC International methods, are 
validated in collaborative studies using several laboratories under 
identical conditions and the AOAC International methods are often cited 
as ``official validated methods.'' Other method validations are 
conducted in a single laboratory by repeating the same test multiple 
times. In the case of methods used to support specific regulatory 
applications to FDA, data and information about methods that are 
developed and conducted in a single laboratory by repeating the test 
multiple times are sent to us, together with appropriate samples and 
reference materials so the test can be repeated in an agency 
laboratory. Typical validation characteristics include accuracy, 
precision, specificity, detection limit, quantitation limit, linearity, 
range, and robustness.
    The process of method validation discussed in the previous 
paragraph is a formal process for demonstrating that procedures are 
suitable for their intended use. Although many methods that are 
scientifically valid have been formally validated, other methods may 
not have been subject to the formal validation process, e.g., by 
collaborative studies using multiple laboratories, but nonetheless 
remain scientifically valid because they are, in fact, suitable for 
their intended use. For this reason, we stated that the 2003 CGMP 
Proposal would permit tests using methods other than those that are 
officially validated (68 FR 12157 at 12163). Consistent with the view 
that we expressed in the 2003 CGMP Proposal, we believe a 
scientifically valid method is one that is accurate, precise, and 
specific for its intended purpose. In other words, a scientifically 
valid test is one that consistently does what it is intended to do.
    Under final Sec.  111.75(h)(1), you must ensure the tests and 
examinations you use to determine whether the specifications are met 
are appropriate, scientifically valid methods. Under final Sec.  
111.75(h)(2) the tests and examinations you use must include at least 
one of the following: (1) Gross organoleptic analysis, (2) macroscopic 
analysis, (3) microscopic analysis, (4) chemical analysis, or (5) other 
scientifically valid methods.
    (Comment 193) One comment questions how a company would know of all 
the available scientifically valid methods when it deals with hundreds 
of items. The comment states it cannot be expected to have expertise in 
the assay methodology for so many different ingredients.
    Several comments suggest we make fuller use of available monographs 
and other resources on test methods and method development. These 
sources include USP and AHP monographs, AOAC International, the 
European Pharmacopoeia, and the WHO. The comments urge us to 
disseminate information on these additional resources.
    Many comments assert that several organizations have published 
relevant analytical methods, such as macroscopic, microscopic, and 
chemical methods, that can be used in identifying herbal ingredients. 
These comments suggest that we should acknowledge those methods and 
organizations as authoritative sources of quality standards.
    (Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157 
at 12209), we acknowledged that validated methods exist in official 
compendia for vitamins, minerals, and several botanicals, and we 
recommended you use validated methods whenever such methods are 
available. We explicitly stated that you may use validated methods that 
can be found in official references, such as AOAC International, USP, 
and others.
    As discussed in this section (see response to comment 196), we 
believe that it is sufficient to provide in this preamble general 
guidance on what we consider to be scientifically valid tests, such as 
those based on scientific data or results published in, for example, 
scientific journals, references, text books, or proprietary research, 
and leave it to the manufacturer to decide what scientifically valid 
tests or examinations to use in a given operation. In the future, we 
may consider issuing guidance as to sources of appropriate tests or 
examinations, along with other guidances that we may find useful that 
relate to certain dietary supplement CGMP.
    (Comment 194) One comment states the act prohibits us from imposing 
testing requirements for which scientifically valid methods are not 
generally available, and other comments believe that not all components 
have scientifically valid identification tests. Given the substantial 
ongoing efforts towards method development, the

[[Page 34854]]

comments believe that the proposed requirements for testing would 
impose standards on many products and ingredients that cannot be met 
through current and generally available methods.
    (Response) We disagree that the statute prohibits us from imposing 
testing requirements. Section 402(g)(2) of the act states that dietary 
supplement CGMP regulations ``may not impose standards for which there 
is no current and generally available analytical methodology.'' We are 
not imposing such standards. The manufacturer must establish 
specifications for its product and components, and we have provided 
flexibility for how the manufacturer can determine whether those 
specifications are met. The manufacturer can test, examine, rely on a 
certificate of analysis (other than to verify the identity of dietary 
ingredients), or, in the case of a specification that is exempted from 
periodic testing of a finished batch, rely on other information that 
ensures that such an exempted product specification is met.
    (Comment 195) One comment requests clarification on the definition 
of ``examination'' and asks whether it includes monitoring of process 
parameters as established in the master manufacturing record. If so, 
the comment questions whether this practice would satisfy the 
requirement now in final Sec.  111.75(h)(1).
    (Response) Under final Sec.  111.75(h), scientifically valid tests 
and examinations include techniques such as gross organoleptic 
analysis, macroscopic analysis, chemical analysis, and other 
scientifically valid methods. As discussed in the response to comment 
169, monitoring in-process parameters could encompass tests such as 
measuring pH or viscosity. Such tests would fall under ``other 
scientifically valid methods.''
    (Comment 196) One comment contends that botanical identification is 
largely ignored in the 2003 CGMP Proposal. The comment states that 
botanical identification forms the basic foundation for botanical 
authenticity and that manufacturers have a legal responsibility to 
ensure the authenticity of claimed ingredients. The comment recommends 
that specific requirements for authentication of botanical ingredients 
be included in the final rule.
    One comment points out the difficulty in identifying and analyzing 
all naturally occurring ingredients in herbs and plants and suggests 
several alternatives to testing for all such ingredients. Another 
comment requests that an herbal product containing 20 percent or more 
ethanol have relaxed testing requirements due to the bacteriostata 
properties of ethanol. One comment lists some alternatives for testing 
naturally occurring ingredients.
    One comment requests clarification on the testing requirements for 
bovine cartilage products. The comment states there is no published 
method for extracting chondroitin sulfate from bovine cartilage. As a 
result, the comment assumes that testing for chondroitin sulfate would 
not be required for these products.
    (Response) We believe that it is sufficient to provide in this 
preamble general guidance about testing, such as our discussion that 
scientifically valid tests include official, validated methods as well 
as tests based on scientific data or results published in, for example, 
scientific journals, references, text books, or proprietary research. 
It is the manufacturer's responsibility to choose which scientifically 
valid tests or examinations to use in a given operation. Therefore, the 
final rule does not address the specific testing circumstances 
described in these comments, such as testing requirements for an herbal 
product that contains 20 percent or more ethanol, or for bovine 
cartilage products. The manufacturer is responsible for establishing 
specifications and meeting such specifications, consistent with the 
requirements in this final rule. In the future, we may consider issuing 
detailed guidance as to specific tests or examinations, along with 
other guidances that may be useful that relate to certain dietary 
supplement CGMP.
    With respect to the comments that discuss botanical identification, 
we note that the 2003 CGMP Proposal referred to the draft report of the 
Dietary Supplement Working Group of FDA's Food Advisory Committee (68 
FR 12157 at 12161) (Ref. 32). The draft report discusses the selection 
of the most appropriate and reliable identity test and the general 
principles for consideration in setting performance standards for such 
tests (Ref. 32). This report may provide useful guidance.
8. Final Sec.  111.75(i)
    Final Sec.  111.75(i) requires you to establish corrective action 
plans for use when an established specification is not met. Final Sec.  
111.75(i) derives from proposed Sec.  111.35(i)(1).
    (Comment 197) One comment asks whether the proposed requirement to 
establish corrective action plans for use when an established 
specification is not met (proposed Sec.  111.35(i)(1)) would apply to 
specifications for raw materials and finished goods as well as to in-
process specifications.
    (Response) The requirement to establish corrective action plans 
(final Sec.  111.75(i)) applies to components, in-process 
specifications, and to the finished batch.
    (Comment 198) One comment states that corrective action plans would 
be difficult to prepare for a variety of situations, such as for 
complex multivitamin and mineral formulas. One comment recommends this 
requirement be deleted. Another comment asserts that establishment of 
corrective action plans should be at the manufacturer's discretion.
    (Response) We disagree that the final rule should not require you 
to establish corrective plans or that having such plans should be at 
the manufacturer's discretion. The purpose of having corrective action 
plans in place before a problem occurs is to help you to deal quickly 
and efficiently with problems as they arise.
    You may have a corrective action plan to determine the steps to 
take if something goes wrong such as not meeting a specification. 
Moreover, a corrective action plan may include steps not only for 
dealing with an acute problem, but also for dealing with steps you 
would take to followup after the acute problem is resolved. For 
example, after you resolve an acute problem, such as a failure to meet 
an in-process specification, your corrective action plan may include 
testing of every finished batch, rather than a subset of finished 
batches, for some period of time to verify that the problem is 
resolved.
    We acknowledge that it may not be practical to establish a 
corrective action plan for all circumstances, because not all 
circumstances are foreseeable. However, the comment asserting that it 
would be difficult to establish corrective action plans for the variety 
of situations that could come up for complex multivitamin and mineral 
formulas provided no basis for why manufacturers of such formulas could 
not anticipate specific situations that present potential problems.
    (Comment 199) Some comments recommend that proposed Sec.  
111.35(i)(1) state ``Establish procedures,'' rather than ``Establish 
corrective action plans.''
    (Response) The comments did not explain what, if any, practical 
difference would exist between ``procedures'' and ``corrective action 
plans.'' A corrective action plan is a procedure for which you must 
have a record in the master manufacturing record (final Sec.  
111.210(h)(5)). Because ``corrective action plans'' is a term that is 
commonly used in the industry, we have retained it in the final rule.

[[Page 34855]]

J. What Must You Do if Established Specifications Are Not Met? (Final 
Sec.  111.77)

1. Final Sec.  111.77
    As we explain in section II of this document, we reorganized the 
final rule to make it more ``user-friendly'' and to clarify the rule's 
applicability to certain persons, items, or activities. Final Sec.  
111.77 is a new provision that clarifies your responsibilities and 
identifies those responsibilities in a more ``user-friendly'' fashion. 
We have identified in final Sec.  111.77 the consequences of not 
meeting the specifications you establish under subpart E and when you 
can consider a treatment, in-process adjustment, or reprocessing to 
correct a failure to meet and established specification for a 
component, dietary supplement, packaging, or label. Subpart F does 
identify these consequences in several provisions which deal with the 
responsibility of quality control personnel to review and approve or 
reject components, dietary supplements, packaging, and labels. We 
determined it would add clarity to state the consequences for not 
meeting a specification in the same subpart in which the requirements 
to establish specifications are located.
2. Final Sec.  111.77(a)
    Final Sec.  111.77(a) requires that for specifications established 
under Sec.  111.70(a), (b)(2), (b)(3), (c), (d), (e), and (g) that you 
do not meet, quality control personnel, in accordance with the 
requirements in subpart F of this part, must reject the component, 
dietary supplement, package, or label unless it approves a treatment, 
an in-process adjustment, or reprocessing that will ensure the quality 
of the finished dietary supplement and that the dietary supplement is 
packaged and labeled as specified in the master manufacturing record. 
No finished batch of dietary supplements may be released for 
distribution unless it complies with final Sec.  111.123(b).
    This provision identifies those specifications, if not fully met, 
that may be able to be corrected by treatment, in-process adjustment, 
or reprocessing and approved by quality control personnel. We 
emphasize, however, that even if, for example, corrections are 
approved, the finished batch of dietary supplement can not be released 
for distribution unless it is compliance with the requirements of final 
Sec.  111.123(b) (discussed in section XI of this document).
    Final Sec.  111.77(a) derives from the following proposed 
provisions:
    <bullet> Proposed Sec.  111.50(d)(2), which would require the 
quality control unit not to approve and release for distribution any 
batch of dietary supplement that does not meet all specifications;
    <bullet> Proposed Sec.  111.50(f), which would require you to not 
reprocess a batch that deviates from the master manufacturing record 
unless approved by the quality control unit.
    <bullet> Proposed Sec.  111.50(g), which would require that a 
reprocessed batch of dietary supplement meet all specifications and 
that the quality control unit approve its release for distribution.
    <bullet> Proposed Sec.  111.35(i)(4)(i), which would require you, 
for any deviation or unanticipated occurrence which resulted in or 
could lead to adulteration of the component, dietary supplement, 
packaging, or label, to reject the component, dietary supplement, 
packaging, or label, unless the quality control unit determines that 
in-process adjustments are possible to correct the deviation or 
occurrence.
    <bullet> Proposed Sec.  111.35(i)(4)(ii), which would require you, 
for any deviation or unanticipated occurrence which resulted in or 
could lead to adulteration of the component, dietary supplement, 
packaging, or label, to not reprocess a rejected component or dietary 
supplement unless approved by the quality control unit.
3. Final Sec.  111.77(b)
    Final Sec.  111.77(b) requires that for specifications established 
under final Sec.  111.70(b)(1) that you do not meet, quality control 
personnel must reject the component and the component must not be used 
in manufacturing the dietary supplement. Final Sec.  111.77(b) 
complements final Sec.  111.70(b)(1) which requires you to establish an 
identity specification for components; final Sec.  111.75(a)(1) which 
requires you to conduct at least one appropriate test or examination to 
verify the identity of any component that is a dietary ingredient; and 
final Sec.  111.75(a)(2) which requires you to confirm the identity of 
all other components. As discussed earlier in this section, many 
comments recommended the final rule include a requirement for an 
identity test of incoming components to ensure quality and safety. We 
agree with these comments and earlier comments that point out it may 
not be possible to confirm the identity of some components after they 
have been processed into the finished batch of the dietary supplement. 
For these reasons, we have concluded that, if the component 
specification for identity is not met, you may not use the component in 
the manufacture of the dietary supplement. This component specification 
must be met and quality control personnel are restricted in what action 
must be taken if this specification is not met.
4. Final Sec.  111.77(c)
    Final Sec.  111.77(c) requires that if you do not meet the 
specifications established under Sec.  111.70(f), quality control 
personnel must reject the product and the product must not be packaged 
or labeled for distribution as a dietary supplement. As with final 
Sec.  111.77(b), final Sec.  111.77(c) limits the actions you can take 
to package and label product you receive for packaging and labeling 
from a supplier for packaging or labeling as a dietary supplement (and 
for distribution rather than for return to the supplier). Final Sec.  
111.77(c) complements final Sec.  111.70(f), which requires you to 
establish a specification for such received product and final Sec.  
111.75(e), which requires you to visually examine the product, before 
you package or label it, and have documentation to determine whether 
the specifications that you established under Sec.  111.70(f) are met. 
If you do not meet the specifications under final Sec.  111.70(f), you 
must reject the product and not package or label the product for 
distribution as a dietary supplement.

K. Comments on Shelf Life

    In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12203), 
we stated that we had considered whether to propose requirements for 
expiration dating, shelf life dating, or ``best if used by'' dating 
(referred to in this preamble as shelf life or expiration dating). We 
recognized that there are current and generally available methods to 
determine the expiration date of some dietary ingredients, such as 
vitamin C. However, we were uncertain whether there are current and 
generally available methods to determine the expiration dating of other 
dietary ingredients, especially botanical dietary ingredients. We did 
not propose to require expiration dating because we had insufficient 
scientific information to determine the biological activity of certain 
dietary ingredients used in dietary supplements, and such information 
would be necessary to determine an expiration date. Further, because 
official validated testing methods (e.g., AOAC International or FDA) 
for dietary supplements are evolving, especially for botanical dietary 
ingredients, such methods are not always available to assess the 
strength of

[[Page 34856]]

a dietary ingredient in a dietary supplement.
    The preamble to the 2003 CGMP Proposal emphasized that, if you use 
an expiration date on a product, you should have data to support that 
date (68 FR 12157 at 12204). We recommended that you have a written 
testing program designed to assess the stability characteristics of the 
dietary supplement, and that you use the results of the stability 
testing to determine appropriate storage conditions and expiration 
dates.
    In the 2003 CGMP Proposal (68 FR 12157 at 12204), we invited 
comment on whether any final rule should contain provisions regarding 
expiration dating and the feasibility of conducting tests needed to 
support such dates. We also invited comment on whether to require 
expiration dating on certain dietary ingredients and not others, for 
example, require expiration dating of vitamin, mineral, and amino acid, 
but not of botanical dietary ingredients.
    (Comment 200) Several comments agree with our decision not to 
require expiration dating on labels for dietary supplements at this 
time, because of the wide range of products and the need for additional 
data. Most of these comments state, however, that manufacturers should 
be allowed to include a ``best if used by'' date. One comment suggests 
addressing the issue in a separate rulemaking. Other comments support 
an expiration date because consumers and retailers expect one, and some 
markets require one. Some comments state that the expiration date or 
statement of product shelf life will help ensure that the product meets 
its label claims and potency.
    Many comments state an expiration date on a label must be supported 
by a rationale or data on stability testing. Some of those comments 
suggest that manufacturers should have flexibility in the type of 
supporting data used. Although label claims should be confirmed by 
shelf life testing when analytical methods exist, data could come from 
a manufacturer's experience with the product or accelerated stability 
testing on similar products with the same storage container. One 
comment points out that some manufacturers already use stability 
testing. Another comment recommends that we provide a guidance document 
on supporting data.
    One comment suggests stringent supporting data are not needed for a 
``best if used by'' date, because that date provides a recommended time 
frame to ensure the best quality. Another comment asserts that the 
discussion about expiration dates in the 2003 CGMP Proposal gives the 
impression that the required level of supporting data is similar to the 
requirements for drug labeling, rather than the requirements for food 
shelf life labeling. Another comment recommends that a general maximum 
shelf life of 4 or 5 years should be included in the rule, with 
shortened or lengthened shelf lives for individual products as data 
become available.
    (Response) These comments do not provide data or information that 
would reduce the uncertainty about the feasibility of conducting tests 
to support an expiration date and, thus, do not persuade us to alter 
our position not to require that you establish an expiration date for 
your product. Indeed, the comments generally concur with that position. 
Because the final rule does not require that you establish an 
expiration date, we decline to offer guidance on the type of data that 
are acceptable to support an expiration date, other than to repeat that 
any expiration date that you place on a product label (including a 
``best if used by'' date) should be supported by data.

L. What Representative Samples Must You Collect? (Final Sec.  111.80)

    Final Sec.  111.80 sets forth requirements to collect 
representative samples of components, packaging, and labels (final 
Sec.  111.80(a)); in-process materials (final Sec.  111.80(b)); the 
finished batch of dietary supplement (final Sec.  111.80(c)); product 
you receive for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier) (final Sec.  
111.80(d)); and packaged and labeled dietary supplements (final Sec.  
111.80(e)). Final Sec.  111.80(a) through (e) derive from proposed 
Sec.  111.37(b)(11)(i) through (b)(11)(iv).
1. Final Sec.  111.80(a)
    Final Sec.  111.80(a) requires you to collect representative 
samples of each unique lot of components, packaging, and labels that 
you use to determine whether the components, packaging, and labels meet 
specifications established in accordance with Sec.  111.70(b) and (d), 
and as applicable, final Sec.  111.70(a) (and, when you receive 
components, packaging, or labels from a supplier, representative 
samples of each unique shipment, and of each unique lot within each 
unique shipment). Final Sec.  111.80(a) derives from proposed Sec.  
111.37(b)(11)(i). Final Sec.  111.80(a) includes changes related to our 
review of the proposed requirements for clarity. We had used the term 
``shipment lot'' in several proposed requirements, including Sec.  
111.35(g)(1)(i) (requirement to test components that you receive), 
Sec.  111.37(b)(11)(i) (requirement to collect representative samples 
of components that you receive), Sec.  111.40(a)(4) (requirements for 
components that you receive), Sec.  111.40(b)(5) (requirements for 
packaging and labels that you receive), and Sec.  111.50(c)(5) 
(requirement to identify materials that you use in the batch production 
record). Some of these proposed requirements (e.g., those in Sec. Sec.  
111.40(a)(4) and (b)(3) and 111.50(b)(5)) make clear that you must be 
able to trace each lot of materials you receive to each separate 
shipment that contains that lot. To clarify and emphasize this meaning 
of shipment lot, we are revising proposed Sec.  111.37(b)(11)(i) so 
that the representative samples you collect must come from ``each 
unique shipment, and of each unique lot within each unique shipment.'' 
We make analogous revisions throughout the final rule as necessary.
    As discussed in this section, final Sec.  111.70(b) sets forth the 
requirements to establish specifications for components, final Sec.  
111.73 requires you to determine if the specifications established are 
met, and final Sec.  111.75(a) sets forth the criteria you use to 
determine whether these specifications are met. Likewise, final Sec.  
111.70(f) sets forth the requirements to establish specifications for 
product that you receive from a supplier for packaging or labeling as a 
dietary supplement (and for distribution rather than for return to the 
supplier), final Sec.  111.73 requires you to determine if 
specifications established are met, and final Sec.  111.75(e) sets 
forth the criteria to use to determine whether these specifications are 
met.
    For consistency with the regulations in final Sec. Sec.  111.70 and 
111.75, we are separating the requirement to collect representative 
samples of components (final Sec.  111.80(a)) from the requirement to 
collect representative samples of product that you receive from a 
supplier for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier) (final Sec.  
111.(80)(d)).
    We did not receive comments specific to proposed Sec.  111.37(b).
2. Final 111.80(b)
    Final Sec.  111.80(b) requires you to collect representative 
samples of in-process materials for each manufactured batch at points, 
steps, or stages, in the manufacturing process as specified in the 
master manufacturing record, where control is necessary to ensure the 
identity, purity, strength, and composition of dietary supplements, to

[[Page 34857]]

determine whether the materials meet specifications established under 
final Sec.  111.70(c), and, as applicable, final Sec.  111.70(a). Final 
Sec.  111.80(b) derives from proposed Sec.  111.37(b)(11)(ii).
    We did not receive comments specific to proposed Sec.  
111.37(b)(11)(ii).
3. Final 111.80(c)
    Final Sec.  111.80(c) requires you to collect representative 
samples of a subset of finished batches of each dietary supplement you 
manufacture, which you identify through a sound statistical sampling 
plan (or otherwise every finished batch), before releasing for 
distribution, to verify that the finished batch of dietary supplement 
meets product specifications established in accordance with final Sec.  
111.70(e), and, as applicable, final Sec.  111.70(a). Final Sec.  
111.80(c) derives from proposed Sec.  111.37(b)(11)(iii). Final Sec.  
111.80(c) includes changes associated with final Sec.  111.75(c) which 
provides flexibility for you to test or examine a subset of finished 
batches you select through a sound statistical sampling plan rather 
than to test or examine all finished batches. Under final Sec.  
111.75(c) the tests or examinations you conduct at the finished batch 
stage verify that your process is in control.
    We did not receive comments specific to proposed Sec.  
111.37(b)(11)(iii).
4. Final Sec.  111.80(d)
    Final Sec.  111.80(d) requires you to collect representative 
samples of each unique shipment, and of each unique lot within each 
unique shipment, of product you receive for packaging or labeling as a 
dietary supplement (and for distribution rather than for return to the 
supplier) to determine whether the received product meets the 
specifications established under final Sec.  111.70(f), and, as 
applicable, final Sec.  111.70(a). Final Sec.  111.80(d) derives from 
proposed Sec.  111.37(b)(11)(i). We did not receive comments specific 
to this proposed requirement. However, we are making changes to final 
Sec.  111.80(d) consistent with those described for final Sec.  
111.80(a).
5. Final Sec.  111.80(e)
    Final Sec.  111.80(e) requires you to collect representative 
samples of each lot of packaged and labeled dietary supplements to 
determine whether the packaging and labeling of the packaged and 
labeled dietary supplements meet specifications established in 
accordance with final Sec. 111.70(g), and, as applicable, final Sec.  
111.70(a). Final Sec.  111.80(e) derives from proposed Sec.  
111.37(b)(11)(iv). Final Sec.  111.80(e) includes revisions associated 
with final Sec.  111.70(g), which requires you to establish 
specifications for the packaging and labeling of the finished packaged 
and labeled dietary supplements. Final Sec.  111.70(g) includes 
specifications that determine whether you used the packaging specified 
in the master manufacturing record and you applied the label specified 
in the master manufacturing record. Under final Sec.  111.70(a) and (g) 
the parameters that we proposed to specify under proposed Sec.  
111.37(b)(11)(iv) are the required specifications for packaged and 
labeled dietary supplements.
    Final Sec.  111.80(e) includes a change to clarify the exact 
specifications by citing the relevant sections. Final Sec.  111.80(e) 
also includes an editorial change in that you are required to 
``determine whether'' specifications are met rather than to ``determine 
that'' specifications are met. We are making this change because 
``determine that specifications are met'' may be interpreted as a 
predetermined outcome, i.e., that specifications will, in fact, be met.
    We did not receive comments specific to proposed Sec.  
111.37(b)(11)(iv).

M. What Are the Requirements for Reserve Samples? (Final Sec.  111.83)

    Final Sec.  111.83 sets forth requirements to collect and hold 
reserve samples of dietary supplements. Final Sec.  111.83 derives from 
proposed Sec. Sec.  111.37(b)(12), 111.50, and 111.83(b)(2).
    Under proposed Sec.  111.37(b)(12) we would require holding reserve 
samples as an operation performed by the quality control unit. Under 
proposed Sec.  111.50(h), we proposed that you collect representative 
reserve samples of each batch of dietary supplement. Consistent with 
the changes that we are making to final Sec.  111.80, final Sec.  
111.83 does not specify who must collect and hold the required reserve 
samples. However, under final Sec.  111.105(g), quality control 
personnel retain oversight of the collection and holding of the 
required reserve samples. Because the requirement to collect and hold 
reserve samples is not an operation that must be performed by quality 
control personnel, we are including the requirement to collect reserve 
samples in subpart E as part of the elements of a production and 
process control system rather than in subpart F as part of the 
requirements for quality control personnel.
    For consistency with terms used elsewhere in the final rule, final 
Sec.  111.83 requires that you ``hold'' reserve samples rather than 
``keep'' them.
1. Final Sec.  111.83(a)
    Final Sec.  111.83(a) requires you to collect and hold reserve 
samples of each lot of packaged and labeled dietary supplements that 
you distribute. Final Sec.  111.83(a) derives, in part, from proposed 
Sec.  111.37(b)(12), which would require the quality control unit to 
keep the reserve samples and, in part, from proposed Sec.  111.50(h), 
which would require you to collect representative reserve samples from 
each batch of dietary supplement.
    (Comment 201) Several comments ask for clarification of the 
requirements for representative and reserve samples as proposed in 
Sec.  111.37(b)(11) and (b)(12). One comment notes that proposed Sec.  
111.37(b)(11) does not indicate whether representative samples are also 
collected to serve as the reserve samples described in proposed Sec.  
111.37(b)(12) and asks whether the items in proposed Sec.  
111.37(b)(11)(i) through (b)(11)(iv) are to be kept as reserve samples.
    (Response) As discussed in section VI of this document, we are 
adding a definition of ``reserve sample'' to reduce the potential for 
confusion between requirements for reserve samples and requirements for 
representative samples. A reserve sample is a representative sample 
that is held for a designated period of time.
2. Final Sec.  111.83(b)(1)
    Final Sec.  111.83(b)(1) requires the reserve samples to be held 
using the same container-closure system in which the packaged and 
labeled dietary supplement is distributed, or if distributing dietary 
supplements to be packaged and labeled, using a container-closure 
system that provides essentially the same characteristics to protect 
against contamination or deterioration as the one in which it is 
distributed for packaging and labeling elsewhere. Final Sec.  
111.83(b)(1) derives from proposed Sec.  111.83(b)(2) which we proposed 
to include with the requirements for holding and distributing. The 
final sections that derive from proposed Sec.  111.83(b)(2) are in 
subpart M (final Sec.  111.465). However, we are duplicating these 
requirements in final Sec.  111.83(b)(1) for clarity and ease of use, 
so that you have information about the requirements for the container-
closure system for holding reserve samples of packaged and labeled 
dietary supplements in the same section as the requirements to collect 
the samples.
3. Final Sec.  111.83(b)(2)
    Final Sec.  111.83(b)(2) requires that reserve samples be 
identified with the batch, lot, or control number. Final

[[Page 34858]]

Sec.  111.83(b)(2) derives from proposed Sec.  111.37(b)(12)(i) with 
editorial changes associated with the reorganization. We have added 
``control number'' to the provision for consistency with other 
provisions of the final rule which refer to a ``control number'' in 
addition to a ``batch or lot number.''
    We did not receive comments specific to proposed Sec.  
111.37(b)(12)(i).
4. Final Sec.  111.83(b)(3)
    Final Sec.  111.83(b)(3) requires that reserve samples be retained 
for 1 year past the shelf life date (if shelf life dating is used), or 
for 2 years from the date of distribution of the last batch of dietary 
supplements associated with those reserve samples, for use in 
appropriate investigations. Final Sec.  111.83(b)(3) derives from 
proposed Sec.  111.37(b)(12) which would require the quality control 
unit to keep the reserve samples for 3 years from the date of 
manufacture for use in appropriate investigations including, but not 
limited to, consumer complaint investigations to determine, for 
example, whether the dietary supplement associated with a consumer 
complaint failed to meet any of its specifications for identity, 
purity, quality, strength, and composition, as well as from proposed 
Sec.  111.50(h) which would require reserve samples to be kept for 3 
years from the date of manufacture. We discuss the change from 3 years 
to 2 years and the change from ``date of manufacture'' to ``the date of 
distribution'' in connection with the recordkeeping requirements in 
subpart P, in section XXI of this document.
    Final Sec.  111.83(b)(3) thus provides flexibility in determining 
how long you must hold reserve samples of packaged and labeled dietary 
supplements.
    Final Sec.  111.83(b)(3) does not include the proposed examples of 
investigations that may require the use of reserve samples because 
these examples are not requirements.
    (Comment 202) Many comments address the requirement to keep the 
reserve samples after manufacture and recommend that expiration dates 
be a factor when determining the amount of time reserve samples should 
be kept and maintained. Most of the comments recommend holding reserve 
samples of packaged and labeled dietary supplements for 3 years from 
the date of manufacture or, when an expiration date has been 
established by the manufacturer, for 1 year after the expiration date. 
Other comments recommend holding reserve samples for time periods 
ranging from 6 months to 2 years after the expiration date.
    (Response) The final rule contains requirements similar to the 
suggestions made by the comments. The final rule provides flexibility 
to hold reserve samples for 1 year past the shelf life date, when such 
dating is used. Any shelf life date that you include on the label of 
the product should be supported by data.
5. Final Sec.  111.83(b)(4)
    Final Sec.  111.83(b)(4) requires that reserve samples consist of 
at least twice the quantity necessary for all tests or examinations to 
determine whether or not the dietary supplement meets product 
specifications. Final Sec.  111.83(b)(4) derives from proposed Sec.  
111.37(b)(12)(ii) which would require that the reserve samples consist 
of at least twice the quantity necessary for tests.
    Final Sec.  111.83(b)(4) provides that the reserve samples may be 
used for examinations or tests and to determine whether or not the 
dietary supplement meets product specifications, as a revision 
associated with final Sec.  111.75.
    (Comment 203) One comment agrees that twice the quantity necessary 
for testing should be collected and held.
    (Response) The final rule is consistent with this comment.

N. Who Conducts a Material Review and Makes a Disposition Decision? 
(Final Sec.  111.87)

    Final Sec.  111.87 requires quality control personnel to conduct 
all required material reviews and make all required disposition 
decisions. Final Sec.  111.87 derives from a number of proposed 
requirements for conducting a material review and making a disposition 
(Sec. Sec.  111.35(i) and (n), 111.37(b)(5) and (b)(14), 111.40(a)(3), 
111.50(d)(1), and 111.85(a) and (c)). Under each of these provisions, 
the quality control unit would have an oversight role and would review 
and approve all material reviews and all disposition decisions. Under 
some of these provisions (i.e., Sec. Sec.  111.50(d)(1) and 111.85(a) 
and 85(c)) the quality control unit would conduct the material review 
itself and make the disposition decision.
    (Comment 204) One comment disagrees that the quality control unit 
must conduct the material review and make the disposition decision. The 
comment argues that manufacturing personnel are better qualified to 
conduct the review and make disposition decisions because they are 
often engineers and have the relevant expertise regarding the use of 
machinery and people to produce a product. In contrast, the comment 
asserts that quality control unit personnel generally are chemists with 
expertise only in testing and little expertise in manufacturing. The 
comment asserts that the quality control unit should not be expected to 
make decisions concerning manufacturing operations; however, it should 
be informed of changes so it can evaluate the results of reprocessing 
on the finished product.
    (Response) We agree, in part, with the comments and the final rule 
simplifies the provisions regarding a material review and disposition 
decision. Quality control personnel can conduct the material review and 
disposition decision by reviewing the underlying information gathered 
or obtained by other qualified personnel and then making the final 
decision. Under the final rule, we retain the principle that qualified 
individuals other than quality control personnel can contribute to the 
quality control personnel's material review and disposition decision. 
The final rule sets forth the following requirements:
    <bullet> Under final Sec.  111.87, quality control personnel must 
conduct all required material reviews and make all required disposition 
decisions;
    <bullet> Under final Sec.  111.103, you must establish and follow 
written procedures for conducting a material review and making a 
disposition decision; and
    <bullet> Under final Sec.  111.140(b)(3)(vii), documentation of a 
material review and disposition decision and followup must include the 
signature of the individual(s) designated to perform the quality 
control operations, who conducted the material review and made the 
disposition decision, and of any qualified individual who provided 
information relevant to that material review and disposition decision.
    Taken in total, the final rule establishes a system in which you 
have flexibility to develop procedures that suit your organization, 
including having qualified individuals, other than the designated 
quality control personnel, provide information relevant to the material 
review and disposition decision. For example, under final Sec.  
111.140(b)(3), you could have a qualified individual in the production 
department prepare a report that includes all the required 
documentation and information and provide a signed copy of that report 
to designated quality control personnel. An individual designated to 
perform quality control operations would then read that report, add to 
it if necessary, conduct any additional investigations if necessary, 
and if he or she agrees with the report, co-sign the report or an 
amended report that includes additional documentation or information, 
thus completing a material review and disposition decision.

[[Page 34859]]

    The final rule provides for the participation of qualified 
individuals, other than those designated to perform quality control 
operations, in conducting the material review. In addition, as already 
discussed, under final Sec.  111.12(b) you may assign a qualified 
individual who has responsibilities for operations other than quality 
control to perform quality control operations, provided that the 
individual has distinct and separate responsibilities related to 
performing quality control operations.

O. What Requirements Apply to Treatments, In-Process Adjustments, and 
Reprocessing When There is a Deviation or Unanticipated Occurrence or 
When a Specification Established in Accordance with Sec.  111.70 Is Not 
Met? (Final Sec.  111.90)

1. Final Sec.  111.90
    Final Sec.  111.90 is a unified provision that clarifies your 
responsibilities regarding treatment or in-process adjustments to a 
component, and in-process adjustments or reprocessing of a dietary 
supplement, in a more ``user-friendly'' fashion. We have identified in 
one provision the restrictions that apply to these operations. Final 
Sec.  111.90 derives from proposed Sec. Sec.  111.35(i)(4)(i), 
(i)(4)(ii), and (i)(4)(iii); 111.50(d)(1), (f), and (g); and 111.65(d).
    Final Sec.  111.90 includes the following changes we are making to 
the proposed provisions for consistency and clarity:
    <bullet> We are making revisions to make the section consistent 
with the definition of ``reprocessing'' in final Sec.  111.3, which 
refers only to ``components or dietary supplements that have been 
previously removed from manufacturing.''
    <bullet> We are adding ``treatments'' as a step that quality 
control personnel could approve, because that term better describes 
actions that could be taken to correct a deviation or unanticipated 
occurrence with a component, packaging, or label.
    <bullet> We are clarifying that it is quality control personnel who 
reject components, packaging, or labels.
    <bullet> We are clarifying that quality control personnel approve 
the treatment, in-process adjustment, or reprocessing rather than 
determine whether the treatment, in-process adjustment, or reprocessing 
is possible.
    <bullet> We are clarifying that, with respect to labels, the 
provision applies to the potential that a label not specified in the 
master manufacturing record could be used.
    <bullet> We are making changes to be consistent with the new 
provision, final Sec.  111.77.
    (Comment 205) One comment recommends deletion of proposed Sec.  
111.35(i)(4) and (i)(4)(i), arguing that the principles of those 
sections are covered under proposed Sec.  111.35(i)(2) and (i)(3).
    (Response) We disagree with the comment's assertion. The 
requirements of proposed Sec.  111.35(i)(4) and (i)(4)(i) are not 
covered by proposed Sec.  111.35(i)(2) and (i)(3). All the sections are 
related, but deal with different aspects of corrective action. Proposed 
Sec.  111.35(i)(2) and (i)(3) would require the firm to conduct a 
material review and make a disposition decision, while proposed Sec.  
111.35(i)(4) would prohibit the use of rejected ingredients unless the 
quality control unit determines that in-process adjustments are 
possible to correct the deviations or occurrence. We are making no 
changes as suggested by this comment and the primary elements of 
proposed Sec.  111.35(i)(4) are retained in final Sec.  111.90.
    (Comment 206) A few comments state their support for the 
requirement that the quality control unit have the authority to 
determine whether adjustments are possible to correct a deviation.
    (Response) We are retaining the proposed requirement for quality 
control personnel in final Sec.  111.90.
2. Final Sec.  111.90(a)
    Final Sec.  111.90(a) requires that you must not reprocess a 
rejected dietary supplement or treat or provide an in-process 
adjustment to a component, packaging, or label to make it suitable for 
use in the manufacture of a dietary supplement, unless: (1) Quality 
control personnel conduct a material review and make a disposition 
decision to approve the reprocessing, treatment, or in-process 
adjustment and (2) the reprocessing, treatment, or in-process 
adjustment is permitted by Sec.  111.77.
    Final Sec.  111.90(a) derives from proposed Sec. Sec.  
111.35(i)(4)(ii) and 111.50(d)(1). We revised this provision to be 
consistent with the changes in final Sec.  111.77.
    (Comment 207) Several comments state their support for proposed 
Sec.  111.35(i)(4)(ii), which would require the quality control unit to 
approve the reprocessing of any rejected component, dietary ingredient, 
or dietary supplement. However, not all comments agree that the quality 
control unit should have to conduct (under proposed Sec.  
111.50(d)(1)), rather than review and approve, a material review and 
disposition decision.
    (Response) As discussed in this section, by ``conduct a material 
review and make a disposition decision,'' we do not intend to limit 
those who may participate in a material review and disposition decision 
to only those persons acting in their capacity as designated quality 
control personnel. Others may assist quality control personnel in 
gathering and considering information relevant to the review and 
decision, however the quality control personnel have the responsibility 
to conduct a material review and make disposition decisions. Thus, we 
are retaining in final Sec.  111.90(a) the requirements in proposed 
Sec. Sec.  111.25(i)(4)(ii) and 111.50(d)(1).
3. Final Sec.  111.90(b)
    Final Sec.  111.90(b) requires that you must not reprocess any 
dietary supplement or treat or provide an in-process adjustment to a 
component to make it suitable for use in the manufacture of a dietary 
supplement, unless: (1) Quality control personnel conduct a material 
review and make a disposition decision based on a scientifically valid 
reason and approve the reprocessing, treatment, or in-process 
adjustment and (2) the reprocessing, treatment or in-process adjustment 
is permitted by Sec.  111.77. Final Sec.  111.90(b) derives from 
proposed Sec. Sec.  111.35(i)(4)(iii), 111.50(f), and 111.65(d). We 
revised this provision to be consistent with the changes in final Sec.  
111.77.
    (Comment 208) As discussed in section VI of this document 
(discussion of the definition of ``reprocessing''), some comments 
object to the restrictions in the definition of reprocessing in 
proposed Sec.  111.3 because the definition would not permit the 
reprocessing of ingredients that may have been removed because of 
insanitary conditions even if there are processes available that are 
safe and effective in removing foreign matter, microorganisms, or 
chemicals that may have rendered the ingredient ``insanitary.'' These 
comments also object to proposed Sec.  111.35(i)(4)(iii) for the same 
reasons. A few comments argue that a manufacturer should be able to 
reprocess a component or dietary supplement if it has been rejected 
because of contamination with microorganisms or types of contamination, 
such as heavy metals, if the quality control unit approves the 
reprocessing. These comments indicate this is the industry practice, 
one based on a scientific rationale for doing the reprocessing and that 
ensures other quality attributes of the product are not affected.
    Some comments state that the requirement is more strict than the 
food or drug CGMP requirements, noting that

[[Page 34860]]

reprocessing is widely accepted and allowed in the food CGMPs. Other 
comments believe that the prohibition in proposed Sec.  
111.35(i)(4)(iii) against reprocessing materials contaminated with 
microorganisms should be limited to materials contaminated with health-
hazardous microorganisms.
    (Response) As we discussed in the response to comment 53 for the 
definition of ``reprocessing,'' we agree with the comments that state 
that in-process materials can be reprocessed when there are suitable 
processes available. However, as noted by the comments, it is critical 
that there be appropriate oversight of the reprocessing so the quality 
of the dietary supplement is not compromised. Final Sec.  111.90(b) 
provides for the flexibility requested by the comments, provided that 
there is oversight by quality control personnel.
    (Comment 209) Proposed Sec.  111.35(i)(4)(iii) mentions 
``microorganism or other contaminants, such as heavy metals.'' One 
comment proposes that other contaminants, such as pesticides and 
aflatoxin, should be mentioned. Another comment suggests that the final 
rule should specify limits for heavy metals in dietary supplements.
    (Response) We decline to revise the final rule as suggested by the 
comments. It is impractical to provide an exhaustive list of relevant 
types of contamination, and a list that is longer, but not exhaustive, 
is more likely to be misunderstood as suggesting that the only types of 
contamination that are significant are the types of contamination in 
the list. For that reason, we have eliminated the reference to 
contamination to clarify that in any instance where it is appropriate 
quality control personnel must ensure that the disposition decision is 
based on a scientifically valid reason and also approve the 
reprocessing.
    (Comment 210) One comment notes that in the May 9, 2003, satellite 
broadcast concerning the 2003 CGMP Proposal, we indicated that treating 
a component or dietary supplement with irradiation as a means to reduce 
or eliminate the microbial load was acceptable as long as the treatment 
was part of the process for producing that material. The comment asks 
for confirmation that irradiation of components or dietary supplements 
is allowed under part 179 (21 CFR part 179), even though such 
treatments are not listed in the table provided in Sec.  179.26(b).
    (Response) We are unable to provide the requested confirmation. 
Under section 201(s) of the act, irradiation intended for use in 
producing, manufacturing, packing, processing, preparing, treating, 
packaging, transporting, or holding food is a food additive that 
requires premarket review and approval before it can be used in food. 
Our Office of Food Additive Safety is currently reviewing a food 
additive petition for the use of irradiation on dietary ingredients and 
dietary supplements. Until that review process is completed and we have 
authorized this use of irradiation through a final rule codified in 
part 179, irradiation of dietary ingredients and dietary supplements as 
a means to reduce or eliminate microbial loads is not permitted. 
However, you may use an irradiated component (such as a spice that is 
used to flavor a dietary supplement) when the irradiation of that 
component is allowed under Sec.  179.26.
4. Final Sec.  111.90(c)
    Final Sec.  111.90(c) requires that any batch of dietary supplement 
that is reprocessed, that contains components that you have treated, or 
to which you have made in-process adjustments to make them suitable for 
use in the manufacture of the dietary supplement must be approved by 
quality control personnel and comply with final Sec.  111.123(b) before 
releasing for distribution. Final Sec.  111.90(c) derives from proposed 
Sec.  111.50(g).
    Final Sec.  111.90(c) also includes conforming revisions to clarify 
that a dietary supplement that contains a component treated before use 
or adjusted in-process, or that has had in-process adjustments to make 
it suitable for use in the manufacture of a dietary supplement, must be 
approved by quality control personnel and comply with final Sec.  
111.123(b) before releasing for distribution. We revised this provision 
to be consistent with the changes in final Sec. Sec.  111.77 and 
111.123(b).
    Final Sec.  111.90(c) also includes revisions to reflect the final 
provisions that relate to reprocessing and in-process adjustments (see 
final Sec. Sec.  111.113, 111.120, and 111.155).
    (Comment 211) One comment asserts that a reprocessed product should 
be retested to confirm that it meets product specifications.
    (Response) Under final Sec.  111.75(c) and (d) quality control 
personnel have flexibility to determine whether tests or examinations 
are necessary to ensure that a reprocessed product meets product 
specifications.

P. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.95)

1. Final Sec.  111.95(a)
    Final Sec.  111.95(a) requires you to make and keep records 
required under this subpart in accordance with subpart P. Final Sec.  
111.95(a) derives from proposed Sec.  111.35(o). Some of the records 
required under subpart E are set forth as recordkeeping requirements in 
other subparts of this final rule, such as those related to receiving 
records for components, packaging, and labels in subpart G, and the 
results of testing or examination in subpart J. The record requirements 
not specifically required in other related subparts are listed in 
subpart E.
    (Comment 212) One comment supports the recordkeeping requirements, 
states that the records provide a valuable paper trail that will allow 
manufacturers to identify and fix problems in the process, and suggests 
the requirements protect consumers from adulterated and misbranded 
products.
    (Response) We agree. Under final Sec.  111.95(a), a firm must make 
and keep records required by subpart E in accordance with subpart P. As 
discussed in this section, firms are required to keep the records 
necessary for determining whether their products are made in accordance 
with specifications. This will help them identify and correct any 
problems. In addition, under subpart P, the records must be kept for 1 
year past the shelf life date (if shelf life dating is used) or 2 years 
beyond the date of distribution of the last batch of dietary 
supplements associated with those records. Moreover, firms must make 
their records available to us for inspection and copying, which will 
permit us to determine whether firms are manufacturing, packaging, 
labeling, and holding dietary supplements in accordance with the 
requirements of this rule.
2. Final Sec.  111.95(b)
    Final Sec.  111.95(b) specifies the records you must make and keep 
under subpart E. Under the reorganization several recordkeeping 
requirements of proposed Sec.  111.35 are set forth in other subparts.
    Final Sec.  111.95(b)(1) requires you to make and keep records of 
the specifications established. Final Sec.  111.95(b)(1) derives from 
proposed Sec.  111.35(o)(1).
    Final Sec.  111.95(b)(2) requires you to make and keep records of 
your qualification of a supplier for the purpose of relying on the 
supplier's

[[Page 34861]]

certificate of analysis. Final Sec.  111.95(b)(2) is a record that is 
required under final Sec.  111.75(a)(2)(B).
    Final Sec.  111.95(b)(3) requires you to make and keep 
documentation for why meeting in-process specifications, in combination 
with meeting component specifications, helps ensure that the dietary 
supplement meets the specifications for identity, purity, strength, and 
composition and for limits on those types of contamination that may 
adulterate or may lead to adulteration of the finished batch of the 
dietary supplement. Final Sec.  111.95(b)(3) refers to records required 
under final Sec.  111.70(c)(2).
    Final Sec.  111.95(b)(4) requires you to make and keep 
documentation for why the results of appropriate tests or examinations 
for the product specifications selected under final Sec.  111.75(c)(1) 
ensures that the dietary supplement meets all product specifications. 
Final Sec.  111.95(b)(4) is a record that is required under final Sec.  
111.75(c)(3).
    Final Sec.  111.95(b)(5) requires you to make and keep 
documentation for why any component and in-process testing, 
examination, or monitoring, and any other information, will ensure that 
a product specification that is exempted under final Sec.  111.75(d) is 
met without verification through periodic testing of the finished 
batch, including documentation that the selected specifications tested 
or examined under final Sec.  111.75(c)(1) are not able to verify that 
the production and process control system is producing a dietary 
supplement that meets the exempted product specification and there is 
no scientifically valid method for testing or examining such exempted 
product specification at the finished batch stage. Final Sec.  
111.95(b)(5) refers to a record required under final Sec.  
111.75(d)(1). As previously discussed in this section, we are issuing 
an interim final rule, published elsewhere in this issue of the Federal 
Register, that sets forth a procedure for requesting an exemption from 
the requirement that the manufacturer conduct at least one appropriate 
test or examination to verify the identity of any component that is a 
dietary ingredient. Included in the interim final rule is an amendment 
to final Sec.  111.95(b) adding a new paragraph (b)(6) requiring the 
retention of FDA's response to a petition submitted under Sec.  
111.75(a)(1)(ii) that provides for an exemption from the provision of 
Sec.  111.75(a)(1)(i).
    (Comment 213) One comment recommends the recordkeeping requirements 
of proposed Sec.  111.35(m) be moved to follow the requirements for 
appropriate test methods because these requirements are related and 
probably best understood without intervening information.
    (Response) Consistent with this comment, the recordkeeping 
requirements of proposed Sec.  111.35(m) are set forth in final subpart 
J instead of subpart E.

XI. Comments on Requirements for Quality Control (Final Subpart F)

A. Organization of Final Subpart F

    Proposed Sec.  111.37 set forth requirements for quality control 
operations. Other proposed requirements related to quality control 
operations were set forth in other sections. For example, proposed 
Sec.  111.40(a) would require the quality control unit to perform 
operations associated with components that you use in the manufacturing 
process. Proposed Sec.  111.45 would establish requirements for the 
master manufacturing record and would have the quality control unit 
review and approve each master manufacturing record. Proposed Sec.  
111.50 would have the quality control unit review batch production 
records.
    As shown in table 7 of this document, the final rule reorganizes 
the requirements related to quality control operations into a distinct 
subpart (final Subpart F--Production and Process Control System: 
Requirements for Quality Control Operations). Table 7 lists the 
sections in final subpart F and identifies the proposed sections that 
form the basis for the sections in the final rule.

           Table 7.--Derivation of Sections in Final Subpart F
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.103 What are the requirements   N/A
 under this subpart F for written
 procedures?
------------------------------------------------------------------------
Sec.   111.105 What must quality control   Sec.   111.37(a), (b)(1),
 personnel do?                              (b)(11), and (b)(12)
------------------------------------------------------------------------
Sec.   111.110 What quality control        Sec.   111.37(b)(9) and
 operations are required for laboratory     (b)(13)
 operations associated with the
 production and process control system?
------------------------------------------------------------------------
Sec.   111.113 What quality control        Sec.   111.35(i)(2), (i)(3),
 operations are required for a material     (i)(4)(i), (i)(4)(ii), (j),
 review and disposition decision?           and (n)
                                           Sec.   111.37(b)(3)
                                           Sec.   111.37(c)
                                           Sec.   111.40(a)(3) and
                                            (b)(2)
                                           Sec.   111.50(d)(1)
                                           Sec.   111.65(d)
                                           Sec.   111.70(c)
------------------------------------------------------------------------
Sec.   111.117 What quality control        Sec.   111.30(b)(4), (b)(6),
 operations are required for equipment,     (b)(7), and (b)(8)
 instruments, and controls?
------------------------------------------------------------------------
Sec.   111.120 What quality control        Sec.   111.35(i)(4)(i) and
 operations are required for components,    (i)(4)(ii)
 packaging, and labels before use in the   Sec.   111.37(b)(2) and
 manufacture of a dietary supplement?       (b)(10)
                                           Sec.   111.40(a)(3) and
                                            (b)(2)
                                           Sec.   111.50(e)(1)
------------------------------------------------------------------------
Sec.   111.123 What quality control        Sec.   111.35(e)(2), (f),
 operations are required for the master     (i)(2), and (o)(2)
 manufacturing record, the batch           Sec.   111.37(b)(2), (b)(4),
 production record, and manufacturing       (b)(5), and (b)(11)(iii)
 operations?                               Sec.   111.45(c)
                                           Sec.   111.50(d)(1) and
                                            (d)(2)
                                           Sec.   111.50(g)
------------------------------------------------------------------------
Sec.   111.127 What quality control        Sec.   111.37(b)(2) and
 operations are required for packaging      (b)(10)
 and labeling operations?                  Sec.   111.40(a)(2) and
                                            (a)(3)
                                           Sec.   111.70(c), (d), and
                                            (e)
------------------------------------------------------------------------
Sec.   111.130 What quality control        Sec.   111.37(b)(2) and
 operations are required for returned       (b)(15)
 dietary supplements?                      Sec.   111.85(a)
------------------------------------------------------------------------
Sec.   111.135 What quality control        Sec.   111.95
 operations are required for product
 complaints?
------------------------------------------------------------------------
Sec.   111.140 Under this subpart F, what  Sec.   111.35(j)
 records must you make and keep?           Sec.   111.37(c) and (d)
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Quality 
Control Operations

1. Revisions
    The final rule:
    <bullet> Reflects that the rule applies to persons who manufacture, 
package, label, or hold dietary supplements

[[Page 34862]]

unless subject to an exclusion under Sec.  111.1;
    <bullet> Changes the requirement for a quality control unit to a 
requirement for quality control operations performed by quality control 
personnel;
    <bullet> Requires quality control personnel to review and approve 
documentation for why meeting in-process specifications will ensure the 
specifications for identity, purity, strength, and composition of a 
dietary supplement are met;
    <bullet> Requires quality control personnel to review and approve 
documentation setting forth the basis for qualifying a supplier of a 
component;
    <bullet> Requires quality control personnel to review and approve 
documentation of your basis for why meeting certain selected 
specifications in a subset of finished batches will ensure your 
finished batch of the dietary supplement meets all product 
specifications for identity, purity, strength, and composition and 
limits on those types of contamination that may adulterate, or that may 
lead to the adulteration of, the dietary supplement; and
    <bullet> Requires quality control personnel to review and approve 
documentation for why a product specification exempted from the 
verification requirements in final subpart E is met without 
verification through periodic testing of the finished batch.
2. Changes Associated With the Reorganization
    The final rule:
    <bullet> Reduces redundant provisions and
    <bullet> Combines parts of various proposed requirements that were 
scattered throughout the 2003 CGMP Proposal.
3. Changes After Considering Comments
    The final rule:
    <bullet> Incorporates a new requirement to establish, and keep as a 
record, written procedures for quality control operations;
    <bullet> Simplifies the requirements associated with conducting a 
material review and making a disposition decision;
    <bullet> Requires quality control personnel to ensure that 
representative samples are collected rather than collecting these 
samples;
    <bullet> Requires quality control personnel to ensure that reserve 
samples are held rather than quality control personnel holding these 
samples;
    <bullet> Requires quality control personnel to ensure tests or 
examinations are appropriate rather than conduct these tests or 
examinations; and
    <bullet> Requires review by quality control personnel of all 
records for calibration of instruments, and for calibrations, 
inspections, and checks of automatic, mechanical, or electronic 
equipment to be performed on a periodic basis rather than at the time 
the record is made.

C. General Comments on Proposed Sec.  111.37 (Final Subpart F)

    (Comment 214) Some comments support the use of a quality control 
unit and recognize it as an important need in manufacturing operations. 
Some comments assert the quality control unit may not have all the 
responsibilities listed in proposed Sec.  111.37 because there may be 
some duties contracted out to someone else, such as testing that could 
be sent to a contract laboratory, or some duties that may be better 
suited for employees in other organizational units. As an example, a 
few comments note that the instrument and equipment calibration 
functions in proposed Sec.  111.37 may be better performed by 
individuals responsible for the equipment in their particular 
operational area, by those in a unit dedicated to equipment maintenance 
and calibration, or possibly by a third party, who is qualified by 
training and/or experience, to do these functions. Similarly, other 
comments note that other groups with the appropriate expertise may be 
assigned or required to review and approve proposed changes or 
procedures in manufacturing operations or to conduct material reviews 
and make disposition decisions. These comments assert the quality 
control unit should have overall responsibility and oversight for 
quality control functions but also should be able to rely on the 
expertise of other persons in the organization to accomplish the tasks.
    (Response) As already discussed with respect to the definition of 
quality control personnel in section VI of this document, these 
comments may have misunderstood the quality control unit's role under 
the proposed rule. Consequently, we have added final Sec.  111.12(b) in 
subpart B, discussed in section VII of this document, to state you must 
identify who is responsible for your quality control operations. Each 
person who is designated to perform quality control operations must be 
qualified to do so and have distinct and separate responsibilities 
related to performing such operations from those responsibilities that 
the person otherwise has when not performing such operations.
    The final rule requires quality control personnel to ensure all 
appropriate tests and examinations are conducted, and review and 
approve the results of all tests and examinations, but does not require 
that quality control personnel conduct the tests or examinations. Thus, 
you would not need to consider that an individual who conducts tests or 
examinations at a laboratory under contract to your organization is 
performing a quality control operation that must be performed by 
quality control personnel. However, you may choose to designate that 
individual as part of your quality control personnel and require that 
the tests or examinations conducted by that individual be quality 
control operations. Importantly, however, for the purposes of this 
final rule, we consider that a quality control operation performed by 
an individual under contract to you or by another third party is no 
different than a quality control operation performed by your employees 
who are designated to perform such operation. If, during the course of 
an inspection, we find the requirements of this final rule were not 
followed, we will hold you, rather than the contractor or other third 
party, responsible. The applicability of this final rule to contractors 
is discussed in detail in section VI of this document.
    (Comment 215) Several comments request that the quality control 
unit focus on reviewing tasks performed by others rather than on 
performing the tasks itself.
    (Response) We agree with these comments and have revised several 
provisions accordingly. For example, in the 2003 CGMP Proposal we would 
require the quality control unit to perform appropriate tests and 
examinations of incoming materials, in-process materials, each finished 
batch of dietary supplements, and each batch of packaged and labeled 
dietary supplements (proposed Sec.  111.37(b)(13)). Under the final 
rule, quality control operations include ensuring appropriate tests and 
examinations are conducted (final Sec.  111.110(b)) but do not include 
conducting these tests and examinations.
    (Comment 216) One comment asks whether we expect the quality 
control unit to approve operational activities as soon as they occur or 
collectively at the end of the process. This and other comments argue 
the quality control function is usually accomplished by a team of 
qualified persons with the quality control unit having the overall 
responsibility and authority to perform a collective, post-processing, 
final approval.
    (Response) The time at which quality control personnel conduct 
assigned duties will vary by the specific operation, the size and 
complexity of the operation, and how quality control functions are 
assigned to qualified

[[Page 34863]]

persons. For example, the final rule requires quality control personnel 
to determine whether components conform to specifications, and to 
release components from quarantine before you use them in the 
manufacture of a dietary supplement (final Sec.  111.120). However, 
this final rule does not require, for example, that quality control 
personnel determine whether components conform to specifications as 
soon as you receive them, although it may be common business practice 
to do so.
    Regardless of when quality control personnel perform their 
operations, quality control personnel have the ultimate responsibility 
for ensuring manufacturing, packaging, labeling, and holding operations 
are performed in a manner that will ensure the quality of the dietary 
supplement and that the dietary supplement is packaged and labeled as 
specified in the master manufacturing record.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.103)

    We received many comments that recommend written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to comments 
on specific provisions in the same section.
    Final Sec.  111.103 requires that you establish and follow written 
procedures for the responsibilities of the quality control operations. 
Final Sec.  111.103 specifically identifies two of the written 
procedures you must establish and follow, i.e., written procedures for 
conducting a material review and making a disposition decision and for 
approving or rejecting any reprocessing.

E. What Must Quality Control Personnel Do? (Final Sec.  111.105)

    Final Sec.  111.105 broadly captures the responsibility of quality 
control personnel to provide oversight for manufacturing, packaging, 
labeling, and holding operations. It requires quality control personnel 
to ensure that your manufacturing, packaging, labeling, and holding 
operations ensure the quality of the dietary supplement and that the 
dietary supplement is packaged and labeled as specified in the master 
manufacturing record. Final Sec.  111.105 derives from proposed Sec.  
111.37(a) which would require you to use a quality control unit to 
ensure your manufacturing, packaging, labeling, and holding operations 
in the production of dietary supplements are performed in a manner that 
prevents adulteration and misbranding, including ensuring dietary 
supplements meet specifications for identity, purity, quality, 
strength, and composition.
    This final rule focuses on ensuring that the manufacturer 
establishes specifications for its dietary supplements; includes those 
specifications in the master manufacturing record; meets those 
specifications and manufactures, packages, labels, and holds the 
product in a manner that will ensure the quality of the dietary 
supplement; and that the dietary supplement is packaged and labeled as 
specified in the master manufacturing record. Because of that focus, 
the labeling requirements of the final rule address the operation of 
putting the label that is specified in the master manufacturing record 
on the product rather than the content of a product label that meets 
all of the labeling requirements of the act and our implementing 
regulations. The failure to put the label identified in the master 
manufacturing record on the finished product would be a violation of 
this final rule. In addition, if the label on the product does not 
correctly reflect the ingredients, the label would misbrand the product 
under section 403 of the act. For purposes of this final rule, the 
labeling operations are CGMP requirements and relate to the label 
identified in the master manufacturing record. Therefore, we are 
deleting ``misbranding'' from proposed Sec.  111.37(a) (final Sec.  
111.105) since the act of misbranding other than applying a label 
different from the one identified in the master manufacturing record is 
not considered a CGMP violation in the context of this final rule. Any 
misbranding is still a violation of the act, however, and manufacturers 
must comply with all applicable statutory and regulatory requirements 
in addition to the requirements of this final rule.
    This series of changes emphasizes the need to ensure the quality of 
a dietary supplement and that the dietary supplement is packaged and 
labeled as specified in the master manufacturing record. As discussed 
in detail in the rest of this section, final Sec.  111.105 also 
requires that quality control personnel perform certain operations and 
groups of operations.
1. Final Sec.  111.105(a)
    Final Sec.  111.105(a) requires that quality control personnel 
approve or reject all processes, specifications, written procedures, 
controls, tests, and examinations, and deviations from or modifications 
to them, that may affect the identity, purity, strength, or composition 
of a dietary supplement. Final Sec.  111.105(a) derives from proposed 
Sec.  111.37(b)(1).
    (Comment 217) One comment recommends revising proposed Sec.  
111.37(b)(1) by replacing ``* * * identity, purity, quality, strength, 
and composition'' with ``* * * identity, purity, quality, strength, or 
composition.'' The comment asserts the quality control unit must be 
responsible for approving or rejecting anything that may affect one of 
these attributes.
    (Response) We agree with this comment. Under proposed Sec.  
111.37(b)(1) we had intended that the quality control unit be 
responsible, for example, for approving a test that would establish the 
identity of a component even if that test did not also establish the 
strength of that component. Final Sec.  111.105(a) changes ``and'' to 
``or'' as requested by this comment.
    (Comment 218) One comment recommends the quality control unit be 
responsible for maintaining the master copies of all current and 
approved written procedures, for distributing copies of approved 
written procedures to relevant personnel, and for collecting and 
destroying outdated Standard Operating Procedures (SOPs) (except 
designated historical SOP files).
    (Response) This comment is consistent with the underlying principle 
that quality control personnel oversee the design and conduct of the 
operations associated with the production of a dietary supplement. 
After considering these comments, final Sec.  111.105(a) requires 
quality control personnel to approve all written procedures that may 
affect the identity, purity, strength, or composition of a dietary 
supplement. With respect to the other suggested duties of quality 
control personnel, we are leaving the decision as to who performs them, 
up to the individual firm to best suit its overall operations.
2. Final Sec.  111.105(b), (c), d), and (e)
    Final Sec.  111.105(b) requires quality control personnel to review 
and approve the documentation setting forth the basis for qualification 
of any supplier. Final Sec.  111.105(c) requires quality control 
personnel to review and approve the documentation setting forth the 
basis for why meeting in-process specifications, in combination with 
meeting component specifications, will help ensure that specifications 
for the identity, purity, strength, and composition of the dietary 
supplement are met. Final Sec.  111.105(d) requires quality control 
personnel to review and approve the documentation setting forth the 
basis for why the results of appropriate tests or examinations for each 
product specification selected under final Sec.  111.75(c)(1) will 
ensure

[[Page 34864]]

that the finished batch of the dietary supplement meets product 
specifications. Final Sec.  111.105(e) requires quality control 
personnel to review and approve the basis and documentation for why any 
product specification is exempted from the verification requirements in 
final Sec.  111.75(c)(1), and for why any component and in-process 
testing, examination, or monitoring, or other methods will ensure that 
such exempted product specification is met without verification through 
periodic testing of the finished batch.
    Final Sec.  111.105(b), (c), (d), and (e) are requirements 
associated with the requirements established in final Sec. Sec.  
111.70(c)(3) and 111.75(a)(ii)(2)(E), (c)(4), (d)(1) and (d)(2).
3. Final Sec.  111.105(f)
    Final Sec.  111.105(f) requires quality control personnel to ensure 
that required representative samples are collected. Final Sec.  
111.105(f) differs slightly from proposed Sec.  111.37(b)(11)(i) 
through (b)(11)(iv) which would require the quality control unit to 
collect representative samples of incoming materials, in-process 
materials, each finished batch of dietary supplements, and each batch 
of packaged and labeled dietary supplements.
    After considering comments requesting the quality control unit 
focus on reviewing tasks performed by others rather than on performing 
the tasks themselves, the final rule does not specify that quality 
control personnel must collect representative samples. Under final 
Sec.  111.105(f), however, quality control personnel retain oversight 
of sample collection.
4. Final Sec.  111.105(g)
    Final Sec.  111.105(g) requires quality control personnel to ensure 
that required reserve samples are collected and held. Final Sec.  
111.105(g) derives from proposed Sec.  111.37(b)(12) which would 
require the quality control unit to keep reserve samples.
    After considering comments requesting the quality control unit 
focus on reviewing tasks performed by others rather than on performing 
the tasks themselves, the final rule does not specify that quality 
control personnel must keep reserve samples. Under final Sec.  
111.105(g), however, quality control personnel retain oversight of 
sample collection and holding.
5. Final Sec.  111.105(h)
    Final Sec.  111.105(h) requires that quality control operations for 
the master manufacturing record, the batch production record, and 
manufacturing operations include determining whether all specifications 
established in accordance with final Sec.  111.70(a) are met. Final 
Sec.  111.105(h) derives from proposed Sec.  111.37(b)(2) which would 
require that the quality control unit determine whether all components, 
dietary supplements, packaging, and labels conform to specifications. 
Under the final rule, we are identifying each of the specifications 
subject to review by quality control personnel under final Sec.  
111.77. The requirement for quality control personnel to determine 
whether specifications established under final Sec.  111.70(a) are met 
is included for consistency. This requirement is also consistent with 
final Sec.  111.73 which requires that the production and process 
control system must include a determination of whether all of the 
established specifications under final Sec.  111.70(a) are met.
6. Final Sec.  111.105(i)
    Final Sec.  111.105(i) requires quality control personnel to 
perform other operations required under subpart F. Final Sec.  
111.105(i) is associated with the reorganization. Under the 2003 CGMP 
Proposal, proposed Sec.  111.37(a) broadly captured the responsibility 
of the quality control unit to provide oversight for your 
manufacturing, packaging, labeling, and holding operations. Proposed 
Sec.  111.37(b) listed specific operations that we would require the 
quality control unit to perform. Final Sec.  111.105 now captures the 
responsibility of quality control personnel to provide oversight for 
your manufacturing, packaging, labeling, and holding operations. The 
specific operations that quality control personnel must perform to 
provide that oversight are set forth in final Sec.  111.105(a) through 
(h) and in final Sec. Sec.  111.110, 111.113, 111.117, 111.120, 
111.123, 111.127, 111.130, 111.135, and 111.140.

F. What Quality Control Operations Are Required for Laboratory 
Operations Associated With the Production and Process Control System? 
(Final Sec.  111.110)

    Final Sec.  111.110 sets forth the minimum required operations that 
quality control personnel must perform with respect to laboratory 
operations associated with the production and process control system.
1. Final Sec.  111.110(a)
    Final Sec.  111.110(a) requires that quality control operations for 
laboratory operations include reviewing and approving all laboratory 
control processes associated with the production and process control 
system. Final Sec.  111.110(a) derives, in part, from proposed Sec.  
111.37(b)(9) which would require that the quality control unit review 
and approve all laboratory control processes. For clarity, we are 
adding that the laboratory operations covered by final Sec.  111.110 
are those associated with the production and process control system. We 
want to make clear that laboratory operations such as those in your 
research and development department are not subject to final Sec.  
111.110.
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.37(b)(9).
2. Final Sec.  111.110(b)
    Final Sec.  111.110(b) requires that quality control operations for 
laboratory operations associated with the production and process 
control system include ensuring all tests and examinations required 
under final Sec.  111.75 are conducted. Final Sec.  111.110(b) derives, 
in part, from proposed Sec.  111.37(b)(13) which would require the 
quality control unit to perform appropriate tests and examinations of 
incoming materials, in-process materials, each finished batch of 
dietary supplements, and each batch of packaged and labeled dietary 
supplements.
    Proposed Sec.  111.37(b)(13) would list the types of materials that 
must be tested, including components, packaging, labels, dietary 
ingredients, and dietary supplements that you receive; the batch 
production at the in-process and finished batch stages; and packaged 
and labeled dietary supplements. This list would include materials 
that, at a minimum, would be tested under the 2003 CGMP Proposal. Under 
the final rule, the minimum requirements for testing or examination of 
the materials listed in proposed Sec.  111.37(b)(13) are set forth in 
final Sec.  111.75. To simplify and clarify proposed Sec.  
111.37(b)(13), final Sec.  111.110(b) replaces this list with ``all 
tests and examinations required under Sec.  111.75.''
3. Final Sec.  111.110(c)
    Final Sec.  111.110(c) requires that quality control operations for 
laboratory operations associated with the production and process 
control system include reviewing and approving the results of all tests 
and examinations required under final Sec.  111.75. Final Sec.  
111.110(c) derives from proposed Sec.  111.37(b)(9), which would 
require, in part, that the quality control unit review and approve all 
testing results. Final Sec.  111.110(c) requires that quality control

[[Page 34865]]

personnel review and approve the results of examinations as well as 
tests. This revision reflects the flexibility provided in the final 
rule to use either tests or examinations to determine whether 
specifications are met, provided that the test or examination is an 
appropriate, scientifically valid method.
    As with final Sec.  111.110(b), we provide in final Sec.  
111.110(c) that the tests and examinations are those required under 
final Sec.  111.75.
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.37(b)(9).

G. What Quality Control Operations Are Required for a Material Review 
and Disposition Decision? (Final Sec.  111.113)

    Final Sec.  111.113 derives from several proposed provisions, 
including Sec. Sec.  111.35(i), (j), and (n); 111.37(b)(3); 
111.40(a)(3) and (b)(2); 111.50(d)(1); 111.65(d); and 111.70(c). All 
these proposed requirements are related to one or more aspects 
associated with a material review and disposition, including the 
circumstances that require a material review and disposition decision, 
the documentation that must be included in a material review and 
disposition decision, any restrictions on who must conduct the material 
review and make the disposition decision, and the need for oversight by 
the quality control unit. As discussed in section X of this document, 
we simplified the provisions regarding a material review and 
disposition decision (final Sec.  111.87), emphasizing the importance 
of oversight by quality control personnel and retaining the principle 
that qualified individuals other than those who are designated quality 
control personnel can contribute to the material review and disposition 
decision. The final rule sets forth the following requirements for 
quality control personnel that relate to final Sec.  111.113:
    <bullet> Under final Sec.  111.87, quality control personnel must 
conduct all required material reviews and make all required disposition 
decisions;
    <bullet> Under final Sec.  111.103, you must establish and follow 
written procedures for conducting a material review and making a 
disposition decision; and
    <bullet> Under final Sec.  111.140(b)(3)(vii), documentation of a 
material review and disposition decision and followup must include the 
signature of the individual, designated to perform the quality control 
operation, who conducted the material review and made the disposition 
decision and of any qualified individual who provided information 
relevant to that material review and disposition decision.
    The final rule establishes a system in which you have the 
flexibility to develop procedures that suit your organization, 
including having qualified individuals, who are not designated to 
perform the quality control operation, provide information relevant to 
the material review and disposition decision. For example, under final 
Sec.  111.140(b)(3), you could have a qualified individual in the 
production department assist quality control personnel in conducting a 
material review by preparing a report that includes all the required 
documentation and information and providing a signed copy of that 
report to quality control personnel. An individual who is designated to 
perform the quality control operation could then use that report as 
part of the material review, conduct any further investigations, as 
necessary, and decide to accept, amend, or reject the report.
1. Final Sec.  111.113(a)
    Under final Sec.  111.113(a) quality control personnel must conduct 
a material review and make a disposition decision if:
    <bullet> A specification established in accordance with Sec.  
111.70 is not met;
    <bullet> A batch deviates from the master manufacturing record, 
including when any step established in the master manufacturing record 
is not completed and including any deviation from specifications;
    <bullet> There is any unanticipated occurrence during the 
manufacturing operations that adulterates or may lead to adulteration 
of the component, dietary supplement, or packaging, or could lead to 
the use of a label not specified in the master manufacturing record;
    <bullet> Calibration of an instrument or control suggests a problem 
that may have resulted in a failure to ensure the quality of a batch or 
batches of a dietary supplement; or
    <bullet> A dietary supplement is returned.
    Final Sec.  111.113(a) is substantially similar to proposed Sec.  
111.35(i)(3), which would require, in part, that you make a material 
disposition decision for any component, dietary supplement, packaging, 
or label:
    <bullet> If a component, dietary supplement, packaging, or label 
fails to meet established specifications;
    <bullet> If any step established in the master manufacturing record 
is not completed;
    <bullet> If there is any unanticipated occurrence during the 
manufacturing operations that adulterates or may lead to adulteration 
of the component, dietary supplement, packaging, or label;
    <bullet> If calibration of an instrument or control suggests a 
problem that may have caused batches of a dietary supplement to become 
adulterated; or
    <bullet> If a dietary supplement is returned.
    Final Sec.  111.113(a) also incorporates elements from other 
proposed sections regarding the circumstances that require a material 
review and disposition decision as follows:
    <bullet> Proposed Sec.  111.35(n), which would require you, for any 
specification that is not met, to conduct a material review and 
disposition decision under proposed Sec.  111.35(i);
    <bullet> Proposed Sec.  111.40(a)(3), which would require you, for 
components, dietary ingredients, or dietary supplements you receive, to 
conduct a material review and make a disposition decision if 
specifications are not met;
    <bullet> Proposed Sec.  111.40(b)(2), which would require that for 
packaging and labels you receive, you must conduct a material review 
and make a disposition decision if specifications are not met;
    <bullet> Proposed Sec.  111.50(d)(1), which would require that if a 
batch deviates from the master manufacturing record, including any 
deviation from specifications, the quality control unit must conduct a 
material review and make a disposition decision and record any decision 
in the batch production record;
    <bullet> Proposed Sec.  111.65(d), which would require you to 
conduct a material review and make a disposition decision in accordance 
with proposed Sec.  111.35(i) for any component, dietary ingredient, or 
dietary supplement that fails to meet specifications or that is or may 
be adulterated; and
    <bullet> Proposed Sec.  111.70(c), which would require you to 
conduct a material review and make a disposition decision of any 
packaged and labeled dietary supplements that do not meet 
specifications.
    In final Sec.  111.113(a) we are incorporating, into a single 
unified provision, the various proposed circumstances that would 
require a material review and disposition decision under the 2003 CGMP 
Proposal. We included revisions associated with final Sec.  111.87 
which requires quality control personnel to conduct any required 
material review and make any required disposition decision. We also 
included revisions associated with final Sec.  111.90 that relate to 
the impact on labeling operations due to deviations and unanticipated 
occurrences.
    In establishing final Sec.  111.113(a)(1), we are deleting the 
specific reference to the articles (components, dietary supplements, 
packaging, and labels)

[[Page 34866]]

required to undergo a material review. We are deleting these 
references, in part, to simplify the provision. Under final Sec.  
111.113(a) quality control personnel must conduct a material review and 
make a disposition decision if any specification established in 
accordance with final Sec.  111.70 is not met. It is not necessary to 
repeat, in final Sec.  111.113, the list of specifications that is 
clearly set forth in final Sec.  111.70.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.35(i)(3) and (n), 111.40(a)(3) and 
(b)(2), 111.50(d)(1), 111.65(d), or 111.70(c).
2. Final Sec.  111.113(b)
    Final Sec.  111.113(b)(1) requires that, when there is a deviation 
or unanticipated occurrence during the production and in-process 
control system that results in or could lead to adulteration of a 
component, dietary supplement, or packaging, or could lead to the use 
of a label not specified in the master manufacturing record, quality 
control personnel must reject the component, dietary supplement, or 
packaging, or label unless it approves a treatment, an in-process 
adjustment, or reprocessing to correct the applicable deviation or 
occurrence.
    Final Sec.  111.113(b)(1) derives from the following proposed 
provisions:
    <bullet> Proposed Sec.  111.35(i)(4)(i) which, in part, would 
require that, for any deviation or unanticipated occurrence which 
resulted in or could lead to adulteration of the component, dietary 
ingredient, dietary supplement, packaging, or label, you reject the 
component, dietary ingredient, dietary supplement, packaging, or label, 
unless the quality control unit determines that in-process adjustments 
are possible to correct the deviation or occurrence;
    <bullet> Proposed Sec.  111.35(i)(4)(ii) which, in part, would 
require that, for any deviation or unanticipated occurrence which 
resulted in or could lead to adulteration of the component, dietary 
ingredient, dietary supplement, packaging, or label, you not reprocess 
a rejected component or dietary supplement unless approved by the 
quality control unit; and
    <bullet> Proposed Sec.  111.37(b)(3) which, in part, would require 
the quality control unit to approve or reject all dietary ingredients, 
dietary supplements, components, packaging, and labels.
    For consistency with other provisions in final subpart F, final 
Sec.  111.113(b)(1) requires that quality control personnel ``reject'' 
a component, dietary supplement, packaging, or label. We also included 
revisions that are associated with final Sec.  111.90.
    Final Sec.  111.113(b)(2) requires that when a specification 
established in accordance with Sec.  111.70 is not met, quality control 
personnel must reject the component, dietary supplement, package, or 
label, unless quality control personnel approve a treatment, an in-
process adjustment, or reprocessing, as permitted in final Sec.  
111.77. This provision has been added as a result of the new provision, 
final Sec.  111.77 which provides for what happens when certain 
specifications are not met, the responsibilities of quality control 
personnel, and the changes made to final Sec.  111.90.
    (Comment 219) Several comments request that the quality control 
unit focus on reviewing tasks performed by others rather than on 
performing the tasks itself.
    (Response) We agree, and final Sec.  111.113(b) provides that 
quality control personnel ``approve'' an in-process adjustment rather 
than ``determine whether'' the in-process adjustment is possible.
3. Final Sec.  111.113(c)
    Final Sec.  111.113(c) requires the person who conducts a material 
review and makes the disposition decision, at the time of performance, 
to document that material review and disposition decision. Final Sec.  
111.113(c) derives from proposed Sec.  111.35(j) which, in part, would 
require that the person who conducts the material review and makes the 
disposition decision must, at the time of performance, document every 
material review and disposition decision in proposed Sec.  111.35(i).
    As an editorial revision, final Sec.  111.113(c) requires 
documentation of ``that'' decision rather than ``every'' decision. As a 
practical matter, under final Sec.  111.113(c) every material review 
and disposition decision is documented.
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.35(j).

H. What Quality Control Operations Are Required for Equipment, 
Instruments, and Controls? (Final Sec.  111.117)

    Final Sec.  111.117 (proposed Sec.  111.37(b)(6) through (b)(8)) 
sets forth the minimum required operations that quality control 
personnel must perform with respect to equipment, instruments, and 
controls.
1. Final Sec.  111.117(a) through (c)
    Final Sec.  111.117(a) through (c) requires the quality control 
operations for equipment, instruments, and controls to include:
    <bullet> Reviewing and approving all processes for calibrating 
instruments and controls;
    <bullet> Periodically reviewing all records for calibration of 
instruments and controls; and
    <bullet> Periodically reviewing all records for calibrations, 
inspections, and checks of automated, mechanical, or electronic 
equipment.
    Final Sec.  111.117(a), (b), and (c) derive from proposed Sec.  
111.37(b)(6), (b)(7), and (b)(8) which would require the quality 
control unit to:
    <bullet> Review and approve all processes for calibrating 
instruments or controls;
    <bullet> Review all records for calibration of instruments, 
apparatus, gauges, and recording devices; and
    <bullet> Review all records for equipment calibrations, 
inspections, and checks.
    Final Sec.  111.117 includes the following changes we are making 
for consistency with the requirements, set forth in subpart D, for 
equipment and utensils:
    <bullet> We have deleted the terms ``apparatus,'' ``gauges,'' and 
``recording devices'' from proposed Sec.  111.37(b)(7) as they would 
fall under the terms ``instruments and controls'' in final Sec.  
111.117, and because subpart D does not use the terms ``apparatus,'' 
``gauges,'' or ``recording devices.''
    <bullet> We are characterizing the records for equipment 
calibrations, inspections, and checks as records for calibrations, 
inspections, and checks of ``automated, mechanical, or electronic 
equipment,'' because final Sec.  111.30(c) requires you to calibrate, 
inspect, or check ``automated, mechanical, or electronic equipment.''
    (Comment 220) One comment argues the requirements for oversight by 
the quality control unit in proposed Sec.  111.37(b)(7) and (b)(8) are 
excessive and go beyond requirements for both the drug CGMPs and food 
CGMPs. The comment recommends revising proposed Sec.  111.37(b)(7) and 
(b)(8) to require a review of all records when there is a negative 
impact on the product due to a calibration failure.
    Other comments refer to the related requirements in proposed Sec.  
111.30(b)(1) that the quality control unit approve calibrations, 
inspections, or checks of automatic, mechanical, or electronic 
equipment. These comments assert the requirement for the quality 
control unit to approve such calibrations, inspections, and checks of 
equipment is too prescriptive and that qualified persons outside of the 
quality control unit should be able to approve these calibrations, 
inspections, or checks. These comments also assert the quality control 
unit should perform audits of the records generated to ensure the 
appropriate calibrations, inspections,

[[Page 34867]]

and checks are being adequately performed at the required intervals.
    (Response) As already discussed with respect to proposed Sec.  
111.30(b)(1) (final Sec.  111.30(c)), we disagree that the review by 
quality control personnel should be limited to circumstances when there 
has been a calibration failure. One of the oversight functions of 
quality control personnel is to prevent problems with the product you 
distribute by finding any problems with the equipment you use to 
produce the product rather than to investigate the cause of a problem 
with a product that you already distributed. However, we agree it is 
sufficient to review the records of calibrations, inspections, and 
checks of automated, mechanical, or electronic equipment periodically, 
for example, on an annual basis, rather than to approve each record 
when it is made. A periodic review can uncover trends in the 
performance of the equipment that have the potential to adversely 
affect the quality of the dietary supplement and that may not be 
obvious by merely approving each record when it is made. Seeing such 
trends would enable quality control personnel to recommend actions to 
correct the trend. Therefore, we have revised the proposed requirement 
so that under final Sec.  111.117(c) quality control personnel must 
review all records of calibrations, inspections, and checks of 
automatic, mechanical, or electronic equipment on a periodic basis. 
Likewise, we have revised the rule so that the quality control 
personnel's review of all records of equipment calibrations also is on 
a periodic basis.
    (Comment 221) A few comments argue the review of calibration 
records may be conducted by a qualified person other than the quality 
control unit, such as by a supervisor or by a separate department 
dedicated to equipment maintenance and calibration. These comments 
assert the quality control unit should approve calibration processes, 
but review of completed calibration records by the dedicated department 
is sufficient to assure compliance with the approved process.
    (Response) As already discussed, many comments about the quality 
control unit may have misunderstood the proposed definition of 
``quality control unit'' (now replaced by ``quality control 
personnel''). Under final Sec.  111.12(b), you must identify who is 
responsible for your quality control operations. Each person who is 
identified to perform quality control operations must be qualified to 
do so and have distinct and separate responsibilities related to 
performing such operations from those responsibilities that the person 
otherwise has when not performing such operations. Thus, in the 
situation described by these comments, you could identify a qualified 
person in a department dedicated to equipment maintenance and 
calibration to perform quality control operations for equipment 
calibration. Neither the definition of ``quality control personnel,'' 
nor the requirements of final Sec.  111.12(b), would preclude a person 
who performs ``Operation X'' from being identified as the person who 
performs quality control operations for ``Operation X.'' However, we 
strongly recommend that the person you identify to perform a given 
quality control operation be a different person than the person who 
performed the operation that is subject to quality control oversight.
2. Final Sec.  111.117(d)
    Final Sec.  111.117(d) requires that quality control operations for 
equipment, instruments, and controls include reviewing and approving 
controls to ensure automated, mechanical, or electronic equipment 
functions in accordance with its intended use. Final Sec.  111.117(d) 
derives, in part, from proposed Sec.  111.30(b)(4) (final Sec.  
111.30(e)) which would require that, for any automated, mechanical, or 
electronic equipment you use, you must establish and use appropriate 
controls and the controls are approved by your quality control unit to 
ensure that the equipment functions in accordance with its intended 
use. We are clarifying the proposed requirement related to quality 
control personnel in final Sec.  111.117(d).
    We did not receive comments specific to this responsibility of the 
quality control unit in proposed Sec.  111.30(b)(4).

I. What Quality Control Operations Are Required for Components, 
Packaging, and Labels Before Use in the Manufacture of a Dietary 
Supplement? (Final Sec.  111.120)

    Final Sec.  111.120 sets forth the minimum required operations that 
quality control personnel must perform with respect to components, 
packaging, and labels before use in the manufacture of a dietary 
supplement. Some of the proposed provisions that form the basis for 
final Sec.  111.120 included requirements for ``dietary supplements 
that you receive.'' For example, proposed Sec.  111.40(a) would require 
you, for components or dietary supplements you receive, to visually 
examine containers and documentation provided by the supplier, 
quarantine the materials until they are released by the quality control 
unit, and identify the materials in a manner that allows you to trace 
the shipment you receive to the product that you manufacture and 
distribute. The final rule separates these and other requirements for 
quality control operations for ``product that you receive from a 
supplier'' for packaging or labeling as a dietary supplement from the 
analogous requirements for components. Thus, the requirements for 
quality control operations for product you receive for packaging and 
labeling as a dietary supplement (and for distribution rather than for 
return to the supplier) are found in final Sec.  111.127 rather than 
final Sec.  111.120.
1. Final Sec.  111.120(a)
    Final Sec.  111.120(a) requires that quality control operations for 
components, packaging, and labels include reviewing all receiving 
records for components, packaging, and labels before use. Final Sec.  
111.120(a) derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.37(b)(10) which, in part, would require 
the quality control unit to review and approve all packaging and label 
records which include, but are not limited to, cross-referencing 
receiving and batch production records;
    <bullet> Proposed Sec.  111.40(a)(3) which, in part, would require 
that you quarantine dietary supplements until your quality control unit 
reviews the supplier's invoice, guarantee, or certification; and
    <bullet> Proposed Sec.  111.50(e)(1) which, in part, would require 
the quality control unit to document its review of component receiving 
records.
    (Comment 222) One comment asserts that the proposed requirement 
that the review of the batch record by the quality control unit include 
cross-referencing of receiving records with the batch production record 
is redundant and should be mandatory only in cases where a 
specification has not been met. This comment asserts the quality 
control unit has already reviewed and approved components, packaging, 
and labels prior to their release and has used unique identifiers for 
these raw materials as they are recorded on related documentation and 
records, which allow traceability back to this documentation for review 
when necessary. This comment also asserts all material review and 
disposition decisions must be documented and these will include the 
unique identifiers that tie them to particular raw or in-process 
materials.
    Another comment asserts that the quality control unit should only 
need to repeat a review of the receiving records as a result of 
conducting an investigation or a material review, as is required for 
drugs, and to require

[[Page 34868]]

otherwise would be redundant. This comment also states requiring the 
quality control unit to repeat its review of the receiving records 
places a fairly large burden on the quality control unit because this 
re-review must be performed for each and every batch production record. 
The comments assert the requirement should be completed properly and 
only once.
    (Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157 
at 12200), we stated that cross-referencing receiving and batch 
production records means the quality control unit must verify that the 
batch record includes certain documentation of the receiving records 
for the components such as the unique identifier assigned to the 
shipment lot of components, testing results, a material review and 
disposition decision, if conducted, and approval for use by the quality 
control unit. We agree with the comments that the review of records 
such as receiving records (including proper documentation of a unique 
identifier for components, packaging, and labels), if done properly the 
first time it is performed, need not be repeated. Therefore, the final 
rule does not include any requirement for cross-referencing receiving 
records with the batch production record as we would require under 
proposed Sec.  111.37(b)(10). As noted, we have changed ``quality 
control unit'' to ``quality control personnel.'' We agree that cross-
referencing receiving and batch production records is an appropriate 
step to take when conducting a material review and making a disposition 
when, for example, a specification is not met. We encourage firms to 
include this activity in the written procedures for conducting a 
material review and making a disposition decision.
2. Final Sec.  111.120(b)
    Final Sec.  111.120(b) requires that quality control operations for 
components, packaging, and labels include determining whether all 
components, packaging, and labels conform to specifications established 
under Sec.  111.70(b) and (d) before use. Final Sec.  111.120(b) 
derives from proposed Sec.  111.37(b)(2).
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.37(b)(2). For clarity, we have identified the 
specifications as those required under final Sec.  111.70(b) and (d).
3. Final Sec.  111.120(c)
    Final Sec.  111.120(c) requires that quality control operations for 
components, packaging, and labels include conducting any required 
material review and making any required disposition decision before 
use. Final Sec.  111.120(c) derives from the following proposed 
provisions:
    <bullet> Proposed Sec.  111.40(a)(3) which, in part, would require 
you to conduct a material review and make a disposition decision if 
specifications are not met for components; and
    <bullet> Proposed Sec.  111.40(b)(2) which, in part, would require 
you to conduct a material review and make a disposition decision if 
specifications are not met for packaging and labels.
    Final Sec.  111.120(c) includes revisions associated with final 
Sec.  111.87 which requires quality control personnel to conduct any 
required material review and make any required disposition decision.
    (Comment 223) One comment recommends the quality control unit have 
authority to allow usage of material that has failed to meet 
specifications if the defect will not significantly affect the overall 
quality of the finished product even if reprocessing is not an option. 
The comment gives an example of a material that fails to meet particle 
size specifications designed to maximize the efficiency of processing 
of the material, but ultimately does not impair strength, and asserts 
the quality unit should have the authority to release the material for 
use.
    (Response) The final rule provides for a process in which quality 
control personnel determine whether a component meets specifications 
and conduct a material review and make a disposition decision if a 
component does not meet one or more specifications. The final rule does 
not prohibit the use of a component that does not meet all component 
specifications other than the identity specification. For example, 
under final Sec.  111.120(d) quality control personnel may approve an 
in-process adjustment of a component to make it suitable for use in the 
manufacture of a dietary supplement (see discussion of final Sec.  
111.120(d) in the following paragraphs). Under final Sec.  111.123(b) 
quality control personnel must not approve and release for distribution 
any batch of dietary supplement, including any reprocessed batch, that 
does not meet all product specifications or is not a quality product. 
Thus, although a disposition decision could be made under final Sec.  
111.120(c) to use a component even if it does not meet certain 
specifications, that decision should take into account whether the 
failure for the component to meet specifications will ultimately cause 
the dietary supplement to fail to meet product specifications.
4. Final Sec.  111.120(d)
    Final Sec.  111.120(d) requires that quality control operations for 
components, packaging, and labels include approving, or rejecting, any 
treatment and in-process adjustments of components, packaging, or 
labels to make them suitable for use in the manufacture of a dietary 
supplement. Final Sec.  111.120(d) derives from the following proposed 
provisions:
    <bullet> Proposed Sec.  111.35(i)(4)(i) which, in part, would 
require that you reject the component, packaging, or label, unless the 
quality control unit determines that in-process adjustments are 
possible to correct the deviation or occurrence and
    <bullet> Proposed Sec.  111.35(i)(4)(ii) which would have 
prohibited you from reprocessing a rejected component unless approved 
by the quality control unit.
    Final Sec.  111.120(d) includes a revision associated with final 
Sec.  111.90(c), and refers to ``treatment and in-process adjustments 
to make them suitable for use in the manufacture of a dietary 
supplement'' (see discussion of final Sec.  111.90(c) in section X of 
this document).
    (Comment 224) Several comments request the quality control unit 
focus on reviewing tasks performed by others rather than on performing 
the tasks itself.
    (Response) Final Sec.  111.120(d) includes a revision that quality 
control personnel ``approve'' a treatment rather than ``determine 
that'' the treatment is possible.
    (Comment 225) A few comments support the proposed requirement that 
the quality control unit have the authority to approve reprocessing 
measures.
    (Response) These comments are consistent with proposed Sec.  
111.35(i) and (i)(4)(ii) and final Sec.  111.120(d), as applicable to 
quality control personnel.
    (Comment 226) One comment states that the decision to reprocess a 
material belongs within the particular operational unit, and that the 
role of the quality control unit should be to approve the results of 
the reprocessing.
    (Response) We disagree that the role of quality control personnel 
should be limited to approving the results of reprocessing or, in this 
case, of the treatment or in-process adjustments of components, 
packaging, or labels. An underlying principle of these CGMP 
requirements is that quality control personnel oversee the design and 
conduct of manufacturing, packaging, labeling, and holding operations. 
A

[[Page 34869]]

decision about when reprocessing is, or is not, appropriate requires 
oversight.
    As already discussed, under final Sec.  111.12(b) you must identify 
who is responsible for your quality control operations. Each person who 
is identified to perform quality control operations must be qualified 
to do so and have distinct and separate responsibilities related to 
performing such operations from those responsibilities that the person 
otherwise has when not performing such operations.
5. Final Sec.  111.120(e)
    Final Sec.  111.120(e) requires that quality control operations for 
components, packaging, and labels include approving and releasing from 
quarantine all components, packaging, and labels before they are used. 
Final Sec.  111.120(e) derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.40(a)(3) which, in part, would require 
that you quarantine components until your quality control unit approves 
the components and releases them from quarantine and
    <bullet> Proposed Sec.  111.40(b)(2) which, in part, would require 
that you quarantine packaging and labels until your quality control 
unit approves the packaging and labels and releases them from 
quarantine.
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.40(a)(3) or (b)(2).

J. What Quality Control Operations Are Required for the Master 
Manufacturing Record, the Batch Production Record, and Manufacturing 
Operations? (Final Sec.  111.123)

    Final Sec.  111.123 sets forth the minimum required operations that 
quality control personnel must perform with respect to the master 
manufacturing record, the batch production record, and manufacturing 
operations.
1. Final Sec.  111.123(a)(1)
    Final Sec.  111.123(a)(1) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include reviewing and approving all master 
manufacturing records and all modifications to the master manufacturing 
records. Final Sec.  111.123(a)(1) derives from duplicate proposed 
requirements, in proposed Sec. Sec.  111.37(b)(4) and 111.45(c), with 
no changes other than the editorial changes associated with the 
reorganization.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.37(b)(4) or 111.45(c), but have combined 
them as final Sec.  111.123(a)(1).
2. Final Sec.  111.123(a)(2)
    Final Sec.  111.123(a)(2) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include reviewing and approving all batch 
production-related records. Final Sec.  111.123(a)(2) derives from 
proposed Sec.  111.37(b)(5), which would require, in part, the quality 
control unit to review and approve all batch production-related 
records. Proposed Sec.  111.37(b)(5) explicitly stated, in part, that 
the batch record would include, but not be limited to, cross-
referencing receiving and batch production records.
    (Comment 227) One comment expresses concern that proposed Sec.  
111.37(b) does not state specifically that the complete batch history, 
including batch record, analytical records, quality control records, 
yields, and packaging records should be reviewed and approved by the 
quality control unit before the batch is shipped. The comment believes 
these are important requirements that should be clearly stated.
    (Response) Proposed Sec.  111.37(b)(5) would require that the 
quality control unit ``review and approve all batch production-related 
records, including but not limited to * * *'' We disagree with the 
comment that this proposed provision would not include what the comment 
describes. To the extent that the comments interpreted the list of 
records to mean that only the partial listing of records was required, 
we have modified final Sec.  111.123(a)(2) to require quality control 
personnel to review all batch production-related records. We do not 
emphasize any particular aspect of the batch production record. This 
reduces the potential to misinterpret the requirement as being limited 
to the specific items cited.
    (Comment 228) As already discussed in detail with respect to final 
Sec.  111.120(a), some comments assert the proposed requirement that 
the review of the batch record by the quality control unit include 
cross-referencing of receiving records with the batch production record 
is redundant to other requirements that the quality control unit review 
receiving records for components, packaging, and labels. In general, 
these comments assert the requirement should be completed properly and 
only once.
    (Response) We agree with the comments that the review of records, 
such as receiving records, if done properly the first time that it is 
performed, need not be repeated. Therefore, the final rule does not 
include any requirements for cross-referencing receiving records with 
the batch production record as we would require under proposed Sec.  
111.37(b)(5).
3. Final Sec.  111.123(a)(3)
    Final Sec.  111.123(a)(3) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include reviewing all monitoring required 
under subpart E. Final Sec.  111.123(a)(3) derives from the following 
proposed provisions:
    <bullet> Proposed Sec.  111.35(f) which would require you to 
monitor the in-process control points, steps, or stages to ensure that 
specifications established under proposed Sec.  111.35(e) are met and 
to detect any unanticipated occurrence that may result in adulteration;
    <bullet> Proposed Sec.  111.35(e)(2) which would require you to 
establish a specification for any point, step, or stage in the 
manufacturing process where control is necessary to prevent 
adulteration, including the in-process controls in the master 
manufacturing record where control is necessary to ensure the identity, 
purity, quality, strength, and composition of dietary supplements;
    <bullet> Proposed Sec.  111.35(i)(2) which would require you to 
review the results of the monitoring required under proposed Sec.  
111.35(f) and conduct a material review if an established specification 
is not met or if there is any unanticipated occurrence that adulterates 
or could result in adulteration;
    <bullet> Proposed Sec.  111.35(o)(2) which would require you to 
make and retain records to ensure you follow the requirements of 
proposed Sec.  111.35, including the actual results obtained during the 
monitoring operation; and
    <bullet> Proposed Sec.  111.37(b)(5) which would require the 
quality control unit to review and approve all batch production-related 
records.
    Under the final rule, the results of the monitoring required under 
proposed Sec.  111.35(f) must be kept in the batch record (see the 
discussion of the batch record in section XIV of this document). 
Quality control personnel must review the results of the required 
monitoring.
    (Comment 229) One comment suggests the phrase ``review the results 
of the monitoring required by this section'' be deleted from proposed 
Sec.  111.35(i)(2) because it is unnecessary and can be read as 
narrowing any final rule. This comments points out the only required 
monitoring in the proposal appears in Sec.  111.35(f) related to

[[Page 34870]]

monitoring of in-process control points, steps, or stages, and that 
such monitoring would not necessarily find all failures in 
specifications, for example, specifications related to raw materials or 
labels.
    (Response) We disagree with the comment that the quoted language 
narrows the final rule. Monitoring that relates to in-process control 
points, steps, or stages would be required under proposed Sec.  
111.35(f) and is now required in final Sec.  111.123(a)(3). However, in 
practice, a manufacturer must monitor its entire operation to ensure 
that the requirements of the final rule are met. For example, under 
final Sec.  111.73, a manufacturer must determine whether 
specifications established under final Sec.  111.70 are met and under 
final Sec.  111.75(a) and (f) a manufacturer must use certain criteria 
to determine whether specifications for components and labels, 
respectively, are met. Thus, there are sufficient controls in other 
requirements to ensure the entire production and process controls are 
functioning as intended.
4. Final Sec.  111.123(a)(4)
    Final Sec.  111.123(a)(4) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include conducting any required material 
review and making any required disposition decision. Final Sec.  
111.123(a)(4) derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.37(b)(5) which, in part, would require 
the quality control unit to approve a material review and disposition 
decision related to batch production records; and
    <bullet> Proposed Sec.  111.50(d)(1) which, in part, would require, 
if a batch deviates from the master manufacturing record, including any 
deviation from specifications, the quality control unit to conduct a 
material review and make a disposition decision.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.37(b)(5) or 111.50(d)(1).
5. Final Sec.  111.123(a)(5)
    Final Sec.  111.123(a)(5) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include approving or rejecting any 
reprocessing. Final Sec.  111.123(a)(5) derives from proposed Sec.  
111.37(b)(5) which would require the quality control unit to approve 
any reprocessing. For consistency with other provisions in this final 
rule (such as final Sec.  111.90), final Sec.  111.123(a)(5) includes a 
revision that quality control personnel must approve--or reject--any 
reprocessing.
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.37(b)(5).
6. Final Sec.  111.123(a)(6)
    Final Sec.  111.123(a)(6) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include determining whether all in-process 
specifications established in accordance with Sec.  111.70(c) are met. 
Final Sec.  111.123(a)(6) derives from the following proposed 
provisions:
    <bullet> Proposed Sec.  111.35(f) which would require you to 
monitor the in-process control points, steps, or stages to ensure 
specifications are met (including the in-process specifications 
required under proposed Sec.  111.35(e)(2)) and
    <bullet> Proposed Sec.  111.37(a) which, in part, would require the 
quality control unit to ensure your manufacturing, packaging, labeling, 
and holding operations are performed in a manner that prevents 
adulteration, including that such operations ensure the dietary 
supplement meets its specifications for identity, purity, quality, 
strength, and composition.
    Final Sec.  111.123(a)(6) is consistent with the overall approach, 
set forth in final Sec. Sec.  111.70, 111.73, and 111.75, that focuses 
on ensuring the quality of the dietary supplement throughout the 
production and process control system.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.35(e)(2) or (f), or 111.37(a).
7. Final Sec.  111.123(a)(7)
    Final Sec.  111.123(a)(7) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include determining whether each finished 
batch conforms to product specifications established in accordance with 
final Sec.  111.70(e). Final Sec.  111.123(a)(7) derives from proposed 
Sec.  111.37(b)(2) which, in part, would require the quality control 
unit to determine whether all dietary supplements conform to 
specifications.
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.37(b)(2).
8. Final Sec.  111.123(a)(8)
    Final Sec.  111.123(a)(8) requires that quality control operations 
for the master manufacturing record, the batch production record, and 
manufacturing operations include approving and releasing, or rejecting, 
each finished batch for distribution, including any reprocessed 
finished batch. Final Sec.  111.123(a)(8) derives from the following 
proposed provisions:
    <bullet> Proposed Sec.  111.37(b)(5) which, in part, would require 
the quality control unit to approve batch production records for 
releasing finished batches for distribution;
    <bullet> Proposed Sec.  111.50(d)(2) which would require the 
quality control unit to not approve and release for distribution any 
batch that does not meet all specifications; and
    <bullet> Proposed Sec.  111.50(g) which would require the quality 
control unit to not approve and release for distribution any 
reprocessed batch of dietary supplement that does not meet all 
specifications.
    We did not receive comments specific to the proposed provisions 
cited above.
9. Final Sec.  111.123(b)
    Final Sec.  111.123(b) requires that quality control personnel must 
not approve and release for distribution:
    <bullet> any batch of dietary supplement for which any component in 
the batch does not meet its identity specification;
    <bullet> any batch of dietary supplement, including any reprocessed 
batch, that does not meet all product specifications established in 
accordance with Sec.  111.70(e);
    <bullet> any batch of dietary supplement, including any reprocessed 
batch, that has not been manufactured, packaged, labeled, and held 
under conditions to prevent adulteration under section 402(a)(1), 
(a)(2), (a)(3), and (a)(4) of the act; and
    <bullet> any product received from a supplier for packaging or 
labeling as a dietary supplement (and for distribution rather than for 
return to the supplier) for which sufficient assurance is not provided 
to adequately identify the product and to determine that the product is 
consistent with your purchase order.
    Final Sec.  111.123(b) derives from the following proposed 
provisions:
    <bullet> Proposed Sec.  111.50(d)(2) which would require the 
quality control unit to not approve and release for distribution any 
batch of dietary supplement that does not meet all specifications;
    <bullet> Proposed Sec.  111.50(g) which would require that a 
reprocessed batch of dietary supplement meet all specifications and 
that the quality control unit approve its release for distribution; and
    <bullet> Proposed Sec.  111.37(b)(11)(iii) which would require the 
quality control unit to collect representative samples of each batch of 
dietary supplement manufactured to determine, before releasing for 
distribution, whether the dietary supplement meets its

[[Page 34871]]

specifications for identity, purity, quality, strength, and 
composition.
    The final provision clarifies all of the responsibilities of 
quality control personnel and includes provisions consistent with 
changes made to final Sec. Sec.  111.73, 111.77, and 111.90.
    We did not receive comments specific to those aspects of proposed 
Sec. Sec.  111.50(g) and 111.37(b)(11)(iii) that are relevant to final 
Sec.  111.123(b). We discuss in the following paragraphs comments we 
received to proposed Sec.  111.50(d)(2).
    (Comment 230) Several comments object to proposed Sec.  
111.50(d)(2) because it would prohibit the release of any batch that 
does not meet all specifications. Other comments suggest the 
prohibition should apply to meeting ``release specifications'' or 
``essential manufacturer specifications'' rather than ``all 
specifications'' because in-process deviations and minor deviations may 
not affect product quality.
    (Response) A finished dietary supplement that is ready for release 
for distribution must meet component specifications for identity 
established under final Sec.  111.70(b) and all product specifications 
established for the batch under final Sec.  111.70(e) and must be 
manufactured in a manner to prevent adulteration under section 
402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. The final rule does 
not prevent you from establishing additional specifications that do not 
affect the identity, purity, strength, composition, or contaminant 
levels of your finished dietary supplement. Such a specification is not 
a component specification for identity or a product specification that 
is required under the final rule. Final Sec.  111.123(b) would not 
preclude you from releasing a product that fails to meet a 
specification that is not a component specification for identity or a 
product specification established under final Sec.  111.70 provided 
quality control personnel approve such release. Final Sec.  111.123(b) 
would not preclude you from releasing a product that you are permitted 
to release under final Sec.  111.77.
    (Comment 231) Some comments note that proposed Sec.  111.50(d)(2) 
would not allow the quality control unit to conduct an investigation, 
and make a disposition decision, of the failure of a batch to meet 
specifications. These comments assert proposed Sec.  111.50(d)(2) 
therefore restricts the provision in proposed Sec.  111.50(d)(1) which 
would require that, if a batch deviates from the master manufacturing 
record, including any deviation from specifications, the quality 
control unit must conduct a material review and make a disposition 
decision. The comments argue the quality control unit should have the 
authority to release products with minor deviations.
    (Response) As discussed previously (see discussion of final Sec.  
111.90 in subpart E in section X of this document), we acknowledge that 
some specifications, such as component, other than for identity, and 
in-process specifications, that are not met may be able to be corrected 
by a treatment or an in-process adjustment. Quality control personnel 
would need to conduct a material review and disposition decision for 
any such specification not met. If there are specifications for any 
point, step, or stage in the manufacturing process where control is 
necessary to ensure the quality of the dietary supplement and that the 
dietary supplement is packaged and labeled as specified in the master 
manufacturing record (final Sec.  111.70(a)), you must determine 
whether these specifications are met (final Sec.  111.73).
    Final Sec.  111.123(b) does not preclude you, for example, from 
releasing a product that was the subject of a material review because 
sampling procedures had not been followed if, as a corrective action, 
the appropriate samples were collected and subjected to appropriate 
tests and examinations.

K. What Quality Control Operations Are Required for Packaging and 
Labeling Operations? (Final Sec.  111.127)

    Final Sec.  111.127 sets forth the required operations that quality 
control personnel must perform with respect to packaging and labeling 
operations.
1. Final Sec.  111.127(a) and (b)
    Final Sec.  111.127(a) and (b) set forth requirements for product 
you receive for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier).
    Final Sec.  111.127(a) and (b) apply to product that has left the 
control of the person who manufactured the batch; for example, the 
purchase of dietary supplements in bulk for packaging or labeling by a 
person who will distribute the packaged and labeled dietary supplements 
under a private label. If you are a packager or labeler who operates 
under contract to the manufacturer, and you will return the dietary 
supplement to the manufacturer, we would not consider that you are 
``receiving'' product within the meaning of final Sec.  111.127(a) and 
(b). We would consider you to be no different than an operating unit of 
the manufacturer. In section VI of this document (subpart A), we 
discuss in detail the scope of this final rule and its applicability to 
contractors.
    a. Final Sec.  111.127(a). Final Sec.  111.127(a) requires that 
quality control operations for packaging and labeling operations 
include reviewing the results of any visual examination and 
documentation to ensure that specifications established under final 
Sec.  111.70(f) are met for product you receive for packaging or 
labeling as a dietary supplement (and for distribution rather than for 
return to the supplier). Final Sec.  111.127(a) derives from the 
following proposed provisions:
    <bullet> Proposed Sec.  111.40(a)(2) which would require you to 
visually examine the supplier's invoice, guarantee, or certification to 
ensure that dietary supplements you receive are consistent with your 
purchase order and perform testing, as needed, to determine whether 
specifications are met and
    <bullet> Proposed Sec.  111.40(a)(3) which would, in part, require 
you to quarantine dietary supplements you receive until your quality 
control unit reviews the supplier's invoice, guarantee, or 
certification and performs testing, as needed, of a representative 
sample to determine that specifications are met.
    Final Sec.  111.127(a) includes revisions associated with final 
Sec. Sec.  111.70(f) and 111.75(e) which set forth requirements for all 
products you receive from a supplier for packaging or labeling as 
dietary supplements (and for distribution rather than for return to the 
supplier). As discussed in section X of this document, under final 
Sec.  111.70(f) if you receive such product, you must establish 
specifications to provide sufficient assurance that the product you 
receive is adequately identified and is consistent with your purchase 
order. In addition, under final Sec.  111.75(e) before you package or 
label such products, you must visually examine the products and have 
documentation to determine whether the specifications that you 
established under final Sec.  111.70(f) are met. The documentation you 
have to satisfy the requirements of final Sec.  111.75(e) is not 
limited to a supplier's invoice, guarantee, or certification and, thus, 
final Sec.  111.127(a) incorporates the standard set by final Sec.  
111.75(e) (i.e., documentation) rather than the proposed standard of 
the supplier's invoice, guarantee, or certification. In addition, 
consistent with final Sec.  111.75(e), final Sec.  111.127(a) requires 
quality control personnel to review the results of the visual 
examination but not otherwise review the results of tests or 
examinations.

[[Page 34872]]

    We did not receive comments specific to quality control operations 
under proposed Sec.  111.40(a)(2) or (a)(3).
    b. Final Sec.  111.127(b). Final Sec.  111.127(b) requires that 
quality control operations for packaging and labeling operations 
include approving, and releasing from quarantine, all products you 
receive for packaging and labeling as a dietary supplement (and for 
distribution rather than for return to the supplier) before the 
products are used for packaging and labeling. Final Sec.  111.127(b) 
derives from proposed Sec.  111.40(a)(3) which, in part, would require 
you to quarantine dietary supplements that you receive until your 
quality control unit reviews the supplier's invoice, guarantee, or 
certification and performs testing, as needed, of a representative 
sample to determine that specifications are met, and approves and 
releases the dietary supplements from quarantine before you use them.
    As with final Sec.  111.127(a), final Sec.  111.127(b) includes 
revisions associated with changes made in final Sec. Sec.  111.70(f) 
and 111.75(e).
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.40(a)(3).
2. Final Sec.  111.127(c)
    Final Sec.  111.127(c) requires that quality control operations for 
packaging and labeling operations include reviewing and approving all 
records for packaging and label operations. Final Sec.  111.127(c) 
derives from proposed Sec.  111.37(b)(10) which, in part, would require 
the quality control unit to review and approve all packaging and label 
records.
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.37(b)(10).
3. Final Sec.  111.127(d)
    Final Sec.  111.127(d) requires that quality control operations for 
packaging and labeling operations include determining whether the 
finished packaged and labeled dietary supplement conforms to 
specifications established in accordance with final Sec.  111.70(g). 
Final Sec.  111.127(d) derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.37(b)(2) which, in part, would require 
the quality control unit to determine whether all dietary supplements 
conform to specifications and
    <bullet> Proposed Sec.  111.37(b)(11)(iv) which, in part, would 
require the quality control unit to collect representative samples of 
each batch of packaged and labeled dietary supplements to determine 
that you used the packaging specified in the master manufacturing 
record and applied the label specified in the master manufacturing 
record.
    For clarity, final Sec.  111.127(d) identifies the specifications 
as those established in final Sec.  111.70(g).
    We did not receive comments specific to quality control operations 
under proposed Sec.  111.37(b)(2) or (b)(11)(iv).
4. Final Sec.  111.127(e)
    Final Sec.  111.127(e) requires that quality control operations for 
packaging and labeling operations include conducting any required 
material review and making any required disposition decision. Final 
Sec.  111.127(e) derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.70(c) which would require you to 
conduct a material review and make a disposition decision of any 
packaged and labeled dietary supplement that does not meet 
specifications and
    <bullet> Proposed Sec.  111.40(a)(3) which, in part, would require 
you, if specifications are not met for a received dietary supplement, 
to conduct a material review and make a disposition decision.
    Final Sec.  111.127(e) includes revisions associated with final 
Sec.  111.87 which requires quality control personnel to conduct any 
required material review and make any required disposition decision.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.70(c) or 111.40(a)(3).
5. Final Sec.  111.127(f) and (g)
    Final Sec.  111.127(f) requires that quality control operations for 
packaging and labeling operations include approving or rejecting any 
repackaging of a packaged dietary supplement. Final Sec.  111.127(g) 
requires that quality control operations for returned dietary 
supplements include approving or rejecting any relabeling of a packaged 
and labeled dietary supplement. Final Sec.  111.127(f) and (g) derive 
from the following proposed provisions:
    <bullet> Proposed Sec.  111.37(b)(10) which, in part, would require 
the quality control unit to approve any repackaging and relabeling and
    <bullet> Proposed Sec.  111.70(d) which would require the quality 
control unit to approve and document any repackaging or relabeling of a 
dietary supplement.
    For consistency with other provisions in this final rule (such as 
final Sec.  111.90), final Sec.  111.127(f) and (g) provide that 
quality control personnel must clearly choose between approving--or 
rejecting--any repackaged or relabeled dietary supplements.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.37(b)(10) or 111.70(d).
6. Final Sec.  111.127(h)
    Final Sec.  111.127(h) requires that quality control operations for 
packaging and labeling operations include approving for release, or 
rejecting, any packaged and labeled dietary supplement (including a 
repackaged or relabeled dietary supplement) for distribution. Final 
Sec.  111.127(h) derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.37(b)(10) which, in part, would require 
the quality control unit to approve the release of packaged and labeled 
dietary supplements for distribution; and
    <bullet> Proposed Sec.  111.70(e) which, in part, would require the 
quality control unit to approve or reject the release of any repackaged 
or relabeled dietary supplement.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.37(b)(10) or 111.70(e).

L. What Quality Control Operations Are Required for Returned Dietary 
Supplements? (Final Sec.  111.130)

    Final Sec.  111.130 sets forth the minimum required operations 
quality control personnel must perform with respect to returned dietary 
supplements.
    Final Sec.  111.130 modifies proposed Sec.  111.85 which set forth 
requirements for returned dietary ingredients and dietary supplements, 
including requirements for quality control operations for returned 
dietary supplements. We did not explicitly include quality control 
operations with respect to returned dietary supplements under proposed 
Sec.  111.37 but did include quality control operations in proposed 
Sec.  111.85 for returned dietary supplements. The provisions of the 
final rule that pertain to returned dietary supplements are set forth 
in final subpart N. However, we are duplicating these requirements in 
subpart F to make clear that once returned products are back within 
your control, quality control personnel must perform appropriate 
operations before the products are redistributed, if they are approved 
for redistribution. Any returned dietary supplements that are 
reprocessed must be returned to your production and process control 
system, and, therefore, must be properly reviewed by quality control 
personnel.
1. Final Sec.  111.130(a)
    Final Sec.  111.130(a) requires that quality control operations for 
returned dietary supplements include conducting any required material 
review and

[[Page 34873]]

making any required disposition decision. Final Sec.  111.130(a) 
differs slightly from proposed Sec.  111.85(a) which, in part, would 
require the quality control unit to conduct a material review and make 
a disposition decision for any returned dietary supplement.
    (Comment 232-233) Some comments support the proposed requirement to 
specify that it is the quality control unit that conducts the material 
review and makes the disposition decision regarding returned dietary 
supplement products.
    (Response) These comments are consistent with proposed Sec.  
111.85(a) which is being incorporated into final Sec.  111.130(a).
2. Final Sec.  111.130(a)(1) and (a)(2)
    Final Sec.  111.130(a)(1) requires that quality control operations 
for returned dietary supplements include determining whether tests or 
examination are necessary to determine compliance with product 
specifications established in accordance with final Sec.  111.70(e).
    Final Sec.  111.130(a)(2) requires that the review and disposition 
decision for returned dietary supplements include review of the results 
of any tests or examinations that are conducted to determine compliance 
with product specifications established in accordance with final Sec.  
111.70(e).
3. Final Sec.  111.130(b)
    Final Sec.  111.130(b) requires that quality control operations for 
returned dietary supplements include approving or rejecting any salvage 
and redistribution of any returned dietary supplement. Final Sec.  
111.130(b) derives from proposed Sec.  111.37(b)(15) which, in part, 
would require the quality control unit to approve the distribution of 
returned dietary supplements. As discussed in the preamble to the 2003 
CGMP Proposal, ``salvage'' means to return to distribution without 
reprocessing (68 FR 12157 at 12215).
    For consistency with other regulations in this final rule (such as 
final Sec.  111.90), final Sec.  111.130(e) provides that quality 
control personnel must clearly choose between approving--or rejecting--
any salvage and redistribution.
    (Comment 234) Some comments support the proposed requirement to 
specify that it is the quality control unit who approves, or rejects, a 
returned dietary supplement for redistribution.
    (Response) These comments are consistent with proposed Sec.  
111.37(b)(15) which is being incorporated into final Sec.  111.130(b).
4. Final Sec.  111.130(c)
    Final Sec.  111.130(c) requires that quality control operations for 
returned dietary supplements include approving or rejecting any 
reprocessing of any returned dietary supplement. Final Sec.  111.130(c) 
derives from proposed Sec.  111.37(b)(15) which, in part, would require 
the quality control unit to approve the reprocessing of returned 
dietary supplements. For consistency with other provisions of this 
final rule (such as final Sec.  111.90), final Sec.  111.130(c) 
provides that quality control personnel must clearly choose between 
approving--or rejecting--any reprocessing.
    (Comment 235) One comment argues that the responsibility to decide 
whether a returned dietary supplement is reprocessed belongs with 
qualified persons in manufacturing operations, and the only 
responsibility of the quality control unit is to approve the 
reprocessed product for distribution.
    (Response) We disagree with the comment. An underlying principle of 
these CGMP requirements is that quality control personnel oversee the 
design and conduct of manufacturing, packaging, labeling, and holding 
operations. A decision about when reprocessing is, or is not, 
appropriate requires oversight.
5. Final Sec.  111.130(d)
    Final Sec.  111.130(d) requires that quality control operations for 
returned dietary supplements include determining whether the 
reprocessed dietary supplement meets product specifications and either 
approving for release, or rejecting, any returned dietary supplement 
that is reprocessed. Final Sec.  111.130(d) derives from the following 
proposed provisions:
    <bullet> Proposed Sec.  111.37(b)(2) which, in part, would require 
the quality control unit to determine whether all dietary supplements 
conform to specifications; and
    <bullet> Proposed Sec.  111.65(d) which, in part, would require 
you, if a material review and disposition decision allows you to 
reprocess a dietary supplement, to ensure it meets specifications and 
is approved by the quality control unit.
    For consistency with other regulations in this final rule (such as 
final Sec.  111.90), final Sec.  111.130(d) provides that quality 
control personnel must clearly choose between approving--or rejecting--
a reprocessed dietary supplement.
    We did not receive comments specific to quality control operations 
under proposed Sec. Sec.  111.37(b)(2) or 111.65(d).

M. What Quality Control Operations Are Required for Product Complaints? 
(Final Sec.  111.135)

    Final Sec.  111.135 requires that quality control operations for 
product complaints include reviewing and approving decisions about 
whether to investigate a product complaint and reviewing and approving 
the findings and followup action of any investigation performed.
    Final Sec.  111.135 derives from proposed Sec.  111.95 which would 
set forth requirements for consumer complaints (now ``product 
complaints''), including requirements for quality control operations 
for consumer complaints. We did not explicitly include quality control 
operations with respect to consumer complaints under proposed Sec.  
111.37 but did include quality control operations in proposed Sec.  
111.95 for review and investigation of consumer complaints. The final 
rule's product complaint requirements are now set forth in final 
subpart O. However, we have duplicated the requirements for quality 
control operations for product complaints in subpart F to make clear 
that your investigation of the product complaint has the potential to 
uncover a problem with your production and process control system and, 
therefore, quality control personnel must exercise appropriate 
oversight of your investigation of any product complaint.

N. What Records Must You Make and Keep? (Final Sec.  111.140)

    Final Sec.  111.140 sets forth the requirements for records that 
quality control personnel must make and keep.
1. Final Sec.  111.140(a)
    Final Sec.  111.140(a) requires quality control personnel to make 
and keep records required under subpart F in accordance with subpart P. 
Final Sec.  111.140(a) derives from proposed Sec.  111.37(d) with 
editorial revisions associated with the reorganization.
    Other than comments that generally opposed the requirements to make 
and keep records, and to have records available for inspection and 
copying by FDA when requested (see the discussion in section V of this 
document), we did not receive comments specific to proposed Sec.  
111.37(d).
2. Final Sec.  111.140(b)(1)
    The final rule (final Sec.  111.103) requires you to establish and 
follow written procedures for the responsibilities of the quality 
control operations, including written procedures for conducting a 
material review and making a disposition decision and for approving or 
rejecting

[[Page 34874]]

reprocessing. The written procedures are records. Therefore, final 
Sec.  111.140(b)(1) requires you to make and keep a record of the 
written procedures for the responsibilities of the quality control 
operations.
3. Final Sec.  111.140(b)(2)
    Final Sec.  111.140(b)(2) requires written documentation, at the 
time of performance, that quality control personnel performed the 
review, approval, or rejection requirements under subpart F. Final 
Sec.  111.140(b)(2)(i) requires quality control personnel to record the 
date that the review, approval, or rejection was performed. Final Sec.  
111.140(b)(2)(ii) requires quality control personnel to record the 
signature of the person performing the review, approval, or rejection. 
Final Sec.  111.140(b)(2) derives from proposed Sec.  111.37(c) with 
revisions associated with the reorganization.
    We did not receive comments specific to proposed Sec.  111.37(c).
4. Final Sec.  111.140(b)(3)
    Final Sec.  111.140(b)(3) requires quality control personnel to 
document any material review and disposition decision and followup and 
include the documentation in the batch record. Final Sec.  
111.140(b)(3) derives from proposed Sec.  111.35(j) with revisions 
associated with the reorganization and a revision, associated with 
final Sec.  111.87 which requires quality control personnel to conduct 
the material review and make the disposition decision.
    Final Sec.  111.140(b)(3) details the type of information that must 
be included as part of this documentation. Five paragraphs derive from 
proposed Sec.  111.35(j)(1) through (j)(5), with editorial changes 
associated with the reorganization. One paragraph is associated with 
final Sec.  111.90(b) which requires that you not reprocess any 
component or dietary supplement that is rejected or treat a component 
or make an in-process adjustment to make it suitable for use in the 
manufacture of a dietary supplement, unless quality control personnel 
conduct a material review and make a disposition decision that is based 
on a scientifically valid reason and approve the reprocessing, 
treatment, or in-process adjustment. Another paragraph derives, in 
part, from proposed Sec.  111.37(c)(2) which would require the 
signature of the quality control unit person performing the 
requirement.
    The documentation that must be included under final Sec.  
111.140(b)(3) is as follows:
    <bullet> Section 111.140(b)(3)(i)--Identification of the specific 
deviation or the unanticipated occurrence;
    <bullet> Section 111.140(b)(3)(ii)--A description of your 
investigation into the cause of the deviation from the specification or 
the unanticipated occurrence;
    <bullet> Section 111.140(b)(3)(iii)--An evaluation of whether the 
deviation or unanticipated occurrence has resulted in or could lead to 
a failure to ensure the quality of the dietary supplement or a failure 
to package and label the dietary supplement as specified in the master 
manufacturing record;
    <bullet> Section 111.140(b)(3)(iv)--Identification of the action(s) 
taken to correct, and prevent a recurrence of, the deviation or the 
unanticipated occurrence;
    <bullet> Section 111.140(b)(3)(v)--An explanation of what you did 
with the component, dietary supplement, packaging, or label;
    <bullet> Section 111.140(b)(3)(vi)--A scientifically valid reason 
for any reprocessing of a dietary supplement that is rejected, or the 
treatment or in-process adjustment of a component that is rejected; and
    <bullet> Section 111.140(b)(3)(vii)--The signature of the 
individual(s) designated to perform the quality control operation, who 
conducted the material review and made the disposition decision, and of 
each qualified individual who provided information relevant to that 
material review and disposition decision.
    We did not receive comments specific to proposed Sec.  111.35(j).

XII. Comments on the Production and Process Control System: 
Requirements for Components, Packaging, and Labels, and for Product 
that You Receive for Packaging or Labeling as a Dietary Supplement 
(Final Subpart G)

A. Organization of Final Subpart G

    In the 2003 CGMP Proposal, the requirements for production and 
process controls related to components, packaging, dietary ingredients, 
labels, and dietary supplements that you receive were set forth in 
proposed Sec.  111.40. As shown in table 8 of this document, we are 
reorganizing the requirements related to components, packaging, labels, 
and product that you receive for packaging and labeling as a dietary 
supplement, into a distinct subpart (final Subpart G--Production and 
Process Control System: Requirements for Components, Packaging, and 
Labels, and for Product that You Receive for Packaging or Labeling as a 
Dietary Supplement). Table 8 lists the sections in final subpart G and 
identifies the sections in the 2003 CGMP Proposal that form the basis 
of the final rule.

           Table 8.--Derivation of Sections in Final Subpart G
------------------------------------------------------------------------
                Final Rule                      2003 CGMP  Proposal
------------------------------------------------------------------------
Sec.   111.153 What Are the requirements   N/A
 under this subpart G for written
 procedures?
------------------------------------------------------------------------
Sec.   111.155 What requirements apply to  Sec.   111.40(a)(1) through
 components of dietary supplements?         (a)(5)
                                           Sec.   111.35(d)(1) throug
                                            (d)(5)
------------------------------------------------------------------------
Sec.   111.160 What requirements apply to  Sec.   111.35(e)(4)
 packaging and labels received?            Sec.   111.40(a)(2) and (b)
------------------------------------------------------------------------
Sec.   111.165 What requirements apply to  Sec.   111.40(a)
 a product received for packaging or
 labeling as a dietary supplement (and
 for distribution rather than for return
 to the supplier)?
------------------------------------------------------------------------
Sec.   111.170 What requirements apply to  Sec.   111.74
 rejected components, packaging, and
 labels, and to rejected products that
 are received for packaging or labeling
 as a dietary supplement?
------------------------------------------------------------------------
Sec.   111.180 Under this subpart G, what  Sec.   111.40(c)(1)(i)
 records must you make and keep?            through (c)(1)(iv) and
                                            (c)(2)
                                           Sec.   111.35(d)(4)
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Components, 
Packaging, and Labels, and Product That You Receive for Packaging or 
Labeling as a Dietary Supplement

1. Revisions
    The final rule:
    <bullet> Applies to persons who manufacture, package, label, or 
hold a dietary supplement unless subject to an exclusion in Sec.  
111.1.
    <bullet> Includes requirements that apply to components, including 
components that are dietary ingredients, regardless of whether you 
receive the components or manufacture them yourself (final Sec. Sec.  
111.70(b) and 111.75(a)).
    <bullet> Separates the requirements for product you receive from a 
supplier for packaging or labeling as a dietary supplement (and for 
distribution rather

[[Page 34875]]

than for return to the supplier) (final Sec.  111.165) from the 
requirements for components (final Sec.  111.155).
2. Changes After Considering Comments
    The final rule incorporates a new requirement to establish and 
follow written procedures for fulfilling the requirements for 
components, packaging, labels, and product you receive from a supplier 
for packaging or labeling as a dietary supplement for distribution 
rather than for return to the supplier.

C. General Comments on Proposed Sec.  111.40 (Final Subpart G)

    (Comment 236) One comment states that many companies use an 
electronic material resource planning system to control the status of 
inventory, and assert this type of system provides suitable controls to 
ensure only materials that are approved by the quality control unit are 
used. The comment notes only the quality control unit has the authority 
to release any material in quarantine and asks whether such a system 
would comply with the requirements of the proposed regulation.
    (Response) Based on the limited information provided by the 
comment, it appears the electronic inventory system that the comment 
describes would comply with the requirements of final Sec.  
111.155(c)(3) to quarantine components until quality control personnel 
release them for use in manufacture, provided that appropriate controls 
are established and used to ensure the system functions in accordance 
with its intended use as required by final Sec.  111.30(e). We are 
making no changes based on this comment.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.153)

    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section.
    Final Sec.  111.153 requires you to establish and follow written 
procedures for fulfilling the requirements of subpart G. Under final 
Sec.  111.180(b)(1), as a conforming requirement, we require you to 
make and keep records of such written procedures. Such records would be 
available to us under the requirements in Subpart P--Records and 
Recordkeeping.

E. What Requirements Apply to Components of Dietary Supplements? (Final 
Sec.  111.155)

    The final rule applies only to persons who manufacture, package, 
label, or hold dietary supplements unless subject to an exclusion under 
final Sec.  111.1. The effect of this revision is that the requirements 
that derive from proposed Sec.  111.40(a) for components you receive 
now apply to all components, whether you receive them or manufacture 
them yourself.
    The final rule separates the requirements for product you receive 
from a supplier for packaging or labeling as a dietary supplement (and 
for distribution rather than for return to the supplier) (final Sec.  
111.165) from the analogous requirements for components, packaging, and 
labels (final Sec.  111.155).
1. Proposed Sec.  111.35(d)
    In proposed Sec.  111.35(d), we would require that any substance, 
other than a ``dietary ingredient'' within the meaning of section 
201(ff) of the act, that is subject to section 409 of the act, be: (1) 
Authorized for use as a food additive under section 409 of the act; or 
(2) authorized by a prior sanction consistent with Sec.  170.3(l) (21 
CFR 170.3(l)); or (3) if used as a color additive, subject to a listing 
that, by the terms of that listing (including a listing for use in 
coloring foods generally), includes the use in a dietary supplement; or 
(4) GRAS for use in a dietary supplement. We also proposed that any 
claim that a substance is GRAS must be supported by a citation to the 
agency's regulations or by an explanation for why there is general 
recognition of safety of the use of the substance in a dietary 
supplement. Further, under Sec.  111.35(d)(5), we proposed to require 
that you comply with all other applicable statutory and regulatory 
requirements under the act.
    We received several comments objecting to one or more of the 
provisions of proposed Sec.  111.35(d) and to our statement in the 
preamble to the 2003 CGMP Proposal regarding how we would apply the 
provisions of proposed Sec.  111.35(d)(4). After considering these 
comments, we have deleted the requirements in Sec.  111.35(d) in this 
final rule.
    (Comment 237) Several comments recommend proposed Sec.  111.35(d) 
be deleted because the statute already requires that ingredients, other 
than ``dietary ingredients,'' be approved as a food additive or a color 
additive, or be GRAS. Some comments assert that proposed Sec.  
111.35(d) and proposed Sec.  111.5 already require compliance with all 
other applicable statutory and regulatory requirements under the act, 
and therefore, there is no need to refer to food additive, color 
additive, and GRAS requirements. Some comments assert that proposed 
Sec.  111.35(d) is unnecessary because there is no such requirement in 
the food CGMPs. Other comments assert this proposed requirement should 
be deleted because it is only tangentially related to the manufacturing 
process, and CGMP should be focused on setting minimum standards for 
manufacturing systems and steps in the production and distribution of 
dietary supplements that are required to produce safe and accurately 
labeled products. Other comments assert that because the drug CGMPs do 
not have such a requirement, dietary supplement CGMPs should not have 
such a requirement.
    Other comments did not object to the principle underlying proposed 
Sec.  111.35(d), i.e., that we need to ensure GRAS substances used in 
dietary supplements are GRAS under the manufacturer's specified use. 
However many comments disagreed, for various reasons, with the proposed 
requirement in Sec.  111.35(d)(4) that a claim that a substance is GRAS 
must be supported by a citation to our regulations or by an explanation 
for why there is general recognition of safety of the use of the 
substance in a dietary supplement.
    (Response) We agree that proposed Sec.  111.35(d) is unnecessary 
because there are already existing statutory and regulatory 
requirements related to the lawful use of ingredients used in dietary 
supplements. We do not have to repeat those requirements in this final 
rule. Ensuring the ingredients you use to manufacture a dietary 
supplement are lawful under the applicable statutory and regulatory 
requirements is the responsibility of the dietary supplement 
manufacturer.
    For the reasons set forth in the previous paragraphs, we are 
deleting proposed Sec.  111.35(d)(4) from the final rule. Because we 
are deleting this provision, it is unnecessary to respond to the 
various comments related to the documentation that proposed Sec.  
111.35(d)(4) would have required, or whether we could not have included 
such requirements in the dietary supplement CGMP final rule because the 
requirements are not in food or drug CGMP regulations.
    We also agree that proposed Sec.  111.35(d)(5) is redundant to 
proposed Sec.  111.5 and final Sec.  111.5 and are therefore not 
repeating proposed Sec.  111.35(d)(5) in final Sec.  111.35.
    Although we are deleting Sec.  111.35(d) from the final rule, there 
were several

[[Page 34876]]

comments that we received, and respond to in the following paragraphs, 
that seemed to question whether existing statutory and regulatory 
requirements apply to the use of ingredients in a dietary supplement.
    (Comment 238) One comment suggests components not found in finished 
goods in a material amount should not be subject to the same GRAS 
requirements as those found in a material amount. Another comment 
states dietary supplements are excluded from the food additive 
definition in section 201(s) of the act, and that components that 
constitute the dietary supplement are also excluded from the food 
additive definition. The comment suggests that, under proposed Sec.  
111.35(d), we are erroneously trying to maintain food additive 
authority for dietary supplements.
    (Response) The assertion that dietary supplements and all of their 
components are not subject to the food additive provisions of the act's 
definition is incorrect. We do maintain authority over the use of 
certain substances, as color additives, food additives,\10\ or GRAS 
substances that may be used in manufacturing dietary supplements.
---------------------------------------------------------------------------

    \10\Although we refer to the term ``food additive'' in the 
preamble, the reader should also consider color additives and 
substances prior-sanctioned for such use as being relevant to the 
discussion.
---------------------------------------------------------------------------

    The food additive definition in section 201(s) of the act excludes 
``an ingredient described in paragraph (ff) in, or intended for use in, 
a dietary supplement.'' Thus, a ``dietary ingredient'' described in 
section 201(ff)(1) of the act is not a ``food additive.'' Nor can the 
use of a dietary ingredient be considered to be GRAS, since the GRAS 
status itself is an exception to the definition of a food additive. 
However, ingredients that may be used in a dietary supplement, other 
than those excepted in section 201(s), are subject to our regulatory 
authority as a food additive, unless their use is GRAS or authorized by 
a prior sanction. Thus, it is incorrect to say, as the comment asserts, 
that dietary supplements and all of their components are not subject to 
the food additive definition.
    We also disagree that components not found in finished goods in a 
material amount should not be subject to the same GRAS requirements as 
those found in a material amount. It is not clear what the comment 
meant by ``material amount.'' A food additive means ``any substance the 
intended use of which results or may reasonably be expected to result, 
directly or indirectly, in its becoming a component or otherwise 
affecting the characteristics of any food'' if the use of such 
substance is not GRAS (section 201(s) of the act).\11\ We have 
discretion to determine whether an ingredient is one where the agency 
would find the presence to be ``de minimis'' (Monsanto v. Kennedy, 613 
F.2d 947, 956 (D.C. Cir. 1979)). However, whether the agency would find 
it appropriate to exercise such discretion with respect to the use of a 
particular ingredient is beyond the scope of this final rule.
---------------------------------------------------------------------------

    \11\It is important to note that it is the use of the substance, 
not the substance itself, that must be GRAS. The amount of a 
substance in the food is a critical factor in determining whether 
the use would be GRAS.
---------------------------------------------------------------------------

    (Comment 239) Several comments questioned whether certain 
ingredients would be considered GRAS. One comment stated excipients 
regularly used in pharmaceuticals for many years and safely used in 
dietary supplements may not be considered GRAS for use in foods, 
approved for use as a food additive, or considered a dietary 
ingredient. An example provided was ``croscarmellose sodium'' used for 
disintegration. The comment asks permission to use any recognized 
excipient, an excipient that is monographed in a recognized compendium, 
used in drug products, or shown to be in use prior to the 
implementation of the final rule. Other comments stated proposed Sec.  
111.35(d) would be overly burdensome since many ingredients are GRAS 
for broad food use, have been used in dietary supplements without 
specific recognition as a GRAS use, and should be permitted. Other 
comments state substances listed in the USP National Formulary, Food 
Chemical Codex, the American Pharmaceutical Associations Handbook of 
Pharmaceutical Excipients, and FDA's inactive ingredient guide are 
considered GRAS based on a history of common use even though there is 
no listing of these substances as GRAS.
    (Response) The GRAS status of specific uses of excipients cannot be 
treated as a general class and is beyond the scope of this final rule. 
It is possible that the data needed to support safe uses as an 
excipient in a drug may be widely known among experts and form a basis 
for a consensus that use in a dietary supplement is safe. However, use 
of drugs containing the excipient may be short term or may be 
intermittent, leading to far less exposure than routine use in some 
dietary supplements. As human exposure increases, not only does the 
safety profile of the intended excipient become more important, but the 
purity specifications also become more critical. We advise persons who 
need more information about the basis for concluding that a use of a 
substance is GRAS to consult Sec.  170.30 and our GRAS Proposal to 
establish a notification program for the use of GRAS substances (62 FR 
18938, April 17, 1997).
    (Comment 240) Some comments assert it is not feasible to require 
that starting materials used by bulk ingredient manufacturers be GRAS 
or approved food additives. The comments state many ingredients are not 
food grade substances or approved for use in food until after 
processing. One comment states raw materials may become dietary 
ingredients after processing, but the materials from which the dietary 
ingredient is derived are not considered to be a GRAS ingredient, a 
dietary ingredient, or a dietary supplement. The comment gives examples 
of Ginkgo biloba leaves or Saw palmetto or cartilage. The comment asks 
us to consider natural products (from animal, mineral, or vegetable 
origin) to be included in the rule as potential raw materials for 
nutritional supplements. Another comment expresses concern that a soy 
isolate, from which natural vitamin E is derived, would not be 
considered a GRAS substance.
    (Response) These comments seem to be concerned about the regulatory 
status of substances used as raw materials in the manufacture of a 
dietary ingredient or dietary supplement. An important consideration, 
however, is whether such materials become a component of the dietary 
ingredient or dietary supplement.
    Dietary ingredient manufacturers who manufacture dietary 
ingredients for further processing by another person into a dietary 
supplement are outside the scope of this final rule. However, such 
manufacturers are still subject to other applicable statutory and 
regulatory provisions. For example, if you are a dietary ingredient 
manufacturer that uses a material in the manufacture of a dietary 
ingredient, and the material becomes part of the dietary ingredient, we 
would consider it to be part of the dietary ingredient and subject to 
the exception to the food additive definition in section 201(s)(6) of 
the act. However, because the material becomes a component of the 
dietary ingredient, you are subject to the applicable statutory and 
regulatory requirements that would apply to the dietary ingredient, 
including the safety of the dietary ingredient.
    If you use a material, other than a dietary ingredient, in the 
manufacture of a dietary supplement, that becomes a

[[Page 34877]]

part of the dietary supplement, you are subject to the applicable 
statutory and regulatory requirements that apply to the use of such 
material, including its safety for such use. In this case, the use of 
the material would be subject to regulation as a food additive (unless 
it is GRAS or prior-sanctioned).
    Alternatively, if you use material in the manufacture of a dietary 
ingredient or a dietary supplement that does not become part of the 
dietary ingredient or dietary supplement, then we would not consider 
the material to be a food.
    (Comment 241) Several comments state the color additive provision 
would be too restrictive if it only allowed colors listed for use in a 
dietary supplement, rather than colors listed for use in foods 
generally. Some comments note none of the color additives currently 
approved generally for ``food'' use is approved specifically for 
dietary supplements within the food category. Another comment argues we 
gave no rationale for requiring a categorical listing under specific 
color additives for dietary supplements. The comment states color 
additives are not used in any greater amount in supplements than in 
foods and, if anything, are probably used less because supplements are 
consumed in smaller amounts than foods and less color additive must be 
used to achieve the desired effect. One comment notes it was not 
familiar with any evidence to indicate that a color additive (whether 
it is certified or exempt) found by us to be safe for use in foods is 
not safe in dietary supplements.
    (Response) We acknowledge that the combination of proposed Sec.  
111.35(d)(3) and several color additive listings is confusing and could 
lead to incorrect conclusions about whether specific color additives 
may lawfully be used in a dietary supplement. As the comments point 
out, some listings for color additives (such as for the certified 
colors FD&C Blue No. 1 (21 CFR 74.101) and FD&C Red No. 40 (21 CFR 
74.340)) list the color additive ``for coloring foods (including 
dietary supplements) generally'' (i.e., the listings specifically 
identify dietary supplements as a food category in which the color 
additive may be used). In contrast, some listings for color additives 
(such as for annatto extract (21 CFR 73.30) and for beta-carotene (21 
CFR 73.95)) list the color additive ``for coloring foods generally'' 
(i.e., without specifically identifying dietary supplements as a food 
category in which the color additive may be used). In general, the 
terms of either of these two kinds of listings (i.e., ``for coloring 
foods (including dietary supplements) generally'' and ``for coloring 
foods generally'') mean we saw no need for restriction of the use of 
the color additive when FDA approved the listing of that color 
additive. Thus, a color additive listed for use in food generally may 
be used in a dietary supplement.
    Although most listings of color additives provide for the use of 
the color additive in food generally, some listings for color additives 
restrict the use of the color additive in terms of the food category in 
which it may be used. For example, under 21 CFR 73.125 sodium copper 
chlorophyllin may be safely used to color citrus-based dry beverage 
mixes in an amount not exceeding 0.2 percent in the dry mix, and the 
terms of this listing would not include the use in a dietary 
supplement. We list a color additive with restrictions such as these 
when for example, the person who submits a petition for us to approve 
the listing of a color additive only requests a specific use, or when 
the available data and information only support the safety of a limited 
consumption of the color additive.
2. Final Sec.  111.155(a)
    Final Sec.  111.155(a) (proposed Sec.  111.40(a)(1)) requires you 
to visually examine each immediate container or grouping of immediate 
containers in a shipment you receive for appropriate content label, 
container damage, or broken seals to determine whether the container 
condition may have resulted in contamination or deterioration of the 
components. Final Sec.  111.155(a) is substantially similar to proposed 
Sec.  111.40(a)(1) which would require you, for components you receive, 
to visually examine each container or grouping of containers in a 
shipment for appropriate content label, container damage, or broken 
seals to determine whether the container condition has resulted in 
contamination or deterioration of the components. Because you do not 
receive shipments for components you make, we are revising proposed 
Sec.  111.40(a) so that it applies only to shipments of components you 
receive. We have added the word ``immediate'' to identify the container 
as the one in contact with the dietary supplement or component. We also 
have changed ``has resulted'' to ``may have resulted'' since in some 
cases you may not be able to make a final determination from a visual 
inspection alone whether the container condition has resulted in 
contamination or deterioration of the components.
    (Comment 242) One comment supports the proposed requirements of 
proposed Sec.  111.40(a) as an effective guideline for the inspection 
of purchased ingredients.
    (Response) The provisions of final Sec.  111.155(a) are 
requirements, not guidelines, as stated by the comment.
3. Final Sec.  111.155(b)
    Final Sec.  111.155(b) (proposed Sec.  111.40(a)(2)) requires you 
to visually examine the supplier's invoice, guarantee, or certification 
in a shipment you receive to ensure that the components are consistent 
with your purchase order. Final Sec.  111.155(b) is substantially 
similar to proposed Sec.  111.40(a)(2) which would require you to 
visually examine the supplier's invoice, guarantee, or certification to 
ensure the components are consistent with your purchase order and 
perform testing, as needed, to determine whether specifications are 
met. As with final Sec.  111.155(a), final Sec.  111.155(b) clarifies 
that the invoice, guarantee, or certification comes in the shipment you 
receive.
    Final Sec.  111.155(b) does not include any requirements related to 
testing components. Final Sec.  111.75(a) sets forth the requirements 
to test or examine components; final Sec. Sec.  111.110 and 111.120 set 
forth requirements for quality control personnel to ensure that 
appropriate tests or examinations are conducted, review the results of 
any tests or examination, determine whether components conform to 
specifications, and approve the components before they are used in the 
manufacture of a dietary supplement. Given this set of requirements, it 
would be redundant to set forth requirements regarding testing for 
components in final subpart G.
    We did not receive comments specific to the requirements of 
proposed Sec.  111.40(a)(2).
4. Final Sec.  111.155(c)
    Final Sec.  111.155(c) (proposed Sec.  111.40(a)(3)) requires you 
to quarantine components before you use them in the manufacture of a 
dietary supplement until:
    <bullet> You collect representative samples of each unique lot of 
components (and, for components that you receive, of each unique 
shipment, and of each unique lot within each unique shipment);
    <bullet> Quality control personnel review and approve the results 
of any test or examinations conducted on components; and
    <bullet> Quality control personnel approve the components for use 
in the manufacture of a dietary supplement, including approval of any 
treatment (including in-process adjustments) of components to make them 
suitable for use in the manufacture of a dietary supplement, and 
release them from quarantine.

[[Page 34878]]

    Final Sec.  111.155 modifies proposed Sec.  111.40(a)(3) which 
would require:
    <bullet> You to quarantine components until your quality control 
unit reviews the supplier's invoice, guarantee, or certification;
    <bullet> The quality control unit to perform testing, as needed, of 
a representative sample to determine that specifications are met;
    <bullet> You to conduct a material review and make a disposition 
decision if specifications are not met; and
    <bullet> The quality control unit to approve and release the 
components from quarantine before you use them.
    Final Sec.  111.155(c) includes revisions related to the following 
changes to other provisions already discussed.
    <bullet> Under final Sec.  111.110, quality control personnel 
ensure that all appropriate tests and examinations are conducted, and 
review and approve the results of tests and examinations conducted on 
components, but quality control personnel are not required to conduct 
the tests or examinations;
    <bullet> Under final Sec.  111.80(a), we establish the convention 
in this final rule of referring to ``each unique lot within each unique 
shipment'' rather than ``each shipment lot;''
    <bullet> The requirements to conduct a material review and make a 
disposition decision are already set forth in final Sec. Sec.  111.87, 
111.113, and 111.120 and, therefore, are not repeated in final Sec.  
111.155; and
    <bullet> Under final Sec.  111.90(c), any batch of dietary 
supplement that is reprocessed, that contains components that you have 
treated, or to which you have made in-process adjustments to make them 
suitable for use in the manufacture of the dietary supplement, must 
meet all product specifications for the dietary supplement and be 
approved by quality control personnel before being released for 
distribution.
    (Comment 243) Some comments address the requirement to quarantine 
components before you use them and assert that it is not feasible to 
quarantine incoming materials in a continuous extraction and 
purification operation, such as one built adjacent to a soy crushing or 
vegetable oil refinery to receive a continuous side stream flow from 
that operation. One comment explains that in such operations, 
quarantine and quality control approval occurs later in the process 
after the material has been isolated and concentrated in a stable 
matrix suitable for holding. One comment suggests proposed Sec.  
111.40(a)(3) state ``quarantine components or dietary supplements as 
applicable * * *''.
    (Response) We decline to revise proposed Sec.  111.40(a)(3) as 
suggested by the comments. The comment describes a situation where a 
manufacturer of a dietary supplement is also manufacturing a dietary 
ingredient or other component but only provides limited information. It 
appears that, however, the procedures described for quarantine of the 
isolated, stable matrix, with subsequent evaluation by quality control 
personnel before release for use in the manufacture of the dietary 
supplement, would satisfy the requirements of final Sec.  111.155(c), 
provided quality control personnel are able to determine that all 
specifications for the component are met.
    (Comment 244) One comment states that plant personnel who are not 
formally part of the manufacturer's quality control unit can conduct 
the quality control functions required for the release of materials 
from quarantine before use.
    (Response) As already discussed with respect to the definition of 
quality control personnel (see section VI of this document), these 
comments may have misunderstood the role of the quality control unit 
(now quality control personnel). To clarify that role, final Sec.  
111.12(b) states you must identify a qualified person who is 
responsible for your quality control operations.
    (Comment 245) One comment suggests components that cannot be used 
in a short time should be retested at least yearly.
    (Response) We are making no changes to the provision after 
considering this comment. Whether any tests or examinations must be 
repeated over time, or whether the information in a certificate of 
analysis remains valid over time, is a matter to be decided by the 
manufacturer based on the established characteristics and shelf life of 
the component.
5. Final Sec.  111.155(d)
    Final Sec.  111.155(d)(1) (proposed Sec.  111.40(a)(4)) requires 
you to identify each unique lot within each unique shipment of 
components you receive and any lot of components that you produce in a 
manner that allows you to trace the lot to the supplier, the date 
received, the name of the component, the status of the component (e.g., 
quarantined, approved, or rejected), and to the dietary supplement you 
manufactured and distributed. Final Sec.  111.155(d)(2) requires you to 
use this unique identifier whenever you record the disposition of each 
unique lot within each unique shipment of components that you receive 
and any lot of components that you produce.
    Final Sec.  111.155(d)(1) and (d)(2) are substantially similar to 
proposed Sec.  111.40(a)(4) which would require you to identify each 
lot of components in a shipment in a manner that allows you to trace 
the shipment to the supplier, the date received, the name of the 
component, and the status (e.g., quarantined, approved, or rejected), 
and to trace the shipment lot to the dietary supplement you 
manufactured and distributed. Proposed Sec.  111.40(a)(4) also would 
require you to use this unique identifier whenever you record the 
disposition of each shipment lot received.
    Final Sec.  111.155(d)(1) and (d)(2) include revisions associated 
with final Sec.  111.80(a).
    We did not receive comments specific to proposed Sec.  
111.40(a)(4).
6. Final Sec.  111.155(e)
    Final Sec.  111.155(e) (proposed Sec.  111.40(a)(5)) requires you 
to hold components under conditions that will protect against 
contamination and deterioration and avoid mixups.
    We did not receive comments specific to proposed Sec.  
111.40(a)(5).

F. What Requirements Apply to Packaging and Labels Received? (Final 
Sec.  111.160)

1. Final Sec.  111.160(a)
    Final Sec.  111.160(a) (proposed Sec.  111.40(b)(1)) requires you 
to visually examine each immediate container or grouping of immediate 
containers in a shipment for appropriate content label, container 
damage, or broken seals to determine whether the container condition 
may have resulted in contamination or deterioration of the packaging 
and labels. Final Sec.  111.160(a) is similar to proposed Sec.  
111.40(b)(1) with the addition of the word ``immediate'' to identify 
the container as the container that is in contact with the packaging or 
labels and substituting ``may have'' for ``has'' before the word 
``resulted'' as discussed in this section.
    We did not receive comments specific to proposed Sec.  
111.40(b)(1).
2. Final Sec.  111.160(b)
    Final Sec.  111.160(b) requires you to visually examine the 
supplier's invoice, guarantee, or certification in a shipment to ensure 
the packaging or labels are consistent with your purchase order. Final 
Sec.  111.160(b) is a new requirement that is analogous to proposed 
Sec.  111.40(a)(2). We are requiring in final Sec.  111.160(b), that, 
as part of your visual identification, you compare what was received, 
based on the supplier's invoice, guarantee, or certification, with

[[Page 34879]]

your purchase order so you can ensure your specifications for packaging 
and labels are met. This is consistent with what you would do with 
respect to components and dietary supplements you receive. Without 
final Sec.  111.160(b), the review by quality control personnel under 
final Sec.  111.120(a) would be a matter of performing receiving 
operations rather than performing quality control operations; as 
already discussed in this section, some comments asserted the quality 
control unit should focus on reviewing the work of others rather than 
conducting the operations themselves. Thus, final Sec.  111.160 is 
consistent with these comments.
3. Final Sec.  111.160(c)
    Final Sec.  111.160(c) requires you to quarantine packaging and 
labels before you use them in the manufacture of a dietary supplement 
until:
    <bullet> You collect representative samples of each unique 
shipment, and of each unique lot within each unique shipment, of 
packaging and labels and, at a minimum, conduct a visual identification 
of the immediate containers and closures;
    <bullet> Quality control personnel review and approve the results 
of any tests or examinations conducted on the packaging and labels; and
    <bullet> Quality control personnel approve the packaging and labels 
for use in the manufacture of a dietary supplement and release them 
from quarantine.
    Final Sec.  111.160(c) is similar to proposed Sec.  111.40(b)(2) 
which would require that:
    <bullet> You quarantine packaging and labels until your quality 
control unit tests or examines a representative sample to determine 
that specifications are met;
    <bullet> You conduct at least a visual identification of the 
containers and closures;
    <bullet> If specifications are not met, you conduct a material 
review and make a disposition decision; and
    <bullet> Your quality control unit approve and release packaging 
and labels from quarantine before you use them.
    Final Sec.  111.160(c) includes revisions that reflect the 
following change already discussed in this final rule:
    <bullet> Refers to ``each unique lot within each unique shipment'' 
rather than ``each shipment lot''.
    We did not receive comments specific to proposed Sec.  
111.40(b)(2).
4. Final Sec.  111.160(d)
    Final Sec.  111.160(d)(1) requires you to identify each unique lot 
within each unique shipment of packaging and labels in a manner that 
allows you to trace the lot to the supplier, the date received, the 
name of the packaging and label, the status of the packaging and label 
(e.g., quarantined, approved, or rejected), and to the dietary 
supplement you distributed. Final Sec.  111.160(d)(2) requires you to 
use this unique identifier whenever you record the disposition of each 
unique lot within each unique shipment of packaging and labels. Final 
Sec.  111.160(d) derives from proposed Sec.  111.40(b)(3) which would 
require you to identify each shipment lot of packaging and labels in a 
manner that allows you to trace the shipment lot to the supplier, the 
date received, the name of the packaging and label and the status 
(e.g., quarantined, approved, or rejected) and to trace the shipment 
lot to the dietary supplement manufactured and distributed. Proposed 
Sec.  111.40(b)(3) also would require that you use this unique 
identifier whenever you record the disposition of each shipment lot 
received.
    Final Sec.  111.160(d) includes revisions that reflect the 
following changes already discussed in this final rule:
    <bullet> Reference to ``each unique lot within each unique 
shipment'' rather than ``each shipment lot.''
    <bullet> As a clarification, final Sec.  111.160(d)(2) refers to 
the ``dietary supplement that you distributed'' rather than to the 
``dietary supplement manufactured and distributed'' to avoid a narrow--
and incorrect--interpretation of ``manufactured.'' Under proposed Sec.  
111.40(b)(3), we used the term ``manufactured'' in a broad sense that 
includes any aspect of the manufacturing process rather than a narrow 
sense that applied to manufacturing operations for producing a batch of 
dietary supplement. Both proposed Sec.  111.40(b)(3) and final Sec.  
111.160(e) address the need to trace the packaging and labels that you 
use to the product that you distribute, regardless of whether your role 
in the manufacturing process includes the production of the batch or 
includes only packaging a dietary supplement you receive from a 
supplier.
    (Comment 246) One comment believes packaging and labels are rarely 
the source of quality problems. This comment suggests proposed Sec.  
111.40(b)(3) allow the use of packaging approved by the quality control 
unit without the need to use a specific lot identification number. The 
comment explains that this type of flexibility is needed when they have 
dozens of short run lots each day and use less than a carton of 
packaging supplies for each run.
    (Response) This comment may have misinterpreted proposed Sec.  
111.40(b)(3). Under proposed Sec.  111.40(b)(3) (final Sec.  
111.160(d)) you must assign the identifier to each unique lot within 
each unique shipment of packaging and labels when you receive them 
rather than each time that you use them. This number would stay the 
same for each of the short runs described by the comment. We are making 
no changes to the requirement.
5. Final Sec.  111.160(e)
    Final Sec.  111.160(e) requires you to hold packaging and labels 
under conditions that will protect against contamination and 
deterioration, and avoid mixups. Final Sec.  111.160(e) is identical to 
proposed Sec.  111.40(b)(4).
    We did not receive comments specific to proposed Sec.  
111.40(b)(4).

G. What Requirements Apply to a Product Received for Packaging or 
Labeling as a Dietary Supplement (and for distribution rather than for 
return to the supplier)? (Final Sec.  111.165)

    Final Sec.  111.165 (proposed Sec.  111.40(a)) sets out actions you 
must take when you receive a product for packaging and labeling and for 
distribution. Final Sec.  111.165 includes editorial changes associated 
with the reorganization and revisions that reflect changes we are 
making to other sections of the final rule.
    Final Sec.  111.165 sets forth requirements for ``product that you 
receive from a supplier for packaging or labeling as a dietary 
supplement (and for distribution rather than for return to the 
supplier)'' rather than for ``dietary supplements that you receive.''
    The final rule separates the requirements in proposed Sec.  
111.40(a) for product that you receive from a supplier for packaging or 
labeling as a dietary supplement (and for distribution rather than for 
return to the supplier) (final Sec.  111.165) from the analogous 
requirements for components, packaging, and labels (final Sec.  
111.155).
1. Final Sec.  111.165(a)
    Final Sec.  111.165(a) requires you to visually examine each 
immediate container or grouping of immediate containers in a shipment 
of product you receive for packaging or labeling as a dietary 
supplement (and for distribution rather than for return to the 
supplier) for appropriate content label, container damage, or broken 
seals to determine whether the container condition may have resulted in 
contamination or deterioration of the received product. Final Sec.  
111.165(a) is substantially similar to proposed Sec.  111.40(a)(1)

[[Page 34880]]

which, in part, would impose this requirement for dietary supplements 
you receive. We have added the word ``immediate'' to identify the 
container as the container that is in contact with the product you 
receive for packaging or labeling as a dietary supplement and 
substituted ``may have'' for ``has'' before the word ``resulted'' as 
explained in this section.
2. Final Sec.  111.165(b)
    Final Sec.  111.165(b) requires you to visually examine the 
supplier's invoice, guarantee, or certification in a shipment of the 
received product to ensure the received product is consistent with your 
purchase order. Final Sec.  111.165(b) is substantially similar to 
proposed Sec.  111.40(a)(2) which, in part, would establish a similar 
requirement for dietary supplements that you receive.
3. Final Sec.  111.165(c)
    Final Sec.  111.165(c) requires you to quarantine the received 
product until:
    <bullet> You collect representative samples of each unique 
shipment, and of each unique lot within each unique shipment, of 
received product;
    <bullet> Quality control personnel review and approve the 
documentation to determine whether the received product meets the 
specifications that you established under Sec.  111.70(f); and
    <bullet> Quality control personnel approve the received product for 
packaging or labeling as a dietary supplement and release the received 
product from quarantine.
    Final Sec.  111.165(c) is similar to proposed Sec.  111.40(a)(3) 
which, in part, would require that:
    <bullet> You quarantine dietary supplements that you receive until 
your quality control unit reviews the suppliers invoice, guarantee, or 
certification;
    <bullet> The quality control unit performs testing, as needed, of a 
representative sample to determine that specifications are met;
    <bullet> You conduct a material review and make a disposition 
decision if specifications are not met; and
    <bullet> The quality control unit approves and releases the dietary 
supplements that you receive from quarantine before you use them.
    Final Sec.  111.165(c) includes revisions that reflect that under 
final Sec.  111.75(e) before you package or label a product you 
received for packaging or labeling as a dietary supplement, you must 
visually examine the product and have documentation to determine 
whether the specifications you established under Sec.  111.70(f) are 
met, but not otherwise examine or conduct tests.
4. Final Sec.  111.165(d)
    Final Sec.  111.165(d)(1) requires that you identify each unique 
lot within each unique shipment of received product in a manner that 
allows you to trace the lot to the supplier, the date received, the 
name of the received product, the status of the received product (e.g., 
quarantined, approved, or rejected), and to the product you packaged or 
labeled and distributed as a dietary supplement. Final Sec.  
111.165(d)(2) requires you to use this unique identifier whenever you 
record the disposition of each unique lot within each unique shipment 
of the received product. Final Sec.  111.165(d) derives from proposed 
Sec.  111.40(a)(4) which would require you, in part, to identify each 
lot of dietary supplements in a shipment in a manner that allows you to 
trace the shipment to the supplier, the date received, the name of the 
dietary supplement, and the status (e.g., quarantined, approved, or 
rejected), and to trace the shipment lot to the dietary supplement 
manufactured and distributed. Proposed Sec.  111.40(a)(4) also would 
require you to use this identifier whenever you record the disposition 
of each shipment lot received.
    Final Sec.  111.165(d) includes a revision associated with final 
Sec.  111.80 referring to ``each unique lot within each unique 
shipment'' rather than ``each shipment lot.''
5. Final Sec.  111.165(e)
    Final Sec.  111.165(e) requires you to hold the received product 
under conditions that will protect against contamination and 
deterioration, and avoid mixups. Final Sec.  111.165(e) derives from 
proposed Sec.  111.40(a)(5) with editorial changes associated with the 
reorganization.

H. What Requirements Apply to Rejected Components, Packaging, and 
Labels, and to Rejected Products That Are Received for Packaging or 
Labeling as a Dietary Supplement? (Final Sec.  111.170)

    Final Sec.  111.170 requires you to clearly identify, hold, and 
control under a quarantine system for appropriate disposition any 
component, packaging, and label, and any product you receive for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier), that is rejected and 
unsuitable for use in manufacturing, packaging, or labeling operations. 
Final Sec.  111.170 is substantially similar to proposed Sec.  111.74 
which would require you to clearly identify, hold, and control under a 
quarantine system any component, dietary supplement, packaging, and 
label that is rejected and unsuitable for use in manufacturing, 
packaging, or labeling operations.
    We did not receive comments specific to proposed Sec.  111.74. 
Final Sec.  111.170 includes revisions associated with the series of 
provisions that distinguish a product you receive for packaging or 
labeling as a dietary supplement (and for distribution rather than for 
return to the supplier) from a dietary supplement you manufacture.

I. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.180)

    Final Sec.  111.180 sets forth the requirements to make and keep 
records associated with components, packaging, labels, and product you 
receive for packaging and labeling as a dietary supplement. Final Sec.  
111.180 derives from proposed Sec.  111.40(c).
1. Final Sec.  111.180(a)
    Final Sec.  111.180(a) requires you to make and keep records 
required under subpart G in accordance with subpart P. Final Sec.  
111.180(a) derives from proposed Sec.  111.40(c)(2), with editorial 
changes associated with the reorganization.
    We did not receive comments specific to the requirements set forth 
in final Sec.  111.180(a).
2. Final Sec.  111.180(b)(1)
    Final Sec.  111.153 requires you to establish and follow written 
procedures to fulfill the requirements of subpart G. These written 
procedures are records. Therefore, final Sec.  111.180(b)(1) requires 
you to make and keep a record of the written procedures for fulfilling 
the requirements of subpart G.
3. Final Sec.  111.180(b)(2)
    Final Sec.  111.180(b)(2) requires you to make and keep receiving 
records (including records such as certificates of analysis, suppliers' 
invoices, and suppliers' guarantees) for components, packaging, and 
labels, and for products you receive for packaging or labeling as 
dietary supplements (and for distribution rather than for return to the 
supplier). Final Sec.  111.180(b)(2) derives from proposed Sec.  
111.40(c)(2) with editorial changes associated with the reorganization. 
Final Sec.  111.180(b)(2) also includes revisions associated with the 
series of provisions that distinguish a product you receive for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier) from a dietary supplement you 
manufacture. Because the final rule provides that you may rely, under

[[Page 34881]]

certain circumstances, on a certificate of analysis to ensure that some 
component specifications are met (final Sec.  111.75(a)(2)(ii)) and 
that you may rely, in part, on documentation to determine whether 
specifications for received products are met, we specifically identify 
a certificate of analysis and common forms of documentation as being 
``receiving records'' for purposes of this rule.
    (Comment 247) One comment on proposed Sec.  111.40(c)(2) points out 
the recordkeeping requirements of any final rule will be a costly 
burden for a company that produces multiple ingredient products in 
several packaging configurations and will be much greater than the 
burden for a company that produces batches of single ingredient 
products in one packaging configuration.
    (Response) We acknowledge that companies that produce multiple 
ingredient products in several packaging configurations will have more 
records to keep than companies that produce single ingredient products 
in one packaging configuration. However, these records are necessary to 
be able to determine the source of the component, packaging, and 
labels, so that if adulteration of the dietary supplement occurs, the 
records will show the source of the material so that its use can be 
stopped.
4. Final Sec.  111.180(b)(3)
    Final Sec.  111.180(b)(3) requires you to make and keep 
documentation that the requirements of subpart G were met. Under final 
Sec.  111.180(b)(3)(i), the person who performs the required activity 
must document, at the time of performance, that the required operation 
was performed. Under final Sec.  111.180(b)(3)(ii), the documentation 
must include:
    <bullet> The date that the components, packaging, labels, or 
products you receive for packaging or labeling as a dietary supplement 
were received;
    <bullet> The initials of the person performing the required 
operation;
    <bullet> The results of any tests or examinations conducted on 
components, packaging, or labels, and of any visual examination of 
product you receive for packaging or labeling as a dietary supplement; 
and
    <bullet> Any material review and disposition decision conducted on 
components, packaging, labels, or products that you receive for 
packaging or labeling as a dietary supplement.
    Final Sec.  111.180(b)(3) differs from proposed Sec.  
111.40(c)(1)(i) through (c)(1)(iv), by referring to ``required 
operation'' rather than ``requirement.'' Additionally as a conforming 
revision associated with final Sec.  111.75(a) which requires 
appropriate tests and examinations, final Sec.  111.180(b)(3) requires 
you to include in the documentation the results of any examinations as 
well as tests. Final Sec.  111.180(b)(3) also includes revisions 
associated with the series of changes that distinguish a product that 
you receive for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier) from a dietary 
supplement that you manufacture.
    (Comment 248) A few comments note proposed Sec.  111.40(c) requires 
the signature of the person performing the requirement, whereas other 
sections of the 2003 CGMP Proposal, such as proposed Sec.  
111.50(c)(2), only require the initials of the person performing the 
requirement. One comment requests the format for the requirement to 
document the person performing the step be made consistent throughout 
the regulations.
    (Response) We agree that the identity of the person performing a 
requirement should be required throughout the final rule and that this 
can be accomplished through initials except for operations that are 
performed by quality control personnel. Therefore, we are revising the 
requirements so that a signature (and not initials) is required for any 
operation performed by quality control personnel (see final Sec.  
111.140). Because Sec.  111.40(c)(1)(ii) is not a quality control 
operation, we also revised proposed Sec.  111.40(c)(1)(ii) (final Sec.  
111.180(b)(3)) to require the initials, rather than the signature, of 
the person performing the required operation. Initials are required for 
other circumstances that do not involve quality control operations, 
including final Sec.  111.180(b)(3). However, whenever this final rule 
requires initials, a signature is also acceptable, because a signature 
would achieve the goal of identifying the person who performed the 
requirement.

XIII. Comments on the Production and Process Control System: 
Requirements for the Master Manufacturing Record (Final Subpart H)

A. Organization of Final Subpart H

    In the 2003 CGMP Proposal, the requirements for the master 
manufacturing record were set forth in proposed Sec.  111.45. As shown 
in table 9 of this document, we are setting forth the requirements for 
the master manufacturing record in a distinct subpart (final Subpart 
H--Production and Process Control System: Requirements for the Master 
Manufacturing Record). Table 9 lists the sections in final subpart H 
and identifies the proposed provisions that form the basis for the 
final rule.

           Table 9.--Derivation of Sections in Final Subpart H
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.205 What is the requirement to  Sec.   111.45(a)(1), (a)(2),
 establish a master manufacturing record?   and (d)
------------------------------------------------------------------------
Sec.   111.210 What must the master        Sec.   111.45(b)
 manufacturing record include?
------------------------------------------------------------------------

    The requirements in final subpart H are set forth from the 
perspective of the manufacture of a batch of a dietary supplement. You 
must comply with all requirements that pertain to your activity. 
However, you must comply with the requirement to prepare and follow a 
``master manufacturing record'' regardless of whether you manufacture a 
batch, or whether you package or label product you receive from a 
supplier for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier). If you are a 
packager or labeler, you only need to include those parts relevant to 
your process. For example, if you are a labeler, under final Sec.  
111.210(c) you would not need to include an accurate statement of the 
weight or measure of each component to be used because you would be 
starting from packages already filled.

B. Highlights of Changes to the Proposed Requirements for the Master 
Manufacturing Record

1. Revisions
    The final rule:
    <bullet> Includes revisions that reflect that the final rule 
applies to persons who manufacture, package, label, or hold dietary 
supplements unless subject to an exclusion in Sec.  111.1;
    <bullet> Includes revisions so the requirements for the master 
manufacturing record are consistent with final Sec.  111.70(a) which 
requires you to establish a specification for any point, step, or stage 
in the manufacturing process where control is necessary to ensure the 
quality of the dietary supplement and that the dietary supplement is 
packaged and labeled as specified in the master manufacturing record; 
and
    <bullet> Includes a revision associated with final Sec.  111.75(h), 
which provides for the use of either tests or examinations for 
complying with the requirements of part 111.

[[Page 34882]]

2. Changes Associated With the Reorganization
    The proposed requirement (Sec.  111.45(c)) that the quality control 
unit approve each master manufacturing record and any modifications to 
a master manufacturing record is set forth as final Sec.  111.123(a) in 
subpart F, rather than in final subpart H, with the changes we made to 
the definition of ``quality control unit'' to ``quality control 
personnel'' as explained in section VI of this document (subpart A).
3. Changes After Considering Comments
    The final rule:
    <bullet> Retains a requirement to state any intentional overage of 
a dietary ingredient but does not require an explanation for such an 
overage;
    <bullet> Provides flexibility to include either a representative 
label, or a cross-reference to the physical location of the actual or 
representative label if an actual label is not provided; and
    <bullet> Provides flexibility for what must be included in written 
instructions when operations are not conducted manually.

C. General Comments on Proposed Sec.  111.45 (Final Subpart H)

1. Comments on Written Procedures
    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section. As discussed in 
section IV of this document, we do not require you to establish and 
follow written procedures for preparing a master manufacturing record.
2. Comments That Support Proposed Sec.  111.45
    (Comment 249) A few comments support the proposed requirements for 
the master manufacturing record. One comment states that properly 
recorded quality control measures, such as the batch production and 
master manufacturing records, will aid manufacturers in producing 
dietary supplements in a consistent and uniform manner, as well as 
serve as tools to assess possible sources of contamination and flaws in 
the production process. Another comment asserts the master 
manufacturing and batch production records probably have the second 
greatest impact on overall product quality, surpassed only by the 
quality of the ``people'' manufacturing the product.
    (Response) We agree the master manufacturing record requirements in 
the 2003 CGMP Proposal are important for reasons that include those 
expressed in the comments. Establishing a master manufacturing record 
will help to ensure the quality of the dietary supplement. The proposed 
requirements for the master manufacturing record have been codified as 
subpart H in this final rule.

D. What Is the Requirement to Establish a Master Manufacturing Record? 
(Final Sec.  111.205)

    Final Sec.  111.205 (proposed Sec.  111.45(a) and (d)) sets forth 
the requirement to prepare and follow a written master manufacturing 
record.
1. Final Sec.  111.205(a)
    Final Sec.  111.205(a) requires you to prepare and follow a written 
master manufacturing record for each unique formulation of dietary 
supplement that you manufacture, and for each batch size, to ensure 
uniformity in the finished batch from batch to batch. Final Sec.  
111.205(a) is similar to proposed Sec.  111.45(a) which would require 
you to prepare and follow a written master manufacturing record for 
each type of dietary supplement you manufacture and for each batch size 
to ensure uniformity from batch to batch.
    (Comment 250) Some comments suggest the phrase ``to ensure 
uniformity from batch to batch'' be changed to ``to ensure that 
specifications are met from batch to batch.'' One comment states the 
term ``uniformity'' could be interpreted to mean that two batches would 
be exactly the same, down to the minutest detail. The comment expresses 
concern about how batches of herbal products will meet this standard of 
``uniformity'' from batch to batch.
    (Response) These comments may have misinterpreted the term 
``uniformity'' as we used it in proposed Sec.  111.45(a). Uniformity 
means that the specifications you establish for identity, purity, 
strength, and composition of the finished batch must be the same 
throughout a given batch, e.g., at the beginning, middle, and end of a 
production run. To emphasize this, we have revised the requirement so 
it is clear that the uniformity relates to ``the finished batch.'' 
Whether two batches must be exactly the same, down to the minutest 
level, would depend on the specifications the manufacturer establishes 
for the finished batch under final Sec.  111.70(e). Although a finished 
batch must meet those specifications ``from batch to batch,'' it is up 
to the manufacturer to determine what those specifications will be. We 
are making no changes to the requirement.
    (Comment 251) Some comments assert that the proposed requirement to 
prepare a separate record ``for each batch size'' is burdensome, 
particularly for smaller firms who specialize in custom blended 
products. These comments would revise the rule so the master 
manufacturing record includes a master formula with instructions for 
how to adjust the amount of ingredients to add depending on the batch 
size, with the actual amounts included in the applicable batch record.
    (Response) We disagree with these comments. Requiring a separate 
master manufacturing record for each batch size will lessen the 
likelihood of mistakes that can happen when a formula is ``multiplied 
up'' or ``divided down,'' particularly in light of the requirement that 
quality control personnel review and approve each master manufacturing 
record (final Sec.  111.123(a)). Moreover, it is not clear that the 
scenario described in the comments would lessen any burden, because a 
new ``formula,'' based on the master formula, would still need to be 
prepared for each batch.
    In essence, these comments suggest shifting the burden from a 
requirement to prepare a master manufacturing record to a requirement 
to prepare a batch record. Under final Sec.  111.123, quality control 
personnel review the master manufacturing record before that record is 
used, but review the batch record only after the batch is prepared. 
Shifting the requirement in the manner suggested by these comments 
would defeat the purpose of having quality control personnel review and 
approve each ``formula.'' We are not making the suggested changes to 
proposed Sec.  111.45(a).
    We are changing the word ``type'' to ``unique formulation'' to 
clarify that the requirement for a master manufacturing record applies 
to each different dietary supplement whether it is a different 
strength, includes any different ingredients, is a capsule or tablet, 
or includes minor variations.
2. Final Sec.  111.205(b)(1)
    Final Sec.  111.205(b)(1) requires that the master manufacturing 
record identify specifications for each point, step, or stage in the 
manufacturing process where control is necessary to ensure the quality 
of the dietary supplement and that the dietary supplement is packaged 
and labeled as specified in the master manufacturing record. Final 
Sec.  111.205(b)(1) derives from proposed Sec.  111.45(a)(1). We 
received no comments specific to proposed

[[Page 34883]]

Sec.  111.45(a)(1). We revised this section to include changes that we 
made to Sec.  111.70(a).
3. Final Sec.  111.205(b)(2)
    Final Sec.  111.205(b)(2) requires that the master manufacturing 
record establish controls and procedures to ensure that each batch of 
dietary supplement you manufacture meets the specifications identified 
in accordance with Sec.  111.205(b)(1). Final Sec.  111.205(b)(2) 
derives from proposed Sec.  111.45(a)(2) with grammatical changes and 
changes associated with the reorganization. We did not receive comments 
specific to proposed Sec.  111.45(a)(2).
4. Final Sec.  111.205(c)
    Final Sec.  111.205(c) requires you to make and keep master 
manufacturing records in accordance with subpart P. Final Sec.  
111.205(c) derives from proposed Sec.  111.45(a) and (d), and clarifies 
that you must prepare and keep the master manufacturing records. We did 
not receive comments specific to proposed Sec.  111.45(d), and comments 
relevant to Sec.  111.45(a) are discussed in the response to comment 
250.

E. What Must the Master Manufacturing Record Include? (Final Sec.  
111.210)

    Final Sec.  111.210 sets forth the requirements for what the master 
manufacturing record must include. Final Sec.  111.210 derives from 
proposed Sec.  111.45(b).
1. Final Sec.  111.210(a)
    Final Sec.  111.210(a) requires that the master manufacturing 
record include the name of the dietary supplement to be manufactured 
and the strength, concentration, weight, or measure of each dietary 
ingredient for each batch size. Final Sec.  111.210(a) derives from 
proposed Sec.  111.45(b)(1).
    (Comment 252) One comment supports listing the weight or measure 
for each ingredient but believes that including the strength and 
concentration is unnecessary. This comment also suggests that the 
identity of each ingredient can be controlled using a unique item 
number identifier, along with a brief description of the ingredient.
    (Response) Proposed Sec.  111.45(b)(1) would require the master 
manufacturing record to include strength, concentration, weight, or 
measure of each dietary ingredient for each batch size. We did not 
intend that all would be required. The purpose of this requirement is 
to ensure the correct dietary ingredient and amount are used in a given 
batch. To the extent that weight or measure best describes what that 
dietary ingredient is and how much is to be used in a given batch, the 
manufacturer could use weight or measure. To the extent that a 
manufacturer determines, for a particular dietary ingredient, strength, 
or concentration would best describe what is to be used in a given 
batch, the manufacturer could use those instead. We are giving firms 
the flexibility to use the measure that they determine best describes 
the amount of dietary ingredient to use in their batch. For example, 
assume you are manufacturing a million tablets of a vitamin C product 
in 250 mg tablets and the only other ingredients in your product are 
starch, microcrystalline cellulose, and dicalcium phosphate. Under 
proposed Sec.  111.45(b)(1) (final Sec.  111.210(a)) your master 
manufacturing record would state: ``Vitamin C 250 mg, 1,000,000 
tablets.'' As another example, if you are manufacturing 100 liters of a 
liquid dietary supplement that provides tuna oil as a dietary 
ingredient, and the only other ingredients are alpha-tocopherols for 
use as an antioxidant, then your master manufacturing record would 
state: ``Tuna oil, 100 liters.''
    The unique identifier comment states ``the identity of each dietary 
ingredient can be controlled instead with the use of a unique item 
identifier, along with a brief description of the ingredient.'' It is 
not clear what the comment meant by ``a brief description of the 
ingredient.'' If the ``brief description of the ingredient'' includes 
the identity, then it would comply with the final rule. Firms are free 
to use unique identifiers in addition to the identity. If, however, the 
comment means something other than identity, the comment fails to 
explain how the identity will be controlled to prevent manufacturing 
errors. In the absence of such an explanation, we have no basis to make 
the requested change.
    Moreover, under final Sec.  111.205(c) the master manufacturing 
record is a record you must make and keep in accordance with final 
Sec.  111.610 in final subpart P. Under final Sec.  111.610, the master 
manufacturing record must be available during the record retention 
period for inspection and copying by us when we request that you do so. 
A master manufacturing record that does not identify the dietary 
ingredient and the weight or measure of the dietary ingredient would 
not allow an FDA investigator to determine, for example, how your 
master manufacturing record relates to the finished dietary supplement 
and to the product label of that dietary supplement.
    (Comment 253) One comment recommends the weight or measure be 
expressed per unit or portion, or per unit of weight or measure of the 
product, for each batch size.
    (Response) The final rule does not prescribe the units you must 
use. Thus, firms have the flexibility to include this information in 
the way that best suits their product.
2. Final Sec.  111.210(b)
    Final Sec.  111.210(b) requires that the master manufacturing 
record include a complete list of components to be used. Final Sec.  
111.210(b) is identical to proposed Sec.  111.45(b)(2). We did not 
receive comments specific to proposed Sec.  111.45(b)(2).
3. Final Sec.  111.210(c)
    Final Sec.  111.210(c) requires that the master manufacturing 
record include an accurate statement of the weight or measure of each 
component to be used. Final Sec.  111.210(c) is identical to proposed 
Sec.  111.45(b)(3). We did not receive comments specific to proposed 
Sec.  111.45(b)(3).
4. Final Sec.  111.210(d)
    Final Sec.  111.210(d) requires that the master manufacturing 
record include the identity and weight or measure of each dietary 
ingredient that will be declared on the Supplement Facts label and the 
identity of each ingredient that will be declared on the ingredients 
list of the dietary supplement. Final Sec.  111.210(d) is similar to 
proposed Sec.  111.45(b)(4). We have removed the phrase ``in compliance 
with section 403(s) of the act'' as it is unnecessary in the context of 
compliance with the dietary supplement CGMP requirements. The 
manufacturer must still comply with section 403(s) and failure to do so 
will result in a misbranding violation, not a CGMP violation under this 
final rule.
    (Comment 254) One comment supports having the identity and weight 
or measure of each dietary ingredient as required by proposed Sec.  
111.45(b)(4), but asserts it is unnecessary for the verbiage to 
identically match the corresponding label statements. This comment also 
asserts that the ingredients can be controlled in the master 
manufacturing record by use of a unique identifier, instead of the 
ingredient name, along with a brief description of the ingredient.
    (Response) We disagree for the reasons stated in response to 
comment 252 and decline to revise the provision in this manner.
5. Final Sec.  111.210(e)
    Final Sec.  111.210(e) requires that the master manufacturing 
record include a statement of any intentional overage

[[Page 34884]]

amount of a dietary ingredient. Final Sec.  111.210(e) derives from 
proposed Sec.  111.45(b)(5) which would require you to explain any 
intentional excess amount of a dietary ingredient.
    (Comment 255) Some comments request us to modify this requirement. 
Several comments note that a manufacturer may design products with 
overage levels adjusted so the product always tests at least 100 
percent of the amount claimed on the label throughout the declared 
shelf life. One comment states it should be sufficient to identify any 
overage amount, rather than having to explain it.
    (Response) We understand that some firms design products using an 
additional amount of certain ingredients to ensure the product meets 
its specifications for the amount of the ingredient during the expected 
shelf life of the product. We agree it is not necessary to include the 
reason for adding the intentional excess amount.
    We also understand it would be more appropriate to refer to the 
additional amount as an ``overage'' amount rather than an ``excess'' 
amount, because ``overage'' is commonly used in the industry to convey 
the practice that is now the subject of final Sec.  111.260(e). 
Therefore, we have revised proposed Sec.  111.45(b)(1) to use the term 
``overage'' rather than ``excess'' and to delete the proposed 
requirement to include the reason for the intended overage. As 
discussed in the preamble to the 2003 CGMP Proposal (68 FR 12157 at 
12203), the amount of overage should be limited to the amount needed to 
meet the amounts listed in accordance with final Sec.  111.210(d).
6. Final Sec.  111.210(f)
    Final Sec.  111.210(f) requires that the master manufacturing 
record include a statement of theoretical yield of a manufactured 
dietary supplement expected at each point, step, or stage of the 
manufacturing process where control is needed to ensure the quality of 
the dietary supplement, and the expected yield when you finish 
manufacturing the dietary supplement, including the maximum and minimum 
percentages of theoretical yield beyond which a deviation investigation 
of a batch is necessary and material review is conducted and 
disposition decision is made. Final Sec.  111.210(f) derives from 
proposed Sec.  111.45(b)(6). We revised the section to state ``beyond 
which a deviation investigation of a batch is necessary'' rather than 
``beyond which a deviation is performed'' for clarity.
    (Comment 256) One comment suggests the term ``maximum and minimum 
percentages'' in proposed Sec.  111.45(b)(6) be replaced with the term 
``normal range.''
    Another comment recommends proposed Sec.  111.45(b)(6) be replaced 
with: ``A statement of theoretical yield of a manufactured dietary 
ingredient or dietary supplement expected at appropriate phases of 
manufacturing.'' This comment states the detail in this proposed 
requirement should be eliminated because the manufacturer should decide 
where and when to include a statement about theoretical yield.
    (Response) Final Sec.  111.210(f) clearly communicates when it is 
necessary to conduct a material review and make a disposition decision. 
The comment's suggestions do not improve the communication or clarify 
this point.
    Final Sec.  111.210(f) gives firms the flexibility to decide what 
steps, in the manufacturing process, are points, steps, or stages where 
control is needed to ensure the quality of the dietary supplement. A 
statement about theoretical yield is necessary at each such point, 
step, or stage including at the finished batch stage so that you will 
know, when you manufacture a batch, whether the process is proceeding 
as expected or whether something is wrong. For example, your master 
manufacturing record could state the theoretical yield after mixing a 
series of components is 100 percent, because nothing about the 
additional step would remove any material from the production system. 
When manufacturing the batch, a yield of less than 100 percent would 
tell you something was wrong, for example, if there was an obstruction 
that prevented a component that was being delivered by automated 
equipment from actually entering the production vessel. For a process 
such as recrystallization, knowing the theoretical yield is critical, 
because if the expected yield is not achieved at a given step it may 
mean that the process did not proceed as intended.
    (Comment 257) One comment argues it is not possible for the 
majority of supplement products, especially botanicals, to provide 100 
percent of the claimed amount of the botanical, because botanicals are 
inherently of uneven consistency, density, and particle size. This 
comment recommends that we allow for variability in yield, especially 
for botanicals.
    (Response) Final Sec.  111.210(f) does not specify what the yield 
must be, so no revision is necessary. It is the manufacturer's 
responsibility to manufacture the product in a way that will ensure 
that a product contains what the manufacturer has established in its 
specifications and its master manufacturing record. The manufacturer 
must establish specifications for the identity, purity, strength, and 
composition and limits on contamination and other specifications the 
manufacturer decides are necessary to ensure the quality of the dietary 
supplements that it makes, and design and implement a production and 
process control system that will ensure those specifications are met. 
In the situation described by the comment, it is the manufacturer's 
responsibility to design and implement a production and process control 
system that will ensure the quality of the dietary supplement 
regardless of the problems presented by the nature of the ingredients.
7. Final Sec.  111.210(g)
    Final Sec.  111.210(g) requires that the master manufacturing 
record include a description of packaging and a representative label, 
or a cross-reference to the physical location of the actual or 
representative label. Final Sec.  111.210(g) derives from proposed 
Sec.  111.45(b)(7), which would require a description of packaging and 
a copy of the label to be used.
    (Comment 258) One comment supports the proposed requirement that 
the master manufacturing record contain a copy of the dietary 
supplement label. Other comments contend that the proposed requirement 
to include a copy of the label is neither appropriate nor necessary. 
Some comments state that companies often do not have a label available 
to include in the master manufacturing record and believe that a 
description of the packaging or label in the master manufacturing 
record should be sufficient. Another comment, by a company that 
produces many different brands for each bulk product, asserts that 
updating labels in the record would be burdensome and suggests wording 
similar to that used by USP, for which a positive identification of all 
labeling used is permitted. One comment asks whether the packaging and 
label copy requirements can be in separate documents cross-referenced 
in the master manufacturing record, because some companies treat tablet 
manufacturing and packaging as two separate and distinct operational 
elements. This comment explains that the master manufacturing record 
includes the specifics required to manufacture the tablets, but the 
actual description of packaging and label copy requirements are 
contained in separate documents cross-referenced to the

[[Page 34885]]

master manufacturing record by a product part number.
    (Response) We understand there may be some circumstances where it 
would be impractical to have actual copies of labels in the master 
manufacturing record. If an actual label is not available, you may 
include a representative label in the master manufacturing record. A 
representative label could be a graphic representation of the label, 
including the exact statements that would be on the product label, or a 
detailed description of the statements and other information (such as 
pictures or graphics) that will be on the actual label. The 
representative label must be an accurate representation of the label 
that will be affixed to the dietary supplement distributed. We also 
agree that it would be acceptable to cross-reference the physical 
location of the actual or representative label.
    Finally, because the actual or representative label is a record 
that you must make and keep in accordance with final Sec.  111.610 in 
final subpart P, it must be readily available during the retention 
period for inspection or copying by FDA. Thus, we are revising proposed 
Sec.  111.45(b)(6) (final Sec.  111.210(g)) as discussed above.
    (Comment 259) One comment states that a company that manufactures a 
dietary supplement under contract to another company would not have 
access to the product label.
    (Response) Under final Sec.  111.210(g) a company that manufactures 
a dietary supplement under contract could comply with the requirement 
by, for example, providing the name and address of the company who 
contracted for the manufacture of the batch as the cross-reference to 
the physical location of the label.
8. Final Sec.  111.210(h)(1)
    Final Sec.  111.210(h)(1) requires that the master manufacturing 
record include written instructions for specifications for each point, 
step, or stage in the manufacturing process where control is necessary 
to ensure the quality of the dietary supplement and that the dietary 
supplement is packaged and labeled as specified in the master 
manufacturing record. Final Sec.  111.210(h)(1) is similar to proposed 
Sec.  111.45(b)(8)(i) which would require that the master manufacturing 
record include written instructions for specifications for each point, 
step, or stage in manufacturing the dietary supplement necessary to 
prevent adulteration. Final Sec.  111.210(h)(1) includes changes that 
we are making for consistency with final Sec.  111.70(a).
    We did not receive comments specific to proposed Sec.  
111.45(b)(8)(i).
9. Final Sec.  111.210(h)(2)
    Final Sec.  111.210(h)(2) requires that the master manufacturing 
record include written instructions for procedures for sampling, and a 
cross-reference to procedures for tests or examinations. Final Sec.  
111.210(h)(2) derives from proposed Sec.  111.45(b)(8)(ii), which would 
require that the master manufacturing record include written 
instructions for sampling and testing.
    (Comment 260) A few comments object to including certain written 
instructions for sampling and testing procedures in the master 
manufacturing record. One comment states that this documentation, such 
as laboratory testing procedures, would be a burdensome task and should 
be maintained separate from the master manufacturing record and be 
retrievable by appropriate cross-referencing information.
    (Response) As we discussed in the preamble to the 2003 CGMP 
Proposal (68 FR 12157 at 12204), the written instructions are similar 
to a recipe. As such, the written instructions must include 
instructions related to procedures for sampling plans so you can 
collect appropriate samples for tests or examinations. We agree, 
however, that it is not necessary for the master manufacturing record 
to include written instructions for tests or examinations. Accordingly, 
we have revised the provision to permit the master manufacturing record 
to include a cross-reference to the procedures for tests or 
examinations. The final rule includes a requirement that you establish 
and follow written procedures for laboratory operations, including for 
tests and examinations that you conduct to determine whether 
specifications are met (final Sec.  111.303). In essence, these written 
procedures for tests and examinations would constitute the written 
instructions that we proposed under Sec.  111.45(b)(8)(ii) for testing 
procedures. This requirement for written procedures is generally 
described in section IV of this document.
10. Final Sec.  111.210(h)(3)
    Final Sec.  111.210(h)(3) requires that the master manufacturing 
record include written instructions for specific actions necessary to 
perform and verify each point, step, or stage in the manufacturing 
process where control is necessary to ensure the quality of the dietary 
supplement and that the dietary supplement is packaged and labeled as 
specified in the master manufacturing record. Final Sec.  111.210(h)(3) 
derives from proposed Sec.  111.45(b)(8)(iii) which would require that 
the master manufacturing record include written instructions for 
specific actions necessary to perform and verify each point, step, or 
stage necessary to meet specifications and otherwise prevent 
adulteration. Final Sec.  111.210(h)(3) includes changes for 
consistency with final Sec.  111.70(a).
    Final Sec.  111.210(h)(3)(i) requires that the specific actions 
include verifying the weight or measure of any component and verifying 
the addition of any component. Final Sec.  111.210(h)(3)(ii) requires 
that, for manual operations, the specific actions include: (1) One 
person weighing or measuring a component and another person verifying 
the weight or measure and (2) one person adding a component and another 
person verifying the addition. Final Sec.  111.210(h)(3)(i) and 
(h)(3)(ii) derive from proposed Sec.  111.45(b)(8))(iii).
    (Comment 261) Some comments suggest the requirement to have more 
than one person involved in performing and verifying each point, step, 
or stage in the manufacturing process is overly prescriptive and that 
alternative, reliable methods for verifying the weighing and addition 
of components should be permitted. One comment explains many 
manufacturers use bar code systems to identify the weight and identity 
of components both before and after weighing. In such cases, a computer 
generated weight record and corresponding bar code can be created and 
affixed to the container by one individual as reliable verification of 
the material's contents and weight. Likewise, the addition of 
components to a blender can be adequately controlled and verified by 
one person through scanning technology that allows reliable 
verification of the identity and weight of components added to a 
blender without the need for a second person.
    (Response) These comments describe a system partially under the 
control of automated equipment. Final Sec.  111.30 establishes a series 
of requirements for automated equipment. We agree that, with such 
requirements in place for an automated system such as that described by 
the comments, the requirement to verify the weight or measure of a 
component, or to verify the addition of a component, can be achieved 
without requiring that one person do the weighing or measuring and 
another person verify the weighing or measuring and without requiring 
that one person add the component and another person verify the 
addition. Therefore, final Sec.  111.210(h)(3) provides both that the 
written instructions must

[[Page 34886]]

include verifying the weight or measure of any component and verifying 
the addition of any component and that, for manual operations, the 
written instructions must include: (1) One person weighing or measuring 
a component and another person verifying the weight or measure and (2) 
one person adding a component and another person verifying the 
addition. The final rule makes clear that there must be a verification 
step and gives firms flexibility, when the weighing or addition is not 
done manually, to determine how they would accomplish the verification.
11. Final Sec.  111.210(h)(4)
    Final Sec.  111.210(h)(4) requires that the master manufacturing 
record include written instructions for special notations and 
precautions to be followed. Final Sec.  111.210(h)(4) derives from 
proposed Sec.  111.45(b)(8)(iv). We did not receive comments specific 
to proposed Sec.  111.45(b)(8)(iv).
12. Final Sec.  111.210(h)(5)
    Final Sec.  111.210(h)(5) requires that the master manufacturing 
record include written instructions for corrective action plans for use 
when a specification is not met. Final Sec.  111.210(h)(5) derives from 
proposed Sec.  111.45(b)(8)(v).
    (Comment 262) Several comments argue pre-established corrective 
action plans are not useful for complex failure scenarios, and that the 
quality control unit should instead approve corrective action 
procedures on a case-by-case basis. One comment suggests the rule 
should refer to ``procedures'' rather than specifying ``corrective 
action plans.''
    (Response) We acknowledge that corrective action plans would be 
focused on each point, step, or stage where control is necessary to 
ensure the quality of the dietary supplement. We also acknowledge that 
it may not be practical to establish a corrective action plan for all 
foreseeable circumstances. In circumstances such as the complex failure 
scenario described by the comments, the documentation of the material 
review and disposition decision (rather than the corrective action 
plan) would identify the action taken to correct, and prevent a 
recurrence of, the deviation and discuss what you did with the batch 
(final Sec.  111.140(b)(3)(iv) and (b)(3)(v)). However, we disagree 
that the fact that it may not be practical to establish a corrective 
action plan for all foreseeable circumstances means you could not 
establish a corrective action plan at each point, step, or stage where 
you can, in fact, predict a scenario and provide a plan for action when 
that scenario presents itself. Therefore, for any circumstance you can 
predict, final Sec.  111.210(h)(5) requires that you establish 
corrective action plan.

F. Quality Control Responsibility (Proposed Sec.  111.45(c))

    In proposed Sec.  111.45(c) we would require the quality control 
unit to review and approve each master manufacturing record and any 
modifications to a master manufacturing record. As part of the 
reorganization, this requirement is set forth under final Sec.  
111.123(a) in subpart F for quality control personnel. There is no 
reason to repeat the requirement in final subpart H and, thus, it does 
not appear in final subpart H.

XIV. Comments on the Production and Process Control System: 
Requirements for the Batch Production Record (Final Subpart I)

A. Organization of Final Subpart I

    In the 2003 CGMP Proposal, the proposed requirements for the batch 
production record were set forth in Sec.  111.50. As shown in table 10 
of this document, we are setting forth the requirements for the batch 
production record in a distinct subpart (final Subpart I--Production 
and Process Control System: Requirements for the Batch Production 
Record) that contains the requirements that derive from proposed Sec.  
111.50. In addition, we are moving some proposed requirements from 
Sec. Sec.  111.35 and 111.37 into final subpart I. Table 10 lists the 
sections in final subpart I and identifies the provisions that form the 
basis for the final rule.

          Table 10.--Derivation of Sections in Final Subpart I
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.255 What is the requirement to  Sec.   111.50(a), (b), and
 establish a batch production record?       (i)
------------------------------------------------------------------------
Sec.   111.260 What must the batch record  Sec.   111.35(i)(2), (j),
 include?                                   (m), and (o)(2)
                                           Sec.   111.37(b)(3), (b)(5),
                                            and (b)(9)
                                           Sec.   111.50(c)(1) through
                                            (c)(11), (c)(13), (c)(14),
                                            (d)(2), (e), and (g)
                                           Sec.   111.70(b)(6), (e), and
                                            (g)
------------------------------------------------------------------------

    The requirements in final subpart I are set forth from the 
perspective of the manufacture of a batch of a dietary supplement. 
However, you must comply with the requirement to prepare and follow a 
``batch production record'' or a ``batch record'' regardless of whether 
you manufacture a batch or whether you package or label product you 
receive from a supplier for packaging or labeling as a dietary 
supplement (and for distribution rather than for return to the 
supplier). As discussed in section VI of this document, if you are a 
packager or labeler, you only need to include those parts relevant to 
your process. For example, if you are a labeler under final Sec.  
111.260(e) you would not need to include the identity and weight or 
measure of each component used, because you would be starting from 
packages that already had been filled.

B. Highlights of Changes to the Proposed Requirements for the Batch 
Production Record

1. Revisions
    The final rule:
    <bullet> Includes revisions that reflect that the final rule 
applies to persons who manufacture, package, label, or hold dietary 
supplements unless subject to an exclusion in Sec.  111.1.
    <bullet> Does not use the term ``shipment lot'' when referring to 
components.
2. Changes Associated With the Reorganization
    <bullet> Several provisions derive in whole or in part from 
proposed Sec. Sec.  111.35, 111.37, or 111.70.
    <bullet> Several requirements in proposed Sec.  111.50 are 
redundant to requirements set forth in other subparts and are not 
repeated in subpart I.
    <bullet> Several proposed requirements for reprocessing are moved 
to final Sec.  111.90 in final subpart E.
    <bullet> The proposed requirement to collect reserve samples of 
each batch of dietary supplement is moved to final Sec.  111.83 in 
subpart E, where we clarify that the requirement relates to each lot of 
packaged and labeled dietary supplement rather than to a finished batch 
awaiting packaging and labeling.
3. Changes After Considering Comments
    The final rule:
    <bullet> Provides flexibility for firms to document information 
about the maintenance, cleaning, and sanitizing of equipment used in 
producing the batch in either the batch production record or in 
individual equipment logs that it cross-references in the batch 
production record.
    <bullet> Provides flexibility for firms to include in the batch 
production record

[[Page 34887]]

either the results of any testing or examination performed, or a cross-
reference to the results of any testing or examination.

C. What Is the Requirement to Establish a Batch Production Record? 
(Final Sec.  111.255)

    Final Sec.  111.255(a) requires you to prepare a batch production 
record every time you manufacture a batch of a dietary supplement. 
Final Sec.  111.255(b) requires that the batch production record 
include complete information relating to the production and control of 
each batch. Final Sec.  111.255(a) and (b) derive from proposed Sec.  
111.50(a), with a nonsubstantive revision that divides the proposed 
requirements into two separate paragraphs.
    Final Sec.  111.255(c) requires your batch production record to 
accurately follow the appropriate master manufacturing record and you 
to perform each step in the production of the batch. Final Sec.  
111.255(c) derives from proposed Sec. 111.50(b).
    Final Sec.  111.255(d) requires you to make and keep batch 
production records in accordance with subpart P. Final Sec.  111.255(d) 
derives from proposed Sec.  111.50(i) with editorial changes associated 
with the reorganization.
    We did not receive comments specific to proposed Sec.  111.50(a), 
(b), or (i).

D. What Must the Batch Record Include? (Final Sec.  111.260)

1. Final Sec.  111.260(a)
    Final Sec.  111.260(a) requires the batch production record to 
include the batch, lot, or control number: (1) Of the finished batch of 
dietary supplement and (2) that you assign in accordance with Sec.  
111.415(f) for each lot of packaged and labeled dietary supplement from 
the finished batch of dietary supplement, and for each lot of dietary 
supplement, from the finished batch of dietary supplement, that you 
distribute to another person for packaging or labeling.
    Final Sec.  111.260(a) derives, in part, from proposed Sec.  
111.50(c)(1), which would require the batch, lot, or control number in 
the batch production record. Consistent with comments that requested 
that we clarify responsibilities when more than one party is involved 
with the manufacturing, packaging, labeling, or holding of a dietary 
supplement (see section VI of this document), we have added the 
requirements of final Sec.  111.260(a)(1), (a)(2)(i), and (a)(2)(ii) to 
ensure that you are able to determine the manufacturing history and 
control of the packaged and labeled dietary supplement from all stages 
of manufacturing through distribution, and to be consistent with other 
provisions of this final rule. In the discussion of subpart L (section 
XVII of this document), we explain in detail final Sec.  111.410(d), 
which requires you to be able to determine the complete manufacturing 
history and control of the packaged and labeled dietary supplement 
through distribution. In that same section, we explain final Sec.  
111.415(f) which requires you to assign a batch, lot, or control number 
to each lot of packaged and labeled dietary supplement from a finished 
batch and each lot of dietary supplement from a finished batch that you 
distribute to another person for packaging and labeling. In that way, 
these batch, lot, or control numbers can be used to determine the 
manufacturing history and control of the batch. However, you can 
determine how you track the batch, lot, or control number of the 
packaged and labeled dietary supplement, or dietary supplement you send 
to another person for packaging and labeling, to a distributed dietary 
supplement.
    We did not receive comments specific to proposed Sec.  
111.50(c)(1). We respond to comments relevant to final subpart L in 
section XVII of this document.
2. Final Sec.  111.260(b)
    Final Sec.  111.260(b) requires that the batch production record 
include the identity of equipment and processing lines used in 
producing the batch and derives from proposed Sec.  111.50(c)(3).
    We did not receive comments specific to proposed Sec.  
111.50(c)(3).
3. Final Sec.  111.260(c)
    Final Sec.  111.260(c) requires that the batch production record 
include the date and time of the maintenance, cleaning, and sanitizing 
of the equipment and processing lines used in producing the batch, or a 
cross-reference to records, such as individual equipment logs, where 
this information is retained. Final Sec.  111.260(c) derives from 
proposed Sec.  111.50(c)(4).
    (Comment 263) Many comments argue that it is not necessary or 
appropriate to retain the records of maintenance, cleaning, and 
sanitizing equipment and processing lines in the batch production 
record. These comments request that the final rule provide flexibility 
to retain such records in individual equipment files or log books for 
easy access. One comment recommends the requirement to retain such 
records be set forth within subpart D.
    (Response) As discussed in section IX of this document (final Sec.  
111.35(b)(2)), we agree with these comments. Consistent with final 
Sec.  111.35(b)(2), final Sec.  111.260(c) provides flexibility to 
retain the records of maintenance, cleaning, and sanitizing equipment 
and processing lines in either the batch production record or another 
record you cross-reference in the batch production record.
4. Final Sec.  111.260(d)
    Final Sec.  111.260(d) requires that the batch production record 
include the unique identifier you assigned to each component (or, when 
applicable, to a product you receive from a supplier for packaging or 
labeling as a dietary supplement), packaging, and label used. Final 
Sec.  111.260(d) derives from proposed Sec.  111.50(c)(5), which would 
require that the batch record include the shipment lot unique 
identifier of each component, dietary supplement, packaging, and label 
used. Consistent with the convention we are establishing under final 
Sec. Sec.  111.80(a), 111.155, and 111.160, final Sec.  111.260(d) does 
not use the term ``shipment lot.''
    We did not receive comments specific to proposed Sec.  
111.50(c)(5).
5. Final Sec.  111.260(e) and (f)
    Final Sec.  111.260(e) requires that the batch production record 
include the identity and weight or measure of each component used and 
derives from proposed Sec.  111.50(c)(6).
    Final Sec.  111.260(f) requires that the batch record include a 
statement of the actual yield and a statement of the percentage of 
theoretical yield at appropriate phases of processing. Final Sec.  
111.260(f) derives from proposed Sec.  111.50(c)(9).
    (Comment 264) A few comments argue that the requirements in 
proposed Sec.  111.50(c)(6) are not applicable to continuous operations 
and that yield information required in proposed Sec.  111.50(c)(9) is 
irrelevant for quality control in continuous operations used for 
producing dietary ingredients. One of these comments also discusses 
``continuous operations,'' such as a continuous operation built 
adjacent to a soy crushing or vegetable oil refinery to receive a 
continuous side stream flow from that operation (see the discussion of 
final Sec.  111.155(c) in section XII of this document). This comment 
explains that in such operations, quarantine and quality control 
approval occurs after the material has been isolated and concentrated 
in a stable matrix suitable for holding.
    (Response) Based on the limited information provided by these 
comments, it appears that they are describing the manufacture of a 
``dietary

[[Page 34888]]

ingredient'' or other component that will subsequently be used in the 
manufacture of a dietary supplement. Therefore, in this scenario, the 
identity and weight or measure of the stable matrix must be taken. The 
statement of the actual yield and the theoretical yield refers to the 
batch in which the stable matrix is added as a component.
6. Final Sec.  111.260(g)
    Final Sec.  111.260(g) requires that the batch production record 
include the actual results obtained during any monitoring operation. 
Final Sec.  111.260(g) derives from proposed Sec.  111.35(o)(2) which 
would require you to make and retain records of the actual results 
obtained during monitoring of the in-process production. Consistent 
with the reorganization we are specifying that the records of 
monitoring be located in the batch production record, because the 
monitoring is associated with the batch production.
    We did not receive comments specific to proposed Sec.  
111.35(o)(2).
7. Final Sec.  111.260(h)
    Final Sec.  111.260(h) requires that the batch production record 
include the results of any testing or examination performed during the 
batch production, or a cross-reference to such results. Final Sec.  
111.260(h) derives from proposed Sec.  111.50(c)(10) which would 
require you to record the actual results of any testing performed 
during production of the batch.
    (Comment 265) A few comments object to the requirement in proposed 
Sec.  111.50(c)(10) that actual test results be included in the batch 
production record. These comments state test results are typically 
retained in other records, such as laboratory records, and that it 
would be duplicative to include such results in the batch production 
record. One comment states the ``actual'' (original record of) test 
results may not be available to the manufacturer when the testing is 
performed electronically or an outside laboratory does the testing. 
This comment adds for test results obtained in-house, original records 
are typically kept as part of the master laboratory records and cross-
referenced in batch records.
    (Response) After considering these comments, we are providing 
flexibility to either include the results of tests or examinations in 
the batch production record, or provide a cross-reference to such 
results. We note that final Sec.  111.260(h) does not require that you 
have the original documentation of the test results. If an outside 
laboratory has performed testing for you, you must obtain a copy of the 
test results and include these in your batch production record or in 
another appropriate record that you can cross-reference and make 
readily available for inspection.
8. Final Sec.  111.260(i)
    Final Sec.  111.260(i) requires that the batch production record 
include documentation that the finished dietary supplement meets 
specifications established in accordance with Sec.  111.70(e) and (g). 
Final Sec.  111.260(i) derives from proposed Sec.  111.50(c)(11). We 
have made a change to identify which required specifications the 
dietary supplement must meet.
    We did not receive comments specific to proposed Sec.  
111.50(c)(11).
9. Final Sec.  111.260(j)
    Final Sec.  111.260(j) sets forth the requirements for 
documentation you must make and include in the batch production record, 
at the time of performance, of the manufacture of the batch. Final 
Sec.  111.260(j) derives from proposed Sec.  111.50(c)(2) and (c)(7).
    a. Final Sec. 111.260(j)(1). Final Sec.  111.260(j)(1) requires 
documentation, at the time of performance, of the date on which each 
step of the master manufacturing record was performed. Final 
Sec. 111.260(j)(1) derives from proposed Sec.  111.50(c)(2). We did not 
receive comments specific to proposed Sec.  111.50(c)(2).
    b. Final Sec. 111.260(j)(2). Final Sec.  111.260(j)(2) requires 
documentation, at the time of performance, of the initials of the 
persons performing each step in the master manufacturing record. Final 
Sec.  111.260(j)(2) derives from the second part of proposed Sec.  
111.50(c)(2),(c)(7) and (c)(8).
    (Comment 266) One comment asks whether the persons responsible for 
batch production must be identified by name or by position.
    (Response) The requirement is for the initials of the name of the 
person rather than for identification of the position. Requiring that 
the record include the initials of the person(s) performing each step 
in the master manufacturing record means that the person performing the 
step is the person who physically initials the batch record at the time 
the person performs the step. The intent is for the person to 
acknowledge that he or she performed the requirement rather than to 
merely provide information that would identify that person.
    (Comment 267) One comment asks whether we will allow electronic 
signatures for batch production records, laboratory test results, and 
quality control unit documentation. The comment notes that many 
companies have fully computerized, automated production and quality 
control management systems that utilize password-protected (or 
otherwise secure) means of entering data at key quality control steps.
    (Response) The use of electronic signatures is governed by our 
regulations in part 11, which control whether electronic signatures are 
permitted. Our guidance entitled ``Guidance for Industry Part 11, 
Electronic Records; Electronic Signatures--Scope and Application,'' 
available at http://www.fda.gov/cder/guidance/5667fnl.htm, discusses 
the use of electronic signatures (Ref. 33).
    c. Final Sec.  111.260(j)(2)(i) through Sec.  111.260(j)(2)(iv). 
Final Sec.  111.260(j)(2)(i) requires you to document at the time of 
performance the initials of the person responsible for weighing or 
measuring each component used in the batch, and final Sec.  
111.260(j)(2)(ii) requires you to document at the time of performance 
the initials of the person responsible for verifying the weight or 
measure of each component used in the batch. Final Sec.  
111.260(j)(2)(i) and (j)(2)(ii) derive from proposed Sec.  
111.50(c)(2)(i) and (c)(7), respectively.
    Final Sec.  111.260(j)(2)(iii) requires you to document, at the 
time of performance, the initials of the person responsible for adding 
the component to the batch; and final Sec.  111.260(j)(2)(iv) requires 
you to document, at the time of performance, the initials of the person 
responsible for verifying the addition of components to the batch. 
Final Sec.  111.260(j)(2)(iii) derives from proposed Sec.  
111.50(c)(2)(ii) and final Sec.  111.260(j)(2)(iv) derives from 
proposed Sec.  111.50(c)(8).
    We did not receive comments specific to proposed Sec.  
111.50(c)(2)(i) and (c)(2)(ii) or Sec.  111.50(c)(7) and (c)(8).
10. Final Sec.  111.260(k)
    Final Sec.  111.260(k) sets forth the requirements for 
documentation you must make and include in the batch production record, 
at the time of performance, of the packaging and labeling operations. 
Final Sec.  111.260(k) derives from proposed Sec.  111.70(g) which we 
discuss in the following paragraphs.
    In final Sec.  111.260(k)(3), we are eliminating proposed Sec.  
111.70(g)(4) which would require that the documentation include any 
material reviews and disposition decisions for packaging and labels, 
because it would be redundant to final Sec.  111.180(b)(4)(ii)(D).
    a. General comments on proposed Sec.  111.70(g).

[[Page 34889]]

    (Comment 268) Some comments assert that the requirement of proposed 
Sec.  111.70(g) that all packaging releases be placed in the batch 
production record is unnecessary. According to the comments, most 
packaging material lots are used in multiple batches. The comments 
assert that a requirement for this disposition information to be copied 
into each batch production record is unnecessary as long as lot 
traceability exists and this information is kept in a central file.
    (Response) These comments may have misinterpreted proposed Sec.  
111.70(g). It would require that the documentation in the batch 
production record for packaging and label operations include: (1) The 
identity and quantity of the packaging and labels used and 
reconciliation of any discrepancies between issuance and use, (2) the 
examination conducted in accordance with proposed Sec.  111.70(b)(7), 
(3) the conclusions reached from retests conducted in accordance with 
proposed Sec.  111.70(e), and (4) any material reviews and disposition 
decisions for packaging and labels. None of these proposed requirements 
would require that ``packaging releases'' be included in the batch 
record.
    The requirements for documentation for packaging you receive are 
set forth in final Sec.  111.180(b) in subpart G.
    b. Final Sec.  111.260(k)(1). Final Sec.  111.260(k)(1) requires 
the documentation of packaging and labeling operations to include the 
unique identifier you assigned to packaging and labels used, the 
quantity of the packaging and labels used, and, when label 
reconciliation is required, reconciliation of any discrepancies between 
issuance and use of labels. Final Sec.  111.260(k)(1) derives from 
proposed Sec.  111.70(g)(1) which would require that the documentation 
include the identity and quantity of the packaging and labels used and 
reconciliation of any discrepancies between issuance and use. For 
consistency with other provisions of this final rule, such as final 
Sec.  111.160(e)(1), final Sec.  111.260(k)(1) requires ``the unique 
identifier you assigned to packaging and labels used,'' rather than 
``the identity of packaging and labels used.'' Final Sec.  
111.260(k)(1) also includes changes we are making after considering 
comments.
    (Comment 269) Some comments assert comprehensive label 
reconciliation should not be required if appropriate electronic 
controls are instituted to ensure that correct labels are used during 
labeling operations. The comments state this alternative is permitted 
for labeling operations for drug products, which are generally 
identical or similar in nature to labeling operations for dietary 
supplements. As such, the comments assert the same flexibility should 
be afforded to dietary supplement manufacturers. Some comments 
specifically suggest changing the language of proposed Sec.  
111.70(g)(1) to read ``The identity and quantity of the packaging and 
labels used and either reconciliation of any discrepancies between 
issuance and use or use of appropriate electronic or electromechanical 
equipment to conduct a 100-percent examination for labeling during or 
after completion of finishing operations.''
    (Response) We agree that label reconciliation need not be required 
for cut or rolled labels if a 100-percent examination for correct 
labels is performed by appropriate electronic or electromechanical 
equipment during or after completion of finishing operations. Thus we 
have made two changes in this final rule in addition to the changes in 
final Sec.  111.260(k)(1) that provide there must be label 
reconciliation when such reconciliation is required either to account 
for discrepancies or to ensure the use of the label that is specified 
in the master manufacturing record. First, we have revised the final 
rule in subpart L (for packaging and labeling operations) to provide 
that you need not conduct label reconciliation if a 100-percent 
examination for correct labels is performed by appropriate electronic 
or electromechanical equipment during or after completion of finishing 
operations (see discussion of final Sec.  111.410(b) in subpart L in 
section XVI of this document). Second, final Sec.  111.260(k)(1), 
requires you to include documentation in the batch production of 
reconciliation of any discrepancies between issuance and use of labels 
only when label reconciliation is required.
    c. Final Sec.  111.260(k)(2). Final Sec.  111.260(k)(2) requires 
the documentation of packaging and labeling operations to include an 
actual or representative label, or a cross-reference to the physical 
location of the actual or representative label specified in the master 
manufacturing record. Final Sec.  111.260(k)(2) derives from proposed 
Sec.  111.50(c)(12) which would require that the batch production 
record include copies of all container labels used and the results of 
examinations conducted during the label operation to ensure that the 
containers have the correct label.
    (Comment 270) A few comments ask that we clarify the container 
labels that proposed Sec.  111.50(c)(12) is referring to. Specifically, 
these comments ask whether proposed Sec.  111.50(c)(12) is referring to 
finished product labels, bulk material labels, or in-process container 
labels. One comment asserts proposed Sec.  111.50(c)(12) is unnecessary 
for ensuring the dosage form of dietary supplements meets 
specifications.
    One comment finds proposed Sec.  111.50(c)(12) confusing, because 
it does not specify what is meant by ``label operation.'' This comment 
notes that during the course of manufacturing operations, containers 
holding in-process materials are often labeled but the comment assumes 
that proposed Sec.  111.50(c)(12) does not require the retention of 
copies of in-process container labels, which would not add significant 
value toward the assurance of a quality product.
    In general, these comments ask for clarification of proposed Sec.  
111.50(c)(12), and suggest it be deleted.
    (Response) Proposed Sec.  111.50(c)(12) referred to the product 
label that would be affixed to the containers that hold the packaged 
and labeled dietary supplement. We did not receive any comments that a 
related requirement (in proposed Sec.  111.45(b)(7) in the master 
manufacturing record) was confusing or needed clarification. We 
therefore believe that the requirement that the batch production record 
include a label will be clearer if we state the requirement in a way 
that is similar to the requirement in proposed Sec.  111.45(b)(7). 
However, because comments to proposed Sec.  111.45(b)(7) persuaded us 
to provide flexibility for (1) having a representative label rather 
than an actual label and (2) cross-referencing the physical location of 
the actual or representative label that is specified in the master 
manufacturing record, we are providing the same flexibility for having 
a label in the batch production record. Therefore, we are revising the 
proposed requirement that the batch production record include ``copies 
of all container labels used'' so that, under final Sec.  
111.260(k)(2), the batch production record must include an actual or 
representative label, or a cross-reference to the physical location for 
the actual or representative label that is specified in the master 
manufacturing record.
    However, we are not requiring in final Sec.  111.260(k)(2) that the 
batch production record include the results of examinations conducted 
during the label operation to ensure that the containers have the 
correct label that is specified in the master manufacturing record, 
because this would be redundant to final Sec.  111.260(k)(3).
    d. Final Sec.  111.260(k)(3). Final Sec.  111.260(k)(3) requires 
that the documentation of packaging and

[[Page 34890]]

labeling operations include the results of any tests or examinations 
conducted on packaged and labeled dietary supplements (including 
repackaged or relabeled dietary supplements), or a cross-reference to 
such results. Final Sec.  111.260(k)(3) combines the proposed 
requirements of proposed Sec.  111.70(g)(2) which would require that 
the documentation include the results of examinations conducted in 
accordance with proposed Sec.  111.70(b)(7), and proposed Sec.  
111.70(g)(3) which would require that the documentation include the 
conclusions from retests conducted in accordance with proposed Sec.  
111.70. For consistency with other requirements for documentation that 
must be in the batch record, final Sec.  111.260(k)(3) requires you to 
include ``the results of any tests or examinations,'' rather than ``the 
examination'' (proposed Sec.  111.70(g)(2)) and ``conclusions'' 
(proposed Sec.  111.70(g)(3)). Final Sec.  111.260(k)(3) also includes 
editorial revisions associated with combining proposed Sec.  
111.70(g)(2) and (g)(3).
    We did not receive comments specific to proposed Sec.  111.70(g)(2) 
or (g)(3).
11. Final Sec.  111.260(l)
    Final Sec.  111.260(l) sets forth the requirements for 
documentation quality control personnel must make at the time of 
performance and that must be included in the batch production record. 
Final Sec.  111.260(l) derives from proposed Sec. Sec.  111.35(i)(2), 
(j), (m), (o)(2); 111.37(b)(3), (b)(5), and (b)(9); 111.50(c)(1) 
through (c)(11), (c)(13), (c)(14), (d)(2), (e), and (g); 111.70(b)(6); 
and 111.70(g).
    a. Final Sec.  111.260(l)(1). Final Sec.  111.260(l)(1) requires 
quality control personnel to document at the time of performance the 
review of the batch production record. Final Sec.  111.260(l)(1) 
derives from the following proposed regulations:
    <bullet> Sec.  111.50(d), which would require that the quality 
control unit review in accordance with Sec.  111.37(b)(5) the batch 
production record established in Sec.  111.50(c); and
    <bullet> Sec.  111.50(e), which would require that the quality 
control unit document at the time of performance in accordance with 
Sec.  111.37(c), the review performed in accordance with Sec.  
111.50(d).
    Final Sec.  111.260(l)(1) includes editorial changes associated 
with the reorganization. We did not receive comments specific to 
proposed Sec.  111.50(d) or (e).
    b. Final Sec.  111.260(l)(1)(i). Final Sec.  111.260(l)(1)(i) 
requires the documentation by quality control personnel to include 
review of any monitoring operation required under subpart E. Final 
Sec.  111.260(l)(1)(i) derives from proposed Sec.  111.35(i)(2) which 
would require that you review, among other things, the results of the 
monitoring of the in-process control points, steps, or stages to ensure 
specifications are met. As discussed in section XI of this document 
(final Sec.  111.123(a)(3)), the final rule requires quality control 
personnel to review the required monitoring.
    We did not receive comments specific to proposed Sec.  
111.35(i)(2).
    c. Final Sec.  111.260(l)(1)(ii). Final Sec.  111.260(l)(1)(ii) 
requires the documentation by quality control personnel to include the 
review by quality control personnel of the results of any tests or 
examinations, including tests or examinations conducted on components, 
in-process materials, finished batches of dietary supplements, and 
packaged and labeled dietary supplements. Final Sec.  111.260(l)(1)(ii) 
derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.50(e)(1) which would require that the 
documentation by the quality control unit include review of component, 
dietary ingredient, and dietary supplement receiving records, including 
review of testing and examination results and
    <bullet> Proposed Sec.  111.37(b)(9) which would require, in part, 
the quality control unit to review all testing results.
    (Comment 271) A few comments assert that the proposed requirement 
that the quality control unit review receiving records as part of its 
review of the batch record is redundant and should be eliminated. One 
comment argues that it is unnecessarily burdensome to require the 
quality control unit to re-review and cross-reference all receiving 
records, noting that the quality control unit already has performed a 
review of these records when the components or dietary supplements were 
received, approved, and released for use. The comment asserts the 
quality control unit should only have to repeat this review if it is 
conducting an investigation or a material review.
    (Response) We agree with the comments. Therefore, final Sec.  
111.260(l)(1)(ii) retains the requirements of proposed Sec. Sec.  
111.37(b)(9) and 111.50(e)(1) to review the results of testing and 
examination, but does not require quality control personnel to 
document, as part of the review of the batch record, receiving records 
for components and dietary supplements.
    d. Final Sec.  111.260(l)(2). Final Sec.  111.260(l)(2) requires 
that the documentation by quality control personnel include that 
quality control personnel approved or rejected any reprocessing or 
repackaging. Final Sec.  111.260(l)(2) derives from proposed Sec.  
111.50(c)(14) which would require that the batch production record 
include the signature of the quality control unit to document its 
review of the batch production record and any approval for reprocessing 
or repackaging. For consistency with other provisions in this final 
rule (such as final Sec.  111.90), final Sec.  111.260(l)(2) includes a 
revision that quality control personnel must clearly choose between 
approving--or rejecting--any reprocessing or repackaging.
    We did not receive comments specific to proposed Sec.  
111.50(c)(14).
    e. Final Sec.  111.260(l)(3). Final Sec.  111.260(l)(3) requires 
the documentation by quality control personnel to include that it 
approved and released, or rejected, the batch for distribution, 
including any reprocessed batch. Final Sec.  111.260(l)(3) derives from 
the following proposed regulations:
    <bullet> Proposed Sec.  111.37(b)(5) which would require, in part, 
the quality control unit to review the batch production record to 
approve the batch for release for distribution;
    <bullet> Proposed Sec.  111.50(d)(2) which would require the 
quality control unit not to approve and release for distribution any 
batch of dietary ingredients or dietary supplement that does not meet 
all specifications; and
    <bullet> Proposed Sec.  111.50(g) which would require, in part, the 
results of the reevaluation by the quality control unit to be 
documented in the batch production record.
    For consistency with other provisions of this final rule (such as 
final Sec.  111.90), final Sec.  111.260(l)(3) requires that quality 
control personnel must clearly choose between approving--or rejecting--
the batch for distribution. We did not receive comments specific to 
those parts of proposed Sec. Sec.  111.37(b)(5) or 111.50(d)(2) that we 
are setting forth in final Sec.  111.260(l)(3).
    f. Final Sec.  111.260(l)(4). Final Sec.  111.260(l)(4) requires 
the batch production record to include documentation, at the time of 
performance, that quality control personnel approved and released, or 
rejected, the packaged and labeled dietary supplement, including any 
repackaged or relabeled dietary supplement. Final Sec.  111.260(l)(4) 
derives from the following proposed regulations:
    <bullet> Proposed Sec.  111.37(b)(3) which would require, in part, 
that the quality

[[Page 34891]]

control unit approve or reject all dietary supplements and
    <bullet> Proposed Sec.  111.70(e) which would require, in part, 
that any repackaged or relabeled dietary supplement meet all 
specifications and that the quality control unit must approve or reject 
their release for distribution.
    We did not receive comments specific to those parts of proposed 
Sec. Sec.  111.37(b)(3) or 111.70(e) that we are setting forth in final 
Sec.  111.260(l)(4).
12. Final Sec.  111.260(m)
    Final Sec.  111.260(m) requires the batch production record to 
include documentation, at the time of performance, of any required 
material review and disposition decision. Final Sec.  111.260(m) 
derives from the following proposed provisions:
    <bullet> Proposed Sec.  111.50(c)(13) which would require that the 
batch production record include any documented review and disposition 
decision and
    <bullet> Proposed Sec.  111.35(j) which would require that the 
person who conducts the material review and makes the disposition 
decision document that activity, at the time of performance, in the 
batch production record.
    We did not receive comments specific to proposed Sec. Sec.  
111.35(j) or 111.50(c)(13).
13. Final Sec.  111.260(n)
    Final Sec.  111.260(n) requires that the batch production record 
include documentation, at the time of performance, of any reprocessing. 
We have added this requirement in conjunction with the requirement for 
written procedures for the quality control operations for approving or 
rejecting any reprocessing, discussed generally in section IV of this 
document.

E. Review of Batch Production Record Deviations (Proposed Sec.  
111.50(d)(1), (e)(2), (e)(3), and (e)(4))

    Proposed Sec. 111.50(d)(1) would require, if a batch deviates from 
the master manufacturing record, including any deviation from 
specifications, the quality control unit to conduct a material review 
and make a disposition decision and record any decision in the batch 
production record. Under final Sec.  111.87 quality control personnel 
must conduct any required material review and make any required 
disposition decision; under final Sec.  111.113(a)(2) quality control 
personnel must conduct a material review and make a disposition 
decision if a batch deviates from the master manufacturing record, 
including any deviation from specifications. Given the requirements of 
final Sec. Sec.  111.87 and 111.113, it would be redundant to include 
proposed Sec.  111.50(d)(1) in final subpart I.
    Proposed Sec.  111.50(e)(2) would require that the review of the 
batch production record and documentation by the quality control unit 
include identification of any deviation from the master manufacturing 
record that may have caused a batch or any of its components to fail to 
meet specifications identified in the master production record. 
Proposed Sec.  111.50(e)(3) would require that the review of the batch 
production record and documentation by the quality control unit include 
records of investigations, conclusions, and corrective actions 
performed in accordance with proposed Sec.  111.50(d). Proposed Sec.  
111.50(e)(4) would require that the review of the batch production 
record and documentation by the quality control unit include the 
identity of the person qualified by training and experience who 
performed the investigation in accordance with Sec.  111.50(d).
    Each of these requirements is already included in final Sec.  
111.140(b)(3) which sets forth the requirements for the documentation 
that quality control personnel must include for any required material 
review and disposition decision. In addition, under final Sec.  
111.260(m), the batch production record must include documentation of 
any required material review and disposition decision. Given the 
requirements of final Sec. Sec.  111.140(b)(3) and 111.260(m), it would 
be redundant to include proposed Sec.  111.50(e)(2), (e)(3), and (e)(4) 
in final subpart I, and we are not including them.

XV. Comments on Production and Process Control System: Requirements for 
Laboratory Operations (Final Subpart J)

A. Organization of Final Subpart J

    In the 2003 CGMP Proposal, the proposed requirements for production 
and process controls for laboratory operations were set forth in 
proposed Sec.  111.60(a) through (d). As shown in table 11 of this 
document, we are reorganizing the requirements for laboratory 
operations into a distinct subpart (final Subpart J--Production and 
Process Control System: Requirements for Laboratory Operations). Table 
11 lists the sections in final subpart J and identifies the proposed 
sections that form the basis of the final rule.

          Table 11.--Derivation of Sections in Final Subpart J
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.303 What are the requirements   N/A
 under this subpart J for written
 procedures?
------------------------------------------------------------------------
Sec.   111.310 What are the requirements   Sec.   111.60(a)
 for the laboratory facilities that you
 use?
------------------------------------------------------------------------
Sec.   111.315 What are the requirements   Sec.   111.60(b)(1)
 for laboratory control processes?
------------------------------------------------------------------------
Sec.   111.320 What requirements apply to  Sec.   111.60(c) and (d)
 laboratory methods for testing and
 examination?
------------------------------------------------------------------------
Sec.   111.325 Under this subpart J, what  Sec.   111.60(b)(2) and
 records must you make and keep?            (b)(3)
------------------------------------------------------------------------

B. Highlights of the Changes to the Proposed Requirements for 
Laboratory Operations

1. Revisions
    The final rule applies to persons who manufacture, package, label, 
or hold dietary supplements unless subject to an exclusion in Sec.  
111.1.
2. Changes Associated With the Reorganization
    This subpart contains fewer details, compared to the 2003 CGMP 
Proposal, regarding the requirements for collecting representative 
samples and for testing, because these details are set forth elsewhere 
in this final rule (i.e., in final Sec. Sec.  111.75 and 111.80) and 
would be redundant in final subpart J.
3. Changes After Considering Comments
    The final rule:
    <bullet> Includes a new requirement to establish and follow written 
procedures for laboratory operations, including written procedures for 
the tests and examinations you conduct to determine whether or not 
specifications are met.
    <bullet> Requires you to identify and use the appropriate 
``scientifically valid method,'' rather than an appropriate ``validated 
testing method,'' for each established specification for which testing 
or examination is required to determine whether the specification is 
met.

[[Page 34892]]

C. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.303)

    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section.
    Final Sec.  111.303 requires you to establish and follow written 
procedures for laboratory operations, including written procedures for 
the tests and examinations you conduct to determine whether 
specifications are met.

D. What Are the Requirements for the Laboratory Facilities That You 
Use? (Final Sec.  111.310)

    Final Sec.  111.310 requires you to use adequate laboratory 
facilities to perform whatever testing and examinations are necessary 
to determine whether: (1) Components that you use meet specifications; 
(2) in-process specifications are met as specified in the master 
manufacturing record; and (3) dietary supplements that you manufacture 
meet specifications. Final Sec.  111.310(a) is substantially similar to 
proposed Sec.  111.60(a). The requirement for ``adequate laboratory 
facilities'' is to ensure that the facilities used are designed and 
suitable for carrying out the necessary tests and examinations. Other 
CGMP requirements of this final rule would apply to the manufacturer's 
laboratory facilities, such as Subpart C--Physical Plant and Grounds, 
and Subpart D--Equipment and Utensils, and should be considered in 
assessing the adequacy of the laboratory facilities. If the tests and 
examinations are carried out by an outside laboratory, you will be 
responsible for ensuring that the test and examinations are adequately 
performed.
    (Comment 272) One comment states that proposed Sec.  111.60(a) 
would be highly disruptive to the dietary supplement industry and would 
impose a great burden on companies that traditionally rely on 
certification of ingredient suppliers. Some comments assert it would be 
redundant to require testing by companies who are suppliers of dietary 
ingredients, as well as by companies who receive the dietary 
supplements, to determine whether the dietary ingredients meet 
specifications.
    (Response) The final rule already includes changes that address the 
concerns raised by these comments. As discussed in section X of this 
document regarding final Sec.  111.75(a), the final rule permits the 
use of certificates of analysis for specifications other than the 
identity of a dietary ingredient.

E. What Are the Requirements for Laboratory Control Processes? (Final 
Sec.  111.315)

    Final Sec.  111.315 sets forth the minimum laboratory control 
processes that you must establish and follow. These laboratory control 
processes must be reviewed and approved by quality control personnel.
1. Final Sec.  111.315(a)
    Final Sec.  111.315(a) requires the laboratory control processes 
you establish and follow to include the use of criteria for 
establishing appropriate specifications. Final Sec.  111.315(a) is 
identical to proposed Sec.  111.60(b)(1)(ii).
    We did not receive comments specific to proposed Sec.  
111.60(b)(1)(ii).
2. Final Sec.  111.315(b)
    Final Sec.  111.315(b) requires you to establish and follow 
laboratory control processes that are reviewed and approved by quality 
control personnel, including the use of sampling plans for obtaining 
representative samples, in accordance with subpart E, of: (1) 
Components, packaging, and labels; (2) in-process materials; (3) 
finished batches of dietary supplements; (4) product you receive for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier); and (5) packaged and labeled 
dietary supplements. Final Sec.  111.315(b) derives from proposed Sec.  
111.60(b)(1)(iii)(A) through (b)(1)(iii)(E).
    Final Sec.  111.315(b) combines the proposed requirements of Sec.  
111.60(b)(1)(iii)(A) and (b)(1)(iii)(D) for consistency with final 
Sec.  111.80(a) which combines the requirements to collect 
representative samples of components, packaging, and labels. However, 
for consistency with other requirements established by this final rule, 
we are separating the requirements to collect representative samples of 
``dietary supplements received'' (which the final rule refers to as 
``product that you receive for packaging or labeling as a dietary 
supplement (and for distribution rather than for return to the 
supplier,'' or ``received product'')) from the requirements to collect 
representative samples of components.
    (Comment 273) Some comments note that proposed Sec.  
111.60(b)(1)(iii) restates the requirements, already contained in 
proposed Sec.  111.37(b)(11)(i) through (b)(11)(iv), that the quality 
control unit collect representative samples. These comments request 
proposed Sec.  111.60(b)(1)(iii) be deleted, because it is more 
appropriately described as a quality control function rather than as a 
laboratory function.
    (Response) We disagree that the proposed requirement to use a 
sampling plan is more appropriately described as a quality control 
function than as a laboratory function. Under both the proposed and the 
final rule, the sampling plans that are part of the laboratory control 
operations are subject to approval by quality control personnel 
(``unit'' in the proposed rule) but are not developed by quality 
control personnel. We are making no changes based on this comment.
    (Comment 274) One comment asserts sampling can be better 
accomplished at the point of packaging rather than at a laboratory 
remote from the packaging operation.
    (Response) This comment misinterprets proposed Sec.  
111.60(b)(1)(iii) which proposed to establish a process (i.e., the use 
of a sampling plan) rather than to direct that a particular operating 
unit (such as a laboratory) collect samples. We are making no changes 
based on this comment.
3. Final Sec.  111.315(c)
    Final Sec.  111.315(c) requires the laboratory control processes 
you establish and follow include use of criteria for selecting 
appropriate examination and testing methods. Final Sec.  111.315(c) is 
identical to proposed Sec.  111.60(b)(1)(i).
    (Comment 275) One comment recommends that a contract laboratory 
hired by a person who is subject to the final rule be able to determine 
the specific type of test that is most appropriate.
    (Response) Nothing in the final rule would preclude you from 
relying on the recommendation of the contract laboratory in selecting 
an appropriate test or examination. However, the manufacturer of the 
dietary supplement has the responsibility to comply with these CGMP 
requirements, including the requirement to select appropriate tests, 
regardless of who conducts the tests.
4. Final Sec.  111.315(d)
    Final Sec.  111.315(d) requires the laboratory control processes 
you establish and follow to include use of criteria for selecting 
standard reference materials used in performing tests and examinations. 
Final Sec.  111.315(d) derives from proposed Sec.  111.60(b)(1)(iv).
    (Comment 276) Several comments support the use of standard 
reference materials. Some comments distinguish between a reference 
standard (which they describe as a highly purified

[[Page 34893]]

compound that is well characterized and is used in quantitative assays 
for single chemical entities) and a reference material (which they 
describe as similar to a reference standard but with less specificity). 
These comments urge us to recognize the difference between reference 
standards and reference materials and to require the use of both in the 
final rule.
    (Response) The comments that request we recognize a difference 
between certain types of reference materials are consistent with 
proposed Sec.  111.60(b)(1)(iv) and with statements that we made in the 
preamble to the 2003 CGMP Proposal. We distinguished two general types 
of reference materials: (1) Compendia reference standards that do not 
require characterization and (2) noncompendia standards that should be 
of the highest purity that can be obtained by reasonable effort and 
that should be thoroughly characterized to ensure their identity, 
purity, quality, and strength. We recommended you use compendia 
reference standards whenever possible, and that you establish 
appropriately characterized in-house materials prepared from 
representative lots if no compendia reference standard exists.
    We also discussed reference materials from the perspective of the 
type of test or examination. For organoleptic examinations, we 
described an authenticated plant reference material as material that 
has been authenticated as the correct plant species and correct plant 
part(s) by a qualified plant taxonomist. For microscopic and chemical 
tests (including calibration tests), we described a reference material 
as a highly purified compound that is well characterized.
    To the extent that the comments are recommending that both 
compendia reference standards and noncompendia reference standards 
comply with any final rule, this final rule would allow for the use of 
both compendia reference standards and noncompendia reference 
standards. However, to the extent that the comments are requesting this 
final rule require that both types of reference materials be used, we 
disagree. We see no reason to require, for example, that a firm with 
access to compendia standards be required to develop noncompendia 
standards. Likewise, given that we have acknowledged that noncompendia 
standards may be used, we see no reason to require the use of compendia 
standards in all circumstances.
    (Comment 277) One comment expresses confusion about the preamble 
discussion of proposed Sec.  111.60(b)(1)(iv) and suggests the preamble 
specify that reference standards be established appropriate to the 
assay procedure for which they are used.
    (Response) Reference materials should be appropriate to the assay 
procedure for which they are used.
    (Comment 278) Several comments recommend we acknowledge certain 
reference materials as authoritative sources for botanical ingredients, 
such as American Herbal Pharmacopoeia, European Pharmacopoeia, and the 
World Health Organization, in part because other sources include only a 
limited number of botanicals as supplements. In the comments' view, 
explicit acknowledgment by FDA would encourage manufacturers to use 
independent standards, increase CGMP compliance, and show that 
validation is not limited to quantitative chemical methods.
    (Response) We decline to acknowledge certain reference materials as 
authoritative sources for botanical ingredients. Such a request is 
outside the scope of this final rule.
    (Comment 279) One comment believes we should designate USP to 
develop appropriate standards.
    (Response) This comment is outside the scope of this final rule.
5. Final Sec.  111.315(e)
    Final Sec.  111.315(e) requires that the laboratory control 
processes you must establish and follow include use of test methods and 
examinations in accordance with established criteria. Final Sec.  
111.315(e) derives from proposed Sec.  111.60(b)(1)(vi).
    We did not receive comments specific to proposed Sec.  
111.60(b)(1)(vi).

F. What Requirements Apply to Laboratory Methods for Testing and 
Examination? (Final Sec.  111.320)

1. Final Sec.  111.320(a)
    Final Sec.  111.320(a) requires you to verify that laboratory 
examination and testing methodologies are appropriate for their 
intended use. Final Sec.  111.320(a) is identical to proposed Sec.  
111.60(c).
    (Comment 280) One comment states that this decision should be made 
by a qualified person, whether in-house or at a contract laboratory.
    (Response) We agree. Nothing in the final rule would preclude you 
from relying on the judgment of a qualified person at a contract 
laboratory to satisfy the requirements of final Sec.  111.320(a). We 
would not consider that a recommendation from a contract laboratory is 
any different from a recommendation from an operating unit of the 
manufacturer. However, the manufacturer of the dietary supplement has 
the responsibility to comply with these CGMP requirements, including 
the requirement to select appropriate tests, regardless of who conducts 
the tests.
    (Comment 281) One comment suggests modifying proposed Sec.  
111.60(c) to add ``reference materials and/or reference standards'' to 
the list of elements that must be verified to be appropriate for their 
intended use.
    (Response) If reference materials and reference standards are used 
as part of the test or examination method, then such materials and 
standards are already required to be verified under the language in 
proposed Sec.  111.60(c). Thus, there is no need for the modification 
and we decline to modify the language of final Sec.  111.320(a).
2. Final Sec.  111.320(b)
    Final Sec.  111.320(b) requires you to identify and use the 
appropriate scientifically valid method for each established 
specification for which testing or examination is required to determine 
whether the specification is met. Final Sec.  111.320(b) derives from 
proposed Sec.  111.60(d) which would require you to identify and use an 
appropriate validated testing method for each established specification 
for which testing is required to determine whether the specification is 
met. Final Sec.  111.320(b) includes a provision associated with final 
Sec.  111.75(h) which provides flexibility to use examinations as well 
as tests to determine whether specifications are met.
    (Comment 282) Many comments express concern about the amount of 
testing required for the validation of the appropriate test method. 
Several comments object to the use of the terms ``validations'' and 
``validated'' which they assert have a specific meaning in a 
pharmaceutical context and would be overly burdensome in this rule. 
Other comments assert that methods already recognized as official 
standards do not need to be ``validated,'' but simply ``verified'' as 
to suitability. Some comments suggest substituting ``scientifically 
valid testing method'' for ``appropriate validated testing method.'' 
One comment suggests ``qualifications'' replace ``validations.'' 
Another comment suggests test methods need not be validated if they are 
``proven to be suitable under actual conditions of use.'' Another 
comment suggests adding ``established by the manufacturer'' after 
``appropriate validated test method.''
    One comment recommends the final rule give companies the 
flexibility to adopt the method most suitable to the ingredient they 
are testing, regardless of whether the method is, or is not, an 
``official method'' such as those

[[Page 34894]]

established by AOAC International or FDA.
    (Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157 
at 12208), we stated that test method validation determines whether a 
newly-developed or existing test method is accurate, precise, and 
specific for its intended purpose and involves evaluating the test 
method on multiple occasions or in multiple test facilities. We 
explained that official methods, such as AOAC International methods, 
are validated in collaborative studies using several laboratories under 
identical conditions and that the AOAC International methods are often 
cited as ``official validated methods.'' We also explained that other 
method validations are conducted in a single laboratory by repeating 
the same test multiple times. Typical validation characteristics 
include accuracy, precision, specificity, detection limit, quantitation 
limit, linearity, range, and robustness.
    The process of method validation discussed above is a formal 
process for demonstrating that procedures are suitable for their 
intended use. Although all methods that are formally validated are 
considered ``scientifically valid,'' other methods that are based on 
scientific data or results published in, for example, scientific 
journals, references, text books, or proprietary research can be 
scientifically valid even if they are not formally ``validated'' in 
collaborative studies (68 FR 12157 at 12198).
    We agree that companies should have flexibility to adopt the method 
most suitable to the ingredient they are testing. Consistent with the 
view that we expressed in the preamble to 2003 CGMP Proposal (68 FR 
12157 at 12198), we believe that a scientifically valid method is one 
that is accurate, precise, and specific for its intended purpose. In 
other words, a scientifically valid method is one that consistently 
does what it is intended to do.
    Because we acknowledge that methods that are based on scientific 
data or results published in, for example, scientific journals, 
references, text books, or proprietary research can be scientifically 
valid even if they are not formally ``validated,'' we are revising 
proposed Sec.  111.60(d). Under final Sec.  111.320(b) you must 
identify and use an appropriate ``scientifically valid method'' (rather 
than a ``validated method'') for each established specification for 
which testing or examination is required to determine whether the 
specification is met. However, we continue to recommend that you use 
tests and examinations that already have been validated when such tests 
are available.
    (Comment 283) One comment specifically asks how much modification 
of a validated method is allowed before the method must be re-validated 
by the laboratory. The comment cites an example of moisture testing in 
which the testing method needs to be modified to provide a more valid 
moisture reading.
    (Response) In the preamble to the 2003 CGMP proposal (68 FR 12157 
at 12209), we recommended that, if you modify an officially validated 
method, you document the reason for the modification and have data to 
show that the modified method produces results that are at least as 
accurate and reliable as the established method for the material being 
tested. We also recommended that you have complete records of any 
testing and standardization of laboratory reference standards, 
reagents, and standard solutions that you use in your laboratory 
operations. We are making no changes to these recommendations in this 
final rule.
    (Comment 284) Several comments request the final rule incorporate 
by reference authoritative sources of compendial methods.
    (Response) We decline this request for the reasons discussed in 
response to comments 193 and 196.

G. Appropriate Test Method Validation (Proposed Sec.  111.60(b)(1)(v))

    Proposed Sec.  111.60(b)(1)(v) would require the laboratory control 
processes you establish and follow to include the use of appropriate 
test method validations. Because the final rule does not require that 
you use a validated method for any tests or examinations that you 
conduct, we are removing proposed Sec.  111.60(b)(1)(v).

H. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.325)

    Final Sec.  111.325 sets forth the requirements for records that 
quality control personnel must make and keep.
1. Final Sec.  111.325(a)
    Final Sec.  111.325(a) requires you to make and keep records 
required under subpart J in accordance with subpart P. Final Sec.  
111.325(a) derives from proposed Sec.  111.60(b)(3), which would 
require you to keep laboratory examination and testing records in 
accordance with proposed Sec.  111.125. Because final Sec.  111.303 
requires you to establish and follow written procedures for laboratory 
operations, the records you must make and keep under final Sec.  
111.325 are not limited to laboratory examination and testing records, 
but also include the written procedures. Final Sec.  111.325(a) also 
includes editorial revisions associated with the reorganization and 
editorial revisions for consistency with the recordkeeping requirements 
in subparts P.
    We did not receive comments specific to proposed Sec.  
111.60(b)(3).
2. Final Sec.  111.325(b)(1)
    The final rule includes a new requirement (final Sec.  111.303) 
that you establish and follow written procedures for laboratory 
operations, including written procedures for the tests and examinations 
you conduct to determine whether specifications are met. Those written 
procedures are records. Therefore, final Sec.  111.325(b)(1) requires 
you to make and keep a record of the written procedures for laboratory 
operations, including written procedures for the tests and examinations 
that you conduct to determine whether specifications are met.
3. Final Sec.  111.325(b)(2)
    Final Sec.  111.325(b)(2) sets forth requirements for documenting 
that you followed the laboratory methodology established in accordance 
with this subpart. Final Sec.  111.325(b)(2)(i) requires that the 
person who conducts the testing and examination document, at the time 
of performance, that laboratory methodology established in accordance 
with this subpart is followed. Final Sec.  111.325(b)(2)(ii) requires 
that the documentation include the results of the testing and 
examination. Final Sec.  111.325(b)(2) derives from proposed Sec.  
111.60(b)(2) with revisions associated with the reorganization.
    (Comment 285) One comment states that, without appropriate 
documentation, there would be no assurance that the appropriate testing 
was indeed performed and that the product's identity, purity, quality, 
strength, and composition are what they are represented to be.
    (Response) We agree and have retained the requirement in this final 
provision.

XVI. Comments on the Production and Process Control System: 
Requirements for Manufacturing Operations (Final Subpart K)

A. Organization of Final Subpart K

    In the 2003 CGMP Proposal, the requirements for manufacturing 
operations were set forth in Sec.  111.65. As shown in table 12 of this 
document, we are establishing the requirements for

[[Page 34895]]

manufacturing operations in a distinct subpart (final Subpart K--
Production and Process Control System: Requirements for Manufacturing 
Operations). In addition, we are incorporating some requirements from 
proposed Sec.  111.74 relating to rejected components, dietary 
supplements, and packaging and labels into final subpart K. Table 12 
lists the sections in final subpart K and identifies the proposed 
sections that form the basis of the final rule.

          Table 12.--Derivation of Sections in Final subpart K
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.353 What are the requirements   N/A
 under this subpart K for written
 procedures?
------------------------------------------------------------------------
Sec.   111.355 What are the design         Sec.   111.65(a)
 requirements for manufacturing
 operations?
------------------------------------------------------------------------
Sec.   111.360 What are the requirements   Sec.   111.65(b)
 for sanitation?
------------------------------------------------------------------------
Sec.   111.365 What precautions must you   Sec.   111.65(c)
 take to prevent contamination?
------------------------------------------------------------------------
Sec.   111.370 What requirements apply to  Sec.   111.74
 rejected dietary supplements?
------------------------------------------------------------------------
Sec.   111.375 Under this subpart K, what  N/A
 records must you make and keep?
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Manufacturing 
Operations

1. Revisions
    The final rule:
    <bullet> Applies to persons who manufacture, package, label, or 
hold dietary supplements unless subject to an exclusion in Sec.  111.1 
and
    <bullet> Reflects changes relevant to this subpart that we are 
making to final subpart C concerning water standards.
2. Changes Made After Considering Comments
    The final rule requires written procedures for manufacturing 
operations.
3. Revisions Associated With the Reorganization
    The final rule sets forth in final Sec.  111.90, rather than in 
subpart K, the requirements for in-process adjustments or reprocessing.

C. General Comments on Manufacturing Operations

    (Comment 286) Some comments support proposed Sec.  111.65 as a 
``good model'' for an appropriate level of flexibility, noting that 
proposed Sec.  111.65 clearly states the requirements and presents 
relevant factors that must be considered when determining how to best 
meet the requirements of the rule.
    (Response) We acknowledge these comments and utilize many elements 
of proposed Sec.  111.65 in final Sec.  111.355.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.353)

    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section.
    We are including a new provision, final Sec.  111.353, to require 
that you establish and follow written procedures for manufacturing 
operations.

E. What Are the Design Requirements for Manufacturing Operations? 
(Final Sec.  111.355)

    Final Sec.  111.355 requires you to design or select manufacturing 
processes to ensure that product specifications are consistently met. 
Final Sec.  111.355 derives from proposed Sec.  111.65(a) which would 
require you to design or select manufacturing processes to ensure that 
dietary supplement specifications are consistently achieved. Final 
Sec.  111.355 refers to ``product specifications'' rather than 
``dietary supplement specifications'' to conform with final Sec.  
111.70(e). We have substituted the word ``met'' for ``achieved'' to 
comply with plain language initiatives and to be consistent with other 
provisions.
    We did not receive comments specific to proposed Sec.  111.65(a).

F. What Are the Requirements for Sanitation? (Final Sec.  111.360)

    Final Sec.  111.360 requires you to conduct all manufacturing 
operations in accordance with adequate sanitation principles. Final 
Sec.  111.360 derives from proposed Sec.  111.65(b). We did not receive 
comments specific to proposed Sec.  111.65(b).

G. What Precautions Must You Take to Prevent Contamination? (Final 
Sec.  111.365)

    Final Sec.  111.365 requires you to take all necessary precautions 
during the manufacture of a dietary supplement to prevent contamination 
of components or dietary supplements. Final Sec.  111.365 derives from 
proposed Sec.  111.65(c)(1) through (c)(11).
1. Final Sec.  111.365(a)
    Final Sec.  111.365(a) requires that the necessary precautions 
include performing manufacturing operations under conditions and 
controls that protect against the potential for growth of 
microorganisms and the potential for contamination. Final Sec.  
111.365(a) derives from proposed Sec.  111.65(c)(1).
    (Comment 287) One comment contends that the requirement in proposed 
Sec.  111.65(c)(1) to protect ``against the potential for growth of 
microorganisms,'' does not take into account processes that have a kill 
step. The comment recommends that proposed Sec.  111.65(c)(1) be 
revised to be more consistent with Sec.  110.80(b)(2) and state, 
``performing manufacturing operations under such conditions and 
controls as are necessary to minimize the potential for the growth of 
undesirable microorganisms, or for the contamination of the product.''
    (Response) We decline to modify final Sec.  111.365(a) as requested 
by the comment because the provision accomplishes what is requested by 
the comment. We defined ``microorganism'' in the 2003 CGMP Proposal 
similar to how we describe ``undesirable microorganisms'' in Sec.  
110.3(i). Further, we decline to use the words ``minimize the potential 
for growth'' instead of ``protect against the potential for growth'' 
because the word ``minimize'' suggests a lesser standard than ``protect 
against'' the potential for growth of microorganisms.
    We would consider that you are not complying with the final rule if 
you do not perform manufacturing operations under conditions and 
controls that protect against the potential for growth of 
microorganisms and the potential for contamination, regardless of 
whether you use a kill step. Although a kill step may be necessary in 
some circumstances, it is not a substitute for conditions and controls 
that protect against the potential for growth of microorganisms and the 
potential for contamination. Therefore, we decline to make the change 
requested by this comment.

[[Page 34896]]

2. Final Sec.  111.365(b)
    Final Sec.  111.365(b) requires that necessary precautions include 
washing or cleaning components that contain soil or other contaminants. 
Final Sec.  111.365(b) is identical to proposed Sec.  111.65(c)(2). We 
did not receive comments specific to proposed Sec.  111.65(c)(2).
3. Final 111.365(c)
    Final Sec.  111.365(c) requires that the necessary precautions 
include using water that, at a minimum, complies with the applicable 
Federal, State, and local requirements and does not contaminate the 
dietary supplement when the water may become a component of the 
finished batch of dietary supplement.
    The proposed requirements would set forth parallel requirements for 
water that is used in the manufacture of a dietary supplement for both 
your physical plant (proposed Sec.  111.15(d)(2)) and for manufacturing 
operations (proposed Sec.  111.65(c)(3)). Thus, proposed Sec.  
111.15(d)(2) would require that water that contacts components, dietary 
ingredients, dietary supplements, or any contact surface must, at a 
minimum, comply with the NPDW regulations prescribed by the 
Environmental Protection Agency under 40 CFR part 141 and any State and 
local requirements.
    As discussed in section VIII of this document (final Sec.  
111.15(e)(2) in subpart C), we are revising proposed Sec.  111.15(d)(2) 
to require in the final rule that water, used in the manufacture of a 
dietary supplement in a manner such that the water may become a 
component of the dietary supplement, i.e., when such water contacts 
components, dietary supplements, or any contact surface, must, at a 
minimum, comply with applicable Federal, State, and local requirements 
and not contaminate the dietary supplement. Given the parallel nature 
of proposed Sec.  111.65(c)(3) and proposed Sec.  111.15(d)(2), we are 
revising proposed Sec.  111.65(c) to be consistent with the revisions 
we are making to proposed Sec.  111.15(d)(2) (final Sec.  
111.15(e)(2)).
    Final Sec.  111.365(c) also includes grammatical changes consistent 
with the structure of final Sec.  111.365.
    (Comment 288) One comment asks that the words ``or equivalent 
quality water'' be added to ``water that meets the National Primary 
Drinking Water regulations'' in proposed Sec.  111.65(c)(3) to allow 
for ingredients manufactured in facilities outside the United States.
    (Response) As stated in response to comment 91, dietary supplements 
manufactured in a foreign country would be subject to the requirements 
of this final rule. Although the Environmental Protection Agency NPDW 
regulations would not apply to a foreign manufacturer, the foreign 
manufacturer would need to use water that is of a standard required in 
this final rule and that achieves the same level of performance 
required of domestic manufacturers. The water used by the foreign 
facility must not contaminate the dietary supplement that is 
manufactured. We decline to add ``or equivalent water quality'' because 
that would suggest domestic firms would not need to follow whatever 
Federal, State, and local requirements are applicable.
    (Comment 289) One comment recommends that proposed Sec.  
111.65(c)(3) be revised to be consistent with proposed Sec.  
111.15(d)(1), which would require you to provide water that is safe and 
of adequate sanitary quality, at suitable temperatures, and under 
pressure as needed, in all areas where water is necessary for: (1) 
Manufacturing dietary ingredients or dietary supplements; (2) making 
ice that comes in contact with components, dietary ingredients, dietary 
supplements, or contact surfaces; (3) cleaning any surface; and (4) 
employee bathrooms and hand-washing facilities.
    (Response) We do not agree with the comment that we should be 
consistent in the water requirement related to proposed Sec.  
111.15(d)(1) and the requirement in proposed Sec.  111.65(c)(3). The 
requirement in proposed Sec.  111.15(d)(1) describes a variety of 
manufacturing operations where water is used. For example, water that 
is safe and of adequate sanitary quality, as described in the proposed 
rule, for purposes of manufacturing dietary supplements or that comes 
into contact with a dietary supplement would be water that would have 
been required to comply with the requirement in proposed Sec.  
111.15(d)(2). Under the proposed rule and under the final rule, if such 
water is subject to Environmental Protection Agency NPDW, then the 
water must meet Environmental Protection Agency NPDW requirements at 
point of use. Proposed Sec.  111.15(d)(1) has been revised and 
simplified in final Sec.  111.15(e)(1) to require you to provide water 
that is safe and sanitary, at suitable temperatures, and under pressure 
as needed, for all uses where water does not become a component of the 
dietary supplement. Water that is safe and sanitary for cleaning the 
floor in a facility would not need to meet standards for drinking 
water, but such water could not be a source of contamination of the 
dietary supplement. The standard ``safe and sanitary'' in final Sec.  
111.15(e)(1) allows some flexibility for the manufacturer in deciding 
what water it can use in various operations for which no other 
requirements in this final rule apply. The requirements of final Sec.  
111.365(c) are consistent with the changes in final Sec.  111.15(e).
4. Final Sec.  111.365(d)
    Final Sec.  111.365(d) requires that the necessary precautions you 
take during the manufacture of a dietary supplement to prevent 
contamination of components or dietary supplements include performing 
chemical, microbiological, or other testing, as necessary to prevent 
the use of contaminated components. Final Sec.  111.365(d) derives from 
proposed Sec.  111.65(c)(4).
    (Comment 290) One comment asserts that requirements for testing 
belong in proposed Sec.  111.25 (proposed requirements for equipment 
and utensils) rather than in proposed Sec.  111.65 (proposed 
requirements for manufacturing operations).
    (Response) In our discussion of proposed Sec.  111.65(c)(4) in the 
2003 CGMP Proposal (68 FR 12157 at 12210), we stated that you consider 
identifying those areas in the processing and production areas where 
chemical, microbial, or other forms of contamination are most likely to 
occur. We also stated that chemical, microbial, or other testing is 
necessary to identify areas where sanitation measures have not been 
adequate or where products may become adulterated. These remarks 
reflect that the proposed requirement in proposed Sec.  111.65(c)(4) is 
directed to facilities rather than to equipment and utensils. For 
example, under proposed Sec.  111.65(c)(4), we encouraged you to 
establish a testing program that monitors levels of microorganisms at 
key places in your physical plant where you process and produce your 
products. Thus, we disagree with the comment that the testing 
requirements belong in proposed Sec.  111.25 and are not making any 
changes in final Sec.  111.365(d).
5. Final Sec.  111.365(e)
    Final Sec.  111.365(e) requires that the necessary precautions you 
take during the manufacture of a dietary supplement to prevent 
contamination of components or dietary supplements include sterilizing, 
pasteurizing, freezing, refrigerating, controlling hydrogen-ion 
concentration (pH), controlling humidity, controlling water activity 
(a<INF>w</INF>), or using any other effective means to remove, destroy, 
or prevent the growth of microorganisms, and prevent

[[Page 34897]]

decomposition. Final Sec.  111.365(e) derives from proposed Sec.  
111.65(c)(5).
    (Comment 291) One comment asserts that only sanitary practices are 
needed to prevent microbial contamination or decomposition, and, 
therefore, requests that we clarify the processes listed in proposed 
Sec.  111.65(c)(5) are optional.
    (Response) We disagree with this comment. Good sanitary practices 
are important, but they are not the only precaution to take to prevent 
a component or dietary supplement from contamination with 
microorganisms. In the preamble to the 2003 CGMP Proposal, we gave the 
example of bovine colostrum, which is the lacteal secretion that 
precedes milk after a cow gives birth and is a substance that is used 
in dietary supplements. We also stated that we consider that bovine 
colostrum likely presents the same potential health risks as bovine 
milk, which can contain pathogenic organisms capable of causing 
diseases in man such as tuberculosis, undulant fever, or 
gastrointestinal disease and, thus, must be pasteurized (21 CFR 
1240.61). Under final Sec.  111.365(e) you must sterilize or pasteurize 
bovine colostrums, or take other steps, to remove or destroy 
microorganisms that could be present in bovine colostrum. Under final 
Sec.  111.365(e) we list various ways that, depending upon the 
particular situation, would be effective in removing, destroying, or 
preventing the growth of microorganisms and preventing decomposition. 
You must decide for your given operation what means to use to remove, 
destroy, or prevent the growth of microorganisms and prevent 
deterioration of your components and dietary supplements so that you 
ensure the quality of the dietary supplement.
    (Comment 292) Some comments recommend adding ``irradiating'' to the 
list of practices to prevent the growth of microorganisms in proposed 
Sec.  111.65(c)(5) similar to the industry CGMP provision, ``Production 
and Process Controls,'' section (d)(5), published in the 1997 ANPRM.
    (Response) We decline to revise the provision as suggested by these 
comments. We are not adding ``irradiating'' to the list of practices 
because, at this time, irradiation of dietary ingredients and dietary 
supplements, as a means to reduce or eliminate microbial loads, is not 
permitted. CFSAN is currently reviewing the use of irradiation for the 
control of microbial contamination on dietary supplements and 
ingredients (including dietary ingredients) used in the manufacture of 
dietary supplements (68 FR 25048, May 9, 2003). If we authorize this 
use of irradiation you could then use irradiation in compliance with 
that rule to comply with final Sec.  111.365(e) as an ``other effective 
means.''
6. Final Sec.  111.365(f)
    Final Sec.  111.365(f) requires that the necessary precautions you 
take during the manufacture of a dietary supplement to prevent 
contamination of components or dietary supplements include holding 
components and dietary supplements that can support the rapid growth of 
microorganisms of public health significance in a manner that prevents 
the components and dietary supplements from becoming adulterated. Final 
Sec.  111.365(f) derives from proposed Sec.  111.65(c)(6). We did not 
receive comments specific to proposed Sec.  111.65(c)(6).
7. Final Sec.  111.365(g)
    Final Sec.  111.365(g) requires that the necessary precautions you 
take during the manufacture of a dietary supplement to prevent 
contamination of components or dietary supplements include identifying 
and holding any components or dietary supplements, for which a material 
review and disposition decision is required, in a manner that protects 
components or dietary supplements that are not under a material review 
against contamination and mixups with those under a material review. 
Final Sec.  111.365(g) is substantially similar to proposed Sec.  
111.65(c)(7). We did not receive comments specific to proposed Sec.  
111.65(c)(7).
8. Final Sec.  111.365(h)
    Final Sec.  111.365(h) requires that the necessary precautions you 
take during the manufacture of a dietary supplement to prevent 
contamination of components or dietary supplements include performing 
mechanical manufacturing steps (such as cutting, sorting, inspecting, 
shredding, drying, grinding, blending, and sifting) by any effective 
means to protect the dietary supplements against contamination. Final 
Sec.  111.365(h) derives from proposed Sec.  111.65(c)(8). Such steps 
must include consideration of: (1) Cleaning and sanitizing contact 
surfaces, (2) using temperature controls, and (3) using time controls.
    (Comment 293) One comment suggests that the time controls required 
in proposed Sec.  111.65(c)(8)(iii) are not always necessary.
    (Response) As written, proposed Sec.  111.65(c)(8) acknowledges 
that time controls are not always necessary, because the provision 
requires that you consider using time controls, and implement them if 
they are necessary to prevent contamination of components or dietary 
supplements. Final Sec.  111.65(h) retains this same language.
9. Final Sec.  111.365(i)
    Final Sec.  111.365(i) requires that the necessary precautions you 
take during the manufacture of a dietary supplement to prevent 
contamination of components or dietary supplements include using 
effective measures to protect against the inclusion of metal or other 
foreign material in components or dietary supplements. Compliance with 
this requirement must include consideration of the use of: (1) Filters 
or strainers, (2) traps, (3) magnets, or (4) electronic metal 
detectors. Final Sec.  111.365(i) derives from proposed Sec.  
111.65(c)(9).
    (Comment 294) One comment contends it is sufficient to require in 
proposed Sec.  111.65(c)(9) that manufacturers inspect their equipment 
before and after use to determine if any piece is missing, and if so, 
the entire batch should be disposed of. The comment states metal 
detection devices are not 100 percent effective and that inspection of 
equipment before and after use would be preferable.
    (Response) We disagree with the comment. As discussed in the 2003 
CGMP Proposal, the purpose behind proposed Sec.  111.65(c)(9) is to 
ensure that no metal or foreign material becomes a source of possible 
contamination and not to establish mechanisms to be used after 
contamination has or is suspected to have occurred (68 FR 12157 at 
12211). The source of metal contamination is not limited to 
manufacturing equipment. For example, metal contamination could occur 
through using utensils such as metal brushes during processing of 
natural products. It would be impractical to determine whether 
contamination has occurred by examining the brush.
10. Final Sec.  111.365(j)
    Final Sec.  111.365(j) requires that the necessary precautions you 
take during the manufacture of a dietary supplement to prevent 
contamination of components or dietary supplements include segregating 
and identifying all containers for a specific batch of dietary 
supplements to identify their contents and, when necessary, the phase 
of manufacturing. Final Sec.  111.365(j) derives from proposed Sec.  
111.65(c)(10). We did not receive comments specific to proposed Sec.  
111.65(c)(10).
11. Final Sec.  111.365(k)
    Final Sec.  111.365(k) requires that the necessary precautions you 
take during the manufacture of a dietary supplement

[[Page 34898]]

to prevent contamination of components or dietary supplements include 
identifying all processing lines and major equipment used during 
manufacturing to indicate their contents, including the name of the 
dietary supplement and the specific batch or lot number and, when 
necessary, the phase of manufacturing. Final Sec.  111.365(k) derives 
from proposed Sec.  111.65(c)(11).
    (Comment 295) One comment suggests continuous processes should be 
excluded from the requirement in proposed Sec.  111.65(c)(11) to 
identify specific batch or lot numbers. The comment explains that in 
continuous bulk operations for manufacturing dietary ingredients, the 
batch or lot number often is not identified until after the materials 
have been blended and moved into a storage bin.
    (Response) We are making no changes to proposed Sec.  111.65(c)(11) 
in final Sec.  111.365(k) because the comment describes a situation 
where the manufacturer is manufacturing a dietary ingredient, and the 
final rule does not apply to the manufacture of a ``dietary 
ingredient'' within the meaning of section 201(ff) of the act.

H. What Requirements Apply to Rejected Dietary Supplements? (Final 
Sec.  111.370)

    Final Sec.  111.370 requires you to clearly identify, hold, and 
control under a quarantine system for appropriate disposition any 
dietary supplement that is rejected and unsuitable for use in 
manufacturing, packaging, or label operations. Final Sec.  111.370 
derives from proposed Sec.  111.74 which would require that you clearly 
identify, hold, and control under a quarantine system any component, 
dietary ingredient, dietary supplement, packaging, and label that is 
rejected and unsuitable for use in manufacturing, packaging, or label 
operations. Because the requirements regarding components, packaging, 
and labels that are rejected and unsuitable for use are already set 
forth in final Sec.  111.170, final Sec.  111.370 addresses only the 
requirements for dietary supplements.
    We did not receive comments specific to proposed Sec.  111.74.

I. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.375)

    In order to ensure that records are maintained as required under 
subpart P, we are adding a new Sec.  111.375. This section requires 
that you make and keep records of the written procedures you establish 
for manufacturing operations. These written procedures are required 
under final Sec.  111.353.

XVII. Comments on the Production and Process Control System: 
Requirements for Packaging and Labeling Operations (Final Subpart L)

A. Organization of Final Subpart L

    In the 2003 CGMP Proposal, the requirements for packaging and 
labeling operations were set forth in Sec.  111.70. As shown in table 
13 of this document, the final rule reorganizes the requirements 
related to quality control operations into a distinct subpart (final 
Subpart L--Production and Process Control System: Requirements for 
Packaging and Labeling Operations). Table 13 lists the sections in 
final subpart L and identifies the proposed sections that form the 
basis of the final rule.

          Table 13.--Derivation of Sections in Final Subpart L
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.403 What are the requirements   N/A
 under this subpart L for written
 procedures?
------------------------------------------------------------------------
Sec.  111.410 What requirements apply to   Sec.   111.70(a), (b)(6), and
 packaging and labels?                      (f)
------------------------------------------------------------------------
Sec.   111.415 What requirements apply to  Sec.   111.70(b)
 filling, assembling, packaging,
 labeling, and related operations?
------------------------------------------------------------------------
Sec.  111.420 What requirements apply to   Sec.   111.70(d) and (e)
 repackaging and relabeling?
------------------------------------------------------------------------
Sec.  111.425 What requirements apply to   Sec.   111.74
 a packaged and labeled dietary
 supplement that is rejected for
 distribution?
------------------------------------------------------------------------
Sec.   111.430 Under this subpart L, what  Sec.   111.70(g) and (h)
 records must you make and keep?
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Packaging and 
Labeling Operations

1. Revisions
    The final rule:
    <bullet> Reflects that the final rule applies to persons who 
manufacture, package, label, or hold dietary supplements unless subject 
to an exclusion in Sec.  111.1.
    <bullet> Reflects that the labeling requirements of the rule 
address the operation of putting the label specified in the master 
manufacturing record on the final product.
    <bullet> Clarifies the applicability of the rule to labeling 
operations.
2. Changes Associated With the Reorganization
    We are moving to final Sec.  111.260(k) in subpart I the 
requirements for the documentation, in the batch production record, of 
packaging and labeling operations (proposed Sec.  111.70(g)).
3. Changes After Considering Comments
    The final rule:
    <bullet> Requires you to establish and follow written procedures 
for packaging and labeling operations.
    <bullet> Provides for an exception to the requirements for label 
reconciliation for cut or rolled labels if a 100-percent examination 
for correct labels is performed by appropriate electronic or 
electromechanical equipment during or after completion of finishing 
operations.
    <bullet> Clarifies the requirement for ``retesting or re-
examining'' any repackaged or relabeled dietary supplements, i.e., 
consistent with final Sec.  111.75(g) you must examine a representative 
sample of each batch of repackaged or relabeled dietary supplements to 
determine whether repackaged or relabeled dietary supplements meet all 
specifications established in accordance with Sec.  111.70(g).

C. General Comments on Proposed Requirements for Packaging and Labeling 
Operations

    (Comment 296) Some comments assert that the proposed packaging and 
labeling requirements are unnecessarily stringent for dietary 
ingredients, because the potential for abuse is primarily at the final 
product stage.
    (Response) To the extent that the comment is saying that a dietary 
ingredient manufacturer who manufactures, packages, labels, and holds a 
dietary ingredient that is further processed and incorporated into a 
dietary supplement by another person should not have to comply with the 
packaging and labeling requirements in subpart L, we agree. We are 
modifying the scope of the rule as to who is subject to the CGMP 
requirements, as discussed in section VI of this document (subpart A). 
The final rule applies to persons who manufacture, package, label, or 
hold dietary supplements unless subject to an exclusion in Sec.  111.1.
    (Comment 297) Several comments assert that it is imperative that a 
dietary supplement contain what it purports on its label. Some comments 
state that the

[[Page 34899]]

amounts of ingredients listed on the label must accurately reflect what 
is in the package.
    (Response) To the extent that the comments are suggesting that 
there need to be requirements for labeling operations as part of CGMP 
to ensure that the label applied to the dietary supplement is the label 
specified in the master manufacturing record for the finished product, 
we agree. To the extent that the comments suggest that CGMP 
requirements should ensure the quality of the dietary supplement 
manufactured, we also agree. If consumers believe that dietary 
supplements contain the ingredients as labeled, as with any other 
product they purchase, then CGMP requirements should help to ensure 
that dietary supplements are manufactured consistently to ensure the 
quality of the dietary supplement and to help ensure the proper 
identity and amount of ingredients identified on the label.

D. General Comments on Requirements for What Must Be on the Product 
Label Rather Than for Labeling Operations

    (Comment 298) Some comments express disappointment that the 2003 
CGMP Proposal does not address product claims included on product 
labels. These comments state that, if FDA is not going to review label 
claims, it should, at a minimum, require the following statement be 
placed on dietary supplement products: ``This product has not been 
reviewed for safety and efficacy by the FDA.'' These comments assert 
that such a statement should be included on all dietary supplement 
products, regardless of whether the product makes structure/function 
claims. These comments also recommend that dietary supplement labeling 
encourage consumers to share information about their use of the dietary 
supplements with their pharmacists and physicians and encourage 
consumers to seek the input of a health care provider if symptoms that 
prompted use of the dietary supplement are not resolved.
    One comment requests we establish specific label content to include 
on dietary supplement labels. The comment asserts that the technology 
and mechanical tools exist to produce expanded labeling for dietary 
supplements efficiently and cost-effectively. The comment asserts that 
the content should include a complete listing of ingredients, relative 
percentages, batch or lot number, intended use, safety information, 
directions, and product information. Specifically, the comment supports 
the labeling recommendations of the U.S. Department of Health and Human 
Services (HHS), Office of the Inspector General (OIG) ``Dietary 
Supplement Labels: Key Elements,'' March 2003, publication no. OEI-01-
01-00120, available at http://oig.hhs.gov/oei/reports/oei-01-01-00120.pdf) (Ref. 34). The comment endorses the HHS/OIG recommendations, 
with the addition of batch or lot number on the label. The comment also 
endorses the OIG's proposed label presentation which calls for: (1) A 
standardized format with similar types of information in a similar 
order across supplements; (2) distinct product features to assist 
consumers in distinguishing supplements from other health care 
products; (3) readability, with language and visual cues that are 
easily understood by consumers; (4) balance to present information in a 
fair and balanced format that omits marketing and sales pitches; and 
(5) constructive use of space whereby innovative packaging is employed 
to expand label space.
    Several comments address whether we should permit manufacturers to 
state on their products that the manufacturer of the product is in 
compliance with FDA CGMP requirements. Several comments assert that a 
CGMP statement on labels should not be allowed. These comments assert 
that the proposed ``made in a CGMP facility'' language is fraught with 
potential misuse, and that the potential for confusion is overwhelming. 
These comments state that the rule also should be modified to exclude 
other similar statements such as ``produced using good laboratory 
practices,'' ``produced using good practices,'' or ``produced in 
compliance with USP good manufacturing practices.'' According to these 
comments, similar statements currently appear on dietary supplement 
labels and also may be misleading. These comments assert that CGMP 
requirements are not voluntary and should not be marketed as such.
    Some comments state that a voluntary label statement that a dietary 
supplement complies with CGMP should be allowed. According to these 
comments, there are several third party organizations such as USP and 
National Nutritional Foods Association (NNFA) that have proposed or 
established CGMP requirements as rigorous as, or more rigorous than, 
those proposed by FDA. These comments assert that a voluntary statement 
that characterizes the nature of the GMP compliance should be allowed.
    (Response) The comments related to requests about specific label 
content, such as ingredient listing, relative percentage of 
ingredients, intended use, safety information, label format, use of 
label space, and directions and product information are outside the 
scope of this final rule. Further, with respect to requiring specific 
statements about dietary supplement product, such as, ``This product 
has not been reviewed for safety and efficacy by the FDA,'' or ``This 
product has been produced using good manufacturing practice,'' we have 
stated previously that the manufacturer is responsible for ensuring 
that any voluntary labeling statements on its dietary supplement 
products are truthful and not misleading (68 FR 12157 at 12164). We 
would review the lawfulness of such statements under sections 403(a)(1) 
and 201(n) of the act.
    We did not propose to require any specific statements. We stated 
that an unqualified statement such as ``produced in compliance with 
dietary supplement current good manufacturing practice requirements,'' 
without more, could suggest a product may be safe and effective or 
somehow superior to other dietary supplement products that are subject 
to the same CGMP requirements (id.). Further, we stated that such a 
statement would likely be considered misleading by us under sections 
403(a)(1) and 201(n) of the act, but that including language clarifying 
to consumers that all dietary supplements must be manufactured in 
compliance with CGMP requirements and that such compliance does not 
mean that the dietary supplement is safe or effective may be a way to 
cure that unqualified statement (id.). Thus, we are not prohibiting 
voluntary statements on the dietary supplement label, provided that 
such statements are truthful and not misleading.
    (Comment 299) Some comments assert that the labeling standards 
found in the 2003 CGMP Proposal should be uniformly applied across 
manufacturers, regardless of size, because consumers are unlikely to 
differentiate between small companies and large ones when selecting 
dietary supplements. These comments assert that we should, therefore, 
only allow 1 year for labeling compliance for all manufacturers 
regardless of their size.
    Some comments assert that small manufacturers are more likely to 
suffer competitively if their labels lack important ingredient and 
other information relative to labeling employed by their larger 
competitors. These comments argue that enhanced labeling is a cost-
effective packaging feature and should not represent a significant cost 
burden when outsourced to a qualified print-packaging vendor. Moreover, 
labels already represent a budgeted cost item

[[Page 34900]]

for dietary supplement producers. Labels with additional content would 
add little to manufacturer overhead.
    (Response) These comments may have misinterpreted the 2003 CGMP 
Proposal. The CGMP requirements do not impose any requirements for the 
specific content of the label. We discuss the requirements necessary to 
determine the complete manufacturing history and control of a packaged 
and labeled dietary supplement through distribution in this subpart in 
our discussion on final Sec.  111.410(d). To the extent that businesses 
with fewer than 500 employees want to comply with the CGMP requirements 
for labeling operations in a shorter timeframe than what we are 
allowing in this final rule, such businesses may do so. However, to 
assist businesses with fewer than 500 employees in complying with 
dietary supplement CGMPs, we are giving businesses with fewer than 500 
but 20 or more employees a compliance date of 24 months after the date 
of publication of this final rule, and we are giving businesses with 
fewer than 20 employees a compliance date of 36 months after the date 
of publication of this final rule.

E. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.403)

    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section.
    Final Sec.  111.403 requires you to establish and follow written 
procedures for packaging and labeling operations. Under final 
111.430(b), relating to records you must make and keep, we require that 
you make and keep records of such written procedures.

F. What Requirements Apply to Packaging and Labels? (Final Sec.  
111.410)

1. Final Sec.  111.410(a)
    Final Sec.  111.410(a) requires that you take necessary actions to 
determine whether the packaging for dietary supplements meets 
specifications so that the condition of the packaging will ensure the 
quality of your dietary supplements. Final Sec.  111.410(a) is similar 
to proposed Sec.  111.70(a) which would require you to take necessary 
actions to ensure that each packaging container for holding dietary 
ingredients or dietary supplements meets specifications so that the 
condition of the packaging container will not contaminate your dietary 
supplements or cause them to deteriorate. We have made changes to be 
consistent with final Sec.  111.70 and the definition of ``quality'' by 
substituting the phrase ``ensure the quality of your dietary 
supplement'' instead of using the words ``contamination'' and 
``deterioration'' which would be encompassed in the definition of 
``quality.'' We are deleting the words ``container'' and ``holding'' 
from final Sec.  111.410(a) to emphasize that all packaging must meet 
specifications and ensure the quality of the dietary supplement.
    (Comment 300) One comment requests the removal of the word ``each'' 
from proposed Sec.  111.70(a) because the inclusion of the word 
mandates that each and every container, rather than a representative 
sample, be inspected.
    (Response) Because the final rule only requires the use of 
representative samples to ensure compliance, as provided in final Sec.  
111.80, to reduce the potential for confusion, we are deleting the word 
``each'' and making associated grammatical revisions.
    (Comment 301) Some comments request we clarify our expectations 
under proposed Sec.  111.70(a) with respect to substantiating that 
packaging containers meet specifications and will not contaminate 
dietary supplements. The comments assert that it is not necessary for a 
manufacturer to test these types of products proactively, and that a 
continuing product guarantee combined with a statement of intended use 
from the manufacturer of the packaging material should suffice to meet 
the proposed requirements. The comments assert this is consistent with 
expected practice in other industries that FDA regulates.
    (Response) Final Sec.  111.410(a) reiterates the requirement of 
final Sec.  111.70(d) to establish packaging specifications and the 
requirement of final Sec.  111.75(f)(1) to determine whether packaging 
specifications are met. Under final Sec.  111.75(f)(1), to determine 
whether packaging meets its specifications, you must conduct a visual 
identification of the containers and closures and review the supplier's 
invoice, guarantee, or certification. Thus, the final rule does not 
require that you test packaging proactively, and does allow you to rely 
on documentation such as a continuing product guarantee combined with a 
statement of intended use from the manufacturer of the packaging.
    As we discussed in the preamble to 2003 CGMP Proposal (68 FR 12157 
at 12212), proposed Sec.  111.70(a) would require you to take into 
account factors such as whether your product is sensitive to light when 
setting specifications for packaging. Other factors to consider include 
whether your product is sensitive to moisture or could interact with 
certain kinds of packaging. (For other requirements related to 
packaging, see final Sec. Sec.  111.70(d), (f), (g), and 111.160.)
2. Final Sec.  111.410(b)
    Final Sec.  111.410(b) requires you to control the issuance and use 
of packaging and labels and reconciliation of any issuance and use 
discrepancies, except that label reconciliation is not required for cut 
or rolled labels if a 100-percent examination for correct labels is 
performed by appropriate electronic or electromechanical equipment 
during or after completion of finishing operations. Final Sec.  
111.410(b) derives from proposed Sec.  111.70(f)(1) which would require 
you to control the issuance and use of packaging and labels and 
reconciliation of any issuance and use discrepancies.
    (Comment 302) Some comments assert that comprehensive label 
reconciliation should not be required if appropriate electronic 
controls are instituted to ensure that correct labels are used during 
labeling operations. The comments state this alternative is permitted 
for labeling operations for drug products, which are generally 
identical or similar in nature to labeling operations for dietary 
supplements. As such, the comments assert that the same flexibility 
should be afforded to dietary supplement manufacturers.
    (Response) We agree with these comments and the revisions are 
reflected in final Sec.  111.410(b) (proposed Sec.  111.70(f)(1)).
3. Final Sec.  111.410(c)
    Final Sec.  111.410(c) requires you to examine, before packaging 
and labeling operations, packaging and labels for each batch of dietary 
supplement to determine whether the packaging and labels conform to the 
master manufacturing record. Final Sec.  111.410(c) derives from 
proposed Sec.  111.70(f)(2). We did not receive comments specific to 
proposed Sec.  111.70(f)(2).
4. Final Sec.  111.410(d)
    Final Sec.  111.410(d) requires you to be able to determine the 
complete manufacturing history and control of the packaged and labeled 
dietary supplement through distribution. We are revising the language 
of proposed Sec.  111.70(b)(6) and including in final Sec.  111.410 the 
similar requirement stated in proposed Sec.  111.70(b)(6). Section 
111.410 is where we chose to place this requirement because it is 
likely that you will affix the batch, lot, or control

[[Page 34901]]

number that you used for the finished batch of dietary supplement on 
the immediate container or on the product label as the means to trace 
the product through distribution, although this is not required. Other 
means are acceptable besides the use of a batch, lot, or control 
number.
    (Comment 303) Some comments assert that we do not propose in the 
2003 CGMP Proposal the affixing of a lot number to the container of 
product marketed to the consumer. These comments assert that all the 
recordkeeping in the 2003 CGMP Proposal is of little value unless 
issues can be traced back from the individual container, perhaps 
received from a customer complaint, to a specific batch. These comments 
state that such labeling should be a requirement.
    (Response) We agree that it is necessary to be able to trace a 
dietary supplement in distribution to a specific batch or lot of 
product. We disagree that we did not provide any requirements in the 
2003 CGMP Proposal that would require you to be able to trace a 
distributed dietary supplement to a specific batch or lot.
    In proposed Sec.  111.70(b)(6) we stated that a batch, lot, or 
control number is necessary for you to trace the manufacturing history 
for a particular batch, which will help you investigate and correct any 
safety problems for a batch or to recall a dietary supplement. We 
discussed the fact that, without such a batch, lot, or control number, 
consumers would be unable to determine which product was the subject of 
a recall and they would not know which product to stop using, or there 
would be a need to recall more product than otherwise may be necessary 
(68 FR 12157 at 12212).
    We also proposed several other requirements related to the need to 
be able to trace the components, packaging, and labeling used in the 
manufacture of a dietary supplement with the distributed dietary 
supplement. Under proposed Sec.  111.40(a) (with respect to components 
and dietary supplements) and proposed Sec.  111.40(b)(3) (with respect 
to packaging and labeling) we would require you to identify each lot of 
product received in a shipment in a manner to allow you to trace the 
shipment lot to the dietary supplement manufactured and distributed. In 
the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12202), we 
stated that using a unique identifier throughout the manufacturing 
process will make it possible to track and account for components and 
dietary supplements received to any necessary investigation of consumer 
complaints. In proposed Sec.  111.50(c)(1) we provided that the batch 
production record must include a batch, lot, or control number, and in 
proposed Sec.  111.50(c)(5) we provided that the batch production 
record must include the shipment lot unique identifier of each 
component, dietary ingredient, dietary supplement, packaging, and label 
used. Further, in proposed Sec.  111.85(d), we required that you 
conduct an investigation if a returned dietary supplement implicates 
associated batches. Thus, we proposed to require that you be able to 
trace a dietary supplement through distribution. However, we did not 
require you to use a specific mechanism, such as affixing a batch, lot, 
or control number to the immediate container or product label. Under 
the 2003 CGMP Proposal, the manufacturer would have flexibility to 
determine the method to trace its product in distribution to the batch, 
lot, or control number assigned to the finished batch or lot of dietary 
supplement.
    In final Sec.  111.415(f), we require you to assign a batch, lot, 
or control number to: (1) Each lot of packaged and labeled dietary 
supplement from a finished batch of dietary supplement and (2) each lot 
of dietary supplement, from a finished batch of dietary supplement, 
that you distribute to another person for packaging or labeling. We do 
not require you to affix this batch, lot, or control number to the 
immediate container or the product label. Instead, we provide 
flexibility for you to determine how you track the batch, lot, or 
control number you assign to each lot of packaged and labeled dietary 
supplement from a finished batch of dietary supplement, and each lot of 
dietary supplement from a finished batch of dietary supplement you 
distribute to another person for packaging or labeling, to distributed 
dietary supplements. To clarify that we do not require you to affix a 
batch, lot, or control number on the immediate container or product 
label, final Sec.  111.410(d) provides that you must be able to 
determine the complete manufacturing history and control of the 
packaged and labeled dietary supplement through distribution by a 
method of your choice. For example, a dietary supplement manufacturer 
may make one type of product that it distributes to a select few 
customers and may be able to trace its dietary supplement using dates 
on distribution records to such customers, or may use different 
containers or labeling, other than a batch, lot, or control number that 
is affixed to the label.
    We are retaining the use of a unique identifier in final Sec. Sec.  
111.155(d), 111.160(d), and 111.260(a), (d), and (k). These 
requirements relate to the tracking of a component, packaging, 
labeling, or dietary supplement throughout the manufacturing process. 
The use of a batch, lot, or control number or other unique identifier, 
as required, for product in the manufacturing process is needed for 
tracking components, packaging, and labels used to manufacture, 
package, or label a dietary supplement so that once a batch is 
identified, the components, packaging, and labels used in a batch will 
also be known. But by contrast, when the distribution of a final 
product may be distributed to a few select customers, or where every 
unique batch is placed in a different type of container, there may not 
be a need to use batch, lot, or control numbers affixed to the 
immediate container or product labels to be able to trace the product.
    This final rule will enhance the benefits of the new statutory 
requirement for mandatory reporting to FDA of serious adverse events as 
the result of the enactment of the ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462), 
signed into law on December 22, 2006. This final rule will facilitate 
the additional traceback activities taking place as a result of the 
additional serious adverse events discovered through mandatory 
reporting. We will evaluate such mandatory reports for patterns or 
``signals'' of problems with particular products so that further harm 
to consumers may be prevented by removing the products and, in some 
cases, related products from the marketplace. This cannot be done 
without first quickly and accurately identifying the products of 
interest. To efficiently determine which specific products or group of 
products are associated with the serious (or non-serious) adverse event 
report, traceback ability is crucial. This final rule includes 
requirements that will provide the information needed to quickly and 
accurately conduct a sufficient traceback. The provisions that require 
maintenance of records for production processes include records such as 
batch records, unique identifiers, and master manufacturing records. 
The recordkeeping provisions of this final rule give us access to those 
records, so we will have an enhanced ability to investigate the serious 
adverse events reported to us, using records such as information on 
ingredients, processing, storage, composition, and distribution. This 
enhanced ability to track information related to serious adverse events 
will increase both the accuracy and the speed of the response to such

[[Page 34902]]

events, which may in many cases reduce the number of illnesses or 
deaths associated with unsafe dietary supplements.

G. What Requirements Apply to Filling, Assembling, Packaging, Labeling, 
and Related Operations? (Final Sec.  111.415)

    Final Sec.  111.415 requires that you fill, assemble, package, 
label, and perform other related operations in a way that ensures the 
quality of the dietary supplement and that the dietary supplement is 
packaged and labeled as specified in the master manufacturing record. 
Final Sec.  111.415 also requires that you do these functions using any 
effective means you choose, including: (1) Cleaning and sanitizing all 
filling and packaging equipment, utensils, and dietary supplement 
packaging, as appropriate; (2) protecting manufactured dietary 
supplements from contamination, particularly airborne contamination; 
(3) using sanitary handling procedures; (4) establishing physical or 
spatial separation of packaging and label operations from operations on 
other components and dietary supplements to prevent mixups; (5) 
identifying, by any effective means, filled dietary supplement 
containers that are set aside and held in unlabeled condition for 
future label operations, to prevent mixups; (6) assigning a batch, lot, 
or control number to each lot of packaged and labeled dietary 
supplement from a finished batch of dietary supplement and each lot of 
dietary supplement from a finished batch of dietary supplement that you 
distribute to another person for packaging or labeling; (7) examining a 
representative sample of each batch of the packaged and labeled dietary 
supplement to determine whether the dietary supplement meets 
specifications established in accordance with final Sec.  111.70(g); 
and (8) suitably disposing of labels and packaging for dietary 
supplements that are obsolete or incorrect to ensure that they are not 
used in any future packaging and labeling operations.
    Final Sec.  111.415 derives from proposed Sec.  111.70(b). We 
revised the section to be consistent with other revisions.
    (Comment 304) Some comments request clarification as to what 
specifications we are referring to in proposed Sec.  111.70(b)(7). The 
comments state that if we are referring to specifications required by 
proposed Sec.  111.35(e), then we should indicate so in any final rule. 
The comment asserts that, if we intend this provision to mean that 
persons who simply package, label, and store dietary supplements must 
conduct full product testing, then proposed Sec.  111.70(b)(7) is 
unwarranted and unreasonable.
    The comments assert that full product testing should not be 
required for companies that merely package, label, and store finished 
products. The comments assert that in-route contamination from the 
facility of a supplier or manufacturer to the facility of a packager, 
labeler, or distributor facility is unlikely to occur if the proper 
environmental conditions are maintained as required by other provisions 
of the 2003 CGMP Proposal. The comments assert that the responsibility 
for raw material and finished product testing should lie solely with 
the companies that handle the raw materials and dietary ingredients and 
that perform manufacturing duties. According to the comments, assuming 
the supplier/manufacturer complies with the final rule and adequately 
performs the required testing, reasonable cost/benefit analysis would 
dictate that redundant testing not be performed. Therefore, the 
comments assert that those who perform packaging and labeling 
operations should only be required to test those areas of contamination 
that are likely to occur during the shipment, or in the receipt, 
identification, packaging, and holding areas of production operations 
(e.g., surface contamination).
    The comments state it is our duty to ensure that the industry is 
complying with any final rule, not the duty of certain segments of the 
industry to ensure that other segments of the industry are complying. 
Since in-route contamination is unlikely and rare, consumers would 
enjoy little or no benefit from redundant testing at a tremendous cost 
to the industry, particularly small businesses.
    (Response) The term ``specifications'' in proposed Sec.  
111.70(b)(7) included any specifications that you established for 
packaged and labeled dietary supplements under proposed Sec.  
111.35(e). In final Sec.  111.415(g), we identify the specifications as 
those you establish in accordance with final Sec.  111.70(g). In final 
Sec.  111.70(g), we require you to establish specifications for the 
packaging and labeling for the finished packaged and labeled dietary 
supplements. We distinguish these specifications (final Sec.  
111.70(g)) from product specifications you must establish for a 
finished batch that you manufacture (final Sec.  111.70(e)). The 
specifications that you establish and follow ensure that your product 
is what you establish in your master manufacturing record. As discussed 
in sections VI and section XII of this document, a master manufacturing 
record for a firm that only packages and labels the dietary supplement 
would include specifications that are applicable to its operations and 
would not include specifications related to, for example, components.

H. What Requirements Apply to Repackaging and Relabeling? (Final Sec.  
111.420)

1. Final Sec.  111.420(a)
    Final Sec.  111.420(a) provides that you may repackage or relabel 
dietary supplements only after your quality control personnel have 
approved such repackaging or relabeling. Final Sec.  111.420(a) is 
similar to proposed Sec.  111.70(d) with a restructuring of the 
provision for clarity. We did not receive comments specific to proposed 
Sec.  111.70(d).
2. Final Sec.  111.420(b) and (c)
    Final Sec.  111.420(b) requires you to examine a representative 
sample of each batch of repackaged or relabeled dietary supplements to 
determine whether the repackaged or relabeled dietary supplements meet 
all specifications established in accordance with Sec.  111.70(g). 
Final Sec.  111.420(c) requires that quality control personnel approve 
or reject each batch of repackaged or relabeled dietary supplement 
prior to its release for distribution. Final Sec.  111.420(b) and (c) 
derive from proposed Sec.  111.70(e) which would require you to retest 
or re-examine any repackaged or relabeled dietary supplements. Proposed 
Sec.  111.70(e) also would require that any repackaged or relabeled 
dietary supplements meet all specifications and that the quality 
control unit approve or reject their release for distribution.
    (Comment 305) Some comments assert that the proposed requirement 
that directs companies to retest or re-examine any repackaged or 
relabeled dietary supplement unnecessarily restricts the ability of the 
quality control unit to make an appropriate disposition decision. These 
comments assert that testing would not be necessary, for example, when 
a packager repackages a multiple vitamin softgel from a 500-count 
bottle to a 60-count bottle. The comments also assert that it would be 
costly to retest such product, and that such testing would not benefit 
consumer health and safety. The comments would revise proposed Sec.  
111.70(e) to give the quality control unit the authority to make an 
appropriate disposition decision, e.g., to assess the repackaged 
dietary supplement for conformity to specifications.

[[Page 34903]]

    (Response) We agree that there are circumstances, such as those 
described by these comments, when testing would not be necessary. 
However, we disagree that it would not be necessary to ``examine'' a 
representative sample of the repackaged and relabeled dietary 
supplement to determine whether the required specifications are met, 
i.e., that you used the specified packaging and applied the specified 
label. If no examination of a representative sample took place, there 
would be no basis for the determination. We believe that final Sec.  
111.420(b) makes this clear.

I. What Requirements Apply to a Packaged and Labeled Dietary Supplement 
That Is Rejected for Distribution? (Final Sec.  111.425)

    Final Sec.  111.425 requires you to clearly identify, hold, and 
control under a quarantine system for appropriate disposition any 
packaged and labeled dietary supplement that is rejected for 
distribution. Final Sec.  111.425 derives from proposed Sec.  111.74 
which would require you to clearly identify, hold, and control under a 
quarantine system any component, dietary ingredient, dietary 
supplement, packaging, and label that is rejected and unsuitable for 
use in manufacturing, packaging, or label operations. Under the final 
rule, the requirements of proposed Sec.  111.74 for components, 
packaging, and labels are being set forth in final Sec.  111.170, and 
the requirements for a finished batch of dietary supplement are set 
forth in final Sec.  111.370. Although the proposal did not include any 
packaged and labeled dietary supplement rejected for distribution, we 
are making this change to be consistent with the principle that 
rejected components, dietary supplements, packaging, or labels 
unsuitable for the distribution supply include finished product already 
packaged and labeled.

J. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.430)

1. Final Sec.  111.430(a)
    Final Sec.  111.430(a) requires you to make and keep records 
required under this subpart in accordance with subpart P. Final Sec.  
111.430(a) derives from proposed Sec.  111.70(h) with revisions 
associated with the reorganization. We did not receive comments 
specific to proposed Sec.  111.70(h).
2. Final Sec.  111.430(b)
    As discussed in this section, final Sec.  111.403 requires you to 
establish and follow written procedures for packaging and labeling 
operations. The written procedures are records. Therefore, final Sec.  
111.430(b) requires you to make and keep records of the written 
procedures for packaging and labeling operations.

XVIII. Comments on Holding and Distributing (Final Subpart M)

A. Organization of Final Subpart M

    In the 2003 CGMP Proposal, the requirements for holding operations 
were set forth in Sec. Sec.  111.80, 111.82, and 111.83 in subpart F; 
the requirements for distribution operations were set forth in proposed 
Sec.  111.90 in subpart F. As shown in table 14 of this document, the 
final rule moves the requirements related to holding and distributing 
operations to a new subpart (final Subpart M--Holding and 
Distributing). Table 14 lists the sections in the final rule and 
identifies the sections that form the basis of the final rule.

          Table 14.--Derivation of Sections in Final Subpart M
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.453 What are the requirements   N/A
 under this subpart M for written
 procedures?
------------------------------------------------------------------------
Sec.   111.455 What requirements apply to  Sec.   111.80
 holding components, dietary supplements,
 packaging, and labels?
------------------------------------------------------------------------
Sec.   111.460 What requirements apply to  Sec.   111.82
 holding in-process material?
------------------------------------------------------------------------
Sec.   111.465 What requirements apply to  Sec.   111.83(b)(1) and
 holding reserve samples of dietary         (b)(2)
 supplements?
------------------------------------------------------------------------
Sec.   111.470 What requirements apply to  Sec.   111.90
 distributing dietary supplements?
------------------------------------------------------------------------
Sec.   111.475 Under this subpart M, what  N/A
 records must you make and keep?
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Holding and 
Distributing

1. Revisions
    The final rule includes changes that reflect that the scope of the 
final rule applies to persons who manufacture, package, label, or hold 
dietary supplements, unless subject to an exclusion in Sec.  111.1.
2. Changes Associated With the Reorganization
    Final Sec.  111.465 in subpart M duplicates the requirement of 
final Sec.  111.83(b)(3) to retain reserve samples of dietary 
supplements for 1 year past the shelf life date (if shelf life dating 
is used) or for 2 years from the date of distribution of the last batch 
of dietary supplements associated with the reserve samples. We are 
duplicating this requirement in this subpart because we believe that it 
will be useful to include the length of time that you must hold reserve 
samples in each place of the codified where it is logical to look for 
this information.
3. Changes After Considering Comments
    The final rule:
    <bullet> Does not require that you collect reserve samples of 
components;
    <bullet> Provides flexibility as to the container-closure system 
used to hold reserve samples of dietary supplements;
    <bullet> Includes a new requirement for written procedures; and
    <bullet> Includes a new requirement to make and keep records of 
product distribution and written procedures.

C. General Comments on Proposed Sec. Sec.  111.80, 111.82, 111.83, and 
111.85

    (Comment 306) One comment requests that factory sealed finished 
products, which have been specifically manufactured to be held and 
transported in a variety of conditions, be excluded from the 
requirements for holding. Another comment states that there are many 
types of companies or individuals in the supply chain who may ``hold'' 
a dietary supplement after final production, packaging, and labeling is 
complete. This comment seeks clarification that brokers, distributors, 
or wholesalers would be subject only to the proposed requirements for 
holding in proposed Sec.  111.90.
    (Response) If you hold a dietary supplement, you are subject to all 
applicable requirements of these CGMP regulations related to your 
operation. For example, if you are a wholesaler, you would be subject 
to the requirements in final Sec.  111.470 for the dietary supplements 
you are holding for distribution as well as other applicable 
requirements, such as those related to personnel, physical plant and 
grounds, equipment and utensils, quality control, returned dietary 
supplements, and product complaints. We decline to list all of the 
requirements that would be applicable because individual operations may 
vary. However, we provide the following examples of

[[Page 34904]]

requirements that would, or would not, apply in some specific 
circumstances. For example, if the dietary supplements that you hold 
require refrigeration, your refrigeration equipment must comply with 
the requirements to be fitted with an indicating thermometer, 
temperature-measuring device, or temperature-recording device that 
shows the temperature accurately within the compartment, and have an 
automated device for regulating temperature or an automatic alarm 
system to indicate a significant temperature change in a manual 
operation. However, you would not be required to establish 
specifications for the finished batch of the dietary supplement, for 
product that is received for packaging or labeling, or for packaged and 
labeled dietary supplements or to determine whether such specifications 
are met if you only hold the product and do not perform any other 
functions.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.453)

    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section.
    We are including a new provision, Sec.  111.453 ``What are the 
requirements under this subpart M for written procedures?'' which 
requires you to establish and follow written procedures for holding and 
distribution operations.

E. What Requirements Apply to Holding Components, Dietary Supplements, 
Packaging, and Labels? (Final Sec.  111.455)

1. Final Sec.  111.455(a)
    Final Sec.  111.455(a) requires you to hold components and dietary 
supplements under appropriate conditions of temperature, humidity, and 
light so that the identity, purity, strength, and composition of the 
components and dietary supplements are not affected. Final Sec.  
111.455(a) derives from proposed Sec.  111.80(a) which would require 
that you hold components, dietary ingredients, and dietary supplements 
under appropriate conditions of temperature, humidity, and light so 
that the identity, purity, quality, strength, and composition of the 
components, dietary ingredients, and dietary supplements are not 
affected.
    We did not receive comments specific to proposed Sec.  111.80(a).
2. Final Sec.  111.455(b)
    Final Sec.  111.455(b) requires you to hold packaging and labels 
under appropriate conditions so that the packaging and labels are not 
adversely affected. Final Sec.  111.455(b) derives from proposed Sec.  
111.80(b) with modifications for consistency with other provisions 
addressing packaging and labels.
    We did not receive comments specific to proposed Sec.  111.80(b).
3. Final Sec.  111.455(c)
    Final Sec.  111.455(c) requires you to hold components, dietary 
supplements, packaging, and labels under conditions that do not lead to 
the mixup, contamination, or deterioration of components, dietary 
supplements, packaging, and labels. Final Sec.  111.455(c) derives from 
proposed Sec.  111.80(c).
    We did not receive comments specific to proposed Sec.  111.80(c).

F. What Requirements Apply to Holding In-Process Material? (Final Sec.  
111.460)

1. Final Sec.  111.460(a)
    Final Sec.  111.460(a) requires you to identify and hold in-process 
material under conditions that protect against mixups, contamination, 
and deterioration. Final Sec.  111.460(a) is similar to proposed Sec.  
111.82(a) with a grammatical change (i.e., a change from ``that will 
protect them'' to ``that protect'').
    We did not receive comments specific to proposed Sec.  111.82(a).
2. Final Sec.  111.460(b)
    Final Sec.  111.460(b) requires you to hold in-process material 
under appropriate conditions of temperature, humidity, and light. Final 
Sec.  111.460(b) is identical to proposed Sec.  111.82(b).
    (Comment 307) One comment asserts it would be impractical, 
unnecessary, and extremely burdensome to maintain reserve samples of 
in-process materials. The comment asserts that collecting and holding 
samples of in-process materials would duplicate the requirement to 
collect and hold reserve samples of finished dietary supplements and 
require significant additional documentation, time, and storage space.
    (Response) This comment may have misinterpreted proposed Sec.  
111.37(b)(11) (final Sec. 111.80(g)) which included requirements for 
collecting representative, rather than reserve, samples of in-process 
materials. The representative sample is used for those tests or 
examinations conducted to determine whether the batch meets 
specifications. A representative sample is held for only a short period 
of time, i.e., the time between the collection and the test or 
examination. Neither the 2003 CGMP Proposal nor this final rule 
includes a requirement to maintain a reserve sample of in-process 
materials.

G. Proposed Requirement for Holding Reserve Samples of Components 
(Proposed Sec.  111.83(a))

    Proposed Sec.  111.83(a) would require you to hold any collected 
reserve samples of components or dietary ingredients in a manner that 
protects against contamination and deterioration.
    (Comment 308) One comment requests the final rule not require that 
manufacturers of dietary supplements collect and hold reserve samples 
of components. The comment asserts that all components can be traced 
back to their source (i.e., the vendor or manufacturer of the material) 
for a more in-depth investigation if a dietary supplement comes under 
investigation due to a product complaint.
    (Response) We agree with this comment. Therefore, the final rule 
contains no requirement for holding reserve samples of components, only 
finished dietary supplements, and, thus, proposed Sec.  111.83(a) has 
no counterpart in the final rule.

H. What Requirements Apply to Holding Reserve Samples of Dietary 
Supplements? (Final Sec.  111.465)

1. Final Sec.  111.465(a)
    Final Sec.  111.465(a) requires you to hold reserve samples of 
dietary supplements in a manner that protects against contamination and 
deterioration. Under final Sec.  111.465(a)(1) this includes holding 
the reserve sample under conditions consistent with product labels or, 
if no storage conditions are recommended on the label, under ordinary 
storage conditions. Final Sec.  111.465(a)(1) derives from proposed 
Sec.  111.83(b)(1) which would require you to hold reserve samples 
under conditions of use recommended or suggested in the label of the 
dietary supplement and, if no conditions of use are recommended or 
suggested in the label, then under ordinary conditions of use.
    Final Sec.  111.465(a)(1) refers to ``conditions consistent with 
product labels'' rather than to ``conditions of use recommended or 
suggested in the label of the dietary supplement'' and refers to 
``storage conditions'' rather than ``conditions of use.'' This change 
is to reflect that the ``conditions of use'' referenced in the 2003 
CGMP Proposal referred to the typical storage of the dietary supplement 
and not the consumption of the product by the consumer.
    We did not receive comments specific to proposed Sec.  
111.83(b)(1).
    Under final Sec.  111.465(a)(2) the manner in which you hold 
reserve samples of dietary supplements

[[Page 34905]]

includes using the same container-closure system in which the packaged 
and labeled dietary supplement is distributed, or if distributing 
dietary supplements to be packaged and labeled, using a container-
closure system that provides essentially the same characteristics to 
protect against contamination or deterioration as the one in which you 
distribute the dietary supplement for packaging and labeling elsewhere. 
Final Sec.  111.465(a)(2) derives from proposed Sec.  111.83(b)(2) 
which would require that the manner in which you hold reserve samples 
of dietary supplements include using the same container-closure system 
in which the dietary supplement is marketed or in one that provides the 
same level of protection against contamination or deterioration.
    (Comment 309) One comment states a substantial amount of its 
product is shipped in bulk for packaging elsewhere. As a result, one 
often does not know the packaging being used to market the dietary 
supplement or how the packaged product is being stored. This comment 
recommends we revise the proposed regulation to require using the same 
container-closure system in which the dietary supplement is marketed 
``if known and if not in a typical market container-closure system.''
    (Response) We acknowledge that some manufacturers of dietary 
supplements will distribute product in bulk and will not know the 
packaging used to market the dietary supplement. In addition, if you 
ship products in bulk, any commitment you make to your customer about 
the quality of the product you shipped would relate to the container 
you used to ship the bulk product. To address these points we provide 
in final Sec.  111.465(a)(2) that you have the flexibility to use a 
container-closure system that provides essentially the same 
characteristics to protect against contamination or deterioration as 
the one in which it is distributed for packaging and labeling 
elsewhere. For example, if you distribute product in bulk using a 
polyethylene bottle that can hold 50 kilograms of the product, and 
there is an air space above the product, you would hold the reserve 
samples in a polyethylene bottle with an air space. However, you would 
use a bottle that is sized to fit the amount that you are holding in 
reserve.
2. Final Sec.  111.465(b)
    Final Sec.  111.465(b) requires you to retain reserve samples for 1 
year past the shelf life date (if shelf life dating is used), or for 2 
years from the date of distribution of the last batch of dietary 
supplements associated with the reserve samples, for use in appropriate 
investigations. Final Sec.  111.465(b) derives from proposed Sec.  
111.37(b)(12), which proposed, in part, that you must keep reserve 
samples for 3 years from the date of manufacture. Proposed Sec.  
111.37(b)(12) is now final Sec.  111.83(b)(3) with a change to 2 years 
for the retention period and with changes that we are making consistent 
with comments that requested that the time frame for retaining reserve 
samples be linked to a shelf life date (or other form of expiration 
dating) when such a date is established. We discuss the reasons for the 
change from 3 years to 2 years and the change from ``date of 
manufacture'' to ``the date of distribution'' in section XXI of this 
document. In essence, final Sec.  111.465(b) duplicates final Sec.  
111.83(b)(3) because we believe it will be useful to include the length 
of time you must hold reserve samples in each place in the codified 
where it is logical to look for this information.

I. What Requirements Apply to Distributing Dietary Supplements? (Final 
Sec.  111.470)

    Final Sec.  111.470 requires you to distribute dietary supplements 
under conditions that will protect the dietary supplements against 
contamination and deterioration. Final Sec.  111.470 derives from 
proposed Sec.  111.90.
    We did not receive comments specific to proposed Sec.  111.90.

J. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.475)

    In the 2003 CGMP Proposal, we invited comment on whether we should 
require you to make and keep records on the distribution of dietary 
supplements that you manufacture, package, or hold.
    (Comment 310) Some comments assert that written records of product 
distribution would provide the ability to trace the shipment of each 
finished batch in the event of a product recall. One comment expresses 
the view that the ability to quickly and efficiently recall a product 
is an important safeguard in ensuring public health in the event of a 
serious problem. Another comment points out that the scope of recall 
would likely be much broader if records of product distribution were 
not available to pinpoint distribution.
    (Response) We agree with these comments. Therefore, final Sec.  
111.475 requires you to make and keep records of product distribution 
in accordance with subpart P. In addition, we are adding a provision to 
complement final Sec.  111.453 to ensure that records are maintained of 
the written procedures you establish for holding and distributing 
operations. As discussed, comments stressed that such procedures must 
be available to us during the course of an inspection.
    (Comment 311) One comment asserts that the final rule should not 
include a requirement for records of product distribution, because such 
records are already common industry practice. This comment also points 
out that neither the food CGMPs in part 110 nor the agency's 1997 ANPRM 
have requirements for records of product distribution.
    (Response) To the extent that the comment asserts that a practice 
that is a common industry practice should not be a requirement in the 
final rule, we disagree. CGMP includes those practices that may be 
commonly used in industry. In fact, the reason that such practices may 
be common in industry is because they are already considered to be 
CGMP. As we noted in the preamble to the 2003 CGMP Proposal (68 FR 
12157 at 12221), however, not all dietary supplement establishments 
follow CGMP and, therefore, may not be keeping records of product 
distribution. Thus, in this final rule we do not exclude practices we 
consider to be CGMP and already may be used by some in industry.
    The industry outline we published in the 1997 ANPR suggested (under 
Warehousing, Distribution, and Post-Distribution Procedures) that the 
CGMP rule require adequate distribution records to be maintained and 
retained for at least 1 year beyond the expected product shelf life, 
whereby an effective product recall can be achieved should one become 
necessary. Therefore, we disagree that the 1997 ANPRM did not suggest a 
requirement to make and retain records of product distribution.

XIX. Comments on Returned Dietary Supplements (Final Subpart N)

A. Organization of Final Subpart N

    In the 2003 CGMP Proposal, the requirements for returned dietary 
supplements were set forth in proposed Sec.  111.85. As shown in table 
15 of this document, we are reorganizing proposed Sec.  111.85 into a 
distinct subpart (final Subpart N--Returned Dietary Supplements). Table 
15 lists the sections in final subpart N and identifies the proposed 
sections that form the basis of the final rule.

[[Page 34906]]



          Table 15.--Derivation of Sections in Final Subpart N
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.503 What are the requirements   N/A
 under this subpart N for written
 procedures?
------------------------------------------------------------------------
Sec.   111.510 What requirements apply     Sec.   111.85(a)
 when a returned dietary supplement is
 received?
------------------------------------------------------------------------
Sec.   111.515 When must a returned        Sec.   111.85(b) and (c)
 dietary supplement be destroyed, or
 otherwise suitably disposed of?
------------------------------------------------------------------------
Sec.   111.520 When may a returned         Sec.   111.37(b)(15)
 dietary supplement be salvaged?
------------------------------------------------------------------------
Sec.   111.525 What requirements apply to  Sec.   111.50(g)
 a returned dietary supplement that
 quality control personnel approve for
 reprocessing?
------------------------------------------------------------------------
Sec.   111.530 When must an investigation  Sec.   111.85(d)
 be conducted of your manufacturing
 processes and other batches?
------------------------------------------------------------------------
Sec.   111.535 Under this subpart N, what  Sec.   111.50(g)
 records must you make and keep?           Sec.   111.85(e) and (f)
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Returned 
Dietary Supplements

1. Revisions
    The final rule includes:
    <bullet> Revisions that reflect that the final rule applies to 
persons who manufacture, package, label, or hold dietary supplements 
unless subject to an exclusion in Sec.  111.1.
    <bullet> A provision (final Sec.  111.520) that we are adding for 
consistency, so that the final rule for returned dietary supplements 
clearly sets forth the requirements for a positive outcome (i.e., when 
you may salvage a returned dietary supplement) as well as a negative 
outcome (i.e., when you must destroy or otherwise suitably dispose of a 
returned dietary supplement); and
    <bullet> A provision (final Sec.  111.525) we are adding for 
consistency, so that the final rule for returned dietary supplements 
clearly sets forth the requirements for reprocessed materials.
2. Changes After Considering Comments
    The final rule:
    <bullet> Includes a new requirement to establish and follow written 
procedures to fulfill the requirements for returned dietary 
supplements;
    <bullet> Includes a revised description of the conditions that 
preclude you from salvaging a returned dietary supplement; and
    <bullet> Provides flexibility for firms to salvage a returned 
dietary supplement without conducting tests to demonstrate that the 
dietary supplement meets all specifications, provided that quality 
control personnel conduct a material review and make a disposition 
decision to approve the salvage.

C. General Comments on Proposed Sec.  111.85

    (Comment 312) Several comments request we clarify the roles of the 
various parties in the ``pre-consumer supply chain'' for dietary 
supplements.
    (Response) We have discussed, in section VI of this document, who 
is subject to the final rule in what the comment describes as the 
``pre-consumer supply chain'' and do not repeat that discussion here. 
The requirements for returned dietary supplements do not distinguish 
between those returned to a person who manufactures a finished batch 
and those returned to a person whose role in the manufacturing process 
is limited to operations such as packaging, labeling, or holding.
    Any reprocessing operations, other than repackaging or relabeling, 
by a packager or labeler who receives a product for packaging or 
labeling as a dietary supplement would make that packager or labeler 
subject to all relevant regulatory requirements under this final rule, 
as explained in section VI of this document. A packager or labeler that 
only conducts repackaging or relabeling operations may conclude that a 
product was returned for reasons related to a problem with the 
manufacture of the product it received for packaging or labeling, and 
therefore cannot be salvaged. In such a case, under final Sec.  111.515 
the packager or labeler would have to destroy or otherwise suitably 
dispose of the dietary supplement. Under final Sec.  111.515, the 
packager or labeler may contact the manufacturer to determine if the 
packager or labeler could suitably dispose of the dietary supplement by 
sending it back to the manufacturer for possible reprocessing (see 
discussion of final Sec.  111.515 in this section). A manufacturer who 
receives a dietary supplement returned by a packager or labeler would 
be required to comply with the requirements of final subpart N for 
returned dietary supplements, including requirements for any 
reprocessing of the returned dietary supplements.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.503)

    We received many comments that recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section.
    Final Sec.  111.503 requires you to establish and follow written 
procedures to fulfill the requirements of subpart N. Under final Sec.  
111.535(b)(1) we are requiring you to make and keep records of such 
written procedures. Such records would be available to us under the 
requirements in subpart P.

E. What Requirements Apply When a Returned Dietary Supplement is 
Received? (Final Sec.  111.510)

    Final Sec.  111.510 requires you to identify and quarantine 
returned dietary supplements until quality control personnel conduct a 
material review and make a disposition decision. Final Sec.  111.510 is 
similar to proposed Sec.  111.85(a).
    We did not receive comments specific to proposed Sec.  111.85(a).

F. When Must a Returned Dietary Supplement Be Destroyed, or Otherwise 
Suitably Disposed Of? (Final Sec.  111.515)

    Final Sec.  111.515(a) requires that you destroy, or otherwise 
suitably dispose of, any returned dietary supplement, unless the 
outcome of a material review and disposition decision is that quality 
control personnel either: (1) Approve the salvage of the returned 
dietary supplement for redistribution or (2) approve the returned 
dietary supplement for reprocessing. Final Sec.  111.515(a) derives 
from the following proposed sections:
    <bullet> Proposed Sec.  111.85(b) which would require that you not 
salvage returned dietary supplements unless: (1) Evidence from their 
packaging (or, if possible, an inspection of the premises where the 
dietary ingredients and dietary supplements were held) indicates that 
the dietary ingredients and dietary supplements were not subjected to 
improper storage conditions and (2) tests demonstrate that the dietary 
ingredients or dietary supplements meet all specifications for 
identity, purity, quality, strength, and composition; and
    <bullet> Proposed Sec.  111.85(c) which would require that you 
destroy or suitably dispose of the returned dietary

[[Page 34907]]

ingredients or dietary supplements if such dietary ingredients and 
dietary supplements do not meet specifications, unless the quality 
control unit conducts a material review and makes a disposition 
decision to allow reprocessing.
    Final Sec.  111.515(a) includes editorial changes and other changes 
made after considering comments.
    (Comment 313) Several comments assert it is unnecessary to conduct 
testing for all specifications for every returned product because 
products may be returned for reasons unrelated to product quality. For 
example, products may be returned due to overstocking, ordering the 
wrong quantity, going out of business, or failing to pay for the 
product on time. In addition, several comments assert that many 
returned products are intact, show no signs of mishandling, and are 
within the time limits for shelf life. These comments assert that a 
material review and disposition decision by the quality control unit to 
restock the material without retesting may be acceptable in these types 
of situations. Some comments assert that proposed Sec.  111.85(b) is 
more restrictive than CGMP requirements for drug products, and suggest 
that testing need be conducted only when some doubt has been cast upon 
the identity, purity, quality, strength, or composition of the product, 
or if the product was returned for some other GMP-related problem.
    Some comments contend that proposed Sec. Sec.  111.35(i)(3)(v) and 
111.85 would make it difficult to salvage any returned product because 
companies receiving returns often cannot verify the conditions under 
which such products were held. One comment refers to a stakeholder 
meeting when we indicated that the extent of testing requirements would 
depend upon the reason such products were returned. The comments state 
that the rule should allow flexibility as to when returned products 
must be tested.
    Some comments specifically suggest the approach used in the USP 
(revised in 2nd supplement USP 26). These comments suggest that 
proposed Sec.  111.85(b) be revised as follows: ``If the conditions 
under which returned products have been held, stored, or shipped before 
or during their return, or if the condition of the product, its 
container, carton or labeling, as a result of storage or shipping, cast 
doubt on the safety, identity, strength, quality, or purity of the 
product, the returned product should be destroyed unless examination, 
testing or other investigations prove the product meets appropriate 
standards of safety, identity, strength, quality, or purity.''
    These comments assert that inspection of the condition of the 
returned product could be used to determine that a product can be 
returned to inventory, and this inspection could be covered by internal 
procedures and based on experience in testing product stored under 
conditions that include extremes in heat and humidity without affecting 
the container or closure system.
    (Response) As already discussed in this section, the final rule 
includes a new requirement that you establish and follow written 
procedures for handling returned dietary supplements. The final rule 
also retains the requirement that quality control personnel (formerly 
``unit'' in the proposed rule) conduct a material review and make a 
disposition decision regarding all returned dietary supplements (see 
discussion of final Sec.  111.113(a)(5) in section XI of this 
document). We agree with the comments that it is not necessary to 
conduct testing for all specifications for every returned product, 
because products may be returned for reasons unrelated to the quality 
of the dietary supplement. Final Sec.  111.130 provides for quality 
control personnel to determine whether tests or examinations are 
necessary for returned dietary supplements to determine compliance with 
product specifications. Therefore, final Sec.  111.515 does not include 
a testing requirement. We believe the combination of written procedures 
and oversight by quality control personnel is adequate to determine the 
appropriate disposition of a returned dietary supplement, without 
requiring a test in every case to demonstrate that the dietary 
supplement meets specifications for identity, purity, strength, and 
composition.
    In final Sec.  111.515(a) we generally accept the comments' 
suggestions and reflect the approach of the USP for returned products. 
Thus, you must destroy or otherwise suitably dispose of the returned 
dietary supplement, unless the outcome of the material review and 
disposition decision is that quality control personnel approve the 
salvage of the returned dietary supplement for redistribution or 
approve the reprocessing of the returned dietary supplement. We provide 
flexibility on how quality control personnel may conduct a material 
review and make a disposition decision and do not require testing in 
every case. We respond in section V of this document to the comment 
asserting that the proposed CGMPs exceed the drug CGMPs.

G. When May a Returned Dietary Supplement Be Salvaged? (Final Sec.  
111.520)

    Final Sec.  111.520 permits the salvage of a returned dietary 
supplement only if quality control personnel conduct a material review 
and make a disposition decision to allow the salvage. Final Sec.  
111.520 is a conforming provision we are adding for consistency, so 
that the final requirement for returned dietary supplements clearly 
sets forth a positive outcome (i.e., when you may salvage a returned 
dietary supplement) as well as a negative outcome (i.e., when you must 
destroy or otherwise suitably dispose of a returned dietary 
supplement). Final Sec.  111.520 is consistent with final Sec.  111.130 
(proposed Sec.  111.37(b)(15)) which requires quality control personnel 
to approve the distribution of returned dietary supplements.

H. What Requirements Apply to a Returned Dietary Supplement That 
Quality Control Personnel Approve for Reprocessing? (Final Sec.  
111.525)

    Final Sec.  111.525(a) requires you to ensure that any returned 
dietary supplements that are reprocessed meet all product 
specifications established in accordance with final Sec.  111.70(e). 
Final Sec.  111.525(b) requires quality control personnel to approve or 
reject the release for distribution of any returned dietary supplement 
that is reprocessed. As with final Sec.  111.520, final Sec.  111.525 
is a provision we are adding for consistency. Final Sec.  111.525 is 
consistent with final Sec.  111.90(c).

I. When Must an Investigation Be Conducted of Your Manufacturing 
Processes and Other Batches? (Final Sec.  111.530)

    Final Sec.  111.530 requires that, if the reason for a dietary 
supplement being returned implicates other batches, you must conduct an 
investigation of your manufacturing processes and each of those other 
batches to determine compliance with specifications. Final Sec.  
111.530 derives from proposed Sec.  111.85(d) which would require that 
if the reason for a dietary supplement being returned implicates 
associated batches, you must conduct an investigation of your 
manufacturing processes and those other batches to determine compliance 
with specifications. Final Sec.  111.530 includes a nonsubstantive 
editorial change of ``associated'' to ``each of those other batches'' 
for clarity.
    We did not receive comments specific to proposed Sec.  111.85(d).

[[Page 34908]]

J. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.535)

    Final Sec.  111.535 sets forth the requirements to make and keep 
records for returned dietary supplements. Final Sec.  111.180 derives 
from proposed Sec.  111.85(e) and (f).
    We did not receive comments specific to proposed Sec.  111.85(e) or 
(f).
1. Final Sec.  111.535(a)
    Final Sec.  111.535(a) requires you to make and keep records 
required under subpart N in accordance with subpart P. Final Sec.  
111.535(a) derives from proposed Sec. 111.85(f) and includes changes 
associated with the reorganization.
2. Final Sec.  111.535(b)(1)
    As discussed in this section, the final rule includes a new 
requirement (final Sec.  111.503) that you establish and follow written 
procedures to fulfill the requirements of subpart N. Those written 
procedures are records. Therefore, final Sec.  111.535(b)(1) requires 
you to make and keep a record of the written procedures for fulfilling 
the requirements of subpart N.
3. Final Sec.  111.535(b)(2)
    Final Sec.  111.535(b)(2) requires you to make and keep a record of 
any material review and disposition decision on a returned dietary 
supplement. Final Sec.  111.535(b) derives from proposed Sec.  
111.85(e), with revisions associated with the reorganization.
4. Final Sec.  111.535(b)(3)
    Final Sec.  111.535(b)(3) requires you to make and keep a record of 
the results of any testing or examination conducted to determine 
compliance with product specifications established under Sec.  
111.70(e). Final Sec.  111.535(b) derives from proposed Sec.  111.85(e) 
which would require you to establish and keep records on any testing 
conducted to determine compliance with established specifications in 
the master manufacturing record for the type of dietary supplement that 
was returned. Final Sec.  111.535(b)(3) includes the following 
revisions:
    <bullet> Consistent with final Sec.  111.70(e), final Sec.  
111.535(b)(3) substitutes ``product specifications established under 
Sec.  111.70(e)'' for ``established specifications in the master 
manufacturing record for the type of dietary ingredient or dietary 
supplement that was returned.''
    <bullet> Consistent with final Sec.  111.75(c), final Sec.  
111.535(b)(3) provides flexibility to use either tests or examinations 
to determine whether specifications are met.
5. Final Sec.  111.535(b)(4)
    Final Sec.  111.535(b)(4) requires you to make and keep a record of 
documentation of the re-evaluation by quality control personnel of any 
dietary supplement that is reprocessed and the determination by quality 
control personnel of whether the reprocessed dietary supplement meets 
product specifications established in accordance with Sec.  111.70(e). 
Final Sec.  111.535(b)(4) is related to final Sec.  111.525. Under 
final Sec.  111.525, you must ensure that any returned dietary 
supplements that are reprocessed meet all product specifications you 
established under Sec.  111.70(e) and quality control personnel must 
approve or reject the release for distribution of any returned dietary 
supplement that is reprocessed.

XX. Comments on Product Complaints (Final Subpart O)

A. Organization of Final Subpart O

    In the 2003 CGMP Proposal, the requirements for consumer complaints 
were set forth in Sec.  111.95. As shown in table 16 of this document, 
we are reorganizing proposed Sec.  111.95 into three provisions in a 
new subpart (final Subpart O--Product Complaints). Table 16 lists the 
sections in final subpart O and identifies the provisions that form the 
basis for the final rule.

          Table 16.--Derivation of Sections in Final Subpart O
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.553 What are the requirements   N/A
 under this subpart O for written
 procedures?
------------------------------------------------------------------------
Sec.   111.560 What requirements apply to  Sec.   111.95(a), (b), (c),
 the review and investigation of a          and (d)
 product complaint?
------------------------------------------------------------------------
Sec.   111.570 Under this subpart O, what  Sec.   111.95(e) and (f)
 records must you make and keep?
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Product 
Complaints

1. Revisions
    The final rule:
    <bullet> Includes changes that reflect the final rule applies to 
persons who manufacture, package, label, or hold dietary supplements 
unless subject to an exclusion in Sec.  111.1.
    <bullet> Uses the term ``product complaint'' rather than ``consumer 
complaint,'' and the definition of ``product complaint'' does not 
include an explanation about the types of complaints that may or may 
not be covered by the CGMP regulations. The definition does, however, 
include examples of product complaints.
2. Changes After Considering Comments
    The final rule modifies the process for handling product complaints 
as follows:
    <bullet> A qualified person investigates any product complaint that 
involves a possible failure of a dietary supplement to meet any 
requirements of part 111, without an intermediate step of having 
quality control personnel first determine whether the complaint should 
be investigated;
    <bullet> Quality control personnel review and approve all decisions 
made by a qualified person about whether to investigate a product 
complaint and the findings and followup action of any investigation 
performed rather than conduct the investigation and followup; and
    <bullet> The review and investigation of the product complaint 
extends to all relevant batches and records, without identifying 
specific records, and specific batches, that must be included in the 
review and investigation.

C. General Comments on Proposed Sec.  111.95 (Final Subpart O)

    (Comment 314) Some comments express general support for the 
proposed procedures for consumer complaints. Other comments request 
proposed Sec.  111.95 be deleted. Most of these comments point out that 
we had announced the development of CFSAN's Adverse Event Reporting 
System (CAERS) for reporting to FDA adverse events attributed to food 
products and suggest that this new system would be the appropriate 
mechanism for handling complaints about dietary supplements.
    (Response) We disagree with these comments. Because the problem 
giving rise to the complaint may be associated with a failure in 
manufacturing, packaging, labeling, or holding, it is CGMP for a firm 
that receives a product complaint to review it and investigate, if 
necessary, regardless of whether we are notified about the complaint. 
An important goal of the firm's review and investigation is to 
determine whether there is a problem with the production and process 
control system for the manufacture, packaging, labeling, or holding of 
the dietary supplement. That

[[Page 34909]]

goal would not be achieved merely by notifying us. A firm subject to 
any of the requirements of this final rule, whether such firm is a 
manufacturer, packager, labeler, or holder, is responsible for the 
requirements in subpart O for a product complaint it receives.
    (Comment 315) Some comments assert that the proposed requirements 
for consumer complaints do not go far enough and urge that any final 
rule require any complaints that involve an adverse event be referred 
to us. The comments stress accurate reporting of adverse events is 
essential to long term evaluations of a product's safety.
    (Response) Mandatory reporting requirements to us regarding adverse 
events related to dietary supplements are outside the scope of this 
rulemaking. This final rule addresses the internal processes and 
controls that persons who manufacture, package, label, or hold dietary 
supplements must follow. Mandatory reporting to FDA of serious adverse 
events, however, is now required as a result of the enactment of the 
``Dietary Supplement and Non-Prescription Drug Consumer Protection 
Act'' (Public Law 109-462) signed into law on December 22, 2006. The 
new law requires manufacturers, packers, or distributors of such 
products to submit reports to FDA about serious adverse events 
involving such products based on specific information that they receive 
from the public. Serious adverse events are defined in the law as those 
events that result in death, a life-threatening situation, an inpatient 
hospitalization, a persistent or significant disability or incapacity, 
or a congenital anomaly or birth defect or one that requires medical or 
surgical intervention to prevent such serious outcomes (based on 
reasonable medical judgment).
    As discussed in the preamble to the 2003 CGMP Proposal (68 FR 12157 
at 12217), however, we continue to strongly recommend that firms that 
receive product complaints, that are not ``serious adverse events,'' 
notify us about any illness or injury, because, for example, we may 
have additional expertise or data that may be helpful in investigating 
the complaint or determining whether the problem applies to more than 
one product. In light of the requirement in the final rule to establish 
and follow written procedures for handling product complaints, we 
encourage you to include our recommendations in the written procedures 
that you develop for handling product complaints (see discussion of 
final Sec.  111.553 in this section).
    (Comment 316) Some comments raise questions about who would be 
subject to the proposed requirements regarding consumer complaints. 
Some comments state the section should apply only to manufacturers of 
dietary supplements, not to manufacturers of dietary ingredients. Other 
comments are concerned that distributors who merely put their label on 
the finished product may be held responsible for keeping records of 
adverse events caused by failures to follow CGMPs during the 
manufacture of the supplements.
    (Response) The final rule only applies to persons who manufacture, 
package, label, or hold a dietary supplement. We discuss the scope of 
this final rule in detail in section VI of this document.
    In most cases, the person who receives a product complaint from a 
consumer will be the manufacturer, packager, or distributor of the 
dietary supplement. A distributor (also a ``holder'' under this final 
rule) who receives a product complaint must review and investigate that 
complaint to determine whether the complaint relates to a failure of 
the processes under the control of the distributor, such as conditions 
of temperature, humidity, and light that could affect the identity, 
purity, strength, or composition of the dietary supplement. If the 
distributor concludes the problem is unrelated to any process under the 
control of the distributor, the distributor should contact the 
manufacturer. Under the final rule, any person in the manufacturing 
chain who receives a product complaint--regardless of the source--must 
comply with the requirements in this subpart O.
    (Comment 317) One comment suggests proposed Sec.  111.95, which 
describes requirements for consumer complaints, could be combined with 
proposed Sec.  111.85 which describes requirements for returned dietary 
supplements.
    (Response) We decline to adopt this suggestion. In this final rule, 
we are incorporating the requirements for returned dietary supplements 
into a distinct subpart (final subpart N) that sets forth requirements 
for returned dietary supplements. The procedures described in final 
subpart O, which relate solely to the handling of product complaints 
rather than returned dietary supplement products, are quite different 
from those described in final subpart N, which addresses the handling, 
review, and possible reprocessing of returned product.
    (Comment 318) Some comments assert the proposed requirements for 
complaints are different from those for food CGMPs.
    (Response) We are making no changes to the requirements after 
considering these comments. We responded in section V of this document 
to similar comments asserting that certain aspects of the proposed 
regulations are different from those for other food CGMP requirements.

D. What Are the Requirements Under This Subpart for Written Procedures? 
(Final Sec.  111.553)

    We received many comments which recommended written procedures for 
various provisions. We address the need for written procedures 
generally in section IV of this document. We also respond to individual 
comments on specific provisions in the same section.
    Final Sec.  111.553 requires that you establish and follow written 
procedures to fulfill the requirements of this subpart O. Under final 
Sec.  111.570(b)(1) we require you to make and keep records of such 
procedures. Such records would be required to be made available to us 
under the requirements in subpart P.
    We encourage you to include in your written procedures the 
recommendation made in the 2003 CGMP Proposal for you to consult with a 
health care provider if you receive complaints that involve serious 
illness or injury. Even if the complaints are not required to be 
submitted to FDA under the newly enacted ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462), we 
encourage your company to notify us about the product complaints. 
Manufacturers and distributors should be aware that this newly enacted 
law, which requires reporting to FDA of ``serious adverse events,'' 
contains new mandatory provisions that require record retention of 
adverse event reports separate from the requirements in this CGMP final 
rule concerning product complaints.

E. What Requirements Apply to the Review and Investigation of a Product 
Complaint? (Final Sec.  111.560)

1. Final Sec.  111.560(a)(1)
    Final Sec.  111.560(a)(1) requires a qualified person to review all 
product complaints to determine whether the product complaint involves 
a possible failure of a dietary supplement to meet any of its 
specifications, or any other requirements of part 111, including those 
specifications and other requirements that, if not met, may result in a 
risk of illness or injury. Final Sec.  111.560(a)(1) derives from 
proposed Sec.  111.95(a).
    We did not receive comments specific to proposed Sec.  111.95(a).

[[Page 34910]]

2. Final Sec.  111.560(a)(2), (b), and (c)
    Final Sec.  111.560(a)(2) requires a qualified person to 
investigate any product complaint that involves a possible failure of a 
dietary supplement to meet any of its specifications, or any other 
requirements of part 111, including those specifications and other 
requirements that, if not met, may result in a risk of illness or 
injury. Final Sec.  111.560(b) requires that quality control personnel 
review and approve decisions by the qualified person about whether or 
not to investigate a product complaint and the findings and followup 
action of any investigation performed. Final Sec.  111.560(c) requires 
that the review and investigation extend to all relevant batches and 
records.
    (Comment 319) Some comments characterize the requirements of 
proposed Sec.  111.95 as a confusing and difficult scheme to review, 
investigate, and resolve customer complaints. These comments state the 
2003 CGMP Proposal would require extensive human resources, 
recordkeeping, and decisionmaking.
    (Response) We disagree that the 2003 CGMP Proposal would require 
extensive human resources, recordkeeping, or decisionmaking. The 
comments provided no rationale for such assertions. The 2003 CGMP 
Proposal sets forth basic steps, i.e., review, evaluation, and 
followup, that one would need to take to appropriately address a 
product complaint. For those product complaints for which there is a 
reasonable possibility of a relationship to an adverse event, the 2003 
CGMP Proposal would require that an investigation be done by the 
quality control unit because we believe such an event would need more 
careful review and followup.
    To address the comments that found proposed Sec.  111.90 confusing, 
we have made the following changes in the final rule to simplify the 
procedures for handling product complaints:
    <bullet> We replaced the proposed procedure in which a qualified 
person determines whether a complaint should be investigated by the 
quality control unit with a procedure in which a qualified person 
investigates any product complaint that involves a possible failure of 
a dietary supplement to meet any requirements of part 111.
    <bullet> We require an oversight function by quality control 
personnel for the review and evaluation of product complaints, but do 
not require that quality control personnel do any investigations. This 
is consistent with other changes that we are making in response to 
comments that requested that the quality control unit focus on 
reviewing tasks performed by others rather than on performing the tasks 
itself.
    <bullet> We refer to ``any product complaint that involves a 
possible failure of a dietary supplement to meet any of its 
specifications, or any other requirements of this part [part 111], 
including those specifications and other requirements that, if not met, 
may result in a risk of illness or injury'' rather than to ``a 
reasonable possibility of a relationship between the quality of a 
dietary supplement and an adverse event.'' This is consistent with 
changes that we are making to the definition of the term ``product 
complaint'' in final Sec.  111.3 (see section VI of this document).
    <bullet> We continue to require that the review and investigation 
of the product complaint extend to all relevant batches and records but 
simplify the language of the requirement by removing the details, i.e., 
that the investigation must include the batch records associated with 
the dietary supplement involved in the consumer complaint and not 
specifying that the investigation must extend to other batches of 
dietary supplement. Rather, we require that the investigation must 
extend to all relevant batches and records.
    The final rule provides firms flexibility on how to use its human 
resources. Nothing in subpart O would preclude a qualified person among 
designated quality control personnel to be designated to actually 
review product complaints and conduct investigations of any product 
complaint. If an individual is so designated and conducts the 
investigation, reviews and approves the findings, and conducts followup 
actions of any investigation performed, final Sec.  111.560(b) would 
not apply.
    (Comment 320) Some comments object to the requirement in proposed 
Sec.  111.95(c) that consumer complaints are to be investigated only 
when there may be a relationship between product quality and an adverse 
event. These comments suggest this provision be extended to any 
possible relationship between dietary supplements and adverse events, 
including those that might be independent of whether the product is 
produced under CGMPs. These comments consider there should be 
consistent procedures for handling product complaints, regardless of 
whether the complaints relate to product quality.
    (Response) The action requested in these comments is outside the 
scope of this rule, which specifically addresses CGMP requirements to 
ensure the quality of the dietary supplement product. However, we 
encourage firms to investigate all product complaints in a consistent 
way, regardless of whether the complaints relate to the quality of the 
dietary supplement.
    (Comment 321) Some comments request clarification of statements 
made or terms used in the preamble to the 2003 CGMP Proposal regarding 
the handling of product complaints. In the preamble discussion of 
proposed Sec.  111.95(c), we stated a consumer complaint about adverse 
effects ``after consuming several dietary supplements'' is worthy of 
quality control unit investigation. One comment asks about the meaning 
of ``several'' and whether this example means that a manufacturer is 
responsible for consumers who take more than the recommended dosage.
    (Response) In our discussion of proposed Sec.  111.95(c) we 
addressed a situation where a consumer had symptoms on more than one 
occasion rather than a situation where a consumer took more than the 
recommended dosage. However, firms must investigate any complaint of 
illness or injury even if a consumer reports that he/she has consumed 
more than the amount recommended on the product label to determine if 
the complaint is related to CGMP.

F. Under This Subpart, What Records Must You Make and Keep? (Final 
Sec.  111.570)

1. Final Sec.  111.570(a)
    Final Sec.  111.570(a) requires you to make and keep the records 
required under subpart O in accordance with subpart P. Final Sec.  
111.570(a) derives from proposed Sec.  111.95(f)(2) with changes 
associated with the reorganization.
    We did not receive comments specific to proposed Sec.  
111.95(f)(2).
2. Final Sec.  111.570(b)(1)
    Final Sec.  111.570(b)(1) requires you to make and keep a record of 
the written procedures for fulfilling the requirements of subpart O. 
Final Sec.  111.553 requires written procedures for fulfilling the 
requirements of subpart O. Those written procedures are considered a 
record under final Sec.  111.570(b)(1).
3. Final Sec.  111.570(b)(2)
    Final Sec.  111.570(b)(2) requires you to make and keep a written 
record of every product complaint that is related to CGMP. Final Sec.  
111.570(b)(2) derives from proposed Sec.  111.95(e) which would require 
that you ``* * * make and keep a written record of every consumer

[[Page 34911]]

complaint that is related to good manufacturing practices. For the 
purposes of the regulations in this part, a consumer complaint about 
product quality may or may not include concerns about a possible hazard 
to health. However, a consumer complaint does not include an adverse 
event, illness, or injury related to the safety of a particular dietary 
ingredient independent of whether the product is produced under good 
manufacturing practices.''
    As a revision for consistency with the definition of ``product 
complaint'' in final Sec.  111.3, final Sec.  111.570(b)(2) does not 
include the two full sentences from proposed Sec.  111.95(e), as quoted 
in the previous paragraph.
4. Final Sec.  111.570(b)(2)(i)
    Final Sec.  111.570(b)(2)(i) requires that the person who performs 
the requirements of subpart O, at the time of performance, document and 
record the performance. Final Sec.  111.570(b)(2)(i) is similar to 
proposed Sec.  111.95(f)(1) with changes associated with the 
reorganization.
5. Final Sec.  111.570(b)(2)(ii)
    Final Sec.  111.570(b)(2)(ii) requires that the written record of 
the product complaint include: (1) The name and description of the 
dietary supplement; (2) the batch, lot, or control number of the 
dietary supplement, if available; (3) the date the complaint was 
received and the name, address, or telephone number of the complainant, 
if available; (4) the nature of the complaint including, if known, how 
the product was used; (5) the reply to the complainant, if any; and (6) 
findings of the investigation and followup action taken when an 
investigation is performed. Final Sec.  111.570(b)(2) is similar to 
proposed Sec.  111.95(e)(1) through (e)(6) and includes a change we are 
making after considering comments to proposed Sec.  111.95(e)(4) 
(discussed in the following paragraphs) which would have required that 
the consumer complaint written record include ``The nature of the 
complaint including how the consumer used the product.'' On our own 
initiative, we also made a change to include the date the complaint was 
received.
    (Comment 322) One comment notes proposed Sec.  111.95(e)(4) would 
require the written record of consumer complaints to include ``how the 
consumer used the product.'' The comment notes this information may not 
always be available and suggests the words ``where known'' should be 
added.
    (Response) We agree that there can be circumstances where the firm 
that receives the product complaint may not know how the product was 
used. For example, a consumer may make a complaint by leaving a 
telephone message before or after business hours and neither describe 
how the product was used, nor leave contact information so that the 
firm could followup with the consumer. To address this comment, we 
provide in the final rule that the written record of the product 
complaint include ``the nature of the complaint including, if known, 
how the product was used.''
    (Comment 323) Some comments request clarification of statements 
made or terms used in the preamble to the 2003 CGMP Proposal regarding 
the handling of product complaints. In our discussion of proposed Sec.  
111.95(e) we recommended that consumer complaints and investigations be 
reported to us when consumption of a dietary supplement may be related 
to ``a serious adverse event.'' Some comments note that ``serious'' is 
not defined.
    (Response) The term ``serious adverse event'' is widely used in the 
industries we regulate. Our current forms for reporting ``serious 
adverse events'' via the MedWatch program do not define the term, but 
instead list outcomes that were attributed to an adverse event. These 
outcomes include death, life-threatening, hospitalization (initial or 
prolonged), disability, congenital anomaly, required intervention to 
prevent permanent impairment/damage, and ``other.'' As discussed in 
this section, however, there is a new statutory requirement for 
mandatory reporting to FDA of serious adverse events enacted in the 
``Dietary Supplement and Non-Prescription Drug Consumer Protection 
Act'' (Public Law 109-462). The new law does define ``serious adverse 
events'' as those events that result in death, a life-threatening 
situation, an inpatient hospitalization, a persistent or significant 
disability or incapacity, or a congenital anomaly or birth defect or 
one that requires medical or surgical intervention to prevent such 
serious outcomes (based on reasonable medical judgment). The law also 
has specific provisions for how these serious adverse events are to be 
submitted to FDA and record retention for records relating to these and 
other adverse event reports. We anticipate issuing guidance on 
implementation of the new statutory provisions. We encourage firms who 
are unsure as to whether the nature of a reported adverse event should 
be reported to FDA to contact us for assistance.

XXI. Comments on Records and Recordkeeping (Final Subpart P)

A. Organization of Final Subpart P

    In the 2003 CGMP Proposal, the requirements for records and 
recordkeeping were set forth in proposed Sec.  111.125. As shown in 
table 17 of this document, we are reorganizing the requirements for 
records and recordkeeping into a distinct subpart (final Subpart P--
Records and Recordkeeping). Table 17 lists the sections in final 
subpart P and identifies the proposed provisions that form the basis 
for the final rule.

          Table 17.--Derivation of Sections in Final Subpart P
------------------------------------------------------------------------
                Final Rule                       2003 CGMP Proposal
------------------------------------------------------------------------
Sec.   111.605 What requirements apply to  Sec.   111.125(a) and (b)
 the records you make and keep?
------------------------------------------------------------------------
Sec.   111.610 What records must be made   Sec.   111.125(b) and (c)
 available to FDA?
------------------------------------------------------------------------

B. Highlights of Changes to the Proposed Requirements for Records and 
Recordkeeping

1. Revisions
    The final rule reflects that it applies to persons who manufacture, 
package, label, or hold a dietary supplement unless subject to an 
exclusion in Sec.  111.1.
2. Changes After Considering Comments
    This final rule requires you to keep written records required by 
this subpart for either 1 year past the shelf life date, if shelf life 
dating is used, or 2 years beyond the date of distribution of the last 
batch of dietary supplements associated with those records (final Sec.  
111.605(a)).

C. General Comments on Proposed Sec.  111.125

    (Comment 324) Some comments support the requirements in proposed 
Sec.  111.125 because documentation helps to ensure CGMPs are 
consistently followed and retention of records provides an effective 
trail when subsequent problems need to be identified and corrected.
    Another comment asserts the recordkeeping requirements would 
represent a large burden for companies that manufacture vitamin and 
mineral supplements with a large number of active ingredients.

[[Page 34912]]

    (Response) We agree that records are useful in identifying 
manufacturing problems and tracking the source of failures in CGMPs.
    We understand the burden on manufacturers may be heavier for 
manufacturers who use many dietary ingredients and discuss the burden 
of the recordkeeping requirements in sections XXVIII and XXIV of this 
document. However, we do not believe that a manufacturer who elects to 
put several components into one finished batch of dietary supplement 
would necessarily have a larger burden than one who, instead, elects to 
manufacture multiple dietary supplements each containing one component. 
We believe that the requirements, for example, for ensuring the 
identity, purity, strength, and composition of each component in a 
dietary supplement need to be the same for a dietary supplement 
containing one ingredient or component and one containing multiple 
ingredients or components. To the extent the comment is suggesting that 
the recordkeeping requirements for those who manufacture multivitamin/
mineral dietary supplements (containing components) are too large and 
should be less, the comment provided no basis for such a change.

D. What Requirements Apply to the Records That You Make and Keep? 
(Final Sec.  111.605)

1. Final Sec.  111.605(a)
    Final Sec.  111.605(a) requires you to keep written records for 1 
year past the shelf life date, if shelf life dating is used, or 2 years 
beyond the date of distribution of the last batch of dietary 
supplements associated with those records. Final Sec.  111.605(a) 
derives from proposed Sec.  111.125(a).
    (Comment 325) Several comments suggest that the requirement in 
proposed Sec.  111.125(a) to keep records for 3 years beyond the date 
of manufacture should be modified. One comment favors record retention 
for 3 years beyond the date of manufacture or for the shelf life of the 
product, whichever is longer. Some comments state the rule should 
require establishment of an expiration date and that the manufacturer 
should have the option of retaining records for 1 year beyond the 
expiration date, when an expiration date has been established by the 
manufacturer. Some comments point out that under section 306(a) of the 
Bioterrorism Act, FDA is authorized to issue recordkeeping regulations 
with a record retention period of ``not longer than two years.'' One 
comment, therefore, asserts CGMP records should not be kept for more 
than 2 years.
    (Response) We believe a record retention period for records related 
to CGMP requirements should correlate generally with the length of time 
that product complaints are likely to arise related to the manufacture 
of a dietary supplement. Such correlation will increase the likelihood 
that, if a problem with a dietary supplement is identified that may be 
associated with a violation of CGMP, the dietary supplement 
manufacturer, packager, labeler, or holder will have access to the CGMP 
records associated with that dietary supplement. In addition, we will 
have access to such records at inspection.
    We have modified the final rule to require a record retention 
period of 2 years beyond the date of distribution of the last batch of 
dietary supplements associated with those records or 1 year past the 
shelf life date, if shelf life dating is used.
    A significant portion of the dietary supplement industry use shelf 
life dating. It is likely that if there are product complaints related 
to a product these will arise during the shelf life of these products. 
To ensure there is adequate time to examine the records, determine if 
there are related manufacturing problems, and implement corrective 
actions, it is necessary to require the retention of records for 1 year 
past the shelf life date. This will help ensure that establishments 
have access to such records to perform the necessary CGMP actions.
    For those dietary supplements without shelf life or expiration 
dating, we believe that 2 years from the date of distribution is a 
reasonable estimate of the time needed to retain records in order to 
address CGMP problems identified in product complaints.
    It is important to note that, as discussed in this section, the 
term ``shelf life dating,'' includes shelf life dating as well as 
expiration dating and ``best if used by'' dating.
    We disagree with the comment that suggests we require an expiration 
date on all products. Many products will not have a determinable 
expiration date due to the state of knowledge about these products. We 
believe the manufacturer is in the best position to determine if its 
product requires an expiration date.
    (Comment 326) One comment requests clarification of the ``date of 
manufacture.'' The comment asserts if an expiration date is shown on 
the label of a product, the date of manufacture should be considered to 
be the date on which the expiration date is based. The comment gives an 
example of vitamin C tablets having a 2-year shelf life. The comment 
explains if the tablets are compressed, tested, and approved for 
packaging in August 2003, they would generally be assigned an 
expiration date of August 2005 regardless of the date of packaging. The 
comment argues if the tablets are held and later packaged in February 
2004, records for this batch should only have to be kept for 1 year 
beyond the expiration date (i.e., August 2006), rather than 3 years 
beyond the packaging date (i.e., February 2007).
    (Response) In the scenario described in the previous paragraph, 
where an expiration date (shelf life) has been determined, records for 
this batch must only be kept for 1 year beyond the expiration date 
(i.e., shelf life date). The packaging date in the scenario has no 
effect on the amount of time records must be kept. However, in the 
final rule, we have decided that it is more appropriate to determine 
the record retention period from the date of distribution rather than 
the ``date of manufacture.'' The date on which the manufacturer 
completes the manufacture of a batch of a dietary supplement (the date 
of manufacture) does not necessarily indicate the availability of the 
dietary supplement product in the marketplace. It is possible that such 
product could be held for a period of time before entry into the 
marketplace and possible consumer consumption. A more accurate time 
period for entry is calculated by the date of distribution. Final Sec.  
111.605(a)(2) requires that manufacturers, packagers, labelers, and 
holders keep their records for 2 years from the date of distribution of 
the last batch of dietary supplement associated with those records. For 
products with a shelf life date, the records associated with those 
dietary supplements are required to be kept for 1 year past the shelf 
life date of that particular dietary supplement. Packagers and labelers 
that return the product to the manufacturer for distribution are not 
required to keep separate records under this subpart.
2. Final Sec.  111.605(b)
    Final Sec.  111.605(b) requires you to keep records as original 
records, true copies (such as photocopies, microfilm, etc.), or as 
electronic records. Final Sec.  111.605(b) derives from proposed Sec.  
111.125(b).
    We did not receive comments specific to proposed Sec.  111.125(b).
3. Final Sec.  111.605(c)
    Final Sec.  111.605(c) requires that all electronic records comply 
with part 11 (21 CFR part 11). Final Sec.  111.605(c) derives from 
proposed Sec.  111.125(b).

[[Page 34913]]

    (Comment 327) One comment believes part 11 should only apply to 
records that do not have paper counterparts.
    (Response) This comment is beyond the scope of this CGMP 
rulemaking.
    (Comment 328) One comment suggests the proposed requirement that 
CGMP electronic records must comply with part 11 should be deleted 
because the FDA guidelines on part 11 have not yet been finalized.
    (Response) Part 11 applies to electronic CGMP records. Therefore, 
final Sec.  111.605(c) requires that all electronic records, including 
electronic signatures, must comply with part 11. We have finalized 
guidance for industry. The guidance entitled ``Part 11, Electronic 
Records; Electronic Signatures Scope and Application,'' sets out our 
enforcement policies with respect to certain aspects of part 11 (Ref. 
33). The guidance is available at http://www.fda.gov/cder/guidance/5667fnl.htm. The guidance applies to any CGMP electronic records and 
signatures.

E. What Records Must Be Made Available to FDA? (Final Sec.  111.610)

1. Final Sec.  111.610(a)
    Final Sec.  111.610(a) requires you to keep records, or copies of 
such records, required by this final rule, readily available during the 
retention period for inspection and copying by FDA when requested. 
Final Sec.  111.610(a) derives from proposed Sec.  111.125(c). We 
responded in section V of this document to comments that we received on 
FDA's statutory authority to inspect and copy records. We made one 
editorial, nonsubstantive change from the language in proposed Sec.  
111.125(c). We removed the word ``authorized'' to prevent any confusion 
regarding whether some authorization other than the statutory authority 
that provides the legal basis for this final rule is necessary for our 
access to inspect and copy records.
2. Final Sec.  111.610(b)
    Final Sec.  111.610(b) requires that if you use reduction 
techniques, such as microfilming, you must make suitable reader and 
photocopying equipment readily available to us. Final Sec.  111.610(b) 
derives from proposed Sec.  111.125(b).
    We did not receive any comments specific to proposed Sec.  
111.125(b) and final Sec.  111.610(b).

XXII. Other Comments and Miscellaneous

A. Comments on Guidance Documents To Be Used With the Final Rule

    In the 2003 CGMP Proposal, we invited comment on the usefulness of 
guidance documents, education, training, or other approaches and 
potential sources of education and training that would assist industry 
efforts to implement the 2003 CGMP Proposal, if finalized as proposed 
(68 FR 12157 at 12163).
    (Comment 329) A few comments state booklets, videos, seminars, and 
other training would be useful on topics such as sanitation, 
recordkeeping, quality assurance methods, microbiological testing, and 
botany. Another comment states a subset of CGMPs that focuses on plant 
authenticity, purity, proper handling, and hygiene should be developed 
for parties who exclusively deal with bulk raw agricultural commodities 
(with the exception of individual wildcrafters). If such CGMPs are not 
developed, the comment requests we develop guidance documents on the 
identification, cultivation, and handling of botanicals. The same 
comment also notes guidance specifically is needed on the use of 
microscopy to identify plants.
    (Response) We acknowledge these comments and, in the future, we may 
issue guidance that relates to certain dietary supplement CGMP 
requirements.

B. Comments on Consideration for Other CGMP Programs

    (Comment 330) One comment asserts several existing dietary 
supplement CGMP programs (e.g., those developed by the NNFA, NSF 
International, ANSI, and USP) are well designed and represent useful 
examples for us to follow. The comment notes section 12(d) of the 
National Technology Transfer and Advancement Act directs Federal 
agencies to use such voluntary consensus standards whenever possible, 
as long as the standards are consistent with Federal law and are 
practical. The comment recommends we include standards from these 
existing CGMP programs where suitable in the final rule.
    (Response) In the development of the 2003 CGMP Proposal and this 
final rule, we carefully considered the comments that recommended 
aspects of other CGMP programs. For example, as discussed previously, 
the 1997 ANPRM for this rule contained the entire text of an outline 
presented to us by representatives of the dietary supplement industry. 
Furthermore, where comments recommended aspects of other CGMP programs, 
we considered those recommendations and, in some cases, incorporated 
certain recommendations into requirements in this final rule (e.g., the 
use of a certificate of analysis).
    In 2006, ANSI updated its Standard 173 (ANSI Standard 173) 
regarding dietary supplements (Ref. 35). ANSI Standard 173 contains 
provisions for dietary supplement CGMP that are based, in part, on the 
industry submission to FDA in November 1995, which the agency published 
as part of its 1997 ANPRM. We considered comments to the 1997 ANPRM, 
many of which commented on the provisions of the industry submission, 
and the comments to the 2003 CGMP Proposal in the course of developing 
this CGMP final rule. We have considered the provisions contained in 
the updated ANSI Standard 173 and many of the specific provisions 
contained in ANSI Standard 173 are similar to provisions adopted in 
this final rule. For example, both the ANSI standard and this CGMP 
final rule have similar requirements on written procedures, personnel 
qualifications, record retention, and quality control. However, we 
determined that adopting the entire ANSI Standard 173 would be 
impracticable. There are key provisions which reflect major differences 
between the latest ANSI Standard 173 and the CGMP final rule. Many of 
these differences are in the product testing environment. For example, 
the ANSI standard contains different product testing frequency and 
production stage requirements. We have extensively discussed the 
justification for the particular testing requirements adopted in this 
CGMP final rule, which we believe are no more burdensome than the ANSI 
Standard 173 requirements. For example, the ANSI Standard 173 contains 
testing methods for metal or microbiological contaminants not included 
in the final rule. We found that providing flexibility for 
manufacturers to choose their own specific test methods was a more 
efficient way of reaching the goals of the CGMP final rule than 
specifying and requiring particular tests. We support, however, the use 
of the ANSI Standard 173 testing methods by manufacturers, where 
appropriate, in complying with the requirements of this rule.
    (Comment 331) Another comment states CGMPs that reflect common 
elements and areas of uniqueness should be placed in subcategories of 
CGMPs as is the case with the current food CGMP model. The comment 
recommends we follow a similar

[[Page 34914]]

approach and establish subcategories of CGMPs for dietary supplements 
(e.g., for vitamin-mineral and probiotic tablets).
    (Response) In the 1997 ANPRM, we asked for comment about whether 
broad CGMP regulations would be adequate, or whether it would be 
necessary to address the operations of particular segments of the 
dietary supplement industry (68 FR 12157 at 12174). Based on the 
comments received to the 1997 ANPRM, we were persuaded that a broad 
final rule is preferable to multiple regulations focused on particular 
segments of the dietary supplement industry, or to general CGMP 
provisions plus subcategories applicable to segments of the dietary 
supplement industry. We stated in the 2003 CGMP Proposal that we would 
consider whether we needed to re-evaluate our decision to establish one 
set of requirements for all dietary supplements (id.). This comment did 
not provide any basis to persuade us to re-evaluate the decision we 
made that a broad CGMP rule was appropriate. Thus, in this final rule, 
we are establishing one set of requirements for all persons who 
manufacture, package, label, or hold dietary supplements and not 
subject to an exclusion under final Sec.  111.1.

C. Comments on Public Involvement

1. Public Involvement
    (Comment 332) Several comments express general concerns with our 
public involvement process. Several comments state additional public 
meetings and workshops are necessary to permit FDA, industry, and other 
stakeholders to work together to seek a more workable solution to 
dietary supplement CGMPs and to resolve differences of opinion. One 
comment states the differences of opinion identified by the comment 
process will not be meaningfully resolved without active and forthright 
communication with stakeholders. According to the comment, we should 
establish a forum prior to the publication of the final rule to 
communicate our perception of these differences of opinion. In another 
comment, a trade association expresses disappointment that our 2003 
CGMP Proposal disregards industry efforts to draft CGMPs over the last 
decade. Another comment contends the proposal was rushed and the 
comment period was established without publication of a core economic 
analysis to support it.
    (Response) We disagree with these comments. We believe there has 
been sufficient public involvement given the public meetings that were 
held and the opportunity for comment during the comment periods 
provided. We discuss the public involvement in section I of this 
document. Further, the 2003 CGMP Proposal did contain an economic 
analysis. We received extensive comments on the economic analysis in 
the 2003 CGMP Proposal. We have made several changes to the economic 
analysis of this final rule in response to these comments as discussed 
in section XXIV of this document. Furthermore, we have made various 
changes in response to comments to the CGMP requirements in this final 
rule.

D. Comments on Implementation and Enforcement

    (Comment 333) Several comments suggest postponing the effective 
date of the rule for 24 months to allow a voluntary inspection and 
compliance program to take effect in the interim. One comment 
recommends adoption of a voluntary program similar to that of OSHA 
regulations in Title 29 of the Code of Federal Regulations, where 
companies would invite FDA inspection without penalty or cost unless a 
serious violation occurs. In cases of serious violation, companies 
would have the option to voluntarily correct the problem and inform the 
public before the effective date of the rule.
    (Response) We disagree with these comments regarding the 
establishment of a voluntary compliance period. The effective date of 
this final rule is 60 days after the date of its publication in the 
Federal Register. However, as discussed in sections VI and XXIV of this 
document, we have staggered compliance dates to 12 months, 24 months, 
and 36 months, respectively, after the final rule's publication date 
for businesses of over 500 employees, businesses with under 500 
employees but 20 or more employees, and businesses with less than 20 
employees.
    (Comment 334) Several comments indicate they want differential 
treatment under the final rule based on the seriousness of a violation, 
others ask for strict enforcement, and others ask how FDA would enforce 
against those who continually adulterate dietary supplements.
    (Response) We consider these comments to be outside the scope of 
this final rule. In general, we would provide guidance on our 
enforcement policy through the issuance of guidance documents if we 
determine that any variance from full enforcement is warranted.
    (Comment 335) Another comment expresses concern the 2003 CGMP 
Proposal works at ``cross purposes'' with recent regulations associated 
with bioterrorism. The comment recommends these rules be harmonized to 
reduce costs and increase efficiencies for manufacturers.
    (Response) It is not clear what the comment means when it states 
the 2003 CGMP Proposal works at ``cross purposes'' with the regulations 
issued under the Bioterrorism Act or that we should ``harmonize'' the 
regulations issued under the Bioterrorism Act with the final rule 
establishing dietary supplement CGMP requirements. We have made every 
effort to consider the regulations issued under the Bioterrorism Act 
and their relationship to this final rule. There are different purposes 
to the Bioterrorism Act and these CGMP requirements; however, we have 
harmonized to the extent possible.
    (Comment 336) One comment states the 1-year compliance period for 
large firms is reasonable as long as we modify the rule to better 
reflect existing CGMPs already in practice among responsible companies. 
The comment also notes the 3-year compliance period for small firms may 
be reasonable, but urges us to enforce compliance of basic food GMP 
requirements, which some of these firms may not be observing.
    (Response) The effective date for this final rule is 60 days after 
its date of publication in the Federal Register, though we are 
staggering the compliance dates as described in sections VI and XXIV of 
this document. Dietary supplement products in the marketplace must 
already be in compliance with all other statutory and regulatory 
provisions that affect dietary supplements.

E. Removal of References to Part 112

    The 2003 CGMP Proposal (68 FR 12157 at 12175) had proposed the 
heading and table of contents for part 112. Proposed part 112 had the 
heading ``Restrictions for Substances Used in Dietary Supplements.'' At 
the time, we said that it was necessary to amend part 112 because at 
that time the proposed rule for dietary supplements containing 
ephedrine alkaloids (62 FR 30678, June 4, 1997) had not been finalized 
and included proposed revisions to part 111. The 2003 CGMP Proposal for 
dietary supplement CGMPs proposed using part 111 and proposed the 
relocation of the ``Restrictions for Substances Used in Dietary 
Supplements'' to part 112. Since the issuance of the 2003 CGMP 
Proposal, the final rule for dietary supplements containing ephedrine 
alkaloids has been finalized (69 FR 6788, February 11, 2004) and has 
been included in 21 CFR part 119. Thus, there is no need to reserve 
part 112 in this final rule. The references to part

[[Page 34915]]

112 have been removed from the final rule.

XXIII. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
title, description, and respondent description of the information 
collection requirements are given in the following paragraphs, with 
estimates of the one-time burden of establishing written procedures and 
the annual recordkeeping burden. Included in the burden estimates are 
the time for reviewing instructions, searching existing data sources, 
gathering and maintaining the data needed, and completing and reviewing 
each collection of information.
    Title: Current Good Manufacturing Practice in Manufacturing, 
Packaging, Labeling, or Holding Operations for Dietary Supplements
    Description: Section 402(g) of the act gives us explicit authority 
to issue a rule establishing current good manufacturing practice 
requirements for dietary supplements. Section 402(g)(1) of the act 
states that a dietary supplement is adulterated if ``it has been 
prepared, packed, or held under conditions that do not meet current 
good manufacturing practice regulations.'' Section 402(g)(2) of the act 
authorizes us to, by regulation, ``prescribe good manufacturing 
practices for dietary supplements.'' Under section 701(a) of the act 
(21 U.S.C. 371), FDA may issue regulations necessary for the efficient 
enforcement of the act. Other relevant legal authority is discussed in 
section V of this document.
    We did not receive any direct comments on the Paperwork Reduction 
Act analysis of the 2003 CGMP Proposal. Many comments on the estimated 
costs of the 2003 CGMP Proposal stated that we underestimated the 
annual number of batches of dietary supplements produced. Due to a 
contractor's error, we did underestimate the number of batches 
produced. This final paperwork reduction analysis corrects for this 
error. The final analysis also has been revised from the analysis of 
the 2003 CGMP Proposal in order to incorporate the effects of revisions 
to the proposed regulation, including reorganization.
    Records are an indispensable component of CGMP. The records 
required by this final rule provide the foundation for the planning, 
control, and improvement processes that constitute a quality control 
system. Implementation of these processes in a manufacturing operation 
serves as the backbone to CGMP. The records will show what is to be 
manufactured; what was, in fact, manufactured; and whether the controls 
that the manufacturer put in place to control the identity, purity, 
strength, and composition and limits on contaminants and to prevent 
adulteration were effective. Further, records will show whether and 
what deviations from control processes occurred, facilitate evaluation 
and corrective action concerning these deviations (including, where 
necessary, whether associated batches of product should be recalled 
from the marketplace), and enable a manufacturer to assure that the 
corrective action was effective. Further, records will show whether and 
what deviations from control processes occurred, facilitate evaluation 
and corrective action concerning these deviations (including, where 
necessary, whether associated batches of product should be recalled 
from the marketplace), and enable a manufacturer to assure that the 
corrective action was effective. In addition, by requiring records, we 
will be able to ensure that you follow CGMPs so that you ensure the 
quality of your dietary supplements during manufacturing, packaging, 
labeling, or holding operations. The final rule establishes the minimum 
manufacturing practices necessary to ensure that dietary supplements 
are manufactured, packaged, labeled, or held in a manner that will 
ensure the quality of the dietary supplements during manufacturing, 
packaging, labeling or holding operations.
    The records requirements of this final rule include written 
procedures and records pertaining to: (1) Personnel; (2) sanitation; 
(3) calibration of instruments and controls; (4) calibration, 
inspection, or checks of automated, mechanical, or electronic 
equipment; (5) maintaining, cleaning, and sanitizing equipment and 
utensils and other contact surfaces; (6) water used that may become a 
component of the dietary supplement; (7) production and process 
controls; (8) quality control; (9) components, packaging, labels and 
product received for packaging and labeling; (10) master manufacturing 
and batch production; (11) laboratory operations; (12) manufacturing 
operations; (13) packaging and labeling operations; (14) holding and 
distributing operations; (15) returned dietary supplements; and (16) 
product complaints.
    Description of Respondents: Manufacturers, dietary supplement 
manufacturers, packagers and re-packagers, labelers and re-labelers, 
holders, distributors, warehousers, exporters, importers, large 
businesses, and small businesses.
    The recordkeeping requirements of the final rule are set forth in 
each subpart. In table 18 of this document we list the one-time burdens 
associated with establishing written procedures. In table 19 of this 
document we list the annual burdens associated with recordkeeping. In 
each table, where the same records are mentioned in more than one 
provision of a subpart, we list the burden under the provisions 
corresponding to the heading, ``Under this subpart, what records must 
you make and keep?'' For some provisions listed in table 19, we did not 
estimate the annual frequency of recordkeeping because recordkeeping 
occasions consist of frequent brief entries of dates, temperatures, 
monitoring results, or documentation that specific actions were taken. 
Information might be recorded a few times a day, week, or month. When 
the records burden involves frequent brief entries, we entered one as 
the default for the annual frequency of recordkeeping. For example, 
many of the records listed under final Sec.  111.35 in table 19, such 
as final Sec.  111.35(b)(2) (documentation, in individual equipment 
logs, of the date of the use, maintenance, cleaning, and sanitizing of 
equipment), involve many short sporadic entries over the course of the 
year, varying across equipment and plants in the industry. We did not 
attempt to estimate the actual number of recordkeeping occasions for 
these provisions, but instead entered an estimate of the average number 
of hours per year. We entered the default value of 1 as the annual 
frequency of recordkeeping for these and similar provisions. For final 
Sec.  111.35, the entry for annual frequency is 1 as a default 
representing a large number of brief recordkeeping occasions.
    In many rows of tables 18 and 19 of this document, we list a burden 
under a single provision that covers the written procedures or records 
described in several provisions. The burden of the master manufacturing 
record listed in table 18 under final Sec.  111.210 includes the burden 
for final Sec.  111.205 because the master manufacturing record must 
include those written procedures. Similarly, the burden of the batch 
production records listed in table 19 under final Sec.  111.260 
includes the burden for records listed under final Sec.  111.255 
because the batch production records must include those records.
    The annual frequency for batch production records (and other 
records kept on a batch basis in table 19 of this document) equals the 
annual number of

[[Page 34916]]

batches. The estimated burden for records kept by batch includes both 
records kept for every batch and records kept for some but not all 
batches. We use the annual number of batches as the frequency for 
records that will not necessarily be kept for every batch, such as test 
results or material review and disposition records, because such 
records are part of records, if they are necessary, that will be kept 
for every batch.
    We estimate the burden of this collection of information as 
follows:

                                         Table 18.--Estimated One-Time Burden to Establish Written Procedures\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Number of        Annual Frequency
                    21 CFR Section                        Recordkeepers      per Recordkeeping     Total Records    Hours per  Record     Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.14                                                             15,000                     1             15,000                3.6             54,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.23                                                             15,000                     1             15,000                1               15,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.35                                                                400                     1                400               36               14,400
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.95                                                                250                     1                250               68               17,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.140                                                               300                     1                300               10.7              3,210
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.180                                                               200                     1                200               10                2,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.210                                                               250                     1                250               12                3,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.325                                                               150                     1                150               45                6,750
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.375                                                               260                     1                260                9                2,340
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.430                                                               250                     1                250               12.6              3,150
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.475                                                            15,000                     1             15,000                2.1             31,500
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.535                                                               200                     1                200                6                1,200
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.570                                                               240                     1                240               12                2,880
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                            156,430
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating costs associated with the collection of information under this final rule.


                                                   Table 19.--Estimated Annual Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Number of        Annual Frequency       Total Annual
                    21 CFR Section                        Recordkeepers      per Recordkeeping        Records       Hours per  Record     Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.14                                                             15,000                     4             60,000                1               60,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.23                                                             15,000                     1             15,000                0.2              3,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.35                                                                400                     1                400               12.5              5,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.95                                                                250                     1                250               45               11,250
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.140                                                               240                 1,163            279,120                1              279,120
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.180                                                               240                 1,163            279,120                1              279,120
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.210                                                               240                     1                240                2.5                600
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.260                                                               145                 1,408            204,160                1              204,160
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.325                                                               120                     1                120               15                1,800
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.375                                                               260                     1                260                2                  520
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.430                                                                50                     1                 50               12.6                630
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.475                                                            15,000                     1             15,000                0.4              6,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.535                                                               110                     4                440               13.5              5,940
--------------------------------------------------------------------------------------------------------------------------------------------------------
111.570                                                               240                   600            144,000                0.5             72,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                            929,140
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating costs associated with the collection of information under this final rule.


[[Page 34917]]

    The burden estimates in tables 18 and 19 of this document are based 
on our institutional experience with other CGMP requirements and on 
data provided by Research Triangle Institute (RTI) in the ``Survey of 
Manufacturing Practices in the Dietary Supplement Industry,'' OMB 
Control Number 0910-0422, expiration date April 4, 2000 (Refs. E1 and 
E2).
    The estimates in both tables of the number of firms affected by 
each provision of the rule are based on the percentage of 
manufacturers, packagers, labelers, holders, distributors, and 
warehousers that reported in the survey that they have not established 
written SOPs or do not maintain records that would be required under 
the final rule. Because we do not have survey results for general 
warehouses, we entered the approximate number of facilities in that 
category for those provisions covering general facilities. For the 
dietary supplement industry, the survey estimated that 1,460 firms 
would be covered by this final rule, including manufacturers, 
packagers, labelers, holders, distributors, and warehousers. The time 
estimates include the burden involved in documenting that certain 
requirements are performed and in recordkeeping. We used an estimated 
annual batch production of 1,408 batches per year to estimate the 
burden of requirements that are related to the number of batches 
produced annually, such as final Sec.  111.260, ``What must the batch 
production record include?'' The estimate of 1,408 batches per year is 
near the midpoint of the number of annual batches reported by survey 
firms.
    The length of time that CGMP records must be maintained is set 
forth in final Sec.  111.605. Tables 18 and 19 of this document reflect 
the estimated burdens for written procedures, record maintenance, 
periodically reviewing records to determine if they may be discarded, 
and for any associated documentation for that activity for records that 
will be required under part 111. We have not included a separate 
estimate of burden for those sections that require maintaining records 
in accordance with final Sec.  111.605, but have included those burdens 
under specific provisions for keeping records. For example, final Sec.  
111.255(a) requires that the batch production records be prepared every 
time a batch is manufactured, and final Sec.  111.255(d) requires that 
batch production records be kept in accordance with final Sec.  
111.605. The estimated burdens for both Sec.  111.255(a) and (d) are 
included under final Sec.  111.260 (what the batch record must 
include).
    The information collection provisions of this final rule have been 
submitted to OMB for review.
    Prior to the effective date of this final rule, we will publish a 
document in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

XXIV. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of this final rule under Executive 
Order 12866. Executive Order 12866 directs agencies to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). 
Executive Order 12866 classifies a rule as significant if it meets any 
one of a number of specified conditions, including: Having an annual 
effect on the economy of $100 million, adversely affecting a sector of 
the economy in a material way, adversely affecting competition, or 
adversely affecting jobs. A regulation is also considered a significant 
regulatory action if it raises novel legal or policy issues. FDA has 
determined that this final rule will be an economically significant 
regulation under Executive Order 12866 because it will have an annual 
effect on the economy of more than $100 million.
    The Small Business Regulatory Enforcement Fairness Act of 1996 
(Public Law 104-121) defines a major rule for the purpose of 
congressional review as being likely to cause one or more of the 
following: An annual effect on the economy of $100 million; a major 
increase in costs or prices; significant adverse effects on 
competition, employment, productivity, or innovation; or significant 
adverse effects on the ability of U.S.-based enterprises to compete 
with foreign-based enterprises in domestic or export markets. In 
accordance with the Small Business Regulatory Enforcement Fairness Act, 
OMB has determined that this final rule will be a major rule for the 
purpose of congressional review.
    FDA has examined the impacts of this final rule under the 
Regulatory Flexibility Act (5 U.S.C. 601-612). If a rule has a 
significant economic impact on a substantial number of small entities, 
the Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would lessen the economic effect of the rule on small 
entities. FDA finds that this final rule will have a significant 
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (Public Law 104-4) 
requires cost-benefit and other analyses for rules that would cost more 
than $100 million in a single year. The current (2005) inflation-
adjusted statutory threshold is $122 million. This final rule qualifies 
as a significant rule under the statute.
1. Summary of the Economic Analysis
    We carry out the cost-benefit analyses required for significant 
rules in the Final Regulatory Impact Analysis, in section XXIV.B of 
this document. We perform the Final Regulatory Flexibility Analysis of 
the effects on the final rule on small businesses in section XXIV.C of 
this document. We estimate that, once it is fully implemented 36 months 
after the date of publication, the quantifiable annual benefits from 
the final rule will be about $44 million. The benefits able to be 
quantified are generated by more consistently produced dietary 
supplements which will increase product safety, which reduces the 
number of acute illnesses and product recalls. In addition, the final 
rule may generate benefits that we lack sufficient data to quantify. 
These benefits we cannot quantify arise from dietary supplements 
manufactured under a system to ensure quality, which leads to a 
reduction in the number of chronic illnesses and conditions.
    The final rule will lead to quantifiable costs of $16 million in 
the first year it takes effect, $120 million in the second year, and 
$190 million in the third year. After 3 years, the annual costs will be 
about $164 million. If we annualize the benefits and costs over 20 
years at a 3 percent rate of discount, the annualized quantifiable 
benefits are $40 million and annualized quantifiable costs are $153 
million. These annualized benefits include only those that we are able 
to quantify. The total annualized benefits may be larger than our 
estimate of $40 million in quantifiable benefits because of the 
benefits that we are not able to quantify.
    We have determined, based on information contained in this 
regulatory impact analysis as well as information contained elsewhere 
in the preamble, that the benefits of this final rule justify the 
costs.
    The final rule will have a significant economic effect on small 
businesses. We estimate that the annual costs will be about $46,000 for 
an establishment with

[[Page 34918]]

fewer than 20 employees and $184,000 for an establishment with 20 to 
499 employees.
2. Summary of Comments on the Economic Analysis
    We received numerous substantive comments on the economic analysis 
of the 2003 CGMP Proposal. In general, comments from the dietary 
supplement industry state that we underestimated the cost of the 2003 
CGMP Proposal. Specific comments from the industry target the 2003 CGMP 
Proposal's testing requirements, which the comments characterize as 
``burdensome.'' Many comments address our estimate of the number of 
batches of dietary supplements firms produce in a year. Many comments 
express the fear that, as a result of this 2003 CGMP Proposal, the 
prices consumers pay for dietary supplements would increase 
dramatically. Nearly all economic comments mention potential adverse 
effects of the 2003 CGMP Proposal on small businesses, stating that 
many firms would have to stop manufacturing. A few comments state that, 
if made final, the 2003 CGMP Proposal would make dietary supplements 
more expensive than pharmaceuticals. Other comments address the 
following topics:
    <bullet> FDA's other assumptions, including the number of tests 
required for each batch and the number of tests already being 
performed.
    <bullet> Development of analytical methods.
    <bullet> Equipment and capital investment costs.
    <bullet> Recordkeeping costs.
    <bullet> FDA's estimation of benefits.
    We will summarize comments on individual substantive issues under 
the appropriate subject headings and respond.

B. Final Regulatory Impact Analysis

1. The Need for the Final Current Good Manufacturing Practice Rule
    The final rule is needed because establishments that manufacture, 
package, label, or hold dietary supplements may not have sufficient 
market incentives to use controls to ensure that the characteristics of 
the supplements are what consumers would choose to buy if they had full 
or adequate information. Dietary supplements have the characteristics 
of both experience goods and credence goods.\12\ In terms of the acute 
illnesses discussed below, it may be difficult for consumers to 
identify the attributes of dietary supplements before the actual 
consumption of the good. Therefore, it may be difficult, in the absence 
of some regulation of dietary supplement manufacturing practices, for 
consumers to differentiate between products produced under good 
manufacturing practices, and those that are not, at the point of 
purchase in the marketplace. In terms of dietary supplements as 
credence goods, consumers may never have adequate information on 
product characteristics even after the consumption of the good, making 
it difficult for consumers to determine what benefits each product 
offers. Because problems can be undetectable, establishments may not 
adopt the necessary practices to ensure product attributes are as they 
are intended unless required to do so by regulation.
---------------------------------------------------------------------------

    \12\An experience good is a product or service where product 
characteristics such as quality or price are difficult to observe in 
advance, but these characteristics can be ascertained upon 
consumption. A credence good is a good whose utility impact is 
difficult or impossible for the consumer to ascertain even after 
consumption of the good.
---------------------------------------------------------------------------

    Of course, the characteristics of dietary supplements, as a type of 
food product, argue for some sort of Government intervention in this 
market in order to alleviate the specific market failures that lead to 
the types of problems with dietary supplements that this rule 
addresses. There are many types of interventions that may be used to 
address market failure; FDA has examined the options and has determined 
that specific CGMPs are necessary for dietary supplements. The rest of 
this regulatory impact analysis, and particularly section III.A of this 
document, discusses why FDA has concluded that specific CGMPs are 
necessary for dietary supplements.
    (Comment 337) We received several comments on the need for the 2003 
CGMP Proposal. Four comments specifically support the proposal, 
stating, in part, that they are pleased we are addressing the issue of 
dietary supplement manufacturing. In addition, one comment states that 
the 2003 CGMP Proposal was a good step toward providing assurance that 
dietary supplements are as safe as prescription and OTC drugs.
    Other comments express concern about the 2003 CGMP Proposal. One 
comment generally supports it, but expresses concern that the 
statements we make regarding market incentives to prevent adulteration 
and misbranding are inaccurate and misleading. The comment points out 
that the incentive exists for firms to prevent adulterated products 
from entering the marketplace because of their desire to avoid damage 
to their reputations. In addition, adulterated products are already 
illegal to market. Two other comments support the 2003 CGMP Proposal 
only with modifications, and another comment supports CGMP regulations, 
provided they reflect the current ``best practices of leading 
manufacturers.'' Two comments assert that a ``more rigorous'' 
enforcement program would be more effective than dietary supplement 
CGMP requirements in preventing adulteration. Two comments state that a 
regulation would serve no useful purpose because of the ``low level of 
harm identified in the industry.''
    One comment states that the 2003 CGMP Proposal spells out design 
standards rather than performance standards. According to the comment, 
the 2003 CGMP Proposal spells out procedures a firm must follow rather 
than defining a specific outcome, such as a specified level of 
contamination. This comment maintains that we should set a performance 
standard and then allow manufacturers flexibility in how that standard 
is reached. Another comment states that, although certain dietary 
supplement ingredients may cause concern, this concern did not justify 
imposing ``overbearing'' and ``broad'' CGMP regulations for an entire 
industry. Another comment asserts that the CGMPs as presented in the 
2003 CGMP Proposal would serve as an anti-competitive tool by allowing 
dominant manufacturers to increase their dominance and make it more 
difficult for new firms to enter the industry.
    (Response) Those comments that disagreed with our analysis provided 
no data or evidence to support the comment. Without such data or 
evidence, we have no basis upon which to revise our analysis and 
continue to use the analysis. Thus, we have not made any changes based 
on these comments.
    Whether or not these provisions are performance or design standards 
is a theoretical issue. Instead of specifically choosing either design 
or performance standards for all provisions of the rule, FDA has chosen 
to provide flexibility to manufacturers whenever possible. For example, 
providing for the use of ``safe and sanitary'' water sources gives 
manufacturers flexibility in deciding the best way to assure that 
``safe and sanitary'' water is used in the manufacture of their 
products. There are many areas of the rule where more than one way is 
given to comply with a particular provision. This flexibility allows 
manufacturers to choose the appropriate means to comply with the 
provision that is the most cost-effective for them.

[[Page 34919]]

    We agree with the comments that point out that existing statutes 
and regulations, concern for brand names, and voluntary industry 
standards provide some product safety and quality. Nonetheless, 
continuing problems in the industry provide evidence for the need for 
this final rule. From 2000 through 2005, there were a total of 75 
recall actions in the dietary supplement industry, including class 1, 
2, and 3 recalls of vitamins and minerals and herbal and botanical 
supplements. We will discuss these recalls, which accounted for about 4 
percent of the 1,937 FDA food recall actions in 2000 through 2005, 
later in this document. Most of these recalls occurred because 
establishments failed to adhere to product manufacturing or labeling 
specifications.
    For a class 1 recall, there is a reasonable probability of serious 
adverse health consequences or death; for a class 2 recall, exposure to 
the product may cause temporary or medically reversible adverse health 
consequences; for a class 3 recall, exposure to the product is not 
likely to cause adverse health consequences. Full compliance with the 
provisions of this final rule could have prevented most of the recalls. 
We note also recall classifications only track acute hazards, not long-
term quality problems. Results from ConsumerLab.com and other 
independent laboratory results provide further evidence of a need for 
this final rule (Refs. E3 through E6). Statistical sampling methods 
were not used to collect the data reported in these analyses. 
Therefore, although this information provides anecdotal evidence of 
problems, the data may not be representative of overall industry 
practices. The information serves as additional evidence of the 
existence of problems.
    Although the final rule will increase the monetary cost of entering 
the dietary supplement industry, the industry will remain highly 
competitive with more than a thousand competing producers and thousands 
more potential entrants.
2. Regulatory Options
    We considered several regulatory options for dealing with current 
manufacturing, packaging, labeling, and holding practices that may not 
ensure the quality of the dietary supplement. The options considered 
include: (1) No new regulatory action, (2) fewer requirements for 
vitamins and minerals, (3) more restrictive regulations than the final 
rule, (4) HACCP without the other elements of the final rule, (5) final 
product testing only, (6) a final rule for high-risk products or 
hazards only, and (7) the 2003 CGMP Proposal.\13\ As a result of 
comments on the 2003 CGMP Proposal and our reconsideration of our 
position on several provisions, this final rule differs from the 2003 
CGMP Proposal.
---------------------------------------------------------------------------

    \13\Options 1 through 6 were discussed in detail in the 2003 
CGMP Proposal (68 FR 12157 at 12221 through 12223; March 13, 2003) 
and analyses of costs were provided when possible. The principles of 
the options discussion have not changed and are still relevant for 
purposes of the requirements of the final rule. The 2003 CGMP 
proposal also included an Analysis of Impacts which contained some 
errors from a contractor's report. We have corrected the analysis 
and have recalculated the costs of the 2003 CGMP Proposal. These 
corrections and recalculations are discussed in section XXIV.B.9 of 
this document.
---------------------------------------------------------------------------

    (Comment 338) We received few comments on the option of fewer 
requirements for vitamins and minerals, and the comments submitted did 
not support this option. One comment supports one set of CGMPs that 
would apply to the entire industry rather than fewer requirements for 
vitamins and minerals than for botanicals. Another comment states that 
having fewer requirements for vitamins and minerals would not be wise 
because of the large number of people who take multivitamin or mineral 
supplements.
    One comment supports more restrictive CGMP requirements, including 
further testing and quality assurance requirements.
    We received two comments that support HACCP without other elements 
of the final rule. One comment echoes an earlier comment made about 
stressing outcomes and points to the HACCP systems in the juice and 
seafood industries as a way of ensuring effective quality control 
design. The comment asserts that the detailed manufacturing controls 
and testing requirements spelled out in the 2003 CGMP Proposal may 
actually stifle innovation. Another comment echoes these thoughts, 
adding that a HACCP approach could work in tandem with a more 
traditional specification and test approach.
    We received one comment that specifically discusses requiring only 
final product testing, but received numerous comments on final product 
testing in general. The specific comment did not support reliance on 
final product testing only, stating it is not the best or most 
appropriate control. In addition, the comment claims it is not 
technically feasible in many cases and is economically burdensome, a 
point repeated in other general comments about final product testing. 
In addition, numerous comments point out that a firm cannot ``test in 
quality,'' meaning that ensuring the quality of the dietary supplement 
will not be achieved through rigorous end-product testing, which 
emphasizes the wrong stage of production, but by ensuring quality 
through an effective process control system.
    Few comments discuss regulation of only high-risk products. Those 
that did note that some ingredients would be of public health concern 
and it would be preferable to test these ingredients only rather than 
all ingredients.
    (Response) The comments on the regulatory options did not provide 
evidence to directly support or oppose those options but instead 
addressed particular issues such as testing or coverage.
    We took the comments on specific issues into account in the 
analysis of this final rule. We discuss them below in the relevant 
parts of the analysis.
    One comment supporting HACCP stated that the detailed manufacturing 
and testing requirements of the 2003 CGMP Proposal would, compared with 
HACCP, stifle innovation. Although regulations that impose costs can 
divert resources away from innovation, the costs of this final rule 
represent less than 1 percent of industry revenues (see table 35 of 
this document). Because research and development expenditures account 
for a small fraction of total expenditures, any reduced expenditures on 
research and development associated with this final rule will be a 
small fraction of 1 percent of revenues. Thus, it seems unlikely that 
this rule would have the effect of stifling innovation. As we explained 
in the economic analysis of the 2003 CGMP Proposal, the HACCP option 
would not specify detailed manufacturing requirements but would also 
fail to ensure product quality (68 FR 12157 at 12222). In section X.I 
of this document, we discuss why HACCP is not appropriate for dietary 
supplements. The comment supporting HACCP failed to provide any data or 
any evidence to support its conclusion. Without such data or evidence, 
we have no basis upon which to revise our analysis and continue to use 
the analysis.
3. Coverage of the Final Rule
    The final rule applies to establishments that manufacture, package, 
label, or hold dietary supplements. Tables 20 and 21 of this document 
list the estimated number of covered manufacturers, packagers, 
labelers, holders, and other establishments subject to the final rule. 
Table 20 shows the number of establishments categorized as 
manufacturers, repackagers or relabelers, holders whose primary 
business is dietary supplements, and other (although not including 
other

[[Page 34920]]

holders and distributors). Table 21 shows our estimate of the number of 
general warehouses, wholesalers, and others that hold dietary 
supplements, but are not otherwise involved in the industry.

 Table 20.--Covered Establishments by Type of Operation from the Dietary
           Supplement Enhanced Establishment Database (DS-EED)
------------------------------------------------------------------------
                                                        Percent of
  Establishment Type     No. of  Establishments       Establishments
------------------------------------------------------------------------
Manufacturer                              1,228                     84.1
------------------------------------------------------------------------
Repackager; relabeler                        26                      1.8
------------------------------------------------------------------------
Holder                                      114                      7.8
------------------------------------------------------------------------
Establishments not                           92                      6.3
 already classified
------------------------------------------------------------------------
Total                                     1,460                    100.0
------------------------------------------------------------------------


     Table 21.--Covered Establishments That Hold Dietary Supplements
------------------------------------------------------------------------
    Type of Holders            NAICS Code         No. of  Establishments
------------------------------------------------------------------------
General grocery                          424410                    4,036
 wholesalers or drug
 wholesalers
------------------------------------------------------------------------
General warehouse                        493110                    4,415
------------------------------------------------------------------------
Drug wholesalers                          42420                    7,418
------------------------------------------------------------------------
Total                                                             15,869
------------------------------------------------------------------------

    We consulted several sources to estimate the number of 
establishments reported in this document. The number, 1,460, is the 
estimated number of establishments in the DS-EED that manufacture, 
package, label, or hold dietary supplement products in the United 
States. In the analysis of the 2003 CGMP Proposal, we included an 
additional 106 U.S. establishments that supplied dietary ingredients. 
Because those establishments are not covered in this final rule, we 
exclude them from the total. RTI developed the DS-EED using FDA's 
Official Establishment Inventory and supplemented that source with 
information from trade organizations, trade shows, and electronic 
databases (Refs. E1 and E2).
    To estimate the total number of establishments that could hold 
dietary supplements but do not consider dietary supplements as their 
primary business, we first looked for a count of establishments that 
had North American Industrial Classification System (NAICS) codes for 
wholesalers of groceries or drugs. Next we looked for a count of firms 
that met the description of warehouses for groceries or drugs. We did 
not find a category devoted exclusively to food and drug warehousing, 
so we concluded that general warehousing most closely corresponded to 
the set of establishments that would hold dietary supplements. The 
results are shown in table 21 of this document. This total differs from 
the total reported in the analysis of the 2003 CGMP Proposal because 
the new classification system allows us to identify more establishments 
that would not hold dietary supplements and therefore exclude them from 
the total.
    Foreign firms that export dietary supplements to the United States 
must satisfy the requirements of this final rule. We do not have data 
on the number of foreign firms that export dietary supplements to the 
United States. The small number of foreign products in the FDA dietary 
supplement sales database suggests that relatively few foreign firms 
export dietary supplements to the United States (Ref. E7). The foreign 
firms that will be most affected by the final rule are suppliers of 
dietary ingredients. Although suppliers of dietary ingredients are not 
directly covered by the final rule, the need of manufacturers to meet 
the ingredient specifications required by the final rule will 
indirectly affect foreign suppliers (as well as domestic suppliers).
    No comments were received on the economic analysis of the coverage 
of the 2003 CGMP Proposal.
4. Baseline Practices
    a. Consumption. Baseline risks depend on baseline consumption of 
dietary supplements. Total sales in 2004 were about $20 billion (Ref. 
E8). Vitamins and minerals accounted for about 42 percent of sales. 
Sales of herbal supplements, which have not grown in recent years, were 
half as large as sales of vitamin and minerals, accounting for about 21 
percent of the total. Amino acids, proteins, animal extracts, tea-like 
supplements, and other supplements not otherwise classified accounted 
for the remainder of sales.
    There were no comments on the consumption baseline.
    b. Manufacturing. We contracted with RTI to conduct a survey of the 
dietary supplement industry to learn about both baseline (existing) 
manufacturing practices and the existing standards used for 
manufacturing dietary ingredients and dietary supplements (Ref. E2). A 
sample of 966 dietary supplement establishments from the DS-EED 
database was selected from an estimated eligible population of 1,566 
firms in the industry (the total number of dietary supplement 
establishments included 106 ingredient manufacturers, who are now 
excluded from the requirements of the final rule). The eligibility 
criteria and the response rate for the survey are fully explained in 
the final report on the survey (Ref. E2). We further classified the 
target firms by product and by size. The product categories were: (1) 
Vitamins and minerals; (2) amino acids and proteins; (3) herbals and 
botanicals, including

[[Page 34921]]

extracts; and (4) supplements not already classified.
    The Small Business Administration classifies companies as ``small'' 
based on the size of the entire company, including both parent and 
subsidiaries. If firms that manufacture dietary supplements have fewer 
than 500 employees, they are classified as small. In addition, for 
purposes of this analysis, we classify firms with fewer than 20 
employees as very small.
    We received 238 completed surveys. Table 22 of this document shows 
the number of completed surveys by product and by size of 
establishment.

                                                Table 22.--Number of Completed Surveys by Sampling Strata
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                     Size
                                                    ----------------------------------------------------------------------------------------------------
                                                       Very Small (fewer    Small (20 to 499   Large (500 or more
                                                      than 20 employees)       employees)          employees)            Unknown             Total
--------------------------------------------------------------------------------------------------------------------------------------------------------
Vitamins and minerals                                                  19                 39                    13                  1                 72
--------------------------------------------------------------------------------------------------------------------------------------------------------
Amino acids, proteins                                                   8                  7                     0                  5                 20
--------------------------------------------------------------------------------------------------------------------------------------------------------
Herbals and botanicals, including extracts                             58                 25                     0                 30                113
--------------------------------------------------------------------------------------------------------------------------------------------------------
Supplements not already classified                                     14                 13                     2                  4                 33
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                  99                 84                    15                 40                238
--------------------------------------------------------------------------------------------------------------------------------------------------------

    (Comment 339) We received two comments on manufacturers' baseline 
practices. One comment expresses concern that, as the information is 
over 3 years old, it may no longer represent current industry 
practices. The second comment questions the way we calculated the 
number of dietary supplement establishments that do not follow any CGMP 
models. In the 2003 CGMP Proposal, we state that survey data reflect 
that 36 percent of surveyed establishments do not follow any CGMP 
models. The comment points out that 26.5 percent of firms responded 
``no'' to the question, ``Does this plant follow a published GMP model 
for the dietary supplement products produced at this plant?'' 
Furthermore, of the 63 that answered ``no,'' ``at least'' 29 of the 
firms provided responses indicating the reason they do not follow a 
published GMP is that they did not manufacture dietary supplement 
products.
    (Response) Although the survey responses are now over 6 years old, 
they represent the best information we have on the industry and its 
practices. We have, however, adjusted our estimated costs to reflect 
the correction of the results from the original survey.
5. Baseline Risk
    The current number of illnesses caused by poor dietary supplement 
manufacturing practices requires data linking illnesses to poor 
practices. Because these data do not exist, we looked for other 
information to provide indirect evidence on the problem. We looked at 
many sources for information, including medical and other literature on 
adverse events, information from poison control centers, reports to the 
agency, newspaper and magazine articles, and surveys of users. The 
literature review was conducted using Medline, Healthstar, Aidsline, 
Cancerlit, and OldMedline (Ref. E9). We found evidence of many adverse 
events associated with dietary supplements. For example, in 2003, the 
American Association of Poison Control Centers received 24,412 reports 
on events associated with herbal dietary supplements and 57,801 reports 
on events associated with vitamin and mineral supplements, with 8,653 
of the herbal and 5,669 or the vitamin and mineral reports treated in 
health care facilities (Ref. E10). In addition, we have received many 
voluntary reports of illnesses caused by dietary supplements (Ref. 
E11).\14\
---------------------------------------------------------------------------

    \14\Mandatory reporting to FDA of serious adverse events is now 
required as a result of the enactment of the ``Dietary Supplement 
and Non-Prescription Drug Consumer Protection Act'' (Public Law 109-
462), signed into law on December 22, 2006. The new law requires 
manufacturers, packers, or distributors of such products to submit 
reports to FDA about serious adverse events involving such products 
based on specific information that they receive from the public.
---------------------------------------------------------------------------

    The vast majority of these events and those described in other 
sources we consulted, however, are reported as associated with the 
ingredients used in the products themselves, not with contamination or 
other results of poor manufacturing processes. Most of the reports from 
poison control centers on vitamins and minerals, for example, involved 
inappropriate ingestion by children (Ref. E10). We have no direct 
evidence on how many illnesses can be attributed to manufacturing 
processes. The anecdotal evidence described elsewhere in the preamble 
suggests that many illnesses could have been caused by poor 
manufacturing processes, but there are only a few examples of evidence 
that explicitly link illnesses to manufacturing processes. Examples of 
illness that were linked directly to poor manufacturing practices 
include vitamin D toxicity from excessive vitamin D in multivitamins 
and cardiac glycoside poisoning from botanical dietary supplements 
contaminated with Digitalis lanata (Ref. E12).
    With no direct evidence on the number of illnesses caused by poor 
manufacturing practices, we had to use an indirect approach. We based 
the approach on our recall records. Class 1 and class 2 recalls all 
involve defective products that could have caused illness if ingested. 
Although the recall data cannot be linked directly to illness data, we 
have found anecdotes, surveys, and some medical literature on illnesses 
that could be caused by avoidable dietary supplement manufacturing 
mistakes. We have recall data that show that manufacturing mistakes 
exist, so we can construct a plausible link between manufacturing 
mistakes and potential illnesses or injuries. The number of illnesses 
associated with a manufacturing problem leading to a recall is both 
variable and uncertain, and could be anything from zero to quite large. 
Based on data from FDA food and dietary supplement recalls, we 
concluded that one reported illness per recall is a plausible average, 
so we assumed that a recall could be a proxy for a single reported 
illness associated with a defective product.

[[Page 34922]]

    Because there are no active surveillance systems for identifying 
adverse health events related to dietary supplements, we assume that 
the total number of illnesses caused by poor manufacturing practices is 
substantially greater than the number reported.\15\ Based on data for 
drug and vaccine reporting rates in other studies, one study concluded 
that for dietary supplements, reported illnesses represent 
approximately 1 percent of total illnesses (Ref. E13). We use the 
associated multiplier, 100, in our baseline estimate and assume that 
reporting adverse health events due to poorly manufactured dietary 
supplements occurs at the same rate as reporting adverse health events 
caused for other reasons by dietary supplements. Other reporting rates 
and associated multipliers are, however, plausible. For some hazards 
that lead to severe events only, we have used a multiplier of 10; the 
Centers for Disease Control and Prevention have used a multiplier of 38 
for Salmonella infections and similar food-related illnesses. We show 
the sensitivity of benefits to the choice of multiplier below.
---------------------------------------------------------------------------

    \15\Mandatory reporting to FDA of serious adverse events is now 
required as a result of the enactment of the ``Dietary Supplement 
and Non-Prescription Drug Consumer Protection Act'' (Public Law 109-
462), signed into law on December 22, 2006.
---------------------------------------------------------------------------

    From 1990 through 1999, we received reports on an annual average of 
11.8 class 1 and class 2 recalls of dietary supplements related to 
manufacturing problems. If we assume that each recall is a proxy for a 
reported illness, then the total number of illnesses per year is 
approximately 1,180. We recognize that our procedure generated 
uncertain estimates of the number of illnesses. With a multiplier of 
10, the estimated number of illnesses per year is 118; with a 
multiplier of 40, the total number of illnesses per year is 472.
    We estimate that the monetary value of the health losses for the 
hazards listed in table 23 of this document as a weighted average of 
the values attached to the different health outcomes associated with 
each hazard. We estimate the health losses or fatal cases as the 
monetary value of a statistical life, defined as the willingness to pay 
for a small change in the probability of death. We estimate the health 
losses for non-fatal illnesses as the sum of: (1) The imputed value of 
lost productivity, (2) the imputed value of pain and suffering, and (3) 
actual expenditures on medical treatment. We measured lost productivity 
(defined to include household and market productivity) indirectly with 
measures of functional state, which includes measures of physical 
function. We estimated the losses caused by pain and suffering with a 
symptom-problem index. We combine the functional losses with the pain 
and suffering into a single index of lost quality-adjusted life years 
(measured by the Quality of Well-Being Index). We then convert the 
quality-adjusted life years to dollars by multiplying the index numbers 
by the dollar value of a quality-adjusted life year. We used direct 
measures of medical costs, such as payments to physicians and 
hospitals. We obtained data on the cost of a hospital day and other 
medical costs from the Health Care Cost and Utilization Project's 
Nationwide Inpatient Sample, administered by the HHS Agency for 
Healthcare Research and Quality (Ref. E14).
    Table 23 of this document contains summaries of our measures of the 
health costs potentially caused by known instances of hazards 
associated with poor dietary supplement manufacturing processes for the 
decade 1990 through 1999. We estimated the health loss per day for the 
different levels of illness severity by summing the lost productivity 
(as measured by functional state) and the loss from pain and suffering 
(as measured by the symptom-problem index). These losses per day can be 
interpreted as the difference between a day of normal health and a day 
of suffering from the health conditions caused by these defective 
products. The numerical scale is a relative baseline that rests on the 
notion of a quality-adjusted life day (QALD). The QALD for a day of 
normal health equals 1; the QALD for death equals 0. The loss of QALDs 
per illness equals the daily loss multiplied by the number of days the 
illness lasts. We converted QALDs to dollars by multiplying the index 
numbers by the dollar value of a QALD. We computed the monetary value 
of a QALD using three values derived from three different values for a 
quality-adjusted life year: $100,000, $300,000, and $500,000. These 
yield values per day of $274, $822, and $1,370. Our base measures use 
$822; we show the effects of using other values in the sensitivity 
analysis.

  Table 23.--Summary of Health Effects Based on Potential Illness Associated With Recalls between 1990 and 1999
----------------------------------------------------------------------------------------------------------------
                                                                                            Expected Value of
                             Recall Class        Number of         Expected Value  of     Illness Times  Number
                                                  Recalls               Illness                 of Recalls
----------------------------------------------------------------------------------------------------------------
Chemical
----------------------------------------------------------------------------------------------------------------
Copper salts                              2                  1                     $489                     $489
----------------------------------------------------------------------------------------------------------------
Digitalis                                 1                 33                  $37,442               $1,235,599
----------------------------------------------------------------------------------------------------------------
Ephedra                                   1                  1                 $177,237                 $177,237
----------------------------------------------------------------------------------------------------------------
Hypervitaminosis A                        1                  2                   $1,264                   $2,528
----------------------------------------------------------------------------------------------------------------
Hypervitaminosis D                        2                  1                   $1,366                   $1,366
----------------------------------------------------------------------------------------------------------------
Lead poisoning (class 1)                  1                  1                  $15,591                  $15,591
----------------------------------------------------------------------------------------------------------------
Lead poisoning (class 2)                  2                 40                  $10,436                 $417,451
----------------------------------------------------------------------------------------------------------------
Niacin                                    2                  2                   $5,802                  $11,603
----------------------------------------------------------------------------------------------------------------
Pyridoxine (Vitamin B6)                   2                  1                  $12,085                  $12,085
----------------------------------------------------------------------------------------------------------------

[[Page 34923]]

 
Selenium poisoning                        1                  1                 $755,338                 $755,338
 (class 1)
----------------------------------------------------------------------------------------------------------------
Selenium poisoning                        2                  6                   $1,288                   $7,731
 (class 2)
----------------------------------------------------------------------------------------------------------------
Stannous fluoride                         1                  1                   $1,266                   $1,266
----------------------------------------------------------------------------------------------------------------
Superpotent zinc                          2                  1                     $389                     $389
----------------------------------------------------------------------------------------------------------------
Biological
----------------------------------------------------------------------------------------------------------------
Botulism (class 1)                        1                  1                 $494,683                 $494,683
----------------------------------------------------------------------------------------------------------------
Botulism (class 2)                        2                  1                   $2,044                   $2,044
----------------------------------------------------------------------------------------------------------------
Klebsiella Pneumonia                      1                  1                 $774,178                 $774,178
----------------------------------------------------------------------------------------------------------------
Salmonella (class 1)                      1                  4                  $15,298                  $61,191
----------------------------------------------------------------------------------------------------------------
Salmonella (class 2)                      2                  4                     $778                   $3,110
----------------------------------------------------------------------------------------------------------------
Allergenic
----------------------------------------------------------------------------------------------------------------
Lactose intolerance                       2                  1                     $396                     $396
----------------------------------------------------------------------------------------------------------------
Undeclared sulfites                       1                  1                     $723                     $723
----------------------------------------------------------------------------------------------------------------
Yellow <greek-i>5                         2                  5                     $723                   $3,616
 sensitivity
----------------------------------------------------------------------------------------------------------------
Yellow <greek-i>6, red                    2                  1                   $1,595                   $1,595
 <greek-i>40, blue
 <greek-i>2
----------------------------------------------------------------------------------------------------------------
Physical
----------------------------------------------------------------------------------------------------------------
Glass fragments                           2                  1                   $4,241                   $4,241
----------------------------------------------------------------------------------------------------------------
Other
----------------------------------------------------------------------------------------------------------------
L-tryptophan                              1                  7                   $1,135                   $7,946
 (Eosinophilia-Myalgia
 Syndrome (EMS))
----------------------------------------------------------------------------------------------------------------
Total                     .................                118  .......................               $3,992,397
----------------------------------------------------------------------------------------------------------------

    The hazards that occurred between 1990 and 1999 are not necessarily 
the same hazards that would occur today. For example, botulism is rare 
and may no longer be a hazard associated with dietary supplements, but 
recalls involving botulism represent generic examples of adulteration 
that could occur with other substances in the absence of good 
manufacturing practices. Also, we base our cost estimates on 
information from 1999, so it is appropriate to estimate benefits from 
the same time.
    (Comment 340) We received a comment that took issue with the way 
the recalls are counted. The comment asserts it is more appropriate to 
count each recall action as a separate recall, regardless of the number 
of different products affected.
    The same comment criticizes the inclusion of the outbreak of 
Eosinophilia-Myalgia Syndrome (EMS) in the table of what is 
characterized as ``ordinary'' recalls, since this case is analyzed 
separately as an example of a ``rare catastrophic event.'' The comment 
states that the outbreak of Digitalis should also have not been 
included in the recall list because it also was a rare event. The 
comment asserts that FDA announcements and media attention should have 
led to full reporting of any adverse events.
    Other comments generally refer to risk associated with dietary 
supplements. One comment states that botanical supplements pose minimal 
risk if dispensed directly to a patient rather than used in an 
unsupervised setting, and that toxicology and adverse event reports 
indicate that end-of-process adulteration in herbal clinics is rare. By 
contrast, another comment states that adverse events related to dietary 
supplement use led to hospital admissions at one location and that 
reports of misbranded and adulterated dietary supplements are common.
    (Response) We are not changing the way we count recalls. Each 
different recall will continue to be counted as a separate recall. How 
recalls are counted, however, does not affect the analysis. The method 
used in this analysis corresponds to an average of about one reported 
illness per recall action. A particular event can lead to many recall 
actions. If we changed the way we counted recalls so as to reduce the 
number of baseline recalls to correspond to events, the average 
reported illnesses per recall would rise in proportion. The estimated 
benefits would not change.
    We are no longer including the outbreak of EMS in our analysis of 
benefits. The product recalls associated with EMS occurred several 
years after the outbreak that we are now excluding. The continued 
benefit associated with preventing EMS is associated with

[[Page 34924]]

incorporating quality controls aimed at such hazards.
6. Benefits
    The benefits of this final rule come from ensuring the quality of 
dietary supplements. Dietary supplements should contain the listed 
ingredients in the listed amounts in product forms that disintegrate 
and dissolve. Dietary supplements should not contain any contaminants 
that would adulterate the product under section 402(a)(1), (a)(2), 
(a)(3), or (a)(4) of the act.
    Estimating the benefits of preventing adulteration and 
contamination is straightforward, at least in theory. These benefits 
are the value of reducing the risk of the acute illnesses and longer-
term complications associated with physical, chemical, and 
microbiological contamination (see table 23 of this document). The 
direct value of preventing recalls is another source of benefits from 
preventing adulteration and contamination. We estimate the benefits of 
preventing adulteration and contamination by first estimating (based on 
recall data) the number and kinds of illnesses prevented, and then 
placing a value on preventing those illnesses. We include the recall 
costs avoided by industry as additional benefits of preventing 
adulteration and contamination.
    Estimating the value of ensuring the quality of the dietary 
supplements and that they are manufactured according to their 
specifications is difficult in practice because we lack the necessary 
data on what is missing and how what is missing affects public health. 
Some dietary supplements have authorized health claim labeling that 
allows them to state their products may reduce the risk of chronic 
illnesses or conditions. Ensuring that those supplements are 
manufactured consistently according to the appropriate specifications 
will increase their effectiveness in reducing the risk of chronic 
illnesses. In this analysis, we describe those benefits but are not 
able to quantify them.
    The benefits from the final rule, then, will be:
    <bullet> Reduced health costs associated with a reduced number of 
acute illnesses (quantified),
    <bullet> Fewer product recalls (quantified), and
    <bullet> Reduced health costs associated with a reduced number of 
chronic illnesses and conditions (not quantified).
    This final rule could also enhance the benefits of the ``Dietary 
Supplement and Non-Prescription Drug Consumer Protection Act'' (Public 
Law 109-462), which requires mandatory reporting to FDA of serious 
adverse events. This final rule includes requirements that will provide 
the information needed to quickly and accurately conduct a sufficient 
traceback in the case of an adverse event. This enhanced ability to 
track information related to serious adverse events will increase both 
the accuracy and the speed of the response to such events, which may in 
many cases reduce the number of illnesses or deaths associated with 
unsafe dietary supplements.
    (Comment 341) We received many comments on the estimated benefits. 
Although we did receive comments that stated the rule would benefit 
consumers by enhancing public confidence in dietary supplements, many 
comments state that the estimated benefits in the 2003 CGMP Proposal 
were overstated. In addition, one comment states that our estimates of 
benefits are double counted, because the outbreak of EMS was included 
in the measure of benefits from preventing a large catastrophic event 
as well as total benefits of reduction of illnesses measured by 
recalls. Furthermore, comments critical of the benefits state the 
search cost model used in the analysis is not applicable or the 
benefits of reduced search costs do not exist, we lack evidence with 
which to base the estimate of reduced health care costs from 
elimination of rare catastrophic events, and recalls will not fall to 
zero as a result of implementing CGMPs.
    (Response) We agree with the comment that benefits were overstated 
because of the inclusion of the outbreak of EMS. We no longer include 
the value of preventing that or similar outbreaks in our estimate of 
benefits. Although we do not agree with the comments on the 
applicability of the search model as a measure of benefits, the 
empirical difficulties associated with quantifying those benefits have 
led us to replace the search model with a qualitative description.
    We now explain each of the three sources of benefits: Reduced acute 
illnesses, fewer recalls, and reduced chronic illnesses and conditions.
    a. Reduced health costs associated with a reduced number of acute 
illnesses. The final rule will help ensure the quality of dietary 
supplements, which will lead to improved safety of dietary supplements, 
reducing the probability of acute illness or deaths caused by 
manufacturing problems. We estimated the reduction of acute illnesses 
by using our recall records as evidence of possible illnesses; class 1 
and class 2 recalls of dietary supplements all involved adulterated 
products that could have caused illness if ingested. In the 2003 CGMP 
Proposal, we estimated the reduction of illnesses from preventing 
catastrophic events by using the public health effects of the outbreak 
of EMS that resulted from consumption of contaminated L-tryptophan. We 
agree with comments questioning the applicability of this outbreak to 
CGMP, so we are no longer including the value of preventing this 
outbreak as a benefit of this rule.
    We estimated the annual expected health benefits for acute 
illnesses prevented by taking the values of preventing particular 
illnesses and weighing them by their likely incidence as indicated by 
recall data. The acute illnesses prevented that we use to estimate 
benefits are not actual illnesses, but statistical illnesses (defined 
as the probability of illness multiplied by the population at risk) 
prevented by the reduction in risk associated with this final rule. 
These recalls indicate recurring failures to ensure the quality of 
dietary supplements. Although each class 1 and 2 recall is estimated to 
have resulted in some illnesses (which may have triggered the recall), 
there may also be other manufacturing problems that did not lead to 
recalls but that did lead to illness. Both situations are part of the 
baseline number of illnesses and deaths estimated.
    We computed the expected health benefits from preventing a single 
illness (of any type) associated with a recall as a weighted average of 
all potential illnesses. We then calculated the average health benefits 
of preventing a single illness associated with a non-fatal class 1 or a 
class 2 recall as:
Health costs prevented = (QALY x value per QALY) + medical costs
We define QALY as the average quality-adjusted life year per illness; 
as explained earlier, we computed the average by weighting the quality 
adjusted life years lost for the probability of each health outcome by 
the expected frequency of that outcome.
    To estimate the number of acute illnesses prevented, we started 
with the average number of recalls per year for the decade 1990 through 
1999. The yearly averages for the decade were six class 1 recalls and 
seven class 2 recalls. As discussed previously, we then assumed that 
these recalls represented about 1 percent of all acute illnesses caused 
by the manufacturing problems leading to the recalls. With that 
assumption, we estimated that the recalls represented about 530 acute 
illnesses from class 1 recalls and 650

[[Page 34925]]

acute illnesses from class 2 recalls.\16\ The illnesses used to 
estimate the benefits of the final rule represent a sample of acute 
illnesses that could occur without this final rule. We assume that the 
benefits computed for the average year from the decade 1990 through 
1999 represent the annual average benefits we should expect in the 
future. We do not assume that the acute illnesses prevented in the 
future will be identical to those that occurred during 1990 through 
1999.
---------------------------------------------------------------------------

    \16\In the uncertainty analysis in section XXIV.B.11 of this 
document, we used a probability distribution to represent the 
uncertainty associated with the number of illnesses. We modeled the 
number of illnesses prevented for each class as the average number 
of recalled products plus a negative binomial distribution 
representing unknown cases. The negative binomial distribution 
estimates the number of failures (unknown cases) that will occur 
before some number of successes (known cases) for a given 
probability of success. In the negative binomial distribution, we 
assumed that the numbers of recalls represented reported cases and 
that the probability of reporting equaled 1 percent (Ref. E13). The 
mean estimated number of illnesses is 100 times the reported number 
of recalls.

Table 24.--Health Benefits Estimated Using Recall Data from 1990 through
                                  1999
Estimated annual number of acute illnesses   1,180
 prevented (530 class 1 and 650 class 2
 recalls)
------------------------------------------------------------------------
Dollar estimate of average health benefit    $33,800
 for preventing an acute illness associated
 with a class 1 or class 2 recall
------------------------------------------------------------------------
Estimated dollar estimate of annual health   $40 million
 benefits
------------------------------------------------------------------------

    The estimated benefits are indeed sensitive to the choice of years. 
For 2000 through 2005, there were 75 recalls: 29 class 1, 25 class 2, 
and 21 class 3. The annual averages for 2000 through 2005 are therefore 
4.8 class 1, 4.2 class 2, and 3.5 class 3 recalls. We estimate that 
about 80 percent of the class 1 and class 2 recalls were related to 
manufacturing problems (for 1990 through 1999 over 95 percent of class 
1 and class 2 recalls stemmed from manufacturing problems). With an 
average of 9 class 1 and class 2 recalls per year, our baseline 
estimate of total associated illnesses using 2000 through 2005 data is 
900 (9 x 100). If this final rule prevents 80 percent of these events, 
then 720 illnesses will be prevented. We do not use this estimate to 
calculate baseline benefits for this final rule because we do not have 
a comparably recent estimate of costs. If the reduced number of recalls 
reflects increased controls in the industry, then the benefits and 
costs of this final rule will be lower than what we have estimated.
    (Comment 342) We received comments critical of the estimates of 
reduced illness due to recalls. One comment points out that drugs, 
despite having stringent CGMP requirements, have a higher rate of 
recalls than dietary supplements, thus providing evidence that such 
requirements do not necessarily reduce recalls. Expanding on this 
thought, other comments state that we seem to assume that new CGMP 
requirements will reduce human error to zero and no more recalls will 
occur, which is said to be unrealistic.
    Other comments express concern about the 100-fold multiplier used 
to estimate the costs related to recall-associated illnesses. The 
comment states that we, besides referencing Walker (2000) (Ref. E13 of 
this document (Ref. E16 in the 2003 CGMP Proposal)), provided no other 
information to substantiate the use of the 100-fold multiplier and 
therefore are being arbitrary. Any other number could be as accurate. 
In addition, other comments state that it is difficult to believe that 
the multiplier would be applicable to recalls associated with 
Klebsiella pneumonia and selenium poisoning, and L-tryptophan, because 
the severity of the illnesses would certainly have been associated with 
the highly publicized recalls; that is, they would not have gone 
unreported.
    Some comments present recalculated benefits. One comment estimates 
benefits from fewer illnesses as a result of the 2003 CGMP Proposal to 
be $10.9 million, rather than our estimate in the analysis of the 2003 
CGMP Proposal of $39 million. This new estimate was arrived at by 
taking into account what was characterized as double-counted benefits 
which, as mentioned earlier, were characterized as the inclusion of EMS 
in the measure of benefits from preventing a large catastrophic event 
as well as total benefits of reduction of illnesses measured by 
recalls. Another comment re-estimates the benefits as $16 million. This 
estimate was calculated assuming 100 percent of potential illnesses 
related to Klebsiella pneumonia were classified as severe (with none 
classified as deaths), and 50 percent of illnesses associated with the 
selenium recall were classified as serious and none were classified as 
deaths. This comment also disagrees with the assumption that 3 percent 
of the 100 potentially ill from the recall associated with undeclared 
ephedra would have died. Furthermore, this comment adjusts the benefits 
to take into account recalls that this comment felt were erroneously 
included in the calculation of benefits from reduced illnesses.
    (Response) We have not seen any new data or other information that 
would lead us to change the 100-fold multiplier for our basic estimate. 
We recognize that the multiplier is uncertain; different multipliers 
lead to different estimated numbers of illnesses and different 
estimated benefits. With a multiplier of 10, estimated benefits are 10 
percent of our baseline; with a multiplier of 40, estimated benefits 
are 40 percent of our baseline. The estimated benefits of this final 
rule, thus, move in proportion to the assumed multiplier. We recognize 
this uncertainty and show how it affects the estimated benefits in the 
sensitivity analysis. The multiplier implicitly assumes that the more 
severe illnesses are more likely to be reported; the average reporting 
rate for all adverse events is assumed to be about 1 percent. The 
average incorporates higher reporting rates for more severe illnesses, 
and lower reporting rates for less severe illnesses.
    The comments on the severity weights for Klebsiella pneumonia and 
ephedra did not persuade us to change these estimates. We based the 
estimates on the outcomes for severe events associated with these 
hazards. The Klebsiella weights come from the medical literature (Ref. 
E9); the ephedra weights are based on adverse events involving 
ephedrine alkaloids.
    The comparison of drug recalls to dietary supplement recalls does 
not provide data that would cause us to change our analysis. The drug 
industry is far larger than the dietary supplement industry and any 
such comparison would have to account for that difference as well as 
other differences. Expenditures on prescription drugs exceeded $200 
billion in 2004.
    (Comment 343) We received many comments regarding the use of the 
outbreak of EMS in 1989 as a basis for estimating health benefits from 
preventing a catastrophic event. The majority of the comments assert 
that CGMPs would not have prevented the outbreak. One comment expands 
this assertion by stating our claim that testing requirements would 
reduce the probability that contaminated ingredients would be released 
to the public is incorrect, because it was not known what, if any, 
contaminants caused the outbreak. Secondly, the comment states that our 
claim that complaint files would allow for fast identification of an 
adverse health event is also incorrect because the victims of

[[Page 34926]]

EMS did not know the L-tryptophan was the cause of their illnesses.
    Two other comments question the periodicity for a cycle of 
potential catastrophic events due to dietary supplements. One comment 
suggests a period of 70 years rather than our 30 years. The other 
comment does not suggest a period but rather states that, since we have 
no data to support the cycle of 30 years, and we admit it is difficult 
to know how likely rare events are, it is possible that the total 
projected benefit could be zero.
    Lastly, other comments state that the benefits from preventing a 
rare catastrophic event are double-counted. These comments state these 
benefits are double-counted because they are also included in the 
estimation of benefits from reduced recalls.
    (Response) As stated previously, we are no longer including 
estimated benefits from preventing a rare catastrophic event in the 
analysis of benefits. We continue to include the benefits of preventing 
statistical cases of EMS in the annual health benefits, because several 
recalls of L-tryptophan, which could be associated with EMS took place 
during the 1990 through 1999 period.\17\
---------------------------------------------------------------------------

    \17\We recognize, however, that the presence of L-trypotophan 
only indicates a small probability of EMS. The estimates in table 23 
of this document assume that L-trypotophan represents a 0.1 percent 
probability of EMS.
---------------------------------------------------------------------------

    b. Fewer products recalled. Implementation of the final rule will 
reduce the number of adulterated products distributed to the public, 
which will reduce the number of products recalled. Process controls and 
better recordkeeping will increase the ability of establishments to 
produce dietary supplements according to specifications and to identify 
problems before distribution. If adulterated products are caught before 
they are distributed or earlier in the production process, they will 
not need to be recalled.
    To estimate the direct benefits from fewer recalled adulterated 
dietary supplements, we estimate the number of annual recalls of 
dietary supplements that would be prevented by adherence to CGMP 
requirements in the final rule. From 1990 to 1999, FDA received reports 
on 195 recalls related to manufacturing problems, an average of 19.5 
recalls per year (Ref. E9). The average figure reported here includes 
class 3 recalls. The number of units of dietary supplements for each 
recalled product varied, so we used a distribution per recall of 1,000 
units to 34,000 units (Ref. E9). Product price (updated to 2004) also 
varies, with most prices falling between $6 per unit and $11 per unit; 
we used a most likely price of $8.50 per unit. We include an adjustment 
for the goodwill lost by the establishment as a result of the recall. 
We multiply the direct cost of the recall by two in order to include 
the lost goodwill. We also adjust for recalls that would likely not be 
prevented by the final rule. The result is an estimated savings of $1.8 
million in direct costs and $1.8 million in goodwill, for a total 
savings of about $3.6 million per year.
    (Comment 344) We received several comments on our estimates of the 
reduction in recalls. As noted previously, a comment generally states 
that drugs, despite having stringent CGMP requirements, have a higher 
rate of recalls than dietary supplements, thus providing evidence that 
CGMPs do not necessarily reduce recalls. Again, other comments state 
that we seem to hold the unrealistic assumption that the final rule 
will reduce human error to zero and no more recalls will occur. Another 
comment points out that the assumption that the final rule would cause 
the discovery of all adulteration is inconsistent with the requirement 
that firms keep complaint files. If the rule eliminates adulteration, 
the comment states, then there should be no complaints to report.
    (Response) We do not believe that recalls will fall to zero. We 
assume that the recalls identified as being preventable by this final 
rule will fall to zero, but that mistakes and other hazards will 
continue to generate recalls. In the sensitivity analysis, however, we 
show the effects of a lower level of effectiveness in preventing 
recalls associated with manufacturing problems.
    c. Reduced health costs associated with a reduced number of chronic 
illnesses and conditions. We cannot quantify the value of ensuring that 
dietary supplements contain everything in the established 
specifications (and nothing that is not in the specifications) because 
we lack the necessary data on what is missing and how what is missing 
affects public health. The public health benefits are derived from the 
reduced number of chronic illnesses and conditions. These benefits may 
arise from known nutritional effects or from uncertain nutritional 
effects.
    d. Benefits from known nutritional effects. Many of the nutritional 
benefits of vitamins and minerals are known and well-documented. For 
example, the Dietary Guidelines for Americans, 2005 states that dietary 
supplements can be used to help meet the recommended intakes of vitamin 
B12, folic acid, and vitamin D (Ref. E15). The Institute of Medicine's 
Dietary Reference Intakes include statements that supplements can be 
sources of several vitamins and minerals (Ref. E16). We have recognized 
the use of supplements in authorized health claims for calcium and 
osteoporosis (Sec.  101.72) and folic acid and neural tube defects 
(Sec.  101.79).
    In table 25 of this document, we list some of the health benefits 
associated with the consumption of various dietary supplements.

   Table 25. Selected Health Benefits from Certain Dietary Supplements
------------------------------------------------------------------------
     Dietary
    Supplement                 User                      Benefit
------------------------------------------------------------------------
Folic acid         Women of child-bearing age    Reduces the risk of
                                                  neural tube defects
------------------------------------------------------------------------
Calcium            Children and adults           Reduces the risk of
                                                  osteoporosis
------------------------------------------------------------------------
Iron               Adolescent females and women  Reduces the risk of
                    of child-bearing age          anemia
------------------------------------------------------------------------
Vitamin D          Children and adults; persons  Reduces the risk of
                    with dark skin, or with too   osteoporosis
                    little exposure to sunlight
------------------------------------------------------------------------
Vitamin B12        Persons over the age of 50    Reduces the risk of
                                                  anemia
------------------------------------------------------------------------


[[Page 34927]]

    e. Benefits from uncertain nutritional effects. We do not know the 
full range of effects (or lack of effects) of most dietary supplements. 
Vitamins and minerals with known nutritional effects in supplement form 
may have other effects that we have yet to discover. Our uncertainty is 
particularly large with respect to the nutritional effects of herbal 
and botanical supplements. The evidence is still too mixed and 
incomplete to determine the effects of most of these substances. If, 
however, herbal dietary supplements do indeed have significant 
beneficial effects on the risk of chronic illnesses and conditions, 
then if the final rule ensures that the supplements consistently meet 
their specifications, we should add those benefits to those from 
supplements having known nutritional effects.
    The benefits of this final rule that we can identify are those 
associated with the known effects. The product deficiency might be, for 
example, that packages contain some percentage less or more of the 
necessary ingredient (such as calcium) than what is listed on the 
label. The relationship between the shortage or excess amount of the 
ingredient and the probability of chronic illness would also have to be 
taken into account in order to determine the risk associated with the 
product deficiencies. The increase in the probability of chronic 
illnesses may be negligible, less than, the same, or more than the 
shortage or excess in the amount of the ingredient. The increase in the 
probability of chronic illness would also depend on how long the 
supplement contained a shortage or excess amount of the ingredient. 
Suppose, for example, that a calcium supplement contains 10 percent 
less calcium than it should for 1 year. If the average consumer takes 
calcium supplements for 20 years, would the 1-year deficiency of 10 
percent increase the probability of osteoporosis by more or less than 
0.5 percent (10 percent x (1/20))?
    If we could determine the change in the number of chronic illnesses 
prevented by dietary supplements as a result of this final rule, we 
could estimate benefits by multiplying the additional number of chronic 
illnesses prevented by the value of preventing those illnesses. The 
values consumers place on preventing illness differ across illnesses 
and across consumers, and are related to the reasons they use dietary 
supplements. We will illustrate the method with two examples: Calcium 
and osteoporosis and folic acid and neural tube defects.
    Calcium and osteoporosis. Many consumers take calcium supplements 
to reduce the probability of osteoporosis, which afflicts as many as 10 
million people over age 50 (about 8 million women and 2 million men). 
An additional 34 million men and women may be at risk for developing 
osteoporosis (Ref. E17). If ensuring that calcium supplements contain 
what they should reduces the risk of osteoporosis, the total 
osteoporosis health benefits associated with the final rule will be the 
number of cases prevented multiplied by the health costs per case. We 
estimated the health costs per case as the sum of the direct medical 
costs, the value of functional disability, and the value of the pain 
and suffering associated with the illness. Cases range in severity from 
mild to severe. A mild case, for example, might lead to a loss of 
utility (measured as quality-adjusted life years--a year of life 
adjusted for the individual's health status) of 0.14 per year for 9 
years. If we apply a discount rate of 7 percent to the years the 
condition lasts, the loss of quality-adjusted life years is about 0.9 
(6.5 discounted years x 0.14 lost utility per year). In other 
rulemakings we have used a range of values for a quality-adjusted life 
year; the range has been from $100,000 to $500,000, with a medium 
monetary value of $300,000 (68 FR 41434, July 11, 2003). With a value 
per year of $300,000, the value of preventing a mild case is about 
$270,000 (0.9 x $300,000).
    A severe case, by contrast, can lead to fractures and permanent 
disability. Also, osteoporosis in women can occur at early ages and 
last decades. If someone suffers from osteoporosis for 30 years, the 
discounted quality adjusted life years lost would be 6.9 (12.4 
discounted years x 0.56 lost utility per year). We estimate that 
medical costs for a severe case can be over $17,000. The value of 
preventing a severe, long-lasting case is therefore about $2.1 million 
((6.9 x $300,000) + $17,000).
    Folic acid and neural tube defects. Many women of child-bearing age 
take dietary supplements to help ensure their own health, and the 
health of their children should they become pregnant. For example, 40 
percent of women aged 18 to 45 take supplements containing folic acid, 
which may reduce the probability that children will be borne with 
neural tube defects (Ref. E18). Neural tube defects affect the spine 
(spina bifida) and the brain (anencephaly). About 3,000 pregnancies are 
affected each year (Ref. E18).
    The benefit of ensuring that folic acid supplements contain what 
they should equals the population at risk multiplied by the reduction 
in the probability of neural tube defects, multiplied by the value of 
preventing a neural tube defect. Neural tube defects involve large 
medical expenses, and either early death or permanent disability. The 
lifetime medical costs alone are between $400,000 and $500,000 for 
spina bifida (Ref. E19, with values updated). In recent rulemakings, we 
have used $5 million as the value of a statistical life, defined as the 
willingness to pay for reductions in small risks of premature death. 
Preventing a statistical death from anencephaly would therefore 
generate benefits of $5 million to $6.5 million. For spina bifida, one 
estimate is that an average case leads to a loss of more than 15 
quality-adjusted life years, for a monetized loss of close to $5 
million for a non-fatal case if valued at $300,000 per quality adjusted 
life year (Ref. E20). The value of preventing a case of spina bifida, 
then, is the sum of medical costs and the value of a saving the 
quality-adjusted life years, or about $5 million ($450 million value of 
quality adjusted life years + $500,000 direct medical costs).
    Estimating the total benefits of this final rule requires estimates 
of the numbers of chronic illnesses and conditions whose incidence can 
be further reduced by ensuring that dietary supplements contain what 
they should. Because we have no information on the baseline number of 
chronic illnesses caused by deficient or excessive ingredients, or on 
the change in the likelihood of chronic illness that will occur as a 
result of the provisions of this final rule, we cannot estimate the 
full benefits of ensuring that dietary supplements contain what they 
should. Our quantified benefits for this final rule must therefore 
consist entirely of the benefits from reducing the risks of acute 
illnesses and reducing the number of product recalls. The total 
benefits will be larger by an amount we are not able to quantify.
    (Comment 345) We received many comments about the estimated 
benefits as measured by the value of hypothetical search time.
    (Response) We are no longer using the search model.
    f. Total benefits. The total benefits from the final rule are the 
sum of the value of health benefits from fewer acute illnesses, the 
value of fewer product recalls, and the value of the health benefits 
from fewer chronic illnesses. Table 26 of this document shows the total 
benefits.
    (Comment 346) One comment states that our total estimated benefits 
could be as little as $21 million.
    (Response) Our current estimate of total quantified benefits is $44 
million

[[Page 34928]]

per year, once the final rule takes full effect. In addition, as 
discussed previously, there are benefits to this rule that have not 
been quantified. The unqualified benefits estimate is the mean of a 
range of estimates based on assumptions about reporting rates and the 
effectiveness of the final rule.
    In the analysis of benefits for this rule there are two large 
uncertainties: Quantified underreporting of acute illnesses and 
injuries and nonquantified benefits associated with chronic illnesses. 
Despite the best efforts by public health authorities, there will 
always be underreporting of illness and injuries. Where fatalities are 
concerned, unless there are litigation problems or the potential for 
the spread of infectious disease, there is no incentive to do extensive 
forensic work to determine whether a fatality is related to the 
ingestion of a dietary supplement. This leads to reporting most 
fatalities under the most general International Classification of 
Diseases codes. We acknowledge the large uncertainties in our estimate 
because of these factors.
    The degree of prevention of chronic illnesses due to preventing 
super- or subpotent dietary supplements depends on two factors, both of 
which are highly uncertain. The first factor concerns product benefit: 
How many dietary supplements have any beneficial effect on chronic 
illnesses and how strong are those effects? Recent work in this area so 
far has examined only a few dietary supplements, with mixed results. Of 
course, ensuring the potency of an ingredient that has adverse effects 
or has adverse interactions with drugs would subtract from the 
benefits. The second factor is the incidence and effects of subpotency 
and superpotency across products and over time: How much of a 
difference in the product need there be to generate a substantial 
adverse health effect? Because of these uncertainties, it is virtually 
impossible to make any sort of quantitative statement about likely 
effects of a regulation ensuring against superpotency and subpotency.
    Because of the uncertainties in estimating the benefits associated 
with both chronic and acute illnesses associated with manufacturing 
practices for dietary supplements, the decision to implement regulatory 
requirements becomes an exercise in weighing quantitative and 
qualitative benefits to public health against expenditure of scarce 
resources. By choosing to go forward with this rule, FDA is exercising 
precaution with respect to uncertain risks.
    In the uncertainty and sensitivity analyses in section XXIV.B.11 of 
this document, we show how uncertainty and different assumptions 
generate higher or lower quantifiable benefits. Using plausible 
assumptions about the uncertain variables, we estimate that total 
quantified benefits (using 1990 through 1999 data) most likely fall 
within a range of $8 million to $64 million per year.

                  Table 26.--Summary of Annual Benefits
------------------------------------------------------------------------
                 Benefits                               Mean
------------------------------------------------------------------------
Fewer acute illnesses                      $40 million
------------------------------------------------------------------------
Fewer product recalls                      $4 million
------------------------------------------------------------------------
Fewer chronic illnesses                    Not quantified
------------------------------------------------------------------------
Total quantified benefits                  $44 million
------------------------------------------------------------------------

7. Costs
    The same changes in manufacturing practices that produce benefits 
also have opportunity costs. Due to the increased expenditures of 
complying with this final rule, firms may spend fewer resources on 
potentially costly activities such as worker safety, product 
development and marketing, or voluntary testing of the efficacy of 
their products. The final rule will require dietary supplement 
establishments to adopt some new practices in order to manufacture, 
package, label, or hold their products in compliance with CGMP 
requirements. In some cases, establishments will make capital 
improvements to the physical plant, add or replace equipment or 
controls, perform additional maintenance, establish written procedures, 
keep records, carry out tests, monitor production and process controls, 
or execute a variety of additional tasks that they may not have 
previously performed. Not all firms will comply; some will go out of 
business or move their plants to other countries and not sell their 
product in the United States. We estimated the additional costs of 
production associated with the final rule and the leading regulatory 
options using the survey to estimate baseline manufacturing practices 
(Ref. E2).
    a. Description of the costs. To estimate costs for the dietary 
supplement industry, we initially divided the industry into four 
product categories and three size categories. Because the survey showed 
that there were only a few establishments in some categories, we 
consolidated the size and product into three size categories. The size 
categories were:
    <bullet> Very small (fewer than 20 employees),
    <bullet> Small (20 to 499 employees), and
    <bullet> Large (500 or more employees).
    Although this consolidation glosses over the important differences 
across products, the purpose is to estimate the broad average costs of 
the rule.
    For each size category, we constructed a cost model that included 
every provision of the final rule. We then attached a cost to each 
provision that had an additional activity associated with it. Most 
provisions did not have costs attached to them, because they were 
either descriptive or the costs were included elsewhere.
    The costs will be the marginal, or additional, costs of the 
activities producers undertake in response to the provisions of the 
final rule. In the cost model, we expressed the cost as cost per unit, 
with the unit being the establishment, the number of employees, or the 
annual number of batches produced or affected.
    b. Summary of general comments on costs. We received many comments 
on the costs of the 2003 CGMP Proposal. Many of the comments were 
general in nature and addressed the belief that our economic analysis 
underestimated the total costs of the 2003 CGMP Proposal, both first 
year costs and annual costs. Numerous comments point to the rule's 
testing requirements as the main cause of the high costs. Comments also 
state that the analysis underestimates costs of hiring new workers, 
capital equipment, and holding and distributing costs. In addition, 
some comments point out that the economic analysis did not include 
estimates of costs of holding reserve samples and tracking product 
complaints.
    As a result of the 2003 CGMP Proposal, comments assert, product 
choice would decline, prices of existing products would increase, and 
many businesses, particularly small businesses, would be forced to shut 
down. One comment states there could be a decrease in spending on 
research and development. Some comments state that the burden on 
business could be alleviated by allowing the use of certificates of 
analysis for incoming raw materials and using a statistical, or more 
flexible, testing regime instead of requiring final product testing on 
all batches.
    A comment from a trade association representing ingredient 
suppliers and manufacturers in the dietary supplement industry accepts 
our assumptions on the following variables:
    <bullet> The number of control points,
    <bullet> The average number of ingredients per product, and
    <bullet> The average cost per test.
    Other comments, however, state that the average number of 
ingredients is

[[Page 34929]]

higher than estimated and that the average cost per test is higher than 
estimated; one comment from a manufacturer states that its average cost 
was 2.5 times our estimate. These comments came from self-described 
small firms.
    (Comment 347) One comment states that we failed to consider start-
up costs.
    (Response) We include start-up costs (also referred to as set-up or 
one-time costs) throughout this analysis.
    (Comment 348) Many comments on the regulatory impact analysis 
targeted our estimates of firms' batches per year. Nearly all comments 
about batches state that our batch estimates are too low. For example, 
an industry trade groups claims our estimate of 309 batches per year 
for large firms is ``implausibly low.'' The same comment states that 
the distribution of the number of batches per firm of 309, 554, and 223 
for large, small, and very small firms is ``illogical'' because it does 
not make sense that large firms would have fewer batches per year than 
small firms.
    (Response) Due to a contractor's error, we used an inaccurate 
estimate of the annual number of batches in the analysis of the 2003 
CGMP Proposal. The analysis of the final rule corrects for this error. 
The corrected mean numbers of batches per firm are 444 for very small, 
2,436 for small, and 1,164 for large firms. The corrected estimates of 
the number of batches continue to show that small firms produce more 
batches than large firms. Comments from self-described small firms 
suggest that this distribution of batches is reasonable. These comments 
state that small firms produce many small batches of product using 
machinery with smaller capacity than that used by large firms. Very 
small firms produce the fewest number of batches per firm of the three 
size categories because of their much lower output.
    (Comment 349) One comment states that we used faulty data in the 
economic analysis.
    (Response) In accordance with our information quality guidelines, 
we have used the best available data in this analysis. As explained in 
the response to comment 348, the survey results used in the analysis of 
the 2003 CGMP Proposal included an inaccurate estimate of the number of 
batches of dietary supplements produced. We use the corrected estimate 
in the analysis of this final rule.
    (Comment 350) Some comments dispute the estimated testing costs. In 
particular, comments question our assumptions on:
    <bullet> The number of tests required per batch,
    <bullet> The number of tests already being performed,
    <bullet> The costs to perform specific analytical tests, and
    <bullet> The development of analytical methods.
    (Response) The final rule reduces the number of required tests. In 
the final rule, we account for tests where no analytical methods have 
been developed. We now require fewer tests, although we anticipate that 
some testing will take place associated with the creation of 
certificates of analysis required for component specifications and as 
verification for process controls. We now assume that the tests will 
be:
    <bullet> One identity test for each shipment lot of incoming 
dietary ingredients (e.g., vitamin C);
    <bullet> Tests of subsets of shipment lots by supplier firms to 
create certificates of analysis for identity of other components (e.g., 
sugar);
    <bullet> Tests of subsets of shipment lots for other specifications 
in the certificates of analysis;
    <bullet> Tests of subsets of batches of dietary supplements for 
microbial, chemical, or physical contaminants;
    <bullet> Tests of subsets of batches of dietary supplements for 
specifications; and
    <bullet> Tests for meeting requirements that water used to 
manufacture dietary supplements complies with Federal, State, and local 
requirements and does not contaminate the dietary supplement.
    We are not changing our estimate of the current prevalence of 
testing, which is based on the survey of manufacturers (Ref. E2). We 
would only revise this estimate in light of new data of comparable 
quality to that provided by the survey.
    (Comment 351) We did receive two comments favorable to 
recordkeeping, stating that master and production batch records were 
good to adopt and that associated costs will be minimal. One of the 
comments states that the level of detail may be unrealistic for a small 
firm, but also states that any final regulation could be made more 
flexible for small manufacturers.
    Although there were favorable comments, we received several 
comments critical of the recordkeeping requirements. These comments 
make general statements that the economic analysis underestimates the 
recordkeeping burden and some added that these requirements go beyond 
the CGMPs for food. In addition, several of the comments include firms' 
own estimates of costs of complying with the recordkeeping requirement. 
Comments estimate costs in the range of $11,000 to $64,000.
    (Response) The recordkeeping requirements in the final rule differ 
from the 2003 CGMP Proposal; revised estimates are included in this 
final regulatory impact analysis and paperwork reduction analysis.
    (Comment 352) We received a favorable comment regarding the 
requirements for physical plant and equipment, saying that, although 
the costs would be moderate, the result would be higher quality 
products. Another comment states that, although not unrealistic, the 
provision would be very costly.
    Other comments are more critical. One comment estimates that 
renovation expenses would amount to approximately $600 million over the 
entire industry, as opposed to our estimate of $45 million. This 
comment states that the reason our estimates in the 2003 CGMP Proposal 
were too low is that we apply a reduction factor which assumes that 18 
percent of very small firms, 10 percent of small firms and 1 percent of 
large firms will have to make capital improvements. It is more 
appropriate, the comment states, to assume that most facilities will 
need to renovate about 10 percent of their plant, regardless of firm 
size. In addition, the requirement that plants have smooth, hard 
surfaces on all floors, walls, and ceilings is unrealistic and would 
add quite a bit of cost. The comment asserts no company will have such 
surfaces throughout the plant and this is not a requirement in either 
the food or drug CGMP requirements. Other comments echo the belief that 
capital expenditures would be greater than our estimates and would be 
excessively burdensome. One comment estimates this cost at 
approximately $83,000 per facility.
    The comment also estimates that a large firm that needs to expand 
its capacity could expect to incur costs of $240,000, as opposed to the 
$2,000 that the comment says we estimated for large firms. In addition, 
it is pointed out that equipment costs could be burdensome to small 
firms, which likely do not have well-equipped labs. This thought is 
affirmed by other comments that estimate that new equipment could cost 
anywhere from $50,000 to $1 million, with annual costs estimated 
between $15,000 and $100,000. In addition, expansion of laboratory 
space is estimated at $200 per square foot, as opposed to the agency's 
estimate of $50 per square foot. Lastly, one comment suggests we work 
with the Internal Revenue Service to allow for more rapid depreciation 
of facility costs to help small businesses make facility upgrades.
    (Response) In the analysis of the 2003 CGMP Proposal, we estimated 
the

[[Page 34930]]

number of firms needing to make capital expenditures associated with 
the rule as a distribution, with the parameters of the distribution 
determined by the size of the facility. We assume that if a firm does 
make a capital investment in response to the rule, it would affect 
about 10 percent of the plant. With an estimated cost of $50 per square 
foot, and the average size of a very small plant of about 25,000 square 
feet, the cost per very small establishment making a capital investment 
would be about $125,000. With the average size of a small plant of 
about 70,000 square feet, the cost per small establishment making a 
capital investment would be about $350,000. With the average size of a 
large plant of about 600,000 square feet, the cost per large 
establishment making a capital investment would be about $3 million 
(Ref. E2). We assume that most facilities will not need to make capital 
investments to meet the sanitation requirements of this final rule as, 
according to the survey results, most establishments already meet the 
sanitation standards of this final rule. This would not be possible if 
their facilities were inadequate. We note that the final rule does not 
require smooth and hard surfaces throughout the plant.
    We estimated the capital costs as the costs of minor renovations to 
help meet sanitation requirements, not as the cost of, for example, 
expanding the size of a laboratory or some other technically 
sophisticated change. Although some facilities may choose to expand 
laboratories, the testing requirements of this final rule should be 
able to be met by existing laboratory facilities within or outside of 
the manufacturing facilities.
    Working with the Internal Revenue Service on depreciation is beyond 
the scope of our authority. We will provide advice on financing capital 
improvements through our small business representatives in the Office 
of Regulatory Affairs.
    (Comment 353) Many comments address costs resulting from what 
industry describes as the exhaustive testing requirements outlined in 
the 2003 CGMP Proposal. Comments point out that the requirement to test 
every ingredient would be very costly for firms large and small, with 
many firms stating that they risk going out of business. In addition, 
several comments add that the testing requirements would do little to 
enhance product quality. Many comments assert that allowing the use of 
a certificate of analysis would reduce the amount of tests performed on 
a shipment of incoming raw materials, reducing redundant testing, and 
also reducing the risk that a firm may go out of business. Other 
comments state that allowing statistical testing regimes would also cut 
down on testing costs.
    (Response) As we already have discussed in this section, we have 
reduced the amount of required testing in this final rule. The final 
rule requires testing the identity of every incoming dietary 
ingredient. However, the final rule allows for use of certificates of 
analysis in place of identity tests of other components and other tests 
of incoming dietary ingredients and other components. The final rule 
also allows sound statistical testing regimes for finished products. We 
recognize, however, that it may be possible for a manufacturer to 
demonstrate, through various methods and processes in use over time for 
its particular operation, that a system of less than 100 percent 
identity testing would provide no material diminution of assurance of 
the identity of the dietary ingredient as compared to the assurance 
provided by 100-percent identity testing. To provide an opportunity for 
a manufacturer to make such a showing and reduce the frequency of 
identity testing of components that are dietary ingredients from 100 
percent to some lower frequency, we decided to provide, in an interim 
final rule published elsewhere in this issue of the Federal Register, a 
procedure that allows for submission to, and review by, FDA of an 
alternative to the required 100-percent identity testing of components 
that are dietary ingredients, provided certain conditions are met.
    (Comment 354) One comment states that our cost estimates are based 
on the assumption of only two ingredient tests, an assumption which the 
comment calls into question. For multivitamins, one comment estimates 
about 8 separate tests and 16 separate assays, depending on the 
nutrients present.
    (Response) In the analysis of this final rule, we assume one 
identity test per incoming shipment lot of dietary ingredients based on 
the revisions made to the final rule compared with the 2003 CGMP 
Proposal.
    (Comment 355) Many comments include individual estimates of testing 
costs. For example, two comments estimate an average cost of about $100 
per test, and other comments estimate averages as high as $360, as 
opposed to our estimate of about $60 per test. Several other comments 
claim that the costs of finished product testing alone would be ``at 
least 100 times'' greater than our estimates; other comments state that 
testing costs would almost equal the costs of manufacturing. One 
comment estimates testing costs for firms of all sizes at $245 million, 
as opposed to our estimate of $24 million, although another contains 
estimates as high as $13.6 million annually for one firm. Two comments 
concede that some finished product testing may be necessary.
    In addition, some comments state that our estimate of finished and 
raw material testing is off by a multiple of three to six. One comment 
states that, for companies that have products which contain a large 
number of ingredients expensive to test, very large costs will be 
incurred. This comment also states that our cost estimates do not 
include in-process testing, which they claim the rule would clearly 
require. Specifically, our analysis suggests that an average of 2.5 in-
process tests per batch are likely to be needed at critical control 
points. In addition, the comment maintains that our analysis showed 
that additional testing may be required for an average of 2.5 
components of herbal products and 7.5 components of vitamin products, 
but our estimates do not include costs of the tests. Finally, comments 
point out that, if the production system is properly controlled, then a 
``reduced schedule'' of final product testing is justified and that 
focusing excessive resources on end-product testing does not constitute 
GMP. Quality controls should be built into the production and process 
system from the beginning of the manufacturing process.
    A comment also states that our estimates of firms that already test 
are inaccurate. The comment asserts that our estimates are overstated 
and they also think we have understated that proportion of finished 
batches not currently being tested. In addition, the comment claims 
that ``even large firms that are testing 90 percent of their products 
are unlikely to be performing the exhaustive level of testing required 
by the 2003 CGMP Proposal, namely testing every component of every 
batch of finished product.''
    The comments point out that our cost estimates do not include 
estimates for the cost of developing methods of analysis for 
ingredients. At a minimum, one comment states this estimate should be 
$2 million (the cost of 100 methods at a minimum of $20,000 each). 
Several comments point out that often there are no existing 
scientifically valid analytical methods to test finished products, 
especially botanical products. Another comment states that costs of 
analytical testing are at least three times our estimate, and could be 
as high as eight times our estimate. Because of this, many comments 
call for the use of a certificate of analysis in place of analytical 
testing.

[[Page 34931]]

    Another comment states some unintended consequences could occur in 
the industry due to the testing requirements, including stress on the 
current contract laboratory facilities and in-house laboratories, and 
also increases in holding costs, due to changes in turn-around time at 
outside labs. Other comments point to the loss of product choice that 
could occur if the testing requirements force manufacturers to go out 
of business or discontinue certain products.
    (Response) In response to comments, we have revised the testing 
requirements in the final rule. We also have revised our estimates of 
the costs of testing. In what follows, we describe the estimated number 
and costs of tests required by this final rule.
    The final rule requires tests for identity for each incoming 
shipment lot of dietary ingredient. Estimating the number of tests per 
batch is complicated, because the tests are required on the shipment 
lots and we have data only on the number of batches of dietary 
supplements produced. For example, if a shipment lot of some dietary 
ingredient is used in six batches of final products, it would need to 
be tested for identity only once. The number of required identity tests 
per batch of final product will equal the number of dietary ingredients 
per batch, divided by the average number of batches per shipment lot 
(to account for the production of multiple batches of dietary 
supplements from single lots of components). In addition to the 
required identity tests, a subset of other components will be tested 
for identity (these tests are likely to be the responsibility of 
suppliers and need only be done once per batch no matter how many 
recipients of those batches).
    The quantity and quality of evidence on the variables used to 
estimate the number of tests varies greatly. In this section, we 
explain the evidence and assumptions we used to construct the formulas 
for the number of tests.
    Number of dietary ingredients. We based our measure of the number 
of dietary ingredients per product on a sample of almost 3,000 dietary 
supplement labels (Ref. E7). Although some ingredients may be missing 
from the labels and some listed ingredients may be missing from the 
products, the ingredient list represents the best evidence we have on 
what ingredients are used in dietary supplements. Although comments 
claimed that we underestimated the number of ingredients, they offered 
no evidence that would persuade us to change our estimates, which are 
based on a sample representing at least 10 percent of the products in 
the market.
    According to the sample of listed ingredients, vitamin and mineral 
products contain about 13 listed dietary ingredients. Other dietary 
supplements, mainly herbals, contain about four listed dietary 
ingredients (Ref. E7).
    Number of unlisted components. Dietary supplements are manufactured 
using solvents, binders, and lubricants that may not show up in the 
final product. An industry source (Ref. E21) says that four to six 
unlisted components are typical per product, although fewer are 
certainly possible. The minimum number is zero. Based on industry data, 
we assume that the number of unlisted components would be zero to six 
for vitamins and minerals, and zero to four for herbal and other 
products.
    Number of shipments (i.e., shipment lots) of ingredients and 
unlisted components. We have no direct information on the number of 
shipment lots of dietary ingredients and other components. We also have 
no information on the number of shipments per lot or on the number of 
shipments per batch. It is costly to store components, so some 
establishments may buy many small lots of dietary ingredients and other 
components rather than a few large lots. Crude botanical and other 
ingredients are inherently unstable and may lose their stability in 
even a short time unless costly temperature, humidity, and light 
controls are in place. We also know, however, that some dietary 
ingredient suppliers produce and ship ingredients in large lots. For 
dietary supplements produced using part of a large production run of a 
dietary ingredient, the number of batches per shipment lot could be 
large. Also, some producers buy a single large shipment lot of a raw 
material and use it in many batches. We assume that as many as 12 
batches per shipment lot of dietary ingredient is a plausible maximum. 
Based on consultation with industry (Ref. E21), we assumed, in the cost 
calculation, that 1 was the minimum and 12 the maximum number of 
batches produced per lot, with 6.5 the average. We received no comments 
on our use of the assumption in the analysis of the proposed rule and 
continue to use it in our analysis of the final rule. In the 
sensitivity analysis, we show how costs change when we change the 
assumption.
    Number of batches produced. We have survey results on the number of 
batches produced per establishment (Ref. E2). Several comments stated 
that we underestimated the number of batches produced, which we found 
to be the case because of an erroneous calculation in the contractor's 
report. In the revised contract survey results, very small 
establishments produce an average of 444 (revised from 223) batches per 
year, small establishments produce an average of 2,436 (revised from 
554) batches per year, and large establishments produce an average of 
1,164 (revised from 309) batches per year.
    Number of final product tests per batch. We have reduced the number 
of tests required for final products. We assume that establishments 
will test a representative sample of batches to ensure that the final 
products meet specifications. We do not specify any particular 
statistical sampling plan.
    Costs per test. We estimate the costs per test partly with 
published prices of independent laboratories as posted on the Internet 
(Refs. E22 and E23), and partly from our conversations with FDA and 
industry experts on testing. Testing costs vary according to frequency 
and complexity. The more frequently technicians perform tests, the 
lower are the costs per test. Many tests require sophisticated 
equipment, such as gas chromatography, high pressure liquid 
chromatography, distillation, extraction, various spectrophotometers, 
and other types of equipment. Using sophisticated equipment requires 
trained personnel. Even simple physical or organoleptic testing 
requires training or experienced personnel. The type of ingredient, 
compound, or product can also affect the cost because some are easily 
identified using routine or single step techniques and others require 
multiple steps or complex techniques, especially if there are similar 
products that can be mistaken for the products being identified. The 
type of defect tested for affects the cost; some defects can be found 
visually if they are found on the surface, but others are latent. Some 
tests require multiple samples or multiple steps. In addition, tests 
require taking and preparing samples, whose cost can vary. By assuming 
a single distribution for testing costs, we may overestimate testing 
costs for sectors or products with below-average costs and 
underestimate testing cost for sectors with above-average costs. In the 
cost model, for example, we distinguish between botanical ingredients 
and nonbotanical ingredients in the number of tests, but not in average 
testing costs. If the average cost of testing botanical products is 
higher than the average cost for vitamins and minerals, the 
distribution of costs may underestimate total testing costs for 
botanical products. We do not have sufficient information

[[Page 34932]]

on the range of testing costs for botanical ingredients to determine if 
the average cost of testing is higher or lower than for other 
ingredients.
    The average cost per test is about $60, based on a range of costs 
we found on the Internet. This cost represents the full cost of 
carrying out a test, including collecting and storing the sample, the 
time for training the personnel who carry out the test, and any 
associated records. We assume that $20 per test represents a lower 
bound. Although some Internet prices for tests are as high as $300, we 
assumed that, with frequent testing, $150 would be a more plausible 
upper bound average cost. The majority of listed prices fell into the 
$20 to $80 range, so we selected $50 (the midpoint) as most likely.
    The number and cost of tests: Summary. We estimate the number of 
tests required of the representative manufacturer as a weighted average 
of the number of tests required for vitamins and minerals and the 
number of tests required for all other supplements (which were mainly 
herbal products). The weights, shown as follows, differ by size of 
manufacturer:
    <bullet> 24 percent of very small manufacturers produce vitamins 
and minerals; 76 percent produce other dietary supplements.
    <bullet> 42 percent of small manufacturers produce vitamins and 
minerals; 58 percent produce other dietary supplements.
    <bullet> 69 percent of large manufacturers produce vitamins and 
minerals; 31 percent produce other dietary supplements.
    Most establishments already conduct some tests, or send samples out 
for testing. We therefore adjusted the estimated testing costs of the 
final rule to include only required tests and to account for the 
testing costs currently borne voluntarily by manufacturers. The survey 
results showed how many respondents were conducting various types of 
tests.

            Table 27.--Values Used to Estimate Testing Costs
------------------------------------------------------------------------
          Name           Value or Distribution Used         Source
------------------------------------------------------------------------
Number of dietary        Vitamins and minerals--13   Sample from 3,000
 ingredients per         All other categories--4      dietary supplement
 product batch                                        labels (Ref. E7)
------------------------------------------------------------------------
Number of identity       1 identity test per         Based on
 tests per dietary        ingredient lot              requirements of
 ingredient lot                                       final rule
------------------------------------------------------------------------
Number of identity       1 identity test per subset  Assumption based on
 tests per other          of component lots           use of
 component lot                                        certificates of
                                                      analysis for
                                                      ingredients
------------------------------------------------------------------------
Number of tests for      1 to 5 tests per subset of  Assumption based on
 specifications per       ingredient lots             use of
 ingredient lot                                       certificates of
                                                      analysis for
                                                      ingredients
------------------------------------------------------------------------
Number of unlisted       0 to 6 components for       Ref. E21
 components               vitamins and minerals, 0
                          to 4 for herbal and other
                          products
------------------------------------------------------------------------
Number of shipments      1 to 12 batches per         Assumption based on
 (lots) of ingredients    shipment lot of dietary     discussions with
 and unlisted             ingredients                 industry
 components
------------------------------------------------------------------------
Number of batches        Very small establishments-  Ref. E2
 produced per year        444
                         Small establishments-2,436
                         Large-1,164
------------------------------------------------------------------------
Number of final product  1 test per subset           Based on
 tests per batch                                      requirements of
                                                      the final rule
------------------------------------------------------------------------
Costs per test           Beta pert distribution      Refs. E22 and E23
                          skewed rightward between
                          $20 and $150; $50 most
                          likely; $60 average
------------------------------------------------------------------------

    (Comment 356) We received comments on labor costs that would be 
incurred as a result of the 2003 CGMP Proposal. All comments state that 
personnel costs will increase significantly. One comment states that 
the average manufacturing wage we used to estimate labor costs, $15.65, 
does not reflect the true cost of additional labor, since higher 
skilled employees, such as quality control engineers and, as one 
comment asserts, Ph.D.-level employees, will need to be hired to comply 
with the rule. This comment states that, including benefits, the wage 
actually ranges between $23.28 and $72.00 per hour, depending on skill. 
Other comments estimate additional annual labor costs ranging between 
$25,000 and $350,000.
    (Response) We used more recent estimates to the average 
manufacturing wage cost of $26 per hour to estimate the cost of labor 
(Ref. E24). The comment that asserted Ph.D.-level employees are needed 
to comply with the rule, provided no basis for this assertion. We 
disagree that Ph.D.-level workers are needed for the tasks required by 
this final rule because most of the costs estimated as labor costs all 
involved ordinary labor tasks such as sanitation, monitoring, and 
recordkeeping. For more difficult or complicated tasks, more skilled 
workers may be required, but the overall average labor cost represents 
the best overall estimate for valuing the average cost of labor in the 
industry. We assume that various tasks required by the final rule would 
take some number of hours per year, per batch of product, or per square 
foot of physical plant.
    Estimating costs. We initially gathered information and made 
assumptions about the full cost of a provision. We then adjusted these 
estimates to account for the many activities already being carried out, 
as well other activities that would not have to be carried out by all 
establishments. We used the survey to estimate the likelihood that an 
establishment will incur a cost. To get an estimate of the average cost 
of a provision (adjusted for baseline activities) for each category, we 
multiply the average cost per establishment by the probability that the

[[Page 34933]]

establishment will need to undertake the expense (one minus the 
probability that the establishment is already doing it). For each 
provision of the final rule, the simulation carried out the following 
calculation:
Cost per unit of analysis for each provision =
number of units of analysis per establishment x
probability that establishment incurs cost x
cost per provision per establishment.
    We estimate both a setup cost (a one-time fixed cost) of the 
provision and an annual recurring cost. To get the total costs of the 
rule, we multiply the number of establishments in each size category 
(from the survey) by the average costs per establishment in that 
category. We then adjust for the establishments that did not respond to 
the survey but are believed to be in the industry. Two hundred thirty-
eight establishments responded to the survey; we estimate that 1,566 
firms are in the industry, including ingredient suppliers. The number 
of firms covered by most of the provisions will therefore be about 
1,460.
    We estimate total costs with the following calculation:
(Number of very small establishments x costs per very small 
establishment) +
(number of small establishments x costs per small establishment) +
(number of large establishments x costs per large establishment) +
(number of warehouses x costs per warehouse).
    The rule is complex and the industry is made up of very different 
kinds of firms, so cost estimates are averages with, in some cases, 
large variances. The cost per unit, number of batches and employees, 
and probability that the establishment would incur the cost all contain 
uncertainty. The values in table 28 of this document are used in the 
cost estimates, and are generated from multiple sources.

         Table 28.--Additional Values Used in Cost Calculations
------------------------------------------------------------------------
                          Value or Distribution
          Name                     Used                   Source
------------------------------------------------------------------------
Average wage per hour    $26                      Employment Index,
                                                   Bureau of Labor
                                                   Statistics (Ref. E24)
------------------------------------------------------------------------
Average size of          very small = 24,674      Ref. E2
 establishments in       small = 71,354
 square feet             large = 596,000
------------------------------------------------------------------------
Average number of        very small = 7.6         Ref. E2
 employees               small = 95
                         large = 1,005
------------------------------------------------------------------------
Procedures               8 to 16 hours setup      Ref. E25
                          time for small firms;
                          30 to 40 hours for
                          large firms; annual
                          cost is 10 percent of
                          setup time per
                          provision
------------------------------------------------------------------------
Personnel sanitation     1 hour per week per      Assumption, based on
                          worker                   requirements of final
                                                   rule
------------------------------------------------------------------------
Sanitation time for      1 hour per week for      Assumption, based on
 physical plant           very small               difference in average
                          establishments; costs    physical plant size
                          per small and large
                          plants scaled in
                          proportion to size of
                          plant
------------------------------------------------------------------------
Sanitation supervisor    1 hour per week          Assumption, based on
                                                   requirements of final
                                                   rule
------------------------------------------------------------------------
Pest control setup       $1,500 to $2,000 for     Ref. E26
 costs                    very small
                          establishments; $1,800
                          to $2,400 for small
                          establishments; $2,600
                          to $3,400 for large
                          establishments.
                          Average for each size
                          establishment was
                          midpoint ($1,750,
                          $2,100, $3,000)
------------------------------------------------------------------------
Pest control annual      $400 to $600 per month   Ref. E26
 costs                    for very small
                          establishments; $480
                          to $720 for small
                          establishments; $700
                          to $1,000 for large
                          establishments.
                          Average for each size
                          establishment was the
                          midpoint ($500, $600,
                          $850)
------------------------------------------------------------------------
Renovation cost          $50 per square foot;     Based on construction
                          with 0 to 20 percent     costs and square feet
                          of physical plant to     (Ref. E2)
                          be renovated, with 10
                          percent most likely
------------------------------------------------------------------------
Equipment replacement    For very small           Assumption, based on
                          establishments, 0 to     size of
                          $1,000; costs per        establishments (Ref.
                          small and large plants   E2)
                          scaled in proportion
                          to size of plant
------------------------------------------------------------------------
Setup costs for          $500 for hardware, 16    Software costs and
 automatic equipment      hours                    assumptions about
                                                   labor hours
------------------------------------------------------------------------
Annual costs for         10 percent of setup      Assumption based on
 automatic equipment      costs                    requirements of the
                                                   final rule
------------------------------------------------------------------------

[[Page 34934]]

 
Sanitation of equipment  5 hours per week for     Assumption based on
 and surfaces             very small               average sizes of
                          establishments; costs    establishments (Ref.
                          per small and large      E2)
                          plants scaled in
                          proportion to size of
                          plant
------------------------------------------------------------------------
Holding products and     Same as costs of         Based on average sizes
 dietary ingredients:     equipment upgrades       of establishments
 Capital requirements                              (Ref. E2)
------------------------------------------------------------------------
Default probabilities    For very small           Based on results of
 that establishments      establishments, 0.2;     survey for other
 are not currently        for small                practices (Ref. E2)
 acting in accordance     establishments, 0.05,
 with a provision         for large
                          establishments, 0.01
------------------------------------------------------------------------

    The total setup costs for this final rule will be $41 million, 
spread out over the 36 months following the publication date of the 
final rule. The annual costs, once the final rule is fully implemented, 
will be $164 million, with the two largest costs being $52 million for 
testing and $24 million for records. The estimated total cost is the 
mean of a range of estimates based on the data and assumptions 
described in tables 27 and 28 of this document. In the uncertainty and 
sensitivity analyses in section XXIV.B.11 of this document, we show how 
uncertainty and different assumptions generate higher or lower 
estimated costs. Using plausible assumptions about the uncertain 
variables, we estimate that total quantified costs most likely will 
fall within a range of $104 million to $322 million per year.
8. Summary of Benefits and Costs
    We estimate that, once it is fully implemented, the annual 
quantified benefits from the final rule will be $8 million to $64 
million, with a mean estimate of $44 million. However, there are 
potentially large benefits of the rule that we were not able to 
quantify. The annual costs will be $104 million to $322 million, with a 
mean estimate of $164 million. The rule will not be fully effective 
until 36 months after the publication date. Table 29 of this document 
shows how the phase-in of the final rule will generate the costs and 
quantifiable benefits for the first 4 years. Table 30 of this document 
shows the present and annualized values of costs and quantifiable 
benefits over 20 years, calculated at discount rates of 3 percent and 7 
percent. We have determined, based in part on the analysis presented 
here, that the benefits, quantified and unquantified, of this final 
rule justify the costs.

                                                   Table 29.--Costs and Quantifiable Benefits by Year
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                       1st year                   2nd year                   3rd year                   4th year
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs (in millions)                                                 $16                       $120                       $190                       $164
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits (in millions)                                               $3                        $29                        $44                        $44
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                       Table 30. Present and Annualized Values of Costs and Quantifiable Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                Annualized Value over 20      Annualized Value over 20
                                            Present value at 3         Present value at 7        years at 3 percent (in        years at 7 percent (in
                                          percent (in billions)      percent (in billions)              millions)                     millions)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs                                                        $2.3                       $1.6                          $153                          $149
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits                                                     $0.6                       $0.4                           $40                           $39
--------------------------------------------------------------------------------------------------------------------------------------------------------

    In table 31 of this document we show the annual costs for each 
subpart of the regulation. We identify selected costs for particular 
activities for some of the subparts. We are unable to estimate benefits 
by subpart, because we estimate the benefits by type of benefit rather 
than by provision of the final rule.

                                           Table 31.--Costs by Subpart
----------------------------------------------------------------------------------------------------------------
              Subpart                      Setup Cost (in millions)              Annual Cost (in millions)
----------------------------------------------------------------------------------------------------------------
A. General provisions                                      not applicable                         not applicable
----------------------------------------------------------------------------------------------------------------
B. Personnel                                                         $1.5                                  $15.7
----------------------------------------------------------------------------------------------------------------
C. Physical plant and grounds                                       $34.0                                  $17.4
----------------------------------------------------------------------------------------------------------------
D. Equipment and utensils                                            $0.9                                   $2.3
----------------------------------------------------------------------------------------------------------------
E. Establish production and                                          $0.5                                  $66.1
 process control system
  Subtotal for identity testing                                negligible                                  $45.0
  Subtotal for all other testing                                     $0.3                                  $ 6.8
----------------------------------------------------------------------------------------------------------------

[[Page 34935]]

 
F. Quality control                                             negligible                                   $2.1
----------------------------------------------------------------------------------------------------------------
G. Components, packaging, labels,                              negligible                                  $31.6
 and dietary supplements received
----------------------------------------------------------------------------------------------------------------
H. Master manufacturing record                                       $0.1                             negligible
----------------------------------------------------------------------------------------------------------------
I. Batch production record                                     negligible                                   $5.4
----------------------------------------------------------------------------------------------------------------
J. Laboratory operations                                             $0.2                             negligible
----------------------------------------------------------------------------------------------------------------
K. Manufacturing operations                                    negligible                                   $2.2
----------------------------------------------------------------------------------------------------------------
L. Packaging and labeling                                            $0.1                                  $10.8
 operations
----------------------------------------------------------------------------------------------------------------
M. Holding and distributing                                          $2.7                                   $0.5
----------------------------------------------------------------------------------------------------------------
N. Returned dietary supplements                                negligible                                   $0.2
----------------------------------------------------------------------------------------------------------------
O. Product complaints                                                $0.1                                   $4.5
----------------------------------------------------------------------------------------------------------------
P. Records and recordkeeping                               not applicable                         not applicable
----------------------------------------------------------------------------------------------------------------
Paperwork cost for all subparts                                      $3.7                                  $24.2
----------------------------------------------------------------------------------------------------------------

    (Comment 357) We received several comments on the summary of the 
costs and benefits. In general, the comments state that we 
overestimated the benefits of the 2003 CGMP Proposal and underestimated 
the costs. Other comments assert that total estimated benefits of the 
2003 CGMP Proposal would not be $216.6 million, as estimated by us, but 
as low as $13.9 million. Comments also estimate first-year costs as 
high as $629 million, with annual costs estimated as high as $860 
million. Other comments predict product prices will increase, and 
consumers will decrease consumption of dietary supplements.
    (Response) We agree with the comments stating that we 
underestimated the costs and overestimated the quantified benefits of 
the 2003 CGMP Proposal. We have increased our estimate of costs in this 
final rule compared with the estimate in the 2003 CGMP Proposal. We 
have decreased our estimate of quantified benefits of the final rule 
compared with the estimate in the 2003 CGMP Proposal. As explained 
previously, we are unable to quantify all of the benefits of the final 
rule. These changes in the estimated benefits and costs of this final 
rule reflect both the changes in the 2003 CGMP Proposal and the changes 
in our analysis in response to comments.
    We agree with the comment that part of the costs of this final rule 
will be passed on to consumers as higher prices for dietary 
supplements. The annual costs of this final rule are less than 1 
percent of total spending on dietary supplements. We expect that the 
majority of these costs will be borne by consumers of dietary 
supplements, who will likely respond to the increase in prices by 
reducing consumption.
    The comments suggesting very high costs and very low benefits did 
not persuade us that those extreme values were more likely than our 
estimates. We recognize, however, that the uncertainties in our 
analysis make a broad range of benefits and costs possible. In the 
analysis of uncertainty, we will show the range of predicted benefits 
and costs. We also will show the sensitivity of costs and benefits to 
certain key assumptions used in the analysis, and how changes in those 
assumptions can generate the extreme values cited in some comments.
9. Benefits and Costs of Regulatory Options
    We considered several regulatory options, including: (1) No new 
regulatory action, (2) fewer requirements for vitamins and minerals, 
(3) more restrictive regulations than the final rule, (4) HACCP without 
the other elements of the final rule, (5) final product testing only, 
(6) a final rule for high-risk products or hazards only, and (7) the 
2003 CGMP Proposal. Although we received no comments on our analysis of 
the benefits and costs of options 2 through 6, we received many 
comments on the estimated benefits and costs of the 2003 CGMP Proposal. 
We have now revised the estimated quantifiable benefits and costs of 
the 2003 CGMP Proposal. The revised estimates are based on the comments 
received and the corrections made to the data.
    Using the same method as used in this final rule to determine 
benefits, we estimate that the quantifiable benefits of the 2003 CGMP 
Proposal would be approximately the same as the quantifiable benefits 
of the final rule, $44 million per year.
    With the corrected estimated number of batches produced, we 
estimate that the setup costs of the 2003 CGMP Proposal would be $51 
million. If the 2003 CGMP Proposal had been finalized, the annual costs 
of complying with the requirements would be $282 million, or about $118 
million more than this final rule. The 2003 CGMP Proposal relied more 
on testing final products and other controls closer to the end-product. 
Under the 2003 CGMP Proposal, for example, annual testing costs would 
be about $97 million.
10. Cost Effectiveness Analysis
    Both benefit-cost analysis and cost-effectiveness analysis provide 
a systematic framework for identifying and evaluating the likely 
outcomes of alternative regulatory choices. OMB Circular A-4 requires 
that major rulemakings be supported by both types of analysis wherever 
possible. A cost-effectiveness analysis is particularly useful when the 
primary benefits of the rulemaking are improved public health

[[Page 34936]]

and safety.\18\ The main advantage of measures of effectiveness are 
that they account for a rule's impact on morbidity (nonfatal illness, 
injury, impairment, and quality of life) as well as premature death. 
The inclusion of morbidity effects is important because some illnesses 
(e.g., asthma) cause more instances of pain and suffering than they do 
premature death.
---------------------------------------------------------------------------

    \18\It should be noted that many of the benefits of this rule 
are quality benefits that are not quantified and will not be part of 
this analysis.
---------------------------------------------------------------------------

    The primary benefits expected to result from this rulemaking are 
reduced numbers of acute and chronic illnesses and reduced number of 
recalls involving dietary supplement products. We were not able to 
quantify chronic illnesses that could be avoided as a result of this 
rulemaking. We were able to determine that we could avoid about $40 
million annually in costs of acute illnesses and $4 million in avoided 
recalls as a result of improved dietary supplement manufacturing.
    We can use the $40 million annually in avoided acute illnesses 
costs to calculate a cost-effectiveness measure for this rule; $40 
million in reduced illness costs translates into 48,662 QALDs saved on 
an annual basis. Given that the annual costs of this final rule are 
expected to be $164 million, the cost of each QALD saved is $3,370. 
This is an overestimate of the cost of a QALD saved because we were 
unable to quantify the benefits of reduced chronic illness as a result 
of this rulemaking.
11. Uncertainties in the Analysis
    We used indirect measures of the benefits of this final rule which 
required several key assumptions that are critical for our estimates. 
With the exception of the recall benefit, which is based directly on 
our recall records, each component of the estimated benefits involves 
assumptions that reflect our uncertainty. The estimated costs also 
embody key assumptions that reflect our uncertainty.
    One assumption that affects both estimated costs and estimated 
benefits is that manufacturing practices in the industry will persist 
in the absence of additional regulation. If the trend in the market is 
toward the adoption of more manufacturing controls than we are 
proposing here, then both the costs and benefits of the rule will be 
less than we estimate. If the market trend is toward fewer voluntary 
controls, then both the costs and benefits of the regulation will be 
greater than we estimate.
    In addition to the general assumption about the effects of the 
rule, we rely on several key assumptions.
    We assume there is an average of one reported illness for each 
class 1 and 2 recall.
    The frequency of actual illnesses is 100 times the frequency of 
reported illnesses. We recognize that there is considerable uncertainty 
about the factor of 100.
    For the baseline estimates, we assume $5 million is the value of a 
statistical life and $300,000 is the value of a quality-adjusted life 
year. The estimated health benefits change with changes in those 
valuations.
    Finally, we assume that the reported recalls that occurred from 
1990 through 1999 represent the number and type of recalls that would 
have occurred but for the implementation of this regulation. The cost 
model also relies on several key assumptions. We assume that single 
shipment lots of ingredients and unlisted components will be used for 
many batches of final dietary supplement products. We assume that all 
testing other than identity testing of incoming ingredients will be 
done on representative samples. The number of batches or lots tested 
will be the square root of n + 1, with n equal to the total number of 
batches or lots.
    We also assume that the costs per test, which include the labor 
costs of selecting the samples and arranging for the tests, will be 
between $20 and $150, with $50 most likely.
    We first characterized the uncertainties as a probability 
distribution. We ran 5,000 computer simulations to estimate both 
benefits and costs. The simulations used distributions (given in the 
tables and the text) in place of point estimates.

                   Table 32.--Distribution of Simulation Results for Annual Benefits and Costs
----------------------------------------------------------------------------------------------------------------
                                            5th Percentile                Mean               95th Percentile
----------------------------------------------------------------------------------------------------------------
Annual costs (in millions)                                $109                     $164                     $260
----------------------------------------------------------------------------------------------------------------
Annual quantified benefits (in                             $36                      $44                      $54
 millions)
----------------------------------------------------------------------------------------------------------------

    The Monte Carlo computer simulations give the distributions of 
estimated benefits and costs. If the underlying distributions fully 
capture the uncertainty of the estimates, then the simulation results 
give a full picture of the uncertainty. With uncertain distributions 
used in the simulations, however, the ranges reported in the tables may 
not fully capture the uncertainties of the analysis. An alternative way 
to show the uncertainty is to see how sensitive the results are to 
plausible changes in certain key assumptions. We start with benefits.
    For our baseline estimated benefits of this final rule, we use a $5 
million value for a statistical life (VSL) and a $300,000 value for a 
quality-adjusted life year. In the sensitivity analysis, we use values 
of $3 million for a statistical life and $100,000 for a quality-
adjusted life year to generate a ``low'' estimate of health benefits 
and values of $7 million and $500,000 to generate a ``high'' estimate.
    The reporting rate of illnesses associated with dietary supplements 
is unknown, which makes our estimate of the total number of illnesses 
highly uncertain. We use 1 percent as the average reporting rate, which 
implies that total illness are 100 times our estimate of reported 
illnesses. Although we assume this reporting rate is the most plausible 
for illnesses associated with dietary supplements, the evidence 
supporting it is not strong. We show the effects of reporting rates of 
2.5 percent and 10 percent.
    (Comment 358) Several comments questioned our assumption that the 
final rule will eliminate the recalls used to estimate benefits.
    (Response) We do not assume that all recalls will be eliminated; we 
only assume that the recalls caused by manufacturing problems 
identified previously will be eliminated if the rule is fully 
effective. If the rule is not fully effective, then the quantified 
benefits will be less than we have estimated. In the following 
discussion we show the effects of different assumptions about the 
effectiveness of the final rule.
    The quantified benefits depend on the hazards found in recalled 
products

[[Page 34937]]

between 1990 and 1999. The 69 recalls in 1998 dominate the estimate, 
accounting for 58 percent of class 1 and class 2 recalls, and 35 
percent of all recalls for the decade. In this sensitivity analysis we 
estimate the effect of excluding 1998 from the data used to estimate 
average annual benefits. We also consider the effects of using the 
annual average number of recalls from 2000 through 2005 to estimate 
benefits.

                   Table 33.--Sensitivity of Benefits
------------------------------------------------------------------------
                                              Estimated Annual Benefits
                Description                      (after 3 years) (in
                                                      millions)
------------------------------------------------------------------------
Final rule                                                           $44
------------------------------------------------------------------------
VSL = $3 million and $/QALY = $100,000                               $24
 (baselines are $5 million and $300,000)
------------------------------------------------------------------------
VSL = $7 million and $/QALY = $500,000                               $64
 (baselines are $5 million and $300,000)
------------------------------------------------------------------------
Each recall represents one illness, with                              $8
 reporting rate of 10 percent (baseline is
 1 percent)
------------------------------------------------------------------------
Each recall represents one illness, with                             $20
 reporting rate of 2.5 percent (baseline
 is 1 percent)
------------------------------------------------------------------------
Final rule reduces manufacturing recalls                             $35
 by 80 percent (baseline is 100 percent)
------------------------------------------------------------------------
Exclude 1998 recalls from estimate, so                               $27
 average annual number of manufacturing
 recalls is 14 (baseline is 19.5)
------------------------------------------------------------------------
Average annual number of manufacturing                               $26
 recalls = 2000-2005 average, so average
 per year is 10 (baseline is 19.5)
------------------------------------------------------------------------

    In the sensitivity analysis of annual costs, we change assumptions 
about the numbers covered by the rule, the number of batches produced 
per establishment, the number of lots per batch, the average costs per 
test, and the rate of verification testing.
    The number of establishments covered is uncertain because we based 
it on voluntary survey responses and other evidence from the 1990s. If 
the number of establishments has increased or decreased, or if our 
original data overstated or understated the correct number, then the 
estimated costs will be either too low or too high. We show the effects 
of different numbers for one arbitrarily lower number covered and one 
arbitrarily higher number covered.
    The number of batches produced is our basic measure of output. 
Annual costs therefore vary directly with this measure and its 
components. We show how the costs depend on the number of batches by 
estimating costs for 50 percent less and 50 percent more batches than 
estimated from the survey.
    The number of shipment lots and the cost per test determine 
identity testing costs, the single largest contributor to annual costs. 
We show how the costs vary if the average number of batches per lot is 
1 or 12. We vary the average cost per test from $20 to $100.

                     Table 34.--Sensitivity of Costs
------------------------------------------------------------------------
                                                Estimated Annual Cost
                Description                      (after 3 years) (in
                                                      millions)
------------------------------------------------------------------------
Final rule                                                          $164
------------------------------------------------------------------------
Number of covered establishments is 1,300                           $148
 (baseline is 1,460)
------------------------------------------------------------------------
Number of covered establishments is 1,600                           $178
 (baseline is 1,460)
------------------------------------------------------------------------
Number of batches are 50 percent of                                 $104
 baseline (baseline is 444, 2,436, and
 1,164)
------------------------------------------------------------------------
Number of batches are 150 percent of                                $224
 baseline (baseline is 444, 2,436, and
 1,164)
------------------------------------------------------------------------
1 batch of dietary supplements per                                  $322
 shipment lot of a dietary ingredient
 (baseline is 6.5)
------------------------------------------------------------------------
12 batches of dietary supplements per                               $136
 shipment lot of a dietary ingredient
 (baseline is 6.5)
------------------------------------------------------------------------
Average cost per test is $20 (baseline is                           $129
 $60)
------------------------------------------------------------------------
Average cost per test is $100 (baseline is                          $197
 $60)
------------------------------------------------------------------------

    We combine the results of the sensitivity analyses to generate 
overall ranges for benefits and costs. We estimate that, once it is 
fully implemented, the annual benefits, able to be quantified, from the 
final rule will be $8 million to $64 million; the annual costs will be 
$104 million to $322 million.

C. Final Regulatory Flexibility Analysis

1. Introduction
    We have examined the economic implications of this final rule as 
required by the Regulatory Flexibility Act (5 U.S.C. 601-612). If a 
rule has a significant economic impact on a substantial number of small 
entities, the Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would lessen the economic effect of

[[Page 34938]]

the rule on small entities. We find that this final rule will have a 
significant economic impact on a substantial number of small entities.
2. Economic Effects on Small Entities
    a. Number of small entities affected. The final rule will affect 
many small entities. A small business in this industry is any 
establishment with fewer than 500 employees. For purposes of the cost-
benefit analysis, we also looked at the category we call very small 
establishments: Establishments with fewer than 20 employees. Based on 
the survey (Ref. E2), we estimated that 774 establishments, 53 percent 
of the total establishments, could be classified as very small (under 
20 employees) and 526 as small (20 to 499 employees), which is 36 
percent of the total establishments. Based on the results of the survey 
(Ref. E2), we estimated the total number of warehouses, wholesalers, 
and other holders likely to be covered by this regulation to be 15,689, 
of which 15,421 are small businesses.
    The small establishments that will be affected by the final rule 
are those establishments that will have to perform the various required 
activities, and would not have done so without the rule. We determined 
estimated baseline (pre-CGMP requirements) manufacturing practices with 
the survey of the industry (Ref. E2). The survey asked representative 
respondents to answer a series of questions, including how many 
employees they had and what their existing practices were. From the 
survey, we determined that small establishments do not now follow all 
of the provisions of the final rule. Those that do not follow all the 
applicable provisions will incur a cost to do so.
    b. Costs to small entities. Implementation costs vary across 
establishments depending on current practices and the types of products 
manufactured, packaged, labeled, or held. We estimated the range of 
current practices using the survey of the industry. The cost model, 
which we describe in detail in section XXIV.B.7 of this document, 
divided establishments by size, which allowed us to estimate the 
distribution of costs per establishment for each size and product 
class. Table 35 of this document shows the cost per establishment for 
very small and small establishments. For comparison, we include the 
estimated average cost per large establishment and the median revenues 
for each size category. As table 35 of this document shows, costs per 
establishment are proportionally higher for very small than for large 
establishments. The table's most striking result is that annual costs 
are highest for small (20 to 499 employees) establishments.

                                   Table 35.--Costs per Establishment, by Size
----------------------------------------------------------------------------------------------------------------
                                      Setup Costs per          Annual Costs per       Median Annual Revenue per
                                       Establishment            Establishment               Establishment
----------------------------------------------------------------------------------------------------------------
Very small establishments                         $26,000                  $46,000              Under $1 million
----------------------------------------------------------------------------------------------------------------
Small establishments                              $20,000                 $184,000             $5 to $10 million
----------------------------------------------------------------------------------------------------------------
Large establishments                              $31,000                  $69,000            $10 to $50 million
----------------------------------------------------------------------------------------------------------------
Warehouses, wholesalers, and                         $360                   $1,000                Not applicable
 other holders
----------------------------------------------------------------------------------------------------------------


                                  Table 36.--Total Costs by Establishment Size
----------------------------------------------------------------------------------------------------------------
                                              Percent of Total Setup                     Percent of Total Annual
                             Setup Costs              Costs              Annual Costs             Costs
----------------------------------------------------------------------------------------------------------------
Very small                      $20 million               49 percent        $38 million               23 percent
 establishments
----------------------------------------------------------------------------------------------------------------
Small establishments            $10 million               24 percent        $98 million               60 percent
----------------------------------------------------------------------------------------------------------------
Large establishments             $5 million               12 percent        $11 million                7 percent
----------------------------------------------------------------------------------------------------------------
Warehouses, wholesalers,         $6 million               15 percent        $17 million               10 percent
 and other holders
----------------------------------------------------------------------------------------------------------------

    Small establishments that do not perform a substantial number of 
the actions required by the final rule will bear relatively high costs 
for compliance with the provisions of this final rule. Although the 
final rule will raise product prices, the price increase (which would 
largely be determined by changes made by large establishments) may be 
much smaller than the increase in the average costs of very small 
producers. The average burden to very small establishments will be 
about 4 percent of annual revenue. The average burden to small 
establishments will be 1.5 to 3 percent of annual revenue. 
Establishments with above average costs, and even establishments with 
average costs, could be hard pressed to continue to operate. Some of 
these may decide it is too costly and either change product lines or go 
out of business.
    We use a model developed under contract by Eastern Research Group 
to estimate the effects of FDA regulations on small businesses (Ref. 
E27). The model is designed to assess the effects of a wide range of 
potential regulatory activities, ranging from HACCP to product 
labeling. CGMP regulations are included as a potential regulatory 
activity. The model allows us to predict the probability and frequency 
of small business failure as a result of our regulations.
    We ran the model for the final rule. The model predicts that, as a 
result of the final rule, 140 very small and 32 small dietary 
supplement manufacturers will be at risk of going out of business. The 
model estimates the number of workers in those firms to be about 2,250.
    The regulatory costs of this final rule will also discourage new 
small businesses from entering the industry. The dietary supplement has 
been characterized by substantial entry of small businesses. Although 
we cannot quantify how much that will change, we expect that the rate 
of entry of very small and small businesses will decrease.

[[Page 34939]]

3. Regulatory Options
    a. Exemptions for small entities. The burden on small 
establishments would be reduced if they were exempt from some 
provisions of the final rule. Most entities (we estimate close to 90 
percent) affected by this final rule, however, are small. Exempting 
small establishments from some or all of its provisions would 
substantially reduce benefits.
    b. Longer compliance periods. Lengthening the compliance period 
provides some regulatory relief for businesses with fewer than 500 
employees. The longer compliance period will allow additional time for 
setting up recordkeeping, making capital improvements to the physical 
plant, purchasing new or replacement equipment, and other one-time 
expenditures. It will also delay the impact of the annual costs of 
compliance. We have given businesses with fewer than 20 employees an 
additional 24 months and businesses with fewer than 500 but 20 or more 
employees an additional 12 months for compliance. The final rule, then, 
will be phased-in over 36 months, with firms with 500 or more employees 
complying after 12 months, firms with under 500 but 20 or more 
employees after 24 months, and firms with fewer than 20 employees after 
36 months. The cost savings of delay may well be larger than simply the 
present value of the delay because the firms with fewer than 500 
employees may also be able to reduce their compliance costs by taking 
advantage of increases in industry knowledge and experience in 
implementing these regulations.
    c. Reduced requirements in the final rule. The modification of 
requirements in this final rule, compared with the 2003 CGMP Proposal, 
significantly reduce the costs borne by small businesses. We estimate 
the average setup costs under the 2003 CGMP Proposal to be $25,000 for 
very small establishments and $40,000 for small establishments. We 
estimate that the annual costs of the 2003 CGMP Proposal would be 
$90,000 for very small establishments and $300,000 for small 
establishments. The final rule therefore reduces annual costs for very 
small establishments to about half of the estimated costs of the 
proposed rule and reduces costs for very small establishments to about 
60 percent of the estimated costs of the 2003 CGMP Proposal. Under the 
2003 CGMP Proposal, 216 very small and 50 small businesses would be at 
risk of going out of business, over 50 percent more than under the 
final rule.
4. Description of Recordkeeping and Reporting
    The Regulatory Flexibility Act requires a description of the 
recordkeeping and reporting required for compliance with this final 
rule. This final rule will require the preparation of records. As 
described in the 2003 CGMP Proposal, Preliminary Regulatory Impact 
Analysis, written records or electronic documents must be kept that 
demonstrate that specific actions occurred in the manufacturing process 
in compliance with the final rule. Records that will be required in 
this final rule will demonstrate that corrective actions were taken; 
that equipment, instruments, and controls used in laboratory operations 
and quality control were installed and calibrated properly; that 
maintenance programs were followed; and that the results of any testing 
show that components or dietary supplements meet the established 
specifications.
    The compliance cost of recordkeeping is the sum of both the initial 
design and printing of the recordkeeping documents and the recurring 
costs of maintaining the records. The cost of training personnel to use 
the new documents is a recurring cost depending on how frequently 
documents are modified, how often personnel turn over, and how 
complicated the tasks are that are being recorded. The recurring costs 
are measured by the workers' wage rate multiplied by the expected labor 
hours necessary for a written or electronic record and the time 
necessary for management to review the records to see that actions are 
documented accurately. In addition, electronic records necessitate 
recurring time spent ensuring that the equipment is serviced and 
maintained properly.
5. Summary
    The final rule will have a significant economic impact on a 
substantial number of small entities.
    (Comment 359) We received many comments on the 2003 CGMP Proposal 
Preliminary Regulatory Flexibility Analysis. Nearly all of the comments 
addressing small business state that the requirements of the 2003 CGMP 
Proposal, the testing requirements in particular, would be an enormous 
burden on small business. Other comments assert that, because of this 
burden, the rule is in violation of the Regulatory Flexibility Act. In 
addition, comments assert small business will be particularly burdened 
by the rule and that consumers will see little improvement in product 
safety as a result.
    Some small firms estimate annual testing costs for the 2003 CGMP 
Proposal as high as $600,000, as opposed to the $60,000 per year 
estimated by us. Another firm estimates setup costs in the range of 4 
to 7 times our estimate and annual costs 8 to 30 times our estimate. 
Comments also express concern that we have underestimated the number of 
businesses forced to close if this rule is made final as proposed; one 
comment states that the rule would cause 50 percent of small businesses 
to shut down. Some comments assert that this rule is anti-competitive: 
That is, the comments claim that this rule will make dietary supplement 
manufacturing so expensive that only large companies will survive. In 
addition, a few comments note the loss of product choice, innovation, 
and domestic employment that accompany firm closures, in addition to 
the increase in prices of products made by remaining firms. In 
addition, another comment suggests that foreign manufacturers will be 
at an advantage because they will not have to comply with the rule's 
requirements.
    Some comments reiterate the points made earlier that the use of 
statistical sampling and supplier certificates of analysis could help 
reduce the burden on small business.
    One comment states that it would be extremely costly for small 
firms to come into compliance with the 2003 CGMP Proposal, especially 
because, as several firms pointed out, small firms often produce 
batches that are small in size. A few comments, however, say that small 
firms should be made to comply with the new rule at the same time as 
large firms.
    We received many comments on the compliance period of this rule. 
Some of these comments favor the extended compliance periods granted to 
small and very small firms. Other comments do not support the 
compliance periods, stating that they are not long enough for firms to 
set up recordkeeping systems, make capital improvements, and so on.
    Other comments do not favor granting small firms more time to 
comply. Three comments state that granting small firms a longer 
compliance period defeats the purpose of the rule, by making it 
difficult for consumers to determine which dietary supplements comply 
with the CGMPs and which do not yet comply. Another comment suggests 
that products made by firms not in compliance 1 year after the rule's 
effective date be labeled to say, ``This product may not conform to 
government standards for purity and potency.''

[[Page 34940]]

 Other comments propose a single compliance period for all firms.
    (Response) We disagree with comments that the burden of this final 
rule violates the Regulatory Flexibility Act. The act requires agencies 
to consider the burden of their regulatory proposals on small entities, 
analyze and consider effective alternatives that reduce the burden on 
small entities, and make their analyses available for public comment. 
We have considered the burden of this final rule on all covered firms, 
including small businesses, and as a result have modified certain 
requirements to reduce the costs of the final rule as compared with the 
2003 CGMP Proposal. In addition, small businesses are allowed more time 
to comply with the rule. The burden on small businesses remains large, 
but the Regulatory Flexibility Act does not require agencies to adopt 
regulations that impose the least burden on small entities. In 
addition, the Data Quality Act has been fulfilled by using the most 
objective data available. In this analysis, we used data from surveys 
and from other Federal agencies. Although more data are desirable, we 
consider the quality of the data used in this analysis and in the 
references to be the best available and sufficient to fulfill the 
requirements of the Regulatory Flexibility and Data Quality Acts.
    We have reduced the amount of testing required in this final rule 
in response to comments on the burden of testing costs on the 2003 CGMP 
Proposal. As explained in Section XXIV.B.7 of this document, we 
underestimated costs in the proposed rule because of an error in a 
contractor's report. We have corrected the cost calculations, including 
estimated testing costs, for this final regulatory flexibility 
analysis.
    We note that foreign firms that sell dietary supplements in the 
United States are required to be in compliance with the final rule.
    In response to comments on the number of firms likely to go out of 
business, we have used our small business model to estimate that 172 
small and very small firms will be at risk of going out of business. 
Many other small firms--some of them already experiencing financial 
difficulties-may see their financial condition worsen as a result of 
this final rule.
    We disagree with the comments that oppose longer compliance periods 
for small businesses. The additional time will only slightly delay the 
full implementation (and full benefits) of this final rule, and may 
provide the margin of survival for some small businesses.

D. Unfunded Mandates

    The Unfunded Mandates Reform Act of 1995 (Public Law 104-4) 
requires cost-benefit and other analyses for rules that would cost more 
than $100 million in a single year. The current (2005) inflation-
adjusted statutory threshold is $122 million. This final rule qualifies 
as a significant rule under the statute. Most of the requirements of 
the Unfunded Mandates are fulfilled in the Executive Order 12866 
analysis. The requirements under the Unfunded Mandates Reform Act of 
1995 include assessing the rule's effects on future costs; 
productivity; particular regions, communities, or industrial sectors; 
economic growth; full employment; job creation; and exports.
    The future costs from the rule are the recurring costs, which reach 
their long-term value in the third year after the effective date of 
this rule. These costs would be incurred, directly or indirectly, by 
the establishments that manufacture, process, pack, label, transport, 
distribute, receive, hold, or import dietary supplements or 
ingredients. Recurring costs from the regulatory requirements will be 
incurred in each future year. Table 29 of this document summarizes the 
annual future recurring costs.
    The costs, direct and indirect, of the rule will be shared among 
manufacturers, processors, packagers, transporters, receivers, holders, 
and importers of dietary supplements or ingredients, as well as 
domestic consumers. Much of the higher costs incurred by domestic 
suppliers of dietary supplement products as a result of these 
regulations will be passed on to consumers as higher prices. The higher 
prices will be offset by the benefits from these regulations.
    Although this final regulation is significant, we do not expect it 
to substantially affect national productivity, growth, jobs, or full 
employment. The dietary supplement industry is too small a part of the 
domestic economy to influence overall economic activity.
    This final rule will require additional controls throughout the 
production and distribution chain for the manufacture of dietary 
supplements. The additional costs will increase the total costs of 
production and distribution for all of the regulated products, 
including products sold within the United States and across national 
borders. These increased costs will be partly passed on to consumers in 
the form of higher prices, which will tend to reduce the quantity 
demanded of the regulated products. The increased prices of U.S. 
exports could reduce the quantity of U.S. exports demanded, 
particularly in comparison with exports from countries that do not 
implement similar regulations. We expect this effect to be 
insignificant, because under the final rule the increases in the price 
of U.S. exports (and resulting decreases in quantity demanded) will be 
quite small.

XXV. Analysis of Environmental Impact

    We have carefully considered the potential environmental effects of 
this action. We have concluded under 21 CFR 25.30(h) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

XXVI. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have determined that the final 
rule does not contain policies that have substantial direct effects on 
the States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Furthermore, we did not receive any 
comments from States or their representative organizations regarding to 
our analysis of the proposed rule regarding the principles set forth in 
Executive Order 13132. Accordingly, we conclude that the final rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

XXVII. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20857, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but FDA is not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)
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SC. Memorandum dated October 25, 1999 by Roslyn F. Powers, Ph.D., 
Center for Food Safety and Applied Nutrition.
    2. U.S. Food and Drug Administration, Memorandum of Site Visit, 
August 11, 1999, to Perrigo Company of South Carolina, Inc., 
Greenville, SC. Memorandum dated October

[[Page 34941]]

25, 1999 by Roslyn F. Powers, Ph.D., Center for Food Safety and 
Applied Nutrition.
    3. U.S. Food and Drug Administration, Memorandum of Site Visit, 
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    4. U.S. Food and Drug Administration, Memorandum of Site Visit, 
September 21, 1999, to Pharmavite Corporation, San Fernando, CA. 
Memorandum dated October 25, 1999 by Roslyn F. Powers, Ph.D., Center 
for Food Safety and Applied Nutrition.
    5. U.S. Food and Drug Administration, Memorandum of Site Visit, 
September 21, 1999, to Shaklee Manufacturing Center, Norman, OK. 
Memorandum dated October 25, 1999 by Roslyn F. Powers, Ph.D., Center 
for Food Safety and Applied Nutrition.
    6. U.S. Food and Drug Administration, Memorandum of Site Visit, 
September 22, 1999, to Botanicals International, Long Beach, CA. 
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for Food Safety and Applied Nutrition.
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Cichowicz SM, Betz JM, Love LA. Contamination of Botanical Dietary 
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International Organization for Standardization. 3rd ed. 2000.
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Dietary Supplements Because of Possible Salmonella Contamination, 
April 26, 2001; Karuna Corporation, Karuna Corporation Recalls HCl 
Nutritional Product Because of Possible Health Risk, May 17, 2001; 
Licata Enterprises, Licata Enterprises Recalls Digestive Aid 
Products Because of Possible Health Risk, May 18, 2001; Natural 
Organics, Inc., Natural Organics, Inc. Cooperates in the Recall of 
Digestive Aid Dietary Supplements Because of Possible Salmonella 
Contaminated Raw Material Supplied by American Laboratories, Inc., 
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List of Subjects in 21 CFR Part 111

    Dietary foods, Drugs, Foods, Packaging and containers.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, FDA is 
amending 21 CFR chapter I by adding part 111 to read as follows:

PART 111--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, 
PACKAGING, LABELING, OR HOLDING OPERATIONS FOR DIETARY SUPPLEMENTS

Subpart A--General Provisions
Sec.
111.1 Who is subject to this part?
111.3 What definitions apply to this part?
111.5 Do other statutory provisions and regulations apply?
Subpart B--Personnel
111.8 What are the requirements under this subpart B for written 
procedures?
111.10 What requirements apply for preventing microbial 
contamination from sick or infected personnel and for hygienic 
practices?
111.12 What personnel qualification requirements apply?
111.13 What supervisor requirements apply?
111.14 Under this subpart B, what records must you make and keep?
Subpart C--Physical Plant and Grounds
111.15 What sanitation requirements apply to your physical plant and 
grounds?
111.16 What are the requirements under this subpart C for written 
procedures?
111.20 What design and construction requirements apply to your 
physical plant?
111.23 Under this subpart C, what records must you make and keep?
Subpart D--Equipment and Utensils
111.25 What are the requirements under this subpart D for written 
procedures?
111.27 What requirements apply to the equipment and utensils that 
you use?
111.30 What requirements apply to automated, mechanical, or 
electronic equipment?
111.35 Under this subpart D, what records must you make and keep?
Subpart E--Requirement to Establish a Production and Process Control 
System
111.55 What are the requirements to implement a production and 
process control system?
111.60 What are the design requirements for the production and 
process control system?
111.65 What are the requirements for quality control operations?
111.70 What specifications must you establish?
111.73 What is your responsibility for determining whether 
established specifications are met?
111.75 What must you do to determine whether specifications are met?
111.77 What must you do if established specifications are not met?
111.80 What representative samples must you collect?
111.83 What are the requirements for reserve samples?
111.87 Who conducts a material review and makes a disposition 
decision?

[[Page 34943]]

111.90 What requirements apply to treatments, in-process 
adjustments, and reprocessing when there is a deviation or 
unanticipated occurrence or when a specification established in 
accordance with Sec.  111.70 is not met?
111.95 Under this subpart E, what records must you make and keep?
Subpart F--Production and Process Control System: Requirements for 
Quality Control
111.103 What are the requirements under this subpart F for written 
procedures?
111.105 What must quality control personnel do?
111.110 What quality control operations are required for laboratory 
operations associated with the production and process control 
system?
111.113 What quality control operations are required for a material 
review and disposition decision?
111.117 What quality control operations are required for equipment, 
instruments, and controls?
111.120 What quality control operations are required for components, 
packaging, and labels before use in the manufacture of a dietary 
supplement?
111.123 What quality control operations are required for the master 
manufacturing record, the batch production record, and manufacturing 
operations?
111.127 What quality control operations are required for packaging 
and labeling operations?
111.130 What quality control operations are required for returned 
dietary supplements?
111.135 What quality control operations are required for product 
complaints?
111.140 Under this subpart F, what records must you make and keep?
Subpart G--Production and Process Control System: Requirements for 
Components, Packaging, and Labels and for Product That You Receive for 
Packaging or Labeling as a Dietary Supplement
111.153 What are the requirements under this subpart G for written 
procedures?
111.155 What requirements apply to components of dietary 
supplements?
111.160 What requirements apply to packaging and labels received?
111.165 What requirements apply to a product received for packaging 
or labeling as a dietary supplement (and for distribution rather 
than for return to the supplier)?
111.170 What requirements apply to rejected components, packaging, 
and labels, and to rejected products that are received for packaging 
or labeling as a dietary supplement?
111.180 Under this subpart G, what records must you make and keep?
Subpart H--Production and Process Control System: Requirements for the 
Master Manufacturing Record
111.205 What is the requirement to establish a master manufacturing 
record?
111.210 What must the master manufacturing record include?
Subpart I--Production and Process Control System: Requirements for the 
Batch Production Record
111.255 What is the requirement to establish a batch production 
record?
111.260 What must the batch record include?
Subpart J--Production and Process Control System: Requirements for 
Laboratory Operations
111.303 What are the requirements under this subpart J for written 
procedures?
111.310 What are the requirements for the laboratory facilities that 
you use?
111.315 What are the requirements for laboratory control processes?
111.320 What requirements apply to laboratory methods for testing 
and examination?
111.325 Under this subpart J, what records must you make and keep?
Subpart K--Production and Process Control System: Requirements for 
Manufacturing Operations
111.353 What are the requirements under this subpart K for written 
procedures?
111.355 What are the design requirements for manufacturing 
operations?
111.360 What are the requirements for sanitation?
111.365 What precautions must you take to prevent contamination?
111.370 What requirements apply to rejected dietary supplements?
111.375 Under this subpart K, what records must you make and keep?
Subpart L--Production and Process Control System: Requirements for 
Packaging and Labeling Operations
111.403 What are the requirements under this subpart L for written 
procedures?
111.410 What requirements apply to packaging and labels?
111.415 What requirements apply to filling, assembling, packaging, 
labeling, and related operations?
111.420 What requirements apply to repackaging and relabeling?
111.425 What requirements apply to a packaged and labeled dietary 
supplement that is rejected for distribution?
111.430 Under this subpart L, what records must you make and keep?
Subpart M--Holding and Distributing
111.453 What are the requirements under this subpart M for written 
procedures?
111.455 What requirements apply to holding components, dietary 
supplements, packaging, and labels?
111.460 What requirements apply to holding in-process material?
111.465 What requirements apply to holding reserve samples of 
dietary supplements?
111.470 What requirements apply to distributing dietary supplements?
111.475 Under this subpart M, what records must you make and keep?
Subpart N--Returned Dietary Supplements
111.503 What are the requirements under this subpart N for written 
procedures?
111.510 What requirements apply when a returned dietary supplement 
is received?
111.515 When must a returned dietary supplement be destroyed, or 
otherwise suitably disposed of?
111.520 When may a returned dietary supplement be salvaged?
111.525 What requirements apply to a returned dietary supplement 
that quality control personnel approve for reprocessing?
111.530 When must an investigation be conducted of your 
manufacturing processes and other batches?
111.535 Under this subpart N, what records must you make and keep?
Subpart O--Product Complaints
111.553 What are the requirements under this subpart O for written 
procedures?
111.560 What requirements apply to the review and investigation of a 
product complaint?
111.570 Under this subpart O, what records must you make and keep?
Subpart P--Records and Recordkeeping
111.605 What requirements apply to the records that you make and 
keep?
111.610 What records must be made available to FDA?

    Authority: 21 U.S.C. 321, 342, 343, 371, 374, 381, 393; 42 
U.S.C. 264.

Subpart A--General Provisions


Sec.  111.1  Who is subject to this part?

    (a) Except as provided by paragraph (b) of this section, you are 
subject to this part if you manufacture, package, label, or hold a 
dietary supplement, including:
    (1) A dietary supplement you manufacture but that is packaged or 
labeled by another person; and
    (2) A dietary supplement imported or offered for import in any 
State or territory of the United States, the District of Columbia, or 
the Commonwealth of Puerto Rico.
    (b) The requirements pertaining to holding dietary supplements do 
not apply to you if you are holding those dietary supplements at a 
retail establishment for the sole purpose of direct retail sale to 
individual consumers. A retail establishment does not include a 
warehouse or other storage facility for a retailer or a warehouse or 
other storage facility that sells directly to individual consumers.


Sec.  111.3  What definitions apply to this part?

    The definitions and interpretations of terms in section 201 of the 
Federal Food, Drug, and Cosmetic Act (the act) apply to such terms when 
used in this part. For the purpose of this part, the following 
definitions also apply:
    Actual yield means the quantity that is actually produced at any 
appropriate step of manufacture or packaging of a particular dietary 
supplement.

[[Page 34944]]

    Batch means a specific quantity of a dietary supplement that is 
uniform, that is intended to meet specifications for identity, purity, 
strength, and composition, and that is produced during a specified time 
period according to a single manufacturing record during the same cycle 
of manufacture.
    Batch number, lot number, or control number means any distinctive 
group of letters, numbers, or symbols, or any combination of them, from 
which the complete history of the manufacturing, packaging, labeling, 
and/or holding of a batch or lot of dietary supplements can be 
determined.
    Component means any substance intended for use in the manufacture 
of a dietary supplement, including those that may not appear in the 
finished batch of the dietary supplement. Component includes dietary 
ingredients (as described in section 201(ff) of the act) and other 
ingredients.
    Contact surface means any surface that contacts a component or 
dietary supplement, and those surfaces from which drainage onto the 
component or dietary supplement, or onto surfaces that contact the 
component or dietary supplement, occurs during the normal course of 
operations. Examples of contact surfaces include containers, utensils, 
tables, contact surfaces of equipment, and packaging.
    Ingredient means any substance that is used in the manufacture of a 
dietary supplement and that is intended to be present in the finished 
batch of the dietary supplement. An ingredient includes, but is not 
necessarily limited to, a dietary ingredient as defined in section 
201(ff) of the act.
    In-process material means any material that is fabricated, 
compounded, blended, ground, extracted, sifted, sterilized, derived by 
chemical reaction, or processed in any other way for use in the 
manufacture of a dietary supplement.
    Lot means a batch, or a specific identified portion of a batch, 
that is uniform and that is intended to meet specifications for 
identity, purity, strength, and composition; or, in the case of a 
dietary supplement produced by continuous process, a specific 
identified amount produced in a specified unit of time or quantity in a 
manner that is uniform and that is intended to meet specifications for 
identity, purity, strength, and composition.
    Microorganisms means yeasts, molds, bacteria, viruses, and other 
similar microscopic organisms having public health or sanitary concern. 
This definition includes species that:
    (1) May have public health significance;
    (2) May cause a component or dietary supplement to decompose;
    (3) Indicate that the component or dietary supplement is 
contaminated with filth; or
    (4) Otherwise may cause the component or dietary supplement to be 
adulterated.
    Must is used to state a requirement.
    Pest means any objectionable insect or other animal including 
birds, rodents, flies, mites, and larvae.
    Physical plant means all or any part of a building or facility used 
for or in connection with manufacturing, packaging, labeling, or 
holding a dietary supplement.
    Product complaint means any communication that contains any 
allegation, written, electronic, or oral, expressing concern, for any 
reason, with the quality of a dietary supplement, that could be related 
to current good manufacturing practice. Examples of product complaints 
are: Foul odor, off taste, illness or injury, disintegration time, 
color variation, tablet size or size variation, under-filled container, 
foreign material in a dietary supplement container, improper packaging, 
mislabeling, or dietary supplements that are superpotent, subpotent, or 
contain the wrong ingredient, or contain a drug or other contaminant 
(e.g., bacteria, pesticide, mycotoxin, glass, lead).
    Quality means that the dietary supplement consistently meets the 
established specifications for identity, purity, strength, and 
composition, and limits on contaminants, and has been manufactured, 
packaged, labeled, and held under conditions to prevent adulteration 
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
    Quality control means a planned and systematic operation or 
procedure for ensuring the quality of a dietary supplement.
    Quality control personnel means any person, persons, or group, 
within or outside of your organization, who you designate to be 
responsible for your quality control operations.
    Representative sample means a sample that consists of an adequate 
number of units that are drawn based on rational criteria, such as 
random sampling, and that are intended to ensure that the sample 
accurately portrays the material being sampled.
    Reprocessing means using, in the manufacture of a dietary 
supplement, clean, uncontaminated components or dietary supplements 
that have been previously removed from manufacturing and that have been 
made suitable for use in the manufacture of a dietary supplement.
    Reserve sample means a representative sample of product that is 
held for a designated period of time.
    Sanitize means to adequately treat cleaned equipment, containers, 
utensils, or any other cleaned contact surface by a process that is 
effective in destroying vegetative cells of microorganisms of public 
health significance, and in substantially reducing numbers of other 
microorganisms, but without adversely affecting the product or its 
safety for the consumer.
    Theoretical yield means the quantity that would be produced at any 
appropriate step of manufacture or packaging of a particular dietary 
supplement, based upon the quantity of components or packaging to be 
used, in the absence of any loss or error in actual production.
    Water activity (a<INF>w</INF>) is a measure of the free moisture in 
a component or dietary supplement and is the quotient of the water 
vapor pressure of the substance divided by the vapor pressure of pure 
water at the same temperature.
    We means the U.S. Food and Drug Administration (FDA).
    You means a person who manufactures, packages, labels, or holds 
dietary supplements.


Sec.  111.5  Do other statutory provisions and regulations apply?

    In addition to this part, you must comply with other applicable 
statutory provisions and regulations under the act related to dietary 
supplements.

Subpart B--Personnel


Sec.  111.8  What are the requirements under this subpart B for written 
procedures?

    You must establish and follow written procedures for fulfilling the 
requirements of this subpart.


Sec.  111.10  What requirements apply for preventing microbial 
contamination from sick or infected personnel and for hygienic 
practices?

    (a) Preventing microbial contamination. You must take measures to 
exclude from any operations any person who might be a source of 
microbial contamination, due to a health condition, where such 
contamination may occur, of any material, including components, dietary 
supplements, and contact surfaces used in the manufacture, packaging, 
labeling, or holding of a dietary supplement. Such measures include the 
following:
    (1) Excluding from working in any operations that may result in 
contamination any person who, by medical examination, the person's

[[Page 34945]]

acknowledgement, or supervisory observation, is shown to have, or 
appears to have, an illness, infection, open lesion, or any other 
abnormal source of microbial contamination, that could result in 
microbial contamination of components, dietary supplements, or contact 
surfaces, until the health condition no longer exists; and
    (2) Instructing your employees to notify their supervisor(s) if 
they have or if there is a reasonable possibility that they have a 
health condition described in paragraph (a)(1) of this section that 
could result in microbial contamination of any components, dietary 
supplements, or any contact surface.
    (b) Hygienic practices. If you work in an operation during which 
adulteration of the component, dietary supplement, or contact surface 
could occur, you must use hygienic practices to the extent necessary to 
protect against such contamination of components, dietary supplements, 
or contact surfaces. These hygienic practices include the following:
    (1) Wearing outer garments in a manner that protects against the 
contamination of components, dietary supplements, or any contact 
surface;
    (2) Maintaining adequate personal cleanliness;
    (3) Washing hands thoroughly (and sanitizing if necessary to 
protect against contamination with microorganisms) in an adequate hand-
washing facility:
    (i) Before starting work; and
    (ii) At any time when the hands may have become soiled or 
contaminated;
    (4) Removing all unsecured jewelry and other objects that might 
fall into components, dietary supplements, equipment, or packaging, and 
removing hand jewelry that cannot be adequately sanitized during 
periods in which components or dietary supplements are manipulated by 
hand. If hand jewelry cannot be removed, it must be covered by material 
that is maintained in an intact, clean, and sanitary condition and that 
effectively protects against contamination of components, dietary 
supplements, or contact surfaces;
    (5) Maintaining gloves used in handling components or dietary 
supplements in an intact, clean, and sanitary condition. The gloves 
must be of an impermeable material;
    (6) Wearing, where appropriate, in an effective manner, hair nets, 
caps, beard covers, or other effective hair restraints;
    (7) Not storing clothing or other personal belongings in areas 
where components, dietary supplements, or any contact surfaces are 
exposed or where contact surfaces are washed;
    (8) Not eating food, chewing gum, drinking beverages, or using 
tobacco products in areas where components, dietary supplements, or any 
contact surfaces are exposed, or where contact surfaces are washed; and
    (9) Taking any other precautions necessary to protect against the 
contamination of components, dietary supplements, or contact surfaces 
with microorganisms, filth, or any other extraneous materials, 
including perspiration, hair, cosmetics, tobacco, chemicals, and 
medicines applied to the skin.


Sec.  111.12  What personnel qualification requirements apply?

    (a) You must have qualified employees who manufacture, package, 
label, or hold dietary supplements.
    (b) You must identify who is responsible for your quality control 
operations. Each person who is identified to perform quality control 
operations must be qualified to do so and have distinct and separate 
responsibilities related to performing such operations from those 
responsibilities that the person otherwise has when not performing such 
operations.
    (c) Each person engaged in manufacturing, packaging, labeling, or 
holding, or in performing any quality control operations, must have the 
education, training, or experience to perform the person's assigned 
functions.


Sec.  111.13  What supervisor requirements apply?

    (a) You must assign qualified personnel to supervise the 
manufacturing, packaging, labeling, or holding of dietary supplements.
    (b) Each supervisor whom you use must be qualified by education, 
training, or experience to supervise.


Sec.  111.14  Under this subpart B, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart B in 
accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for fulfilling the requirements of this 
subpart B; and
    (2) Documentation of training, including the date of the training, 
the type of training, and the person(s) trained.

Subpart C--Physical Plant and Grounds


Sec.  111.15  What sanitation requirements apply to your physical plant 
and grounds?

    (a) Grounds. You must keep the grounds of your physical plant in a 
condition that protects against the contamination of components, 
dietary supplements, or contact surfaces. The methods for adequate 
ground maintenance include:
    (1) Properly storing equipment, removing litter and waste, and 
cutting weeds or grass within the immediate vicinity of the physical 
plant so that it does not attract pests, harbor pests, or provide pests 
a place for breeding;
    (2) Maintaining roads, yards, and parking lots so that they do not 
constitute a source of contamination in areas where components, dietary 
supplements, or contact surfaces are exposed;
    (3) Adequately draining areas that may contribute to the 
contamination of components, dietary supplements, or contact surfaces 
by seepage, filth or any other extraneous materials, or by providing a 
breeding place for pests;
    (4) Adequately operating systems for waste treatment and disposal 
so that they do not constitute a source of contamination in areas where 
components, dietary supplements, or contact surfaces are exposed; and
    (5) If your plant grounds are bordered by grounds not under your 
control, and if those other grounds are not maintained in the manner 
described in this section, you must exercise care in the plant by 
inspection, extermination, or other means to exclude pests, dirt, and 
filth or any other extraneous materials that may be a source of 
contamination.
    (b) Physical plant facilities. (1) You must maintain your physical 
plant in a clean and sanitary condition; and
    (2) You must maintain your physical plant in repair sufficient to 
prevent components, dietary supplements, or contact surfaces from 
becoming contaminated.
    (c) Cleaning compounds, sanitizing agents, pesticides, and other 
toxic materials. (1) You must use cleaning compounds and sanitizing 
agents that are free from microorganisms of public health significance 
and that are safe and adequate under the conditions of use.
    (2) You must not use or hold toxic materials in a physical plant in 
which components, dietary supplements, or contact surfaces are 
manufactured or exposed, unless those materials are necessary as 
follows:
    (i) To maintain clean and sanitary conditions;
    (ii) For use in laboratory testing procedures;
    (iii) For maintaining or operating the physical plant or equipment; 
or
    (iv) For use in the plant's operations.
    (3) You must identify and hold cleaning compounds, sanitizing 
agents, pesticides, pesticide chemicals, and other toxic materials in a 
manner that

[[Page 34946]]

protects against contamination of components, dietary supplements, or 
contact surfaces.
    (d) Pest control. (1) You must not allow animals or pests in any 
area of your physical plant. Guard or guide dogs are allowed in some 
areas of your physical plant if the presence of the dogs will not 
result in contamination of components, dietary supplements, or contact 
surfaces;
    (2) You must take effective measures to exclude pests from the 
physical plant and to protect against contamination of components, 
dietary supplements, and contact surfaces on the premises by pests; and
    (3) You must not use insecticides, fumigants, fungicides, or 
rodenticides, unless you take precautions to protect against the 
contamination of components, dietary supplements, or contact surfaces.
    (e) Water supply. (1) You must provide water that is safe and 
sanitary, at suitable temperatures, and under pressure as needed, for 
all uses where water does not become a component of the dietary 
supplement.
    (2) Water that is used in a manner such that the water may become a 
component of the dietary supplement, e.g., when such water contacts 
components, dietary supplements, or any contact surface, must, at a 
minimum, comply with applicable Federal, State, and local requirements 
and not contaminate the dietary supplement.
    (f) Plumbing. The plumbing in your physical plant must be of an 
adequate size and design and be adequately installed and maintained to:
    (1) Carry sufficient amounts of water to required locations 
throughout the physical plant;
    (2) Properly convey sewage and liquid disposable waste from your 
physical plant;
    (3) Avoid being a source of contamination to components, dietary 
supplements, water supplies, or any contact surface, or creating an 
unsanitary condition;
    (4) Provide adequate floor drainage in all areas where floors are 
subject to flooding-type cleaning or where normal operations release or 
discharge water or other liquid waste on the floor; and
    (5) Not allow backflow from, or cross connection between, piping 
systems that discharge waste water or sewage and piping systems that 
carry water used for manufacturing dietary supplements, for cleaning 
contact surfaces, or for use in bathrooms or hand-washing facilities.
    (g) Sewage disposal. You must dispose of sewage into an adequate 
sewage system or through other adequate means.
    (h) Bathrooms. You must provide your employees with adequate, 
readily accessible bathrooms. The bathrooms must be kept clean and must 
not be a potential source of contamination to components, dietary 
supplements, or contact surfaces.
    (i) Hand-washing facilities. You must provide hand-washing 
facilities that are designed to ensure that an employee's hands are not 
a source of contamination of components, dietary supplements, or any 
contact surface, by providing facilities that are adequate, convenient, 
and furnish running water at a suitable temperature.
    (j) Trash disposal. You must convey, store, and dispose of trash 
to:
    (1) Minimize the development of odors;
    (2) Minimize the potential for the trash to attract, harbor, or 
become a breeding place for pests;
    (3) Protect against contamination of components, dietary 
supplements, any contact surface, water supplies, and grounds 
surrounding your physical plant; and
    (4) Control hazardous waste to prevent contamination of components, 
dietary supplements, and contact surfaces.
    (k) Sanitation supervisors. You must assign one or more employees 
to supervise overall sanitation. Each of these supervisors must be 
qualified by education, training, or experience to develop and 
supervise sanitation procedures.


Sec.  111.16  What are the requirements under this subpart C for 
written procedures?

    You must establish and follow written procedures for cleaning the 
physical plant and for pest control.


Sec.  111.20  What design and construction requirements apply to your 
physical plant?

    Any physical plant you use in the manufacture, packaging, labeling, 
or holding of dietary supplements must:
    (a) Be suitable in size, construction, and design to facilitate 
maintenance, cleaning, and sanitizing operations;
    (b) Have adequate space for the orderly placement of equipment and 
holding of materials as is necessary for maintenance, cleaning, and 
sanitizing operations and to prevent contamination and mixups of 
components and dietary supplements during manufacturing, packaging, 
labeling, or holding;
    (c) Permit the use of proper precautions to reduce the potential 
for mixups or contamination of components, dietary supplements, or 
contact surfaces, with microorganisms, chemicals, filth, or other 
extraneous material. Your physical plant must have, and you must use, 
separate or defined areas of adequate size or other control systems, 
such as computerized inventory controls or automated systems of 
separation, to prevent contamination and mixups of components and 
dietary supplements during the following operations:
    (1) Receiving, identifying, holding, and withholding from use, 
components, dietary supplements, packaging, and labels that will be 
used in or during the manufacturing, packaging, labeling, or holding of 
dietary supplements;
    (2) Separating, as necessary, components, dietary supplements, 
packaging, and labels that are to be used in manufacturing from 
components, dietary supplements, packaging, or labels that are awaiting 
material review and disposition decision, reprocessing, or are awaiting 
disposal after rejection;
    (3) Separating the manufacturing, packaging, labeling, and holding 
of different product types including different types of dietary 
supplements and other foods, cosmetics, and pharmaceutical products;
    (4) Performing laboratory analyses and holding laboratory supplies 
and samples;
    (5) Cleaning and sanitizing contact surfaces;
    (6) Packaging and label operations; and
    (7) Holding components or dietary supplements.
    (d) Be designed and constructed in a manner that prevents 
contamination of components, dietary supplements, or contact surfaces.
    (1) The design and construction must include:
    (i) Floors, walls, and ceilings that can be adequately cleaned and 
kept clean and in good repair;
    (ii) Fixtures, ducts, and pipes that do not contaminate components, 
dietary supplements, or contact surfaces by dripping or other leakage, 
or condensate;
    (iii) Adequate ventilation or environmental control equipment such 
as airflow systems, including filters, fans, and other air-blowing 
equipment, that minimize odors and vapors (including steam and noxious 
fumes) in areas where they may contaminate components, dietary 
supplements, or contact surfaces;
    (iv) Equipment that controls temperature and humidity, when such 
equipment is necessary to ensure the quality of the dietary supplement; 
and
    (v) Aisles or working spaces between equipment and walls that are 
adequately

[[Page 34947]]

unobstructed and of adequate width to permit all persons to perform 
their duties and to protect against contamination of components, 
dietary supplements, or contact surfaces with clothing or personal 
contact.
    (2) When fans and other air-blowing equipment are used, such fans 
and equipment must be located and operated in a manner that minimizes 
the potential for microorganisms and particulate matter to contaminate 
components, dietary supplements, or contact surfaces;
    (e) Provide adequate light in:
    (1) All areas where components or dietary supplements are examined, 
processed, or held;
    (2) All areas where contact surfaces are cleaned; and
    (3) Hand-washing areas, dressing and locker rooms, and bathrooms.
    (f) Use safety-type light bulbs, fixtures, skylights, or other 
glass or glass-like materials when the light bulbs, fixtures, skylights 
or other glass or glass-like materials are suspended over exposed 
components or dietary supplements in any step of preparation, unless 
your physical plant is otherwise constructed in a manner that will 
protect against contamination of components or dietary supplements in 
case of breakage of glass or glass-like materials.
    (g) Provide effective protection against contamination of 
components and dietary supplements in bulk fermentation vessels, by, 
for example:
    (1) Use of protective coverings;
    (2) Placement in areas where you can eliminate harborages for pests 
over and around the vessels;
    (3) Placement in areas where you can check regularly for pests, 
pest infestation, filth or any other extraneous materials; and
    (4) Use of skimming equipment.
    (h) Use adequate screening or other protection against pests, where 
necessary.


Sec.  111.23  Under this subpart C, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart C in 
accordance with subpart P of this part.
    (b) You must make and keep records of the written procedures for 
cleaning the physical plant and for pest control.
    (c) You must make and keep records that show that water, when used 
in a manner such that the water may become a component of the dietary 
supplement, meets the requirements of Sec.  111.15(e)(2).

Subpart D--Equipment and Utensils


Sec.  111.25  What are the requirements under this subpart D for 
written procedures?

    You must establish and follow written procedures for fulfilling the 
requirements of this subpart D, including written procedures for:
    (a) Calibrating instruments and controls that you use in 
manufacturing or testing a component or dietary supplement;
    (b) Calibrating, inspecting, and checking automated, mechanical, 
and electronic equipment; and
    (c) Maintaining, cleaning, and sanitizing, as necessary, all 
equipment, utensils, and any other contact surfaces that are used to 
manufacture, package, label, or hold components or dietary supplements.


Sec.  111.27  What requirements apply to the equipment and utensils 
that you use?

    (a) You must use equipment and utensils that are of appropriate 
design, construction, and workmanship to enable them to be suitable for 
their intended use and to be adequately cleaned and properly 
maintained.
    (1) Equipment and utensils include the following:
    (i) Equipment used to hold or convey;
    (ii) Equipment used to measure;
    (iii) Equipment using compressed air or gas;
    (iv) Equipment used to carry out processes in closed pipes and 
vessels; and
    (v) Equipment used in automated, mechanical, or electronic systems.
    (2) You must use equipment and utensils of appropriate design and 
construction so that use will not result in the contamination of 
components or dietary supplements with:
    (i) Lubricants;
    (ii) Fuel;
    (iii) Coolants;
    (iv) Metal or glass fragments;
    (v) Filth or any other extraneous material;
    (vi) Contaminated water; or
    (vii) Any other contaminants.
    (3) All equipment and utensils you use must be:
    (i) Installed and maintained to facilitate cleaning the equipment, 
utensils, and all adjacent spaces;
    (ii) Corrosion-resistant if the equipment or utensils contact 
components or dietary supplements;
    (iii) Made of nontoxic materials;
    (iv) Designed and constructed to withstand the environment in which 
they are used, the action of components or dietary supplements, and, if 
applicable, cleaning compounds and sanitizing agents; and
    (v) Maintained to protect components and dietary supplements from 
being contaminated by any source.
    (4) Equipment and utensils you use must have seams that are 
smoothly bonded or maintained to minimize accumulation of dirt, filth, 
organic material, particles of components or dietary supplements, or 
any other extraneous materials or contaminants.
    (5) Each freezer, refrigerator, and other cold storage compartment 
you use to hold components or dietary supplements:
    (i) Must be fitted with an indicating thermometer, temperature-
measuring device, or temperature-recording device that indicates and 
records, or allows for recording by hand, the temperature accurately 
within the compartment; and
    (ii) Must have an automated device for regulating temperature or an 
automated alarm system to indicate a significant temperature change in 
a manual operation.
    (6) Instruments or controls used in the manufacturing, packaging, 
labeling, or holding of a dietary supplement, and instruments or 
controls that you use to measure, regulate, or record temperatures, 
hydrogen-ion concentration (pH), water activity, or other conditions, 
to control or prevent the growth of microorganisms or other 
contamination must be:
    (i) Accurate and precise;
    (ii) Adequately maintained; and
    (iii) Adequate in number for their designated uses.
    (7) Compressed air or other gases you introduce mechanically into 
or onto a component, dietary supplement, or contact surface or that you 
use to clean any contact surface must be treated in such a way that the 
component, dietary supplement, or contact surface is not contaminated.
    (b) You must calibrate instruments and controls you use in 
manufacturing or testing a component or dietary supplement. You must 
calibrate:
    (1) Before first use;
    (2) At the frequency specified in writing by the manufacturer of 
the instrument and control; or
    (3) At routine intervals or as otherwise necessary to ensure the 
accuracy and precision of the instrument and control.
    (c) You must repair or replace instruments or controls that cannot 
be adjusted to agree with the reference standard.
    (d) You must maintain, clean, and sanitize, as necessary, all 
equipment, utensils, and any other contact surfaces used to 
manufacture, package, label, or hold components or dietary supplements.

[[Page 34948]]

    (1) Equipment and utensils must be taken apart as necessary for 
thorough maintenance, cleaning, and sanitizing.
    (2) You must ensure that all contact surfaces, used for 
manufacturing or holding low-moisture components or dietary 
supplements, are in a dry and sanitary condition when in use. When the 
surfaces are wet-cleaned, they must be sanitized, when necessary, and 
thoroughly dried before subsequent use.
    (3) If you use wet processing during manufacturing, you must clean 
and sanitize all contact surfaces, as necessary, to protect against the 
introduction of microorganisms into components or dietary supplements. 
When cleaning and sanitizing is necessary, you must clean and sanitize 
all contact surfaces before use and after any interruption during which 
the contact surface may have become contaminated. If you use contact 
surfaces in a continuous production operation or in consecutive 
operations involving different batches of the same dietary supplement, 
you must adequately clean and sanitize the contact surfaces, as 
necessary.
    (4) You must clean surfaces that do not come into direct contact 
with components or dietary supplements as frequently as necessary to 
protect against contaminating components or dietary supplements.
    (5) Single-service articles (such as utensils intended for one-time 
use, paper cups, and paper towels) must be:
    (i) Stored in appropriate containers; and
    (ii) Handled, dispensed, used, and disposed of in a manner that 
protects against contamination of components, dietary supplements, or 
any contact surface.
    (6) Cleaning compounds and sanitizing agents must be adequate for 
their intended use and safe under their conditions of use;
    (7) You must store cleaned and sanitized portable equipment and 
utensils that have contact surfaces in a location and manner that 
protects them from contamination.


Sec.  111.30  What requirements apply to automated, mechanical, or 
electronic equipment?

    For any automated, mechanical, or electronic equipment that you use 
to manufacture, package, label, or hold a dietary supplement, you must:
    (a) Design or select equipment to ensure that dietary supplement 
specifications are consistently met;
    (b) Determine the suitability of the equipment by ensuring that 
your equipment is capable of operating satisfactorily within the 
operating limits required by the process;
    (c) Routinely calibrate, inspect, or check the equipment to ensure 
proper performance. Your quality control personnel must periodically 
review these calibrations, inspections, or checks;
    (d) Establish and use appropriate controls for automated, 
mechanical, and electronic equipment (including software for a computer 
controlled process) to ensure that any changes to the manufacturing, 
packaging, labeling, holding, or other operations are approved by 
quality control personnel and instituted only by authorized personnel; 
and
    (e) Establish and use appropriate controls to ensure that the 
equipment functions in accordance with its intended use. These controls 
must be approved by quality control personnel.


Sec.  111.35  Under this subpart D, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart D in 
accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for fulfilling the requirements of this 
subpart, including written procedures for:
    (i) Calibrating instruments and controls that you use in 
manufacturing or testing a component or dietary supplement;
    (ii) Calibrating, inspecting, and checking automated, mechanical, 
and electronic equipment; and
    (iii) Maintaining, cleaning, and sanitizing, as necessary, all 
equipment, utensils, and any other contact surfaces that are used to 
manufacture, package, label, or hold components or dietary supplements;
    (2) Documentation, in individual equipment logs, of the date of the 
use, maintenance, cleaning, and sanitizing of equipment, unless such 
documentation is kept with the batch record;
    (3) Documentation of any calibration, each time the calibration is 
performed, for instruments and controls that you use in manufacturing 
or testing a component or dietary supplement. In your documentation, 
you must:
    (i) Identify the instrument or control calibrated;
    (ii) Provide the date of calibration;
    (iii) Identify the reference standard used including the 
certification of accuracy of the known reference standard and a history 
of recertification of accuracy;
    (iv) Identify the calibration method used, including appropriate 
limits for accuracy and precision of instruments and controls when 
calibrating;
    (v) Provide the calibration reading or readings found;
    (vi) Identify the recalibration method used, and reading or 
readings found, if accuracy or precision or both accuracy and precision 
limits for instruments and controls were not met; and
    (vii) Include the initials of the person who performed the 
calibration and any recalibration.
    (4) Written records of calibrations, inspections, and checks of 
automated, mechanical, and electronic equipment;
    (5) Backup file(s) of current software programs (and of outdated 
software that is necessary to retrieve records that you are required to 
keep in accordance with subpart P of this part, when current software 
is not able to retrieve such records) and of data entered into computer 
systems that you use to manufacture, package, label, or hold dietary 
supplements.
    (i) Your backup file (e.g., a hard copy of data you have entered, 
diskettes, tapes, microfilm, or compact disks) must be an exact and 
complete record of the data you entered.
    (ii) You must keep your backup software programs and data secure 
from alterations, inadvertent erasures, or loss; and
    (6) Documentation of the controls that you use to ensure that 
equipment functions in accordance with its intended use.

Subpart E--Requirement to Establish a Production and Process 
Control System


Sec.  111.55  What are the requirements to implement a production and 
process control system?

    You must implement a system of production and process controls that 
covers all stages of manufacturing, packaging, labeling, and holding of 
the dietary supplement to ensure the quality of the dietary supplement 
and that the dietary supplement is packaged and labeled as specified in 
the master manufacturing record.


Sec.  111.60  What are the design requirements for the production and 
process control system?

    (a) Your production and in-process control system must be designed 
to ensure that the dietary supplement is manufactured, packaged, 
labeled, and held in a manner that will ensure the quality of the 
dietary supplement and that the dietary supplement is packaged and 
labeled as specified in the master manufacturing record; and
    (b) The production and in-process control system must include all 
requirements of subparts E through L of this part and must be reviewed 
and approved by quality control personnel.

[[Page 34949]]

Sec.  111.65  What are the requirements for quality control operations?

    You must implement quality control operations in your 
manufacturing, packaging, labeling, and holding operations for 
producing the dietary supplement to ensure the quality of the dietary 
supplement and that the dietary supplement is packaged and labeled as 
specified in the master manufacturing record.


Sec.  111.70  What specifications must you establish?

    (a) You must establish a specification for any point, step, or 
stage in the manufacturing process where control is necessary to ensure 
the quality of the dietary supplement and that the dietary supplement 
is packaged and labeled as specified in the master manufacturing 
record.
    (b) For each component that you use in the manufacture of a dietary 
supplement, you must establish component specifications as follows:
    (1) You must establish an identity specification;
    (2) You must establish component specifications that are necessary 
to ensure that specifications for the purity, strength and composition 
of dietary supplements manufactured using the components are met; and
    (3) You must establish limits on those types of contamination that 
may adulterate or may lead to adulteration of the finished batch of the 
dietary supplement to ensure the quality of the dietary supplement.
    (c) For the in-process production:
    (1) You must establish in-process specifications for any point, 
step, or stage in the master manufacturing record where control is 
necessary to help ensure that specifications are met for the identity, 
purity, strength, and composition of the dietary supplements and, as 
necessary, for limits on those types of contamination that may 
adulterate or may lead to adulteration of the finished batch of the 
dietary supplement;
    (2) You must provide adequate documentation of your basis for why 
meeting the in-process specifications, in combination with meeting 
component specifications, will help ensure that the specifications are 
met for the identity, purity, strength, and composition of the dietary 
supplements and for limits on those types of contamination that may 
adulterate or may lead to adulteration of the finished batch of the 
dietary supplement; and
    (3) Quality control personnel must review and approve the 
documentation that you provide under paragraph (c)(2) of this section.
    (d) You must establish specifications for dietary supplement labels 
(label specifications) and for packaging that may come in contact with 
dietary supplements (packaging specifications). Packaging that may come 
into contact with dietary supplements must be safe and suitable for its 
intended use and must not be reactive or absorptive or otherwise affect 
the safety or quality of the dietary supplement.
    (e) For each dietary supplement that you manufacture you must 
establish product specifications for the identity, purity, strength, 
and composition of the finished batch of the dietary supplement, and 
for limits on those types of contamination that may adulterate, or that 
may lead to adulteration of, the finished batch of the dietary 
supplement to ensure the quality of the dietary supplement.
    (f) If you receive a product from a supplier for packaging or 
labeling as a dietary supplement (and for distribution rather than for 
return to the supplier), you must establish specifications to provide 
sufficient assurance that the product you receive is adequately 
identified and is consistent with your purchase order.
    (g) You must establish specifications for the packaging and 
labeling of the finished packaged and labeled dietary supplements, 
including specifications that ensure that you used the specified 
packaging and that you applied the specified label.


Sec.  111.73  What is your responsibility for determining whether 
established specifications are met?

    You must determine whether the specifications you establish under 
Sec.  111.70 are met.


Sec.  111.75  What must you do to determine whether specifications are 
met?

    (a) Before you use a component, you must:
    (1) Conduct at least one appropriate test or examination to verify 
the identity of any component that is a dietary ingredient; and
    (2) Confirm the identity of other components and determine whether 
other applicable component specifications established in accordance 
with Sec.  111.70(b) are met. To do so, you must either:
    (i) Conduct appropriate tests or examinations; or
    (ii) Rely on a certificate of analysis from the supplier of the 
component that you receive, provided that:
    (A) You first qualify the supplier by establishing the reliability 
of the supplier's certificate of analysis through confirmation of the 
results of the supplier's tests or examinations;
    (B) The certificate of analysis includes a description of the test 
or examination method(s) used, limits of the test or examinations, and 
actual results of the tests or examinations;
    (C) You maintain documentation of how you qualified the supplier;
    (D) You periodically re-confirm the supplier's certificate of 
analysis; and
    (E) Your quality control personnel review and approve the 
documentation setting forth the basis for qualification (and re-
qualification) of any supplier.
    (b) You must monitor the in-process points, steps, or stages where 
control is necessary to ensure the quality of the finished batch of 
dietary supplement to:
    (1) Determine whether the in-process specifications are met; and
    (2) Detect any deviation or unanticipated occurrence that may 
result in a failure to meet specifications.
    (c) For a subset of finished dietary supplement batches that you 
identify through a sound statistical sampling plan (or for every 
finished batch), you must verify that your finished batch of the 
dietary supplement meets product specifications for identity, purity, 
strength, composition, and for limits on those types of contamination 
that may adulterate or that may lead to adulteration of the finished 
batch of the dietary supplement. To do so:
    (1) You must select one or more established specifications for 
identity, purity, strength, composition, and the limits on those types 
of contamination that may adulterate or that may lead to adulteration 
of the dietary supplement that, if tested or examined on the finished 
batches of the dietary supplement, would verify that the production and 
process control system is producing a dietary supplement that meets all 
product specifications (or only those product specifications not 
otherwise exempted from this provision by quality control personnel 
under paragraph (d) of this section);
    (2) You must conduct appropriate tests or examinations to determine 
compliance with the specifications selected in paragraph (c)(1) of this 
section;
    (3) You must provide adequate documentation of your basis for 
determining compliance with the specification(s) selected under 
paragraph (c)(1) of this section, through the use of appropriate tests 
or examinations conducted under paragraph (c)(2) of this section, will 
ensure that your finished batch of the dietary supplement meets all 
product specifications for identity, purity, strength, and composition, 
and the limits on those types of contamination that may adulterate, or 
that may lead to

[[Page 34950]]

the adulteration of, the dietary supplement; and
    (4) Your quality control personnel must review and approve the 
documentation that you provide under paragraph (c)(3) of this section.
    (d)(1) You may exempt one or more product specifications from 
verification requirements in paragraph (c)(1) of this section if you 
determine and document that the specifications you select under 
paragraph (c)(1) of this section for determination of compliance with 
specifications are not able to verify that the production and process 
control system is producing a dietary supplement that meets the 
exempted product specification and there is no scientifically valid 
method for testing or examining such exempted product specification at 
the finished batch stage. In such a case, you must document why, for 
example, any component and in-process testing, examination, or 
monitoring, and any other information, will ensure that such exempted 
product specification is met without verification through periodic 
testing of the finished batch; and
    (2) Your quality control personnel must review and approve the 
documentation that you provide under paragraph (d)(1) of this section.
    (e) Before you package or label a product that you receive for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier), you must visually examine the 
product and have documentation to determine whether the specifications 
that you established under Sec.  111.70 (f) are met.
    (f)(1) Before you use packaging, you must, at a minimum, conduct a 
visual identification of the containers and closures and review the 
supplier's invoice, guarantee, or certification to determine whether 
the packaging specifications are met; and
    (2) Before you use labels, you must, at a minimum, conduct a visual 
examination of the label and review the supplier's invoice, guarantee, 
or certification to determine whether label specifications are met.
    (g) You must, at a minimum, conduct a visual examination of the 
packaging and labeling of the finished packaged and labeled dietary 
supplements to determine whether you used the specified packaging and 
applied the specified label.
    (h)(1) You must ensure that the tests and examinations that you use 
to determine whether the specifications are met are appropriate, 
scientifically valid methods.
    (2) The tests and examinations that you use must include at least 
one of the following:
    (i) Gross organoleptic analysis;
    (ii) Macroscopic analysis;
    (iii) Microscopic analysis;
    (iv) Chemical analysis; or
    (v) Other scientifically valid methods.
    (i) You must establish corrective action plans for use when an 
established specification is not met.


Sec.  111.77  What must you do if established specifications are not 
met?

    (a) For specifications established under Sec.  111.70(a), (b)(2), 
(b)(3), (c), (d), (e), and (g) that you do not meet, quality control 
personnel, in accordance with the requirements in subpart F of this 
part, must reject the component, dietary supplement, package or label 
unless such personnel approve a treatment, an in-process adjustment, or 
reprocessing that will ensure the quality of the finished dietary 
supplement and that the dietary supplement is packaged and labeled as 
specified in the master manufacturing record. No finished batch of 
dietary supplements may be released for distribution unless it complies 
with Sec.  111.123(b).
    (b) For specifications established under Sec.  111.70(b)(1) that 
you do not meet, quality control personnel must reject the component 
and the component must not be used in manufacturing the dietary 
supplement.
    (c) For specifications established under Sec.  111.70(f) that you 
do not meet, quality control personnel must reject the product and the 
product may not be packaged or labeled for distribution as a dietary 
supplement.


Sec.  111.80  What representative samples must you collect?

    The representative samples that you must collect include:
    (a) Representative samples of each unique lot of components, 
packaging, and labels that you use to determine whether the components, 
packaging, and labels meet specifications established in accordance 
with Sec.  111.70(b) and (d), and as applicable, Sec.  111.70(a) (and, 
when you receive components, packaging, or labels from a supplier, 
representative samples of each unique shipment, and of each unique lot 
within each unique shipment);
    (b) Representative samples of in-process materials for each 
manufactured batch at points, steps, or stages, in the manufacturing 
process as specified in the master manufacturing record where control 
is necessary to ensure the identity, purity, strength, and composition 
of dietary supplements to determine whether the in-process materials 
meet specifications established in accordance with Sec.  111.70(c), and 
as applicable, Sec.  111.70(a);
    (c) Representative samples of a subset of finished batches of each 
dietary supplement that you manufacture, which you identify through a 
sound statistical sampling plan (or otherwise every finished batch), 
before releasing for distribution to verify that the finished batch of 
dietary supplement meets product specifications established in 
accordance with Sec.  111.70(e), and as applicable, Sec.  111.70(a);
    (d) Representative samples of each unique shipment, and of each 
unique lot within each unique shipment, of product that you receive for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier) to determine whether the 
received product meets specifications established in accordance with 
Sec.  111.70(f), and as applicable, Sec.  111.70(a); and
    (e) Representative samples of each lot of packaged and labeled 
dietary supplements to determine whether the packaging and labeling of 
the finished packaged and labeled dietary supplements meet 
specifications established in accordance with Sec.  111.70(g), and as 
applicable, Sec.  111.70(a).


Sec.  111.83  What are the requirements for reserve samples?

    (a) You must collect and hold reserve samples of each lot of 
packaged and labeled dietary supplements that you distribute.
    (b) The reserve samples must:
    (1) Be held using the same container-closure system in which the 
packaged and labeled dietary supplement is distributed, or if 
distributing dietary supplements to be packaged and labeled, using a 
container-closure system that provides essentially the same 
characteristics to protect against contamination or deterioration as 
the one in which it is distributed for packaging and labeling 
elsewhere;
    (2) Be identified with the batch, lot, or control number;
    (3) Be retained for 1 year past the shelf life date (if shelf life 
dating is used), or for 2 years from the date of distribution of the 
last batch of dietary supplements associated with the reserve sample, 
for use in appropriate investigations; and
    (4) Consist of at least twice the quantity necessary for all tests 
or examinations to determine whether or not the dietary supplement 
meets product specifications.

[[Page 34951]]

Sec.  111.87  Who conducts a material review and makes a disposition 
decision?

    Quality control personnel must conduct all required material 
reviews and make all required disposition decisions.


Sec.  111.90  What requirements apply to treatments, in-process 
adjustments, and reprocessing when there is a deviation or 
unanticipated occurrence or when a specification established in 
accordance with Sec.  111.70 is not met?

    (a) You must not reprocess a rejected dietary supplement or treat 
or provide an in-process adjustment to a component, packaging, or label 
to make it suitable for use in the manufacture of a dietary supplement 
unless:
    (1) Quality control personnel conduct a material review and make a 
disposition decision to approve the reprocessing, treatment, or in-
process adjustment; and
    (2) The reprocessing, treatment, or in-process adjustment is 
permitted by Sec.  111.77;
    (b) You must not reprocess any dietary supplement or treat or 
provide an in-process adjustment to a component to make it suitable for 
use in the manufacture of a dietary supplement, unless:
    (1) Quality control personnel conduct a material review and make a 
disposition decision that is based on a scientifically valid reason and 
approves the reprocessing, treatment, or in-process adjustment; and
    (2) The reprocessing, treatment or in-process adjustment is 
permitted by Sec.  111.77;
    (c) Any batch of dietary supplement that is reprocessed, that 
contains components that you have treated, or to which you have made 
in-process adjustments to make them suitable for use in the manufacture 
of the dietary supplement must be approved by quality control personnel 
and comply with Sec.  111.123(b) before releasing for distribution.


Sec.  111.95  Under this subpart E, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart E in 
accordance with subpart P of this part.
    (b) Under this subpart E, you must make and keep the following 
records:
    (1) The specifications established;
    (2) Documentation of your qualification of a supplier for the 
purpose of relying on the supplier's certificate of analysis;
    (3) Documentation for why meeting in-process specifications, in 
combination with meeting component specifications, helps ensure that 
the dietary supplement meets the specifications for identity, purity, 
strength, and composition; and for limits on those types of 
contamination that may adulterate or may lead to adulteration of the 
finished batch of the dietary supplement; and
    (4) Documentation for why the results of appropriate tests or 
examinations for the product specifications selected under Sec.  
111.75(c)(1) ensure that the dietary supplement meets all product 
specifications;
    (5) Documentation for why any component and in-process testing, 
examination, or monitoring, and any other information, will ensure that 
a product specification that is exempted under Sec.  111.75(d) is met 
without verification through periodic testing of the finished batch, 
including documentation that the selected specifications tested or 
examined under Sec.  111.75 (c)(1) are not able to verify that the 
production and process control system is producing a dietary supplement 
that meets the exempted product specification and there is no 
scientifically valid method for testing or examining such exempted 
product specification at the finished batch stage.

Subpart F--Production and Process Control System: Requirements for 
Quality Control


Sec.  111.103  What are the requirements under this subpart F for 
written procedures?

    You must establish and follow written procedures for the 
responsibilities of the quality control operations, including written 
procedures for conducting a material review and making a disposition 
decision, and for approving or rejecting any reprocessing.


Sec.  111.105  What must quality control personnel do?

    Quality control personnel must ensure that your manufacturing, 
packaging, labeling, and holding operations ensure the quality of the 
dietary supplement and that the dietary supplement is packaged and 
labeled as specified in the master manufacturing record. To do so, 
quality control personnel must perform operations that include:
    (a) Approving or rejecting all processes, specifications, written 
procedures, controls, tests, and examinations, and deviations from or 
modifications to them, that may affect the identity, purity, strength, 
or composition of a dietary supplement;
    (b) Reviewing and approving the documentation setting forth the 
basis for qualification of any supplier;
    (c) Reviewing and approving the documentation setting forth the 
basis for why meeting in-process specifications, in combination with 
meeting component specifications, will help ensure that the identity, 
purity, strength, and composition of the dietary supplement are met;
    (d) Reviewing and approving the documentation setting forth the 
basis for why the results of appropriate tests or examinations for each 
product specification selected under Sec.  111.75(c)(1) will ensure 
that the finished batch of the dietary supplement meets product 
specifications;
    (e) Reviewing and approving the basis and the documentation for why 
any product specification is exempted from the verification 
requirements in Sec.  111.75(c)(1), and for why any component and in-
process testing, examination, or monitoring, or other methods will 
ensure that such exempted product specification is met without 
verification through periodic testing of the finished batch;
    (f) Ensuring that required representative samples are collected;
    (g) Ensuring that required reserve samples are collected and held;
    (h) Determining whether all specifications established under Sec.  
111.70(a) are met; and
    (i) Performing other operations required under this subpart.


Sec.  111.110  What quality control operations are required for 
laboratory operations associated with the production and process 
control system?

    Quality control operations for laboratory operations associated 
with the production and process control system must include:
    (a) Reviewing and approving all laboratory control processes 
associated with the production and process control system;
    (b) Ensuring that all tests and examinations required under Sec.  
111.75 are conducted; and
    (c) Reviewing and approving the results of all tests and 
examinations required under Sec.  111.75.


Sec.  111.113  What quality control operations are required for a 
material review and disposition decision?

    (a) Quality control personnel must conduct a material review and 
make a disposition decision if:
    (1) A specification established in accordance with Sec.  111.70 is 
not met;
    (2) A batch deviates from the master manufacturing record, 
including when any step established in the master manufacturing record 
is not completed and including any deviation from specifications;
    (3) There is any unanticipated occurrence during the manufacturing

[[Page 34952]]

operations that adulterates or may lead to adulteration of the 
component, dietary supplement, or packaging, or could lead to the use 
of a label not specified in the master manufacturing record;
    (4) Calibration of an instrument or control suggests a problem that 
may have resulted in a failure to ensure the quality of a batch or 
batches of a dietary supplement; or
    (5) A dietary supplement is returned.
    (b)(1) When there is a deviation or unanticipated occurrence during 
the production and in-process control system that results in or could 
lead to adulteration of a component, dietary supplement, or packaging, 
or could lead to the use of a label not specified in the master 
manufacturing record, quality control personnel must reject the 
component, dietary supplement, packaging, or label unless it approves a 
treatment, an in-process adjustment, or reprocessing to correct the 
applicable deviation or occurrence.
    (2) When a specification established in accordance with Sec.  
111.70 is not met, quality control personnel must reject the component, 
dietary supplement, package or label, unless quality control personnel 
approve a treatment, an in-process adjustment, or reprocessing, as 
permitted in Sec.  111.77.
    (c) The person who conducts a material review and makes the 
disposition decision must, at the time of performance, document that 
material review and disposition decision.


Sec.  111.117  What quality control operations are required for 
equipment, instruments, and controls?

    Quality control operations for equipment, instruments, and controls 
must include:
    (a) Reviewing and approving all processes for calibrating 
instruments and controls;
    (b) Periodically reviewing all records for calibration of 
instruments and controls;
    (c) Periodically reviewing all records for calibrations, 
inspections, and checks of automated, mechanical, or electronic 
equipment; and
    (d) Reviewing and approving controls to ensure that automated, 
mechanical, or electronic equipment functions in accordance with its 
intended use.


Sec.  111.120  What quality control operations are required for 
components, packaging, and labels before use in the manufacture of a 
dietary supplement?

    Quality control operations for components, packaging, and labels 
before use in the manufacture of a dietary supplement must include:
    (a) Reviewing all receiving records for components, packaging, and 
labels;
    (b) Determining whether all components, packaging, and labels 
conform to specifications established under Sec.  111.70 (b) and (d);
    (c) Conducting any required material review and making any required 
disposition decision;
    (d) Approving or rejecting any treatment and in-process adjustments 
of components, packaging, or labels to make them suitable for use in 
the manufacture of a dietary supplement; and
    (e) Approving, and releasing from quarantine, all components, 
packaging, and labels before they are used.


Sec.  111.123  What quality control operations are required for the 
master manufacturing record, the batch production record, and 
manufacturing operations?

    (a) Quality control operations for the master manufacturing record, 
the batch production record, and manufacturing operations must include:
    (1) Reviewing and approving all master manufacturing records and 
all modifications to the master manufacturing records;
    (2) Reviewing and approving all batch production-related records;
    (3) Reviewing all monitoring required under subpart E;
    (4) Conducting any required material review and making any required 
disposition decision;
    (5) Approving or rejecting any reprocessing;
    (6) Determining whether all in-process specifications established 
in accordance with Sec.  111.70(c) are met;
    (7) Determining whether each finished batch conforms to product 
specifications established in accordance with Sec.  111.70(e); and
    (8) Approving and releasing, or rejecting, each finished batch for 
distribution, including any reprocessed finished batch.
    (b) Quality control personnel must not approve and release for 
distribution:
    (1) Any batch of dietary supplement for which any component in the 
batch does not meet its identity specification;
    (2) Any batch of dietary supplement, including any reprocessed 
batch, that does not meet all product specifications established in 
accordance with Sec.  111.70(e);
    (3) Any batch of dietary supplement, including any reprocessed 
batch, that has not been manufactured, packaged, labeled, and held 
under conditions to prevent adulteration under section 402(a)(1), 
(a)(2), (a)(3), and (a)(4) of the act; and
    (4) Any product received from a supplier for packaging or labeling 
as a dietary supplement (and for distribution rather than for return to 
the supplier) for which sufficient assurance is not provided to 
adequately identify the product and to determine that the product is 
consistent with your purchase order.


Sec.  111.127  What quality control operations are required for 
packaging and labeling operations?

    Quality control operations for packaging and labeling operations 
must include:
    (a) Reviewing the results of any visual examination and 
documentation to ensure that specifications established under Sec.  
111.70(f) are met for all products that you receive for packaging and 
labeling as a dietary supplement (and for distribution rather than for 
return to the supplier);
    (b) Approving, and releasing from quarantine, all products that you 
receive for packaging or labeling as a dietary supplement (and for 
distribution rather than for return to the supplier) before they are 
used for packaging or labeling;
    (c) Reviewing and approving all records for packaging and label 
operations;
    (d) Determining whether the finished packaged and labeled dietary 
supplement conforms to specifications established in accordance with 
Sec.  111.70(g);
    (e) Conducting any required material review and making any required 
disposition decision;
    (f) Approving or rejecting any repackaging of a packaged dietary 
supplement;
    (g) Approving or rejecting any relabeling of a packaged and labeled 
dietary supplement; and
    (h) Approving for release, or rejecting, any packaged and labeled 
dietary supplement (including a repackaged or relabeled dietary 
supplement) for distribution.


Sec.  111.130  What quality control operations are required for 
returned dietary supplements?

    Quality control operations for returned dietary supplements must 
include:
    (a) Conducting any required material review and making any required 
disposition decision; including:
    (1) Determining whether tests or examination are necessary to 
determine compliance with product specifications established in 
accordance with Sec.  111.70(e); and
    (2) Reviewing the results of any tests or examinations that are 
conducted to determine compliance with product specifications 
established in accordance with Sec.  111.70(e);

[[Page 34953]]

    (b) Approving or rejecting any salvage and redistribution of any 
returned dietary supplement;
    (c) Approving or rejecting any reprocessing of any returned dietary 
supplement; and
    (d) Determining whether the reprocessed dietary supplement meets 
product specifications and either approving for release, or rejecting, 
any returned dietary supplement that is reprocessed.


Sec.  111.135  What quality control operations are required for product 
complaints?

    Quality control operations for product complaints must include 
reviewing and approving decisions about whether to investigate a 
product complaint and reviewing and approving the findings and followup 
action of any investigation performed.


Sec.  111.140  Under this subpart F, what records must you make and 
keep?

    (a) You must make and keep the records required under this subpart 
F in accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for the responsibilities of the quality 
control operations, including written procedures for conducting a 
material review and making a disposition decision and written 
procedures for approving or rejecting any reprocessing;
    (2) Written documentation, at the time of performance, that quality 
control personnel performed the review, approval, or rejection 
requirements by recording the following:
    (i) Date that the review, approval, or rejection was performed; and
    (ii) Signature of the person performing the review, approval, or 
rejection; and
    (3) Documentation of any material review and disposition decision 
and followup. Such documentation must be included in the appropriate 
batch production record and must include:
    (i) Identification of the specific deviation or the unanticipated 
occurrence;
    (ii) Description of your investigation into the cause of the 
deviation from the specification or the unanticipated occurrence;
    (iii) Evaluation of whether or not the deviation or unanticipated 
occurrence has resulted in or could lead to a failure to ensure the 
quality of the dietary supplement or a failure to package and label the 
dietary supplement as specified in the master manufacturing record;
    (iv) Identification of the action(s) taken to correct, and prevent 
a recurrence of, the deviation or the unanticipated occurrence;
    (v) Explanation of what you did with the component, dietary 
supplement, packaging, or label;
    (vi) A scientifically valid reason for any reprocessing of a 
dietary supplement that is rejected or any treatment or in-process 
adjustment of a component that is rejected; and
    (vii) The signature of the individual(s) designated to perform the 
quality control operation, who conducted the material review and made 
the disposition decision, and of each qualified individual who provides 
information relevant to that material review and disposition decision.

Subpart G--Production and Process Control System: Requirements for 
Components, Packaging, and Labels and for Product That You Receive 
for Packaging or Labeling as a Dietary Supplement


Sec.  111.153  What are the requirements under this subpart G for 
written procedures?

    You must establish and follow written procedures for fulfilling the 
requirements of this subpart G.


Sec.  111.155  What requirements apply to components of dietary 
supplements?

    (a) You must visually examine each immediate container or grouping 
of immediate containers in a shipment that you receive for appropriate 
content label, container damage, or broken seals to determine whether 
the container condition may have resulted in contamination or 
deterioration of the components;
    (b) You must visually examine the supplier's invoice, guarantee, or 
certification in a shipment you receive to ensure the components are 
consistent with your purchase order;
    (c) You must quarantine components before you use them in the 
manufacture of a dietary supplement until:
    (1) You collect representative samples of each unique lot of 
components (and, for components that you receive, of each unique 
shipment, and of each unique lot within each unique shipment);
    (2) Quality control personnel review and approve the results of any 
tests or examinations conducted on components; and
    (3) Quality control personnel approve the components for use in the 
manufacture of a dietary supplement, including approval of any 
treatment (including in-process adjustments) of components to make them 
suitable for use in the manufacture of a dietary supplement, and 
releases them from quarantine.
    (d)(1) You must identify each unique lot within each unique 
shipment of components that you receive and any lot of components that 
you produce in a manner that allows you to trace the lot to the 
supplier, the date received, the name of the component, the status of 
the component (e.g., quarantined, approved, or rejected); and to the 
dietary supplement that you manufactured and distributed.
    (2) You must use this unique identifier whenever you record the 
disposition of each unique lot within each unique shipment of 
components that you receive and any lot of components that you produce.
    (e) You must hold components under conditions that will protect 
against contamination and deterioration, and avoid mixups.


Sec.  111.160  What requirements apply to packaging and labels 
received?

    (a) You must visually examine each immediate container or grouping 
of immediate containers in a shipment for appropriate content label, 
container damage, or broken seals to determine whether the container 
condition may have resulted in contamination or deterioration of the 
packaging and labels.
    (b) You must visually examine the supplier's invoice, guarantee, or 
certification in a shipment to ensure that the packaging or labels are 
consistent with your purchase order.
    (c) You must quarantine packaging and labels before you use them in 
the manufacture of a dietary supplement until:
    (1) You collect representative samples of each unique shipment, and 
of each unique lot within each unique shipment, of packaging and labels 
and, at a minimum, conduct a visual identification of the immediate 
containers and closures;
    (2) Quality control personnel review and approve the results of any 
tests or examinations conducted on the packaging and labels; and
    (3) Quality control personnel approve the packaging and labels for 
use in the manufacture of a dietary supplement and release them from 
quarantine.
    (d)(1) You must identify each unique lot within each unique 
shipment of packaging and labels in a manner that allows you to trace 
the lot to the supplier, the date received, the name of the packaging 
and label, the status of the packaging and label (e.g., quarantined, 
approved, or rejected); and to the dietary supplement that you 
distributed; and
    (2) You must use this unique identifier whenever you record the 
disposition of each unique lot within

[[Page 34954]]

each unique shipment of packaging and labels.
    (e) You must hold packaging and labels under conditions that will 
protect against contamination and deterioration, and avoid mixups.


Sec.  111.165  What requirements apply to a product received for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier)?

    (a) You must visually examine each immediate container or grouping 
of immediate containers in a shipment of product that you receive for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier) for appropriate content label, 
container damage, or broken seals to determine whether the container 
condition may have resulted in contamination or deterioration of the 
received product.
    (b) You must visually examine the supplier's invoice, guarantee, or 
certification in a shipment of the received product to ensure that the 
received product is consistent with your purchase order.
    (c) You must quarantine the received product until:
    (1) You collect representative samples of each unique shipment, and 
of each unique lot within each unique shipment, of received product;
    (2) Quality control personnel review and approve the documentation 
to determine whether the received product meets the specifications that 
you established under Sec.  111.70(f); and
    (3) Quality control personnel approve the received product for 
packaging or labeling as a dietary supplement and release the received 
product from quarantine.
    (d)(1) You must identify each unique lot within each unique 
shipment of received product in a manner that allows you to trace the 
lot to the supplier, the date received, the name of the received 
product, the status of the received product (e.g., quarantined, 
approved, or rejected), and to the product that you packaged or labeled 
and distributed as a dietary supplement.
    (2) You must use this unique identifier whenever you record the 
disposition of each unique lot within each unique shipment of the 
received product.
    (e) You must hold the received product under conditions that will 
protect against contamination and deterioration, and avoid mixups.


Sec.  111.170  What requirements apply to rejected components, 
packaging, and labels, and to rejected products that are received for 
packaging or labeling as a dietary supplement?

    You must clearly identify, hold, and control under a quarantine 
system for appropriate disposition any component, packaging, and label, 
and any product that you receive for packaging or labeling as a dietary 
supplement (and for distribution rather than for return to the 
supplier), that is rejected and unsuitable for use in manufacturing, 
packaging, or labeling operations.


Sec.  111.180  Under this subpart G, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart G in 
accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for fulfilling the requirements of this 
subpart.
    (2) Receiving records (including records such as certificates of 
analysis, suppliers' invoices, and suppliers' guarantees) for 
components, packaging, and labels and for products that you receive for 
packaging or labeling as a dietary supplement (and for distribution 
rather than for return to the supplier); and
    (3) Documentation that the requirements of this subpart were met.
    (i) The person who performs the required operation must document, 
at the time of performance, that the required operation was performed.
    (ii) The documentation must include:
    (A) The date that the components, packaging, labels, or products 
that you receive for packaging or labeling as a dietary supplement were 
received;
    (B) The initials of the person performing the required operation;
    (C) The results of any tests or examinations conducted on 
components, packaging, or labels, and of any visual examination of 
product that you receive for packaging or labeling as a dietary 
supplement; and
    (D) Any material review and disposition decision conducted on 
components, packaging, labels, or products that you receive for 
packaging or labeling as a dietary supplement.

Subpart H--Production and Process Control System: Requirements for 
the Master Manufacturing Record


Sec.  111.205  What is the requirement to establish a master 
manufacturing record?

    (a) You must prepare and follow a written master manufacturing 
record for each unique formulation of dietary supplement that you 
manufacture, and for each batch size, to ensure uniformity in the 
finished batch from batch to batch.
    (b) The master manufacturing record must:
    (1) Identify specifications for the points, steps, or stages in the 
manufacturing process where control is necessary to ensure the quality 
of the dietary supplement and that the dietary supplement is packaged 
and labeled as specified in the master manufacturing record; and
    (2) Establish controls and procedures to ensure that each batch of 
dietary supplement that you manufacture meets the specifications 
identified in accordance with paragraph (b)(1) of this section.
    (c) You must make and keep master manufacturing records in 
accordance with subpart P of this part.


Sec.  111.210  What must the master manufacturing record include?

    The master manufacturing record must include:
    (a) The name of the dietary supplement to be manufactured and the 
strength, concentration, weight, or measure of each dietary ingredient 
for each batch size;
    (b) A complete list of components to be used;
    (c) An accurate statement of the weight or measure of each 
component to be used;
    (d) The identity and weight or measure of each dietary ingredient 
that will be declared on the Supplement Facts label and the identity of 
each ingredient that will be declared on the ingredients list of the 
dietary supplement;
    (e) A statement of any intentional overage amount of a dietary 
ingredient;
    (f) A statement of theoretical yield of a manufactured dietary 
supplement expected at each point, step, or stage of the manufacturing 
process where control is needed to ensure the quality of the dietary 
supplement, and the expected yield when you finish manufacturing the 
dietary supplement, including the maximum and minimum percentages of 
theoretical yield beyond which a deviation investigation of a batch is 
necessary and material review is conducted and disposition decision is 
made;
    (g) A description of packaging and a representative label, or a 
cross-reference to the physical location of the actual or 
representative label;
    (h) Written instructions, including the following:
    (1) Specifications for each point, step, or stage in the 
manufacturing process where control is necessary to ensure the quality 
of the dietary supplement and

[[Page 34955]]

that the dietary supplement is packaged and labeled as specified in the 
master manufacturing record;
    (2) Procedures for sampling and a cross-reference to procedures for 
tests or examinations;
    (3) Specific actions necessary to perform and verify points, steps, 
or stages in the manufacturing process where control is necessary to 
ensure the quality of the dietary supplement and that the dietary 
supplement is packaged and labeled as specified in the master 
manufacturing record.
    (i) Such specific actions must include verifying the weight or 
measure of any component and verifying the addition of any component; 
and
    (ii) For manual operations, such specific actions must include:
    (A) One person weighing or measuring a component and another person 
verifying the weight or measure; and
    (B) One person adding the component and another person verifying 
the addition.
    (4) Special notations and precautions to be followed; and
    (5) Corrective action plans for use when a specification is not 
met.

Subpart I--Production and Process Control System: Requirements for 
the Batch Production Record


Sec.  111.255  What is the requirement to establish a batch production 
record?

    (a) You must prepare a batch production record every time you 
manufacture a batch of a dietary supplement;
    (b) Your batch production record must include complete information 
relating to the production and control of each batch;
    (c) Your batch production record must accurately follow the 
appropriate master manufacturing record and you must perform each step 
in the production of the batch; and
    (d) You must make and keep batch production records in accordance 
with subpart P of this part.


Sec.  111.260  What must the batch record include?

    The batch production record must include the following:
    (a) The batch, lot, or control number:
    (1) Of the finished batch of dietary supplement; and
    (2) That you assign in accordance with Sec.  111.415(f) for the 
following:
    (i) Each lot of packaged and labeled dietary supplement from the 
finished batch of dietary supplement;
    (ii) Each lot of dietary supplement, from the finished batch of 
dietary supplement, that you distribute to another person for packaging 
or labeling;
    (b) The identity of equipment and processing lines used in 
producing the batch;
    (c) The date and time of the maintenance, cleaning, and sanitizing 
of the equipment and processing lines used in producing the batch, or a 
cross-reference to records, such as individual equipment logs, where 
this information is retained;
    (d) The unique identifier that you assigned to each component (or, 
when applicable, to a product that you receive from a supplier for 
packaging or labeling as a dietary supplement), packaging, and label 
used;
    (e) The identity and weight or measure of each component used;
    (f) A statement of the actual yield and a statement of the 
percentage of theoretical yield at appropriate phases of processing;
    (g) The actual results obtained during any monitoring operation;
    (h) The results of any testing or examination performed during the 
batch production, or a cross-reference to such results;
    (i) Documentation that the finished dietary supplement meets 
specifications established in accordance with Sec.  111.70(e) and (g);
    (j) Documentation, at the time of performance, of the manufacture 
of the batch, including:
    (1) The date on which each step of the master manufacturing record 
was performed; and
    (2) The initials of the persons performing each step, including:
    (i) The initials of the person responsible for weighing or 
measuring each component used in the batch;
    (ii) The initials of the person responsible for verifying the 
weight or measure of each component used in the batch;
    (iii) The initials of the person responsible for adding the 
component to the batch; and
    (iv) The initials of the person responsible for verifying the 
addition of components to the batch;
    (k) Documentation, at the time of performance, of packaging and 
labeling operations, including:
    (1) The unique identifier that you assigned to packaging and labels 
used, the quantity of the packaging and labels used, and, when label 
reconciliation is required, reconciliation of any discrepancies between 
issuance and use of labels;
    (2) An actual or representative label, or a cross-reference to the 
physical location of the actual or representative label specified in 
the master manufacturing record; and
    (3) The results of any tests or examinations conducted on packaged 
and labeled dietary supplements (including repackaged or relabeled 
dietary supplements), or a cross-reference to the physical location of 
such results;
    (l) Documentation at the time of performance that quality control 
personnel:
    (1) Reviewed the batch production record, including:
    (i) Review of any monitoring operation required under subpart E of 
this part; and
    (ii) Review of the results of any tests and examinations, including 
tests and examinations conducted on components, in-process materials, 
finished batches of dietary supplements, and packaged and labeled 
dietary supplements;
    (2) Approved or rejected any reprocessing or repackaging; and
    (3) Approved and released, or rejected, the batch for distribution, 
including any reprocessed batch; and
    (4) Approved and released, or rejected, the packaged and labeled 
dietary supplement, including any repackaged or relabeled dietary 
supplement.
    (m) Documentation at the time of performance of any required 
material review and disposition decision.
    (n) Documentation at the time of performance of any reprocessing.

Subpart J--Production and Process Control System: Requirements for 
Laboratory Operations


Sec.  111.303  What are the requirements under this subpart J for 
written procedures?

    You must establish and follow written procedures for laboratory 
operations, including written procedures for the tests and examinations 
that you conduct to determine whether specifications are met.


Sec.  111.310  What are the requirements for the laboratory facilities 
that you use?

    You must use adequate laboratory facilities to perform whatever 
testing and examinations are necessary to determine whether:
    (a) Components that you use meet specifications;
    (b) In-process specifications are met as specified in the master 
manufacturing record; and
    (c) Dietary supplements that you manufacture meet specifications.


Sec.  111.315  What are the requirements for laboratory control 
processes?

    You must establish and follow laboratory control processes that are

[[Page 34956]]

reviewed and approved by quality control personnel, including the 
following:
    (a) Use of criteria for establishing appropriate specifications;
    (b) Use of sampling plans for obtaining representative samples, in 
accordance with subpart E of this part, of:
    (1) Components, packaging, and labels;
    (2) In-process materials;
    (3) Finished batches of dietary supplements;
    (4) Product that you receive for packaging or labeling as a dietary 
supplement (and for distribution rather than for return to the 
supplier); and
    (5) Packaged and labeled dietary supplements.
    (c) Use of criteria for selecting appropriate examination and 
testing methods;
    (d) Use of criteria for selecting standard reference materials used 
in performing tests and examinations; and
    (e) Use of test methods and examinations in accordance with 
established criteria.


Sec.  111.320  What requirements apply to laboratory methods for 
testing and examination?

    (a) You must verify that the laboratory examination and testing 
methodologies are appropriate for their intended use.
    (b) You must identify and use an appropriate scientifically valid 
method for each established specification for which testing or 
examination is required to determine whether the specification is met.


Sec.  111.325  Under this subpart J, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart J in 
accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for laboratory operations, including written 
procedures for the tests and examinations that you conduct to determine 
whether specifications are met;
    (2) Documentation that laboratory methodology established in 
accordance with this subpart J is followed.
    (i) The person who conducts the testing and examination must 
document, at the time of performance, that laboratory methodology 
established in accordance with this subpart J is followed.
    (ii) The documentation for laboratory tests and examinations must 
include the results of the testing and examination.

Subpart K--Production and Process Control System: Requirements for 
Manufacturing Operations


Sec.  111.353  What are the requirements under this subpart K for 
written procedures?

    You must establish and follow written procedures for manufacturing 
operations.


Sec.  111.355  What are the design requirements for manufacturing 
operations?

    You must design or select manufacturing processes to ensure that 
product specifications are consistently met.


Sec.  111.360  What are the requirements for sanitation?

    You must conduct all manufacturing operations in accordance with 
adequate sanitation principles.


Sec.  111.365  What precautions must you take to prevent contamination?

    You must take all the necessary precautions during the manufacture 
of a dietary supplement to prevent contamination of components or 
dietary supplements. These precautions include:
    (a) Performing manufacturing operations under conditions and 
controls that protect against the potential for growth of 
microorganisms and the potential for contamination;
    (b) Washing or cleaning components that contain soil or other 
contaminants;
    (c) Using water that, at a minimum, complies with the applicable 
Federal, State, and local requirements and does not contaminate the 
dietary supplement when the water may become a component of the 
finished batch of dietary supplement;
    (d) Performing chemical, microbiological, or other testing, as 
necessary to prevent the use of contaminated components;
    (e) Sterilizing, pasteurizing, freezing, refrigerating, controlling 
hydrogen-ion concentration (pH), controlling humidity, controlling 
water activity (a<INF>w</INF>), or using any other effective means to 
remove, destroy, or prevent the growth of microorganisms and prevent 
decomposition;
    (f) Holding components and dietary supplements that can support the 
rapid growth of microorganisms of public health significance in a 
manner that prevents the components and dietary supplements from 
becoming adulterated;
    (g) Identifying and holding any components or dietary supplements, 
for which a material review and disposition decision is required, in a 
manner that protects components or dietary supplements that are not 
under a material review against contamination and mixups with those 
that are under a material review;
    (h) Performing mechanical manufacturing steps (such as cutting, 
sorting, inspecting, shredding, drying, grinding, blending, and 
sifting) by any effective means to protect the dietary supplements 
against contamination, by, for example:
    (1) Cleaning and sanitizing contact surfaces;
    (2) Using temperature controls; and
    (3) Using time controls.
    (i) Using effective measures to protect against the inclusion of 
metal or other foreign material in components or dietary supplements, 
by, for example:
    (1) Filters or strainers,
    (2) Traps,
    (3) Magnets, or
    (4) Electronic metal detectors.
    (j) Segregating and identifying all containers for a specific batch 
of dietary supplements to identify their contents and, when necessary, 
the phase of manufacturing; and
    (k) Identifying all processing lines and major equipment used 
during manufacturing to indicate their contents, including the name of 
the dietary supplement and the specific batch or lot number and, when 
necessary, the phase of manufacturing.


Sec.  111.370  What requirements apply to rejected dietary supplements?

    You must clearly identify, hold, and control under a quarantine 
system for appropriate disposition any dietary supplement that is 
rejected and unsuitable for use in manufacturing, packaging, or 
labeling operations.


Sec.  111.375  Under this subpart K, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart K in 
accordance with subpart P of this part.
    (b) You must make and keep records of the written procedures for 
manufacturing operations.

Subpart L--Production and Process Control System: Requirements for 
Packaging and Labeling Operations


Sec.  111.403  What are the requirements under this subpart L for 
written procedures?

    You must establish and follow written procedures for packaging and 
labeling operations.


Sec.  111.410  What requirements apply to packaging and labels?

    (a) You must take necessary actions to determine whether packaging 
for dietary supplements meets specifications so that the condition of 
the packaging will

[[Page 34957]]

ensure the quality of your dietary supplements;
    (b) You must control the issuance and use of packaging and labels 
and reconciliation of any issuance and use discrepancies. Label 
reconciliation is not required for cut or rolled labels if a 100-
percent examination for correct labels is performed by appropriate 
electronic or electromechanical equipment during or after completion of 
finishing operations; and
    (c) You must examine, before packaging and labeling operations, 
packaging and labels for each batch of dietary supplement to determine 
whether the packaging and labels conform to the master manufacturing 
record; and
    (d) You must be able to determine the complete manufacturing 
history and control of the packaged and labeled dietary supplement 
through distribution.


Sec.  111.415  What requirements apply to filling, assembling, 
packaging, labeling, and related operations?

    You must fill, assemble, package, label, and perform other related 
operations in a way that ensures the quality of the dietary supplement 
and that the dietary supplement is packaged and labeled as specified in 
the master manufacturing record. You must do this using any effective 
means, including the following:
    (a) Cleaning and sanitizing all filling and packaging equipment, 
utensils, and dietary supplement packaging, as appropriate;
    (b) Protecting manufactured dietary supplements from contamination, 
particularly airborne contamination;
    (c) Using sanitary handling procedures;
    (d) Establishing physical or spatial separation of packaging and 
label operations from operations on other components and dietary 
supplements to prevent mixups;
    (e) Identifying, by any effective means, filled dietary supplement 
containers that are set aside and held in unlabeled condition for 
future label operations, to prevent mixups;
    (f) Assigning a batch, lot, or control number to:
    (1) Each lot of packaged and labeled dietary supplement from a 
finished batch of dietary supplement; and,
    (2) Each lot of dietary supplement, from a finished batch of 
dietary supplement, that you distribute to another person for packaging 
or labeling.
    (g) Examining a representative sample of each batch of the packaged 
and labeled dietary supplement to determine whether the dietary 
supplement meets specifications established in accordance with Sec.  
111.70(g); and
    (h) Suitably disposing of labels and packaging for dietary 
supplements that are obsolete or incorrect to ensure that they are not 
used in any future packaging and label operations.


Sec.  111.420  What requirements apply to repackaging and relabeling?

    (a) You may repackage or relabel dietary supplements only after 
quality control personnel have approved such repackaging or relabeling.
    (b) You must examine a representative sample of each batch of 
repackaged or relabeled dietary supplements to determine whether the 
repackaged or relabeled dietary supplements meet all specifications 
established in accordance with Sec.  111.70(g).
    (c) Quality control personnel must approve or reject each batch of 
repackaged or relabeled dietary supplement prior to its release for 
distribution.


Sec.  111.425  What requirements apply to a packaged and labeled 
dietary supplement that is rejected for distribution?

    You must clearly identify, hold, and control under a quarantine 
system for appropriate disposition any packaged and labeled dietary 
supplement that is rejected for distribution.


Sec.  111.430  Under this subpart L, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart L in 
accordance with subpart P of this part.
    (b) You must make and keep records of the written procedures for 
packaging and labeling operations.

Subpart M--Holding and Distributing


Sec.  111.453  What are the requirements under this subpart for M 
written procedures?

    You must establish and follow written procedures for holding and 
distributing operations.


Sec.  111.455  What requirements apply to holding components, dietary 
supplements, packaging, and labels?

    (a) You must hold components and dietary supplements under 
appropriate conditions of temperature, humidity, and light so that the 
identity, purity, strength, and composition of the components and 
dietary supplements are not affected.
    (b) You must hold packaging and labels under appropriate conditions 
so that the packaging and labels are not adversely affected.
    (c) You must hold components, dietary supplements, packaging, and 
labels under conditions that do not lead to the mixup, contamination, 
or deterioration of components, dietary supplements, packaging, and 
labels.


Sec.  111.460  What requirements apply to holding in-process material?

    (a) You must identify and hold in-process material under conditions 
that protect against mixup, contamination, and deterioration.
    (b) You must hold in-process material under appropriate conditions 
of temperature, humidity, and light.


Sec.  111.465  What requirements apply to holding reserve samples of 
dietary supplements?

    (a) You must hold reserve samples of dietary supplements in a 
manner that protects against contamination and deterioration. This 
includes:
    (1) Holding the reserve samples under conditions consistent with 
product labels or, if no storage conditions are recommended on the 
label, under ordinary storage conditions; and
    (2) Using the same container-closure system in which the packaged 
and labeled dietary supplement is distributed, or if distributing 
dietary supplements to be packaged and labeled, using a container-
closure system that provides essentially the same characteristics to 
protect against contamination or deterioration as the one in which you 
distribute the dietary supplement for packaging and labeling elsewhere.
    (b) You must retain reserve samples for 1 year past the shelf life 
date (if shelf life dating is used), or for 2 years from the date of 
distribution of the last batch of dietary supplements associated with 
the reserve samples, for use in appropriate investigations.


Sec.  111.470  What requirements apply to distributing dietary 
supplements?

    You must distribute dietary supplements under conditions that will 
protect the dietary supplements against contamination and 
deterioration.


Sec.  111.475  Under this subpart M, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart M in 
accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for holding and distributing operations; and
    (2) Records of product distribution.

[[Page 34958]]

Subpart N--Returned Dietary Supplements


Sec.  111.503  What are the requirements under this subpart N for 
written procedures?

    You must establish and follow written procedures to fulfill the 
requirements of this subpart.


Sec.  111.510  What requirements apply when a returned dietary 
supplement is received?

    You must identify and quarantine returned dietary supplements until 
quality control personnel conduct a material review and make a 
disposition decision.


Sec.  111.515  When must a returned dietary supplement be destroyed, or 
otherwise suitably disposed of?

    You must destroy, or otherwise suitably dispose of, any returned 
dietary supplement unless the outcome of a material review and 
disposition decision is that quality control personnel do the 
following:
    (a) Approve the salvage of the returned dietary supplement for 
redistribution or
    (b) Approve the returned dietary supplement for reprocessing.


Sec.  111.520  When may a returned dietary supplement be salvaged?

    You may salvage a returned dietary supplement only if quality 
control personnel conduct a material review and make a disposition 
decision to allow the salvage.


Sec.  111.525  What requirements apply to a returned dietary supplement 
that quality control personnel approve for reprocessing?

    (a) You must ensure that any returned dietary supplements that are 
reprocessed meet all product specifications established in accordance 
with Sec.  111.70(e); and
    (b) Quality control personnel must approve or reject the release 
for distribution of any returned dietary supplement that is 
reprocessed.


Sec.  111.530  When must an investigation be conducted of your 
manufacturing processes and other batches?

    If the reason for a dietary supplement being returned implicates 
other batches, you must conduct an investigation of your manufacturing 
processes and each of those other batches to determine compliance with 
specifications.


Sec.  111.535  Under this subpart N, what records must you make and 
keep?

    (a) You must make and keep records required under this subpart N in 
accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for fulfilling the requirements of this 
subpart N.
    (2) Any material review and disposition decision on a returned 
dietary supplement;
    (3) The results of any testing or examination conducted to 
determine compliance with product specifications established under 
Sec.  111.70(e); and,
    (4) Documentation of the reevaluation by quality control personnel 
of any dietary supplement that is reprocessed and the determination by 
quality control personnel of whether the reprocessed dietary supplement 
meets product specifications established in accordance with Sec.  
111.70(e).

Subpart O--Product Complaints


Sec.  111.553  What are the requirements under this subpart O for 
written procedures?

    You must establish and follow written procedures to fulfill the 
requirements of this subpart O.


Sec.  111.560  What requirements apply to the review and investigation 
of a product complaint?

    (a) A qualified person must:
    (1) Review all product complaints to determine whether the product 
complaint involves a possible failure of a dietary supplement to meet 
any of its specifications, or any other requirements of this part 111, 
including those specifications and other requirements that, if not met, 
may result in a risk of illness or injury; and
    (2) Investigate any product complaint that involves a possible 
failure of a dietary supplement to meet any of its specifications, or 
any other requirements of this part, including those specifications and 
other requirements that, if not met, may result in a risk of illness or 
injury.
    (b) Quality control personnel must review and approve decisions 
about whether to investigate a product complaint and review and approve 
the findings and followup action of any investigation performed.
    (c) The review and investigation of the product complaint by a 
qualified person, and the review by quality control personnel about 
whether to investigate a product complaint, and the findings and 
followup action of any investigation performed, must extend to all 
relevant batches and records.


Sec.  111.570  Under this subpart O, what records must you make and 
keep?

    (a) You must make and keep the records required under this subpart 
O in accordance with subpart P of this part.
    (b) You must make and keep the following records:
    (1) Written procedures for fulfilling the requirements of this 
subpart,
    (2) A written record of every product complaint that is related to 
good manufacturing practice,
    (i) The person who performs the requirements of this subpart must 
document, at the time of performance, that the requirement was 
performed.
    (ii) The written record of the product complaint must include the 
following:
    (A) The name and description of the dietary supplement;
    (B) The batch, lot, or control number of the dietary supplement, if 
available;
    (C) The date the complaint was received and the name, address, or 
telephone number of the complainant, if available;
    (D) The nature of the complaint including, if known, how the 
product was used;
    (E) The reply to the complainant, if any; and
    (F) Findings of the investigation and followup action taken when an 
investigation is performed.

Subpart P--Records and Recordkeeping


Sec.  111.605  What requirements apply to the records that you make and 
keep?

    (a) You must keep written records required by this part for 1 year 
past the shelf life date, if shelf life dating is used, or 2 years 
beyond the date of distribution of the last batch of dietary 
supplements associated with those records.
    (b) Records must be kept as original records, as true copies (such 
as photocopies, microfilm, microfiche, or other accurate reproductions 
of the original records), or as electronic records.
    (c) All electronic records must comply with part 11 of this 
chapter.


Sec.  111.610  What records must be made available to FDA?

    (a) You must have all records required under this part, or copies 
of such records, readily available during the retention period for 
inspection and copying by FDA when requested.
    (b) If you use reduction techniques, such as microfilming, you must 
make suitable reader and photocopying equipment readily available to 
FDA.

    Dated: May 8, 2007.
Andrew C. von Eschenbach,
Commissioner of Food and Drugs.

    Dated: May 8, 2007.
Michael O. Leavitt,
Secretary of Health and Human Services.
[FR Doc. 07-3039 Filed 6-22-07; 8:45 am]
BILLING CODE 4160-01-S