Number range CHAPTERDEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

\[Docket No. 96N-0417\]

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.

SUMMARY: The Food and Drug Administration (FDA, we) 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 \[[insert date 60 days after date of
publication in the Federal Register]{.underline}\].

*Compliance Dates*: The compliance date is \[[insert date 12 months
after date of publication in the Federal Register]{.underline}\]; except
that for businesses employing fewer than 500, but 20 or more full-time
equivalent employees, the compliance date is \[[insert date 24 months
after date of publication in the Federal Register]{.underline}\]; and
except that for businesses that employ fewer than 20 full-time
equivalent employees, the compliance date is \[[insert date 36 months
after date of publication in the Federal Register]{.underline}\].

FOR FURTHER INFORMATION CONTACT:

Vasilios Frankos

Center for Food Safety and Applied Nutrition (HFS-xxx),

Food and Drug Administration,

5100 Paint Branch Pkwy.,

College Park, MD 20740,

301-436-1850.

SUPPLEMENTARY INFORMATION:

Table of Contents

I.  Background & 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?

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1.  Overview

2.  Written Procedures that Are Required by This Final Rule.

    a.  Written procedures for personnel (final subpart B).

    b.  Written procedures for cleaning the physical plant, including
        pest control (final subpart C).

    c.  Written procedures for calibrating instruments and controls and
        for calibrating, inspecting, and checking automated, mechanical,
        or electronic equipment (final subpart D).

    d.  Written procedures for maintaining, cleaning, and sanitizing
        equipment and utensils (final subpart D).

    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
        reprocessing (final subpart F).

    f.  Written procedure for components, packaging, labels, and product
        that is received for packaging and labeling as a dietary
        supplement (final subpart G).

    g.  Written procedures for laboratory operations (final subpart J).

    h.  Written procedures for manufacturing operations (final subpart
        K).

    i.  Written procedures for packaging and labeling operations (final
        subpart L).

    j.  Written procedures for holding and distributing operations
        (final subpart M).

    k.  Written procedures for returned dietary supplements (final
        subpart N).

    l.  Written procedures for product complaints (final subpart O).

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).

    b.  Written procedures for preparing the master manufacturing record
        (final subpart H) and for preparing the batch record (final
        subpart I).

    c.  Written procedures for Records and Recordkeeping (final subpart
        P).

    d.  Written procedures for product recalls.

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    A.  Other Comments on Written Procedures

    B.  What Other General Comments Did We Receive?

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V.  What Legal Authority Comments Did We Receive?

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1.  Modeled After CGMP for Food

2.  Records Authority

3.  Public Health Service Act Authority

    a.  The communicable disease risk posed by dietary supplements.

    b.  Activities for which we are asserting legal authority under the
        PHS Act.

    c.  The interstate commerce nexus for the final rule.

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i.  The PHS Act.

ii. The act.

iii. Commerce Clause.

iv. Fifth Amendment.

v.  Miscellaneous.

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VI. What Comments Did We Receive on the General Provisions?

(Subpart A)

A.  Organization of Final Subpart A

B.  Who Is Subject to These Regulations? (Final § 111.1)

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

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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?

a.  Identity.

b.  Purity.

c.  Strength.

d.  Composition.

e.  Other terms.

26\. What Definitions Did the Comments Want

> Us to Delete?
>
> D. Do Other Statutory Provisions and Regulations Apply?
>
> (Final § 111.5)

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

> 1\. "What Are These Regulations Intended to
>
> Accomplish?"
>
> 2\. "Exclusions" (Proposed § 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

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1.  Revisions

2.  Changes After Considering Comments

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C.  General Comments on Proposed Subpart B

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

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

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1.  Final § 111.10(a)

2.  Final § 111.10(b)

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

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

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

    Number range CHAPTERVIII. 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? (Final §
    111.15)

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1.  Final § 111.15(a)

2.  Final § 111.15(b)(1)

3.  Final § 111.15(c)

4.  Final § 111.15(d)

5.  Final § 111.15(e)

6.  Final § 111.15(f)

7.  Final § 111.15(g)

8.  Final § 111.15(h)

9.  Final § 111.15(i)

10. Final § 111.15(j)

11. Final § 111.15(k)

    E. What Are the Requirements Under This Subpart for Written

    Procedures?(Final § 111.16)

    F. What Design and Construction Requirements Apply to Your

    Physical Plant?(Final § 111.20)

    1\. Final § 111.20(a) and (b)

    2\. Final § 111.20(c)

    3\. Final § 111.20(d)

4\. Final § 111.20(e)

> 5\. Final § 111.20(f)
>
> 6\. Final § 111.20(g)

7\. Final § 111.20(h)

G. Under This Subpart, What Records Do You Make and Keep?

(Final § 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 § 111.25)

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1.  Final § 111.25

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E.  What Requirements Apply to the Equipment and Utensils?(Final §
    111.27)

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1.  Final 111.27(a)

    a.  Final § 111.27(a).

    b.  Final § 111.27(a)(2).

    c.  Final § 111.27(a)(3).

    d.  Final § 111.27(a)(4).

    e.  Final § 111.27(a)(5).

    f.  Final § 111.27(a)(6).

    g.  Final § 111.27(a)(7).

2.  Final § 111.27(b)

3.  Final § 111.27(c)

4.  Final § 111.27(d)

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a.  Final § 111.27(d)(1)

b.  Final § 111.27(d)(2)

c.  Final § 111.27(d)(3)

d.  Final § 111.27(d)(4)

e.  Final § 111.27(d)(5)

f.  Final § 111.27(d)(6)

g.  Final § 111.27(d)(7)

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F.  Reorganization of Certain Paragraphs in Proposed § 111.25.

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

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1.  Comments on the Organization and Framework of Proposed § 111.30

2.  Comments Specific to Proposed § 111.30

    a.  Final § 111.30(a) and (b)

    b.  Final § 111.30(c)

    c.  Final § 111.30(d)

    d.  Final § 111.30(e)

> 3\. Reorganization of Certain Paragraphs in Proposed §

111.30

H. Under this Subpart, What Records Must You Make and

Keep? (Final § 111.35)

1.  Final § 111.35(a)

2.  Final § 111.35(b)(1) and (b)(2)

3.  Final § 111.35(b)(3)

4.  Final § 111.35(b)(4)

5.  Final § 111.35(b)(5)

6.  Final § 111.35(b)(6)

X. Comments on Requirement to Establish a Production and Process Control
System

(Final Subpart E)

A.  Reorganization of Proposed § 111.35 into Final Subpart E

B.  General Comments on Proposed § 111.35

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

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1.  Revisions

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

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

F.  What Are the Requirements For Quality Control Operations? (Final
    § 111.65)

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

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1.  Final § 111.70(a)

2.  Final § 111.70(b)

3.  Final § 111.70(c)

4.  Final § 111.70(d)

5.  Final § 111.70(e)

6.  Final § 111.70(f)

7.  Final § 111.70(g)

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

I.  What Must You do to Determine Whether Specifications are Met? (Final
    § 111.75)

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1.  Final § 111.75(a)

2.  Final § 111.75(b)

3.  Final § 111.75(c) and (d)

4.  Final § 111.75(e)

5.  Final § 111.75(f)

6.  Final § 111.75(g)

7.  Final § 111.75(h)

8.  Final § 111.75(i)

> J. What Must You do if Established Specifications are Not
>
> Met? (Final § 111.77)
>
> 1\. Final § 111.77
>
> 2\. Final § 111.77 (a)
>
> 3\. Final § 111.77 (b)
>
> 4\. Final § 111.77 (c)
>
> K. Comments on Shelf-Life

L. What Representative Samples Must You Collect?

(Final § 111.80)

1.  Final § 111.80(a)

2.  Final § 111.80(b)

3.  Final § 111.80(c)

4.  Final § 111.80(d)

5.  Final § 111.80(e)

M. What Are the Requirements for Reserve Samples?

(Final § 111.83)

1.  Final § 111.83(a)

2.  Final § 111.83(b)(1)

3.  Final § 111.83(b)(2)

4.  Final § 111.83(b)(3)

5.  Final § 111.83(b)(4)

N. Who Conducts a Material Review and Makes a Disposition

Decision? (Final § 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 § 111.70 is not
> Met? (Final § 111.90)

1.  Final § 111.90

2.  Final § 111.90(a)

3.  Final § 111.90(b)

4.  Final § 111.90(c)

> P. Under this Subpart, What Records Must You Make and Keep?
>
> (Final § 111.95)

1.  § 111.95(a)

2.  § 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

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1.  Revisions

2.  Changes associated With the Reorganization

3.  Changes After Considering Comments

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

    D. What Are the Requirements Under This Subpart for Written

    Procedures? (Final § 111.103)

    E. What must Quality Control Personnel Do? (Final § 111.105)

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1.  Final § 111.105(a)

2.  Final § 111.105(b), (c), d), and (e)

3.  Final § 111.105(f)

4.  Final § 111.105(g)

5.  Final § 111.105(h)

6.  Final § 111.105(i)

F. What Quality Control Operations Are Required for

Laboratory Operations Associated With the Production and

Process Control System? (Final § 111.110)

1.  Final § 111.110(a)

2.  Final § 111.110(b)

3.  Final § 111.110(c)

    G. What Quality Control Operations Are Required for

a Material Review and Disposition Decision?

(Final § 111.113)

1.  Final § 111.113(a)

2.  Final § 111.113(b)

3.  Final § 111.113(c)

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H.  What Quality Control Operations Are Required for

> Equipment, Instruments, and Controls? (Final § 111.117)

1.  Final § 111.117(a) through (c)

2.  Final § 111.117(d)

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I.  What Quality Control Operations Are Required for

    Components, Packaging, and Labels Before Use in the

    Manufacture of a Dietary Supplement? (Final § 111.120)

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1.  Final § 111.120(a)

2.  Final § 111.120(b)

3.  Final § 111.120(c)

4.  Final § 111.120(d)

5.  Final § 111.120(e)

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J.  What Quality Control Operations Are Required for the

    Master Manufacturing Record, the Batch Production

    Record, and Manufacturing Operations? (Final § 111.123)

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1.  Final § 111.123(a)(1)

2.  Final § 111.123(a)(2)

3.  Final § 111.123(a)(3)

4.  Final § 111.123(a)(4)

5.  Final § 111.123(a)(5)

6.  Final § 111.123(a)(6)

7.  Final § 111.123(a)(7)

8.  Final § 111.123(a)(8)

9.  Final § 111.123(b)

    K. What Quality Control Operations Are Required for

    Packaging and Labeling Operations? (Final § 111.127)

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1.  Final § 111.127(a) and (b)

    a.  Final § 111.127(a)

    b.  Final § 111.127(b)

2.  Final § 111.127(c)

3.  Final § 111.127(d)

4.  Final § 111.127(e)

5.  Final § 111.127(f) and (g)

6.  Final § 111.127(h)

    L. What Quality Control Operations Are Required for

    Returned Dietary Supplements? (Final § 111.130)

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1.  Final § 111.130(a)

2.  Final § 111.130(a)(1) and (2)

3.  Final § 111.130(b)

4.  Final § 111.130(c)

5.  Final § 111.130(d)

    M. What Quality Control Operations Are Required for

    Product Complaints? (Final § 111.135)

    N. What Records Must Quality

    Control Personnel Make and Keep? (Final § 111.140)

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1.  Final § 111.140(a)

2.  Final § 111.140(b)(1)

3.  Final § 111.140(b)(2)

4.  Final § 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

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1.  Revisions

2.  Changes After Considering Comments

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

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

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

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1.  Proposed § 111.35(d)

2.  Final § 111.155(a)

3.  Final § 111.155(b)

4.  Final § 111.155(c)

5.  Final § 111.155(d)

6.  Final § 111.155(e)

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F.  What Requirements Apply to Packaging and Labels

> Received? (Final § 111.160)

1.  Final § 111.160(a)

2.  Final § 111.160(b)

3.  Final § 111.160(c)

4.  Final § 111.160(d)

5.  Final § 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 § 111.165)

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1.  Final § 111.165(a)

2.  Final § 111.165(b)

3.  Final § 111.165(c)

4.  Final § 111.165(d)

5.  Final § 111.165(e)

    H. What Requirements Apply to Rejected Components,

    Packaging, Labels, and to Rejected Products That are

    Received for Packaging or Labeling as a Dietary

    Supplement? (Final § 111.170)

    I. Under this Subpart, What Records Must You Make and Keep

    (Final § 111.180)

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1.  Final § 111.180(a)

2.  Final § 111.180(b)(1)

3.  Final § 111.180(b)(2)

4.  Final § 111.180(b)(3)

Number range CHAPTERXIII. 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 § 111.45 (Final Subpart H)

    1.  Comments on Written Procedures

    2.  Comments That Support Proposed § 111.45

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

    1.  Final § 111.205(a)

    2.  Final § 111.205(b)(1)

    3.  Final § 111.205(b)(2)

    4.  Final § 111.205(c)

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

    § 111.210)

    1.  Final § 111.210(a)

    2.  Final § 111.210(b)

    3.  Final § 111.210(c)

    4.  Final § 111.210(d)

    5.  Final § 111.210(e)

    6.  Final § 111.210(f)

    7.  Final § 111.210(g)

    8.  Final § 111.210(h)(1)

    9.  Final § 111.210(h)(2)

    10. Final § 111.210(h)(3)

    11. Final § 111.210(h)(4)

    12. Final § 111.210(h)(5)

F.  Quality Control Responsibility (Proposed § 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 § 111.255)

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

    1.  Final § 111.260(a)

    2.  Final § 111.260(b)

    3.  Final § 111.260(c)

    4.  Final § 111.260(d)

    5.  Final § 111.260(e) and (f)

    6.  Final § 111.260(g)

    7.  Final § 111.260(h)

    8.  Final § 111.260(i)

    9.  Final § 111.260(j)

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    a.  Final § 111.260(j)(1)

    b.  Final § 111.260(j)(2)

    c.  Final § 111.260(j)(2)(i) through (j)(2)(iv)

10\. Final § 111.260(k)

a.  General comments on proposed § 111.70(g)

b.  Final § 111.260(k)(1)

c.  Final § 111.260(k)(2)

d.  Final § 111.260(k)(3)

11\. Final § 111.260(l)

a.  Final § 111.260(l)(1)

b.  Final § 111.260(l)(1)(i)

c.  Final § 111.260(l)(1)(ii)

d.  Final § 111.260(l)(2)

e.  Final § 111.260(l)(3)

f.  Final § 111.260(l)(4)

> 12\. Final § 111.260(m)

13\. Final § 111.260(n)

E. Review of Batch Production Record Deviations (Proposed

§ 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 § 111.303)

D. What Are the Requirements for the Laboratory Facilities?

(Final § 111.310)

E. What Are the Requirements for Laboratory Control

Processes? (Final § 111.315)

1\. Final § 111.315(a)

2\. Final § 111.315(b)

3\. Final § 111.315(c)

4\. Final § 111.315(d)

5\. Final § 111.315(e)

F. What Requirements Apply to Laboratory Methods for

Testing and Examination? (Final § 111.320)

1\. Final § 111.320(a)

2\. Final § 111.320(b)

G. Appropriate Test Method Validation

(Proposed § 111.60(b)(1)(v))

H. Under This Subpart, What Records must You Make and Keep?

(Final § 111.325)

1\. Final § 111.325(a)

2\. Final § 111.325(b)(1)

3\. Final § 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

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

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1.  Revisions

2.  Changes Made After Considering Comments

3.  Revisions Associated With the Reorganization

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C.  General Comments on Manufacturing Operations

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

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

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

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

1\. Final § 111.365(a)

> 2\. Final § 111.365(b)
>
> 3\. Final § 111.365(c)
>
> 4\. Final § 111.365(d)
>
> 5\. Final § 111.365(e)
>
> 6\. Final § 111.365(f)
>
> 7\. Final § 111.365(g)
>
> 8\. Final § 111.365(h)
>
> 9\. Final § 111.365(i)
>
> 10\. Final § 111.365(j)
>
> 11\. Final § 111.365(k)

H. What Requirements Apply to Rejected Dietary Supplements?

(Final § 111.370)

I. Under This Subpart, What Records Must You Make and Keep?

(Final § 111.375)

XVII\. Comments on 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

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1.  Revisions

2.  Changes Associated With the Reorganization

3.  Changes After Considering Comments

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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 § 111.403)

F.  What Requirements Apply to Packaging and Labels?

    (Final § 111.410)

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1.  Final § 111.410(a)

2.  Final § 111.410(b)

3.  Final § 111.410(c)

4.  Final § 111.410(d)

    G. What Requirements Apply to Filling, Assembling,

    Packaging, Labeling, and Related Operations?

    (Final § 111.415)

    H. What Requirements Apply to Repackaging and Relabeling?

    (Final § 111.420)

    1\. Final § 111.420(a)

    2\. Final § 111.420 (b) and (c)

    I. What Requirements Apply to a Packaged and Labeled

    Dietary Supplement That is Rejected for Distribution?

    (Final § 111.425)

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J.  Under this Subpart L, What Records Must You Make and

    Keep? (Final § 111.430)

    1\. Final § 111.430(a)

    2\. Final § 111.430(b)

    XVIII\. Comments on Holding and Distributing

    (Final Subpart M)

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A.  Organization of Final Subpart M

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

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1.  Revisions

2.  Changes Associated With the Reorganization

3.  Changes After Considering Comments

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C.  General Comments on Proposed §§ 11.80, 111.82, 111.83, and 111.85

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

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

    1\. Final § 111.455(a)

    2\. Final § 111.455(b)

    3\. Final § 111.455(c)

F.  What Requirements Apply to Holding In-process Material? (Final
    § 111.460)

    1\. Final § 111.460(a)

    2\. Final § 111.460(b)

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

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

> 1\. Final § 111.465(a)

2\. Final § 111.465(b)

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

J.  Under this Subpart, What Records Must You Make and Keep? (Final
    § 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 § 111.85

D.  What are the Requirements under This Subpart for Written Procedures?
    (Final § 111.503)

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

F.  When Must a Returned Dietary Supplement be Destroyed, or Otherwise
    Suitably Disposed of? (Final § 111.515)

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

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

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

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

    1.  Final § 111.535(a)

    2.  Final § 111.535(b)(1)

    3.  Final § 111.535(b)(2)

    4.  Final § 111.535(b)(3)

    5.  Final § 111.535(b)(4)

        XX\. Comments on Product Complaints (Final Subpart O)

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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 § 111.95(Final Subpart O)

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

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

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1.  Final § 111.560(a)(1)

2.  Final § 111.560(a)(2), (b), and (c)

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

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1.  Final § 111.570(a)

2.  Final § 111.570(b)(1)

3.  Final § 111.570(b)(2)

4.  Final § 111.570(b)(2)(i)

5.  Final § 111.570(b)(2)(ii)

Number range CHAPTERXXI. 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 § 111.125

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

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1.  Final § 111.605(a)

2.  Final § 111.605(b)

3.  Final § 111.605(c)

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E.  What Records Must Be Made Available to FDA?

    (Final § 111.610)

    1\. Final § 111.610(a)

> 2\. Final § 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

    1.  Public Involvement

D.  Comments on Implementation and Enforcement

E. Removal of References to Part 112

XXNumber range CHAPTERIII. Paperwork Reduction Act of 1995

XXINumber range CHAPTERV. 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

a\. Consumption

> b\. Manufacturing

5\. Baseline Risk

6\. Benefits

> a\. Reduced health costs associated with a reduced
>
> number of acute illnesses
>
> b\. Fewer products recalled
>
> c\. Reduced health costs associated with a reduced
>
> number of chronic illnesses and conditions

d\. Benefits from known nutritional effects

> e\. Benefits form uncertain nutritional effects
>
> f\. Total benefits
>
> 7\. Costs

a\. Description of the costs

b\. Summary of general comments on costs

8\. Summary of Benefits and Costs

9\. Uncertainties in the Analysis

C. Final Regulatory Flexibility Analysis

> 1\. Introduction
>
> 2\. Economic Effects on Small Entities

a\. Number of small entities affected

b\. Costs to small entities

> 3\. Regulatory Options

a\. Exemptions for small entities

b\. Longer compliance periods

> 4\. Description of Recordkeeping and Reporting
>
> 5\. Summary

D. Unfunded Mandates

XXV\. Analysis of Environmental Impact

XXVI\. Federalism

XXVII\. References

I. Background [& Related Information]{.mark}

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.

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 part).

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. 1-6). 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 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 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]{.mark} [other interested
parties]{.mark} [which are reflected in the public docket.]{.mark}

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 FEDERAL REGISTER we are also issuing an
interim final regulation that sets forth a procedure for requesting an
exception to a CGMP requirement in this final rule. The]{.mark} [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, Subpart E),
provided certain conditions are met and also includes a requirement for
retention of records related]{.mark} [to the]{.mark} [FDA grant]{.mark}
[of an exception request.]{.mark}

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.

The following table 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

+---------------+----------+---------------+---------------------------+
| Proposed      | Proposed | Final Subpart | Final Sections in the     |
| Subpart and   | Sections | and Title     | Subpart                   |
| Title         | in the   |               |                           |
|               | Subpart  |               |                           |
+---------------+----------+---------------+---------------------------+
| A -- General  | 111.1    | A -- General  | 111.1                     |
| Provisions    |          | Provisions    |                           |
|               | 111.2    |               | 111.3                     |
|               |          |               |                           |
|               | 111.3    |               | 111.5                     |
|               |          |               |                           |
|               | 111.5    |               |                           |
|               |          |               |                           |
|               | 111.6    |               |                           |
+---------------+----------+---------------+---------------------------+
| B --          | 111.10   | B --          | 111.8 (new)               |
| Personnel     |          | Personnel     |                           |
|               | 111.12   |               | 111.10                    |
|               |          |               |                           |
|               | 111.13   |               | 111.12                    |
|               |          |               |                           |
|               |          |               | 111.13                    |
|               |          |               |                           |
|               |          |               | 111.14 (new)              |
+---------------+----------+---------------+---------------------------+
| C -- Physical | 111.15   | C -- Physical | 111.15                    |
| Plant         |          | Plant and     |                           |
|               | 111.20   | Grounds       | 111.16 (new)              |
|               |          |               |                           |
|               |          |               | 111.20                    |
|               |          |               |                           |
|               |          |               | 111.23 (formerly proposed |
|               |          |               | § 111.15(d)(3) and        |
|               |          |               | (e)(2))                   |
+---------------+----------+---------------+---------------------------+
| D --          | 111.25   | D --          | 111.25 (formerly proposed |
| Equipment and |          | Equipment and | § 111.25(c)(1) and        |
| Utensils      | 111.30   | Utensils      | (e)(1))                   |
|               |          |               |                           |
|               |          |               | 111.27 (formerly proposed |
|               |          |               | § 111.25 (a), (b),        |
|               |          |               | (d)^1^, and (e))          |
|               |          |               |                           |
|               |          |               | 111.30                    |
|               |          |               |                           |
|               |          |               | 111.35 (formerly proposed |
|               |          |               | §§ 111.25 (c)(1), (c)(2), |
|               |          |               | (d), (f), 111.30(b)(2),   |
|               |          |               | (b)(5), and (c),          |
|               |          |               | 111.50(c)(4))             |
+---------------+----------+---------------+---------------------------+
| E --          | 111.35   | E --          | 111.55 (formerly proposed |
| Production    |          | Requirement   | § 111.35(a))              |
| and Process   | 111.37   | to Establish  |                           |
| Controls      |          | a Production  | 111.60 (formerly proposed |
|               | 111.40   | and Process   | § 111.35(b))              |
|               |          | Control       |                           |
|               | 111.45   | System        | 111.65 (formerly proposed |
|               |          |               | § 111.35(c))              |
|               | 111.50   |               |                           |
|               |          |               | 111.70 (formerly proposed |
|               | 111.60   |               | § 111.35(e),(f),(g), and  |
|               |          |               | (k))                      |
|               | 111.65   |               |                           |
|               |          |               | 111.73 (formerly proposed |
|               | 111.70   |               | § 111.35 (f), (g), and    |
|               |          |               | (h)                       |
|               | 111.74   |               |                           |
|               |          |               | 111.75 (formerly proposed |
|               |          |               | § 111.35(e) through (i),  |
|               |          |               | (k), (l)), § 111.37       |
|               |          |               | (b)(11(iv), and           |
|               |          |               |                           |
|               |          |               | § 111.40(a)(2)            |
|               |          |               |                           |
|               |          |               | 111.77 (new)              |
|               |          |               |                           |
|               |          |               | 111.80 (formerly proposed |
|               |          |               | § 111.37(b)(11))          |
|               |          |               |                           |
|               |          |               | 111.83 (formerly proposed |
|               |          |               | §§ 111.37(b)(12),         |
|               |          |               | 111.50(h), and            |
|               |          |               | 111.83(b)(2))             |
|               |          |               |                           |
|               |          |               | 111.87 (formerly proposed |
|               |          |               | §§ 111.35(i), and (n),    |
|               |          |               | 111.37(b)(5) and (b)(14), |
|               |          |               | 111.40(a)(3),             |
|               |          |               | 111.50(d)(1), 111.85(a)   |
|               |          |               | and (c))                  |
|               |          |               |                           |
|               |          |               | 111.90 (formerly proposed |
|               |          |               | §§ 111.35(i)(4),          |
|               |          |               | 111.50(d)(1), 111.50(f)   |
|               |          |               | and (g), and 111.65(d))   |
|               |          |               |                           |
|               |          |               | 111.95 (formerly proposed |
|               |          |               | § 111.35 and (o))         |
+---------------+----------+---------------+---------------------------+
|               |          | F --          | 111.103 (new)             |
|               |          | Production    |                           |
|               |          | and Process   | 111.105 (formerly         |
|               |          | Control       | proposed § 111.37(a),     |
|               |          | System:       | (b)(1), (b)(11), and      |
|               |          | Requirements  | (b)(12))                  |
|               |          | for Quality   |                           |
|               |          | Control       | 111.110 (formerly         |
|               |          |               | proposed § 111.37(b)(9)   |
|               |          |               | and (b)(13))              |
|               |          |               |                           |
|               |          |               | 111.113 (formerly         |
|               |          |               | proposed §§               |
|               |          |               | 111.35(i)(2),(i)(3),      |
|               |          |               | (i)(4)(i), (i)(4)(ii),    |
|               |          |               | (j), and (n),             |
|               |          |               | 111.37(b)(3), (c),        |
|               |          |               | 111.40(a)(3) and (b)(2),  |
|               |          |               | 111.50(d)(1), 111.65(d),  |
|               |          |               | and 111.70(c))            |
|               |          |               |                           |
|               |          |               | 111.117 (formerly         |
|               |          |               | proposed §§ 111.30(b)(4), |
|               |          |               | 111.37(b)(6) through      |
|               |          |               | (b)(8))                   |
|               |          |               |                           |
|               |          |               | 111.120 (formerly         |
|               |          |               | proposed §§               |
|               |          |               | 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 §§               |
|               |          |               | 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),   |
|               |          |               | 111.50(d)(1), (d)(2), and |
|               |          |               | (g))                      |
|               |          |               |                           |
|               |          |               | 111.127 (formerly         |
|               |          |               | proposed §§ 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 §§ 111.37(b)(2)  |
|               |          |               | and (b)(15), and          |
|               |          |               | 111.85(a))                |
|               |          |               |                           |
|               |          |               | 111.135 (new)             |
|               |          |               |                           |
|               |          |               | 111.140 (formerly         |
|               |          |               | proposed §§ 111.35(j),    |
|               |          |               | 111.37(c) and (d),        |
+---------------+----------+---------------+---------------------------+
|               |          | G --          | 111.153 (new)             |
|               |          | Production    |                           |
|               |          | and Process   | 111.155 (formerly         |
|               |          | Control       | proposed §§               |
|               |          | System:       | 111.35(d)(1)-(5) and      |
|               |          | Requirements  | 111.40(a)(1)-(5))         |
|               |          | for           |                           |
|               |          | Components,   | 111.160 (formerly         |
|               |          | Packaging,    | proposed §§ 111.35(e)(4), |
|               |          | and Labels    | and 111.40(a)(2) and      |
|               |          | and for       | (b)(1)-(4))               |
|               |          | Product that  |                           |
|               |          | You Receive   | 111.165 (formerly         |
|               |          | for Packaging | proposed §                |
|               |          | or Labeling a | 111.40(a)(1)-(5))         |
|               |          | Dietary       |                           |
|               |          | Supplement    | 111.170 (formerly         |
|               |          |               | proposed § 111.74)        |
|               |          |               |                           |
|               |          |               | 111.180 (formerly         |
|               |          |               | proposed §§ 111.35(d)(4), |
|               |          |               | and 111.40(c)(1)(i)-(iv)  |
|               |          |               | and (c)(2))               |
+---------------+----------+---------------+---------------------------+
|               |          | H --          | 111.205 (formerly         |
|               |          | Production    | proposed § 111.45(a)(1),  |
|               |          | and Process   | (a)(2), and (d))          |
|               |          | Control       |                           |
|               |          | System:       | 111.210 (formerly         |
|               |          | Requirements  | proposed § 111.45(b))     |
|               |          | for the       |                           |
|               |          | Master        |                           |
|               |          | Manufacturing |                           |
|               |          | Record        |                           |
+---------------+----------+---------------+---------------------------+
|               |          | I --          | 111.255 (formerly         |
|               |          | Production    | proposed § 111.50(a), (b) |
|               |          | and Process   | and (i))                  |
|               |          | Control       |                           |
|               |          | System:       | 111.260 (formerly         |
|               |          | Requirements  | proposed §§               |
|               |          | for the Batch | 111.35(i)(2),(j), (m),    |
|               |          | Production    | and (o)(2),               |
|               |          | Record        | 111.37(b)(3),(5),(9) and  |
|               |          |               | 111.50(c)(1) through      |
|               |          |               | (c)(11), (c)(13),         |
|               |          |               | (c)(14), (d)(2), and (e), |
|               |          |               | (g) and 111.70 (b)(6) and |
|               |          |               | (g))                      |
+---------------+----------+---------------+---------------------------+
|               |          | J --          | 111.303 (new)             |
|               |          | Production    |                           |
|               |          | and Process   | 111.310 (formerly         |
|               |          | Control       | proposed § 111.60(a))     |
|               |          | System:       |                           |
|               |          | Requirements  | 111.315 (formerly         |
|               |          | for           | proposed § 111.60(b)(1))  |
|               |          | Laboratory    |                           |
|               |          | Operations    | 111.320 (formerly         |
|               |          |               | proposed § 111.60(c), and |
|               |          |               | (d))                      |
|               |          |               |                           |
|               |          |               | 111.325 (formerly         |
|               |          |               | proposed § 111.60(b)(2)   |
|               |          |               | and (b)(3))               |
+---------------+----------+---------------+---------------------------+
|               |          | K --          | 111.353 (new)             |
|               |          | Production    |                           |
|               |          | and Process   | 111.355 (formerly         |
|               |          | Control       | proposed § 111.65(a))     |
|               |          | System:       |                           |
|               |          | Requirements  | 111.360 (formerly         |
|               |          | for           | proposed § 111.65(b))     |
|               |          | Manufacturing |                           |
|               |          | Operations    | 111.365 (formerly         |
|               |          |               | proposed § 111.65(c))     |
|               |          |               |                           |
|               |          |               | 111.370 (formerly         |
|               |          |               | proposed § 111.74)        |
|               |          |               |                           |
|               |          |               | 111.375 (new)             |
+---------------+----------+---------------+---------------------------+
|               |          | L --          | 111.403 (new)             |
|               |          | Production    |                           |
|               |          | and Process   | 111.410 (formerly         |
|               |          | Control       | proposed § 111.70(a),     |
|               |          | System:       | (b)(6) and (f))           |
|               |          | Requirements  |                           |
|               |          | for Packaging | 111.415 (formerly         |
|               |          | and Labeling  | proposed § 111.70(b))     |
|               |          | Operations    |                           |
|               |          |               | 111.420 (formerly         |
|               |          |               | proposed § 111.70(d) and  |
|               |          |               | (e))                      |
|               |          |               |                           |
|               |          |               | 111.425 (formerly         |
|               |          |               | proposed § 111.74)        |
|               |          |               |                           |
|               |          |               | 111.430 (formerly         |
|               |          |               | proposed § 111.70 (g) and |
|               |          |               | (h))                      |
+---------------+----------+---------------+---------------------------+
| F -- Holding  | 111.80   | M -- Holding  | 111.453 (new)             |
| and           |          | and           |                           |
| Distributing  | 111.82   | Distributing  | 111.455 (formerly         |
|               |          |               | proposed § 111.80)        |
|               | 111.83   |               |                           |
|               |          |               | 111.460 (formerly         |
|               | 111.85   |               | proposed § 111.82)        |
|               |          |               |                           |
|               | 111.90   |               | 111.465 (formerly         |
|               |          |               | proposed §                |
|               |          |               | 111.83(b)(1)and (b)(2))   |
|               |          |               |                           |
|               |          |               | 111.470 (formerly         |
|               |          |               | proposed § 111.90)        |
|               |          |               |                           |
|               |          |               | 111.475 (new)             |
+---------------+----------+---------------+---------------------------+
|               |          | N -- Returned | 111.503 (new)             |
|               |          | Dietary       |                           |
|               |          | Supplements   | 111.510 (formerly         |
|               |          |               | proposed § 111.85(a))     |
|               |          |               |                           |
|               |          |               | 111.515 (formerly         |
|               |          |               | proposed § 111.85(b) and  |
|               |          |               | (c))                      |
|               |          |               |                           |
|               |          |               | 111.520 (formerly         |
|               |          |               | proposed § 111.37(b)(15)) |
|               |          |               |                           |
|               |          |               | 111.525 (formerly         |
|               |          |               | proposed § 111.50(g))     |
|               |          |               |                           |
|               |          |               | 111.530 (formerly         |
|               |          |               | proposed § 111.85(d))     |
|               |          |               |                           |
|               |          |               | 111.535 (formerly         |
|               |          |               | proposed §§ 111.50(g) and |
|               |          |               | 111.85(e)and (f))         |
+---------------+----------+---------------+---------------------------+
| G -- Consumer | 111.95   | O -- Product  | 111.553 (new)             |
| Complaints    |          | Complaints    |                           |
|               |          |               | 111.560 (formerly         |
|               |          |               | proposed § 111.95(a)      |
|               |          |               | through (d))              |
|               |          |               |                           |
|               |          |               | 111.570 (formerly         |
|               |          |               | proposed §                |
|               |          |               | 111.95(e)and(f))          |
+---------------+----------+---------------+---------------------------+
| H -- Records  | 111.125  | P -- Records  | 111.605 (formerly         |
| and           |          | and           | proposed § 111.125((a)    |
| Recordkeeping |          | Recordkeeping | and (b))                  |
|               |          |               |                           |
|               |          |               | 111.610 (formerly         |
|               |          |               | proposed § 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, 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 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 21 CFR 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 -- 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), thermally processed low-acid canned food (part 113),
acidified food (part 114), and bottled water (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. 7-8). 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
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). 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."

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 the
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 sections 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 sections 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 (proposed § 111.35(d)(21 CFR 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 component, in the
manufacture of a dietary supplement that would adulterate the product
under relevant provisions of the act, such as sections 402(a)(1) or
402(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
§ 111.35(e)). Thus, the manufacturer would not have been able to
establish a specification, consistent with proposed § 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
§ 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 § 111.35(e)(1)) and
for the finished batch of dietary supplement (proposed § 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 § 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 (proposed §§  111.45(b)((7);
111.50(c)(12); 111.70(b)(7)) so that the dietary supplement label would
accurately identify the dietary supplement. 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 (proposed § 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 generally recognized as safe (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 codified to
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, 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.

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 sections 402(a)(1), (a)(2), (a)(3) and (a)(4) of the act.
For example, under § 110.5 (food CGMP), the criteria and definitions
apply in determining whether a food is adulterated under sections
402(a)(3) and (a)(4) of the act. Specifically, § 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, § 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 sections 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 sections
402(a)(1), (a)(2),(a)(3), and (a)(4) of the act. Thus, this final rule
is not designed to specifically prevent all 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 § 111.35(e) (now final
§ 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 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 mix-up in your process control and you do not put
the representative label specified in the master manufacturing record on
the product. Such a mix-up would be a violation of dietary supplement
CGMP requirements (see *e.g.*, final §§ 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 current good
manufacturing practice regulations 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 § 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 §
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:

● Applies to persons who manufacture, package, label or hold dietary
supplements unless subject to an exclusion in § 111.1;

● Establishes minimum requirements for personnel, physical plant and
grounds, and equipment and utensils;

● 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;

● 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;

● 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;

● Requires testing of a subset of finished batches of dietary
supplements based on a sound statistical sampling or, alternatively,
testing all finished batches;

● Requires implementation of quality control operations to ensure the
quality of a dietary supplement;

● 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;

● 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;

● Requires the establishment and use of laboratory control processes
related to establishing specifications and to the selection and use of
testing and examination methods;

● Requires reserve samples of dietary supplements to be held in a manner
that protects against contamination and deterioration;

● Requires identification and quarantine of returned dietary supplements
until quality control personnel conduct a material review and make a
disposition decision;

● Requires quality control personnel to conduct a material review and
make a disposition decision under certain circumstances;

● 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

● 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 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.

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A.  [What Comments Did We Receive on the Structure and Organization of
    the Rule?]{.underline}

(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 § 111.35(e)) than to list such contaminants as part of the
testing requirements (proposed § 111.35(k)). Other comments say it would
be more logical to list the tests that are considered appropriate as
part of proposed § 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 § 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 re-write 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
inter-related nature of the proposed rule by combining most similar
requirements. Both proposed §§ 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 (§ 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?]{.underline}

(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 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, 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 sections 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, 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 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 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 nonfood-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, 10; see, also, 68 FR 12157, at 12162-63, March
13, 2003) 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 post marketing adverse event reports or
consumers' illnesses[.]{.mark}[^3]

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 sections
411(c)(1)(B)(i) and (c)(1)(B)(ii) of the act, which describe 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 sections 402(f) and 402(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?]{.underline}

1\. Overview

In the 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 § 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 § 111.15 (68 FR 12157 at 12187); calibrating instruments
and controls under proposed § 111.25(b), (c), and (d) (68 FR 12157 at
12191); maintaining, cleaning, and sanitizing equipment and utensils
under proposed § 111.25(e) (68 FR 12157 at 12192); calibrating,
inspecting, and checking automatic equipment under proposed § 111.30 (68
FR 12157 at 12193); the duties of the quality control unit under
proposed § 111.37 (68 FR 12157 at 12201); implementing the proposed
requirements for receipt of components, dietary supplements, packaging,
and labels under proposed § 111.40(a) and (b) (68 12157 at FR 12203);
preparing the master manufacturing record under proposed § 111.45 (68 FR
12157 at 12205); laboratory operations under proposed § 111.60 (68 FR
12157 at 12209); manufacturing operations under proposed § 111.65 (68 FR
12157 at 12211); packaging and labeling operations under proposed §
111.70 (68 FR 12157 at 12213); holding components, dietary supplements,
packaging, labels, and in-process materials under proposed §§ 111.80 and
111.82 (68 FR 12157 at 12214); identifying, quarantining, and salvaging
returned dietary supplements under proposed § 111.85 (68 FR 12157 at
12216); and receiving, reviewing, and investigating consumer complaints
under proposed § 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 (IOS), 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 § 111.37(b)(l) 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:

• Employee training;

• Cleaning the physical plant, including pest control;

• Maintenance, cleaning and sanitizing of equipment and utensils;

• Calibration of equipment used in manufacturing or testing;

• 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;

• All quality control operations;

• Reprocessing of batches or start-up materials that do not conform to
specifications;

• Receipt, identification, examination, handling, sampling, testing and
approval or rejection of components, packaging, and labels;

• 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;

• Packaging and labeling operations, including issuance and use of
appropriate labels, labeling, and packaging materials;

• Holding and distribution procedures, including procedures for
quarantine and parameters for storage;

• Return and salvage operations;

• Handling of consumer complaints; and

• 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 §
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 § 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 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 § 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 § 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 § 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 § 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 § 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 § 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 §§ 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 mix-ups 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 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 this section immediately below, 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 with 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 §
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).]{.underline}

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 § 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).]{.underline}

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 § 111.16).

c\. [Written procedures for calibrating instruments and controls and for
calibrating, inspecting, and checking automated, mechanical, or
electronic equipment (final subpart D).]{.underline}

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 §
111.25(a)) and for calibrating, inspecting, and checking automated,
mechanical, and electronic equipment (final § 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 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 § 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).]{.underline}

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 § 111.25(c)). Final § 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 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 § 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 §
111.25(c) relates to proposed § 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 § 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 § 111.70(e) in section X, 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).]{.underline}

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 §
111.103). We agree with the comments that there should be written
procedures for investigating failures in manufacturing operations. In
the 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 below in section X and XI, 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 § 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 §§
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 § 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).]{.underline}

We agree with the comments that the 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 § 111.153).

g\. [Written procedures for laboratory operations (final subpart
J).]{.underline}

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 § 111.303).

h\. [Written procedures for manufacturing operations (final subpart
K).]{.underline}

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 § 111.353).

i\. [Written procedures for packaging and labeling operations (final
subpart L).]{.underline}

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 mix-ups, 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, mix-ups 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 §
111.403).

j\. [Written procedures for holding and distributing operations (final
subpart M).]{.underline}

We agree with the comments that written procedures for holding and
distributing operations are an effective means to hold operators
accountable to a CGMP standards, and that mix-ups 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 mix-up, 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 and distributing operations (final §
111.453).

k\. [Written procedures for returned dietary supplements (final subpart
N).]{.underline}

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 § 111.503).

l\. [Written procedures for product complaints (final subpart
O).]{.underline}

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 § 111.553).

[3. Written Procedures That Are Not Required by This Final
Rule]{.underline}

[a. Written procedures for final subpart E (Requirement to Establish a
Production and Process Control System)]{.underline}

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 § 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 §§ 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 § 111.65); establish specifications
(final § 111.70); determine whether specifications are met (final §
111.73 and § 111.75); collect representative samples (final § 111.80);
hold reserve samples of packaged and labeled dietary supplements (final
§ 111.83); have quality control personnel conduct all required material
reviews and make all required disposition decisions (final § 111.87);
and adhere to certain requirements for treatment, in-process
adjustments, and for reprocessing (final § 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 §§ 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 § 111.315(a); use of sampling plans for obtaining
representative samples (final § 111.315(b)); use of criteria for
selecting appropriate examination and testing methods (final §
111.315(c)); use of criteria for selecting standard reference materials
used in performing tests and examinations (final § 111.315(d)); and use
of test methods and examinations in accordance with established criteria
(final § 111.315(e)). In addition, under final § 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 the
requirements of final §§ 111.70, 111.75, and 111.80 in subpart E.

Final subpart M establishes requirements for holding reserve samples.
Under final § 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 § 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 §
111.113); approve any reprocessing (final § 111.123(a)(5)); and document
any material review and disposition (final § 111.140(b)(3)). In
addition, as discussed, under final § 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 §§ 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).]{.underline}

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 with the requirements for the master manufacturing record
in final subpart H.

[c. Written procedures for Records and Recordkeeping (final subpart
P)]{.underline}

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.]{.underline}

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]{.underline}

(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 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) 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 § 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?]{.underline}

(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. 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. 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:

● Cleaning and maintaining equipment and utensils used in the
manufacture of products;

● The receipt, identification, examination, handling, sampling, testing,
and approval or rejection of raw materials;

● Appropriate tests and/or examinations to be conducted to assure the
purity, composition, and quality of the finished product;

● The method for reprocessing batches or operational start-up materials
that do not conform to finished goods standards or specifications;

● 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;

● Ensuring correct labels, labeling, and packaging materials are issued
and used for dietary products; and

● Describing the handling of all written and oral complaints regarding a
product.

(62 FR 5699 at pages 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.

[1. Modeled After CGMP for Food]{.underline}

(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 current good manufacturing
practice 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 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 (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. 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
current good manufacturing practice 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's 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") (s*ee* *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 201(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 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 current good
manufacturing practice 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]

Congress has also spoken to the precise question of which requirements
constitute current good manufacturing practice "regulations for food."
The plain meaning of "[regulations"]{.underline} 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
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 and 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
(§ 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) (§ 106.20); preparation of a master
manufacturing order and a system to assure and verify the addition of
each ingredient (§ 106.25); either in-process batch testing (§
106.25(b)) or sampling and testing of each batch to ensure nutrient
requirements are met (§ 106.30); and coding to enable ready
identification of lots during their sale and distribution (§ 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 (§ 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 (§
106.100(K)). Quality control records must contain enough information to
permit a public health evaluation of any batch of infant formula (§
106.100(o)). All required records must be available for authorized
inspection (§ 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 § 111.75(a)); preparation of a master manufacturing
record (final § 111.205); in-process batch monitoring (final §
111.75(b)) or batch testing or examination (final § 111.75(c)); and
coding to provide a batch, lot, or control number (final § 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 §§
111.180(b)(2), 111.95, 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 §§ 111.553 and 111.570(b)(1)); to investigate
certain complaints (final § 111.560(a)(2)); and to keep records of
complaints (final § 111.570(b)(2)). Required dietary supplement records
must also, as with infant formula records, be available for inspection
by FDA (final § 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 33239 (June 8, 1979)). Promulgated primarily under the
adulteration provisions of sections 402(a)(3) and 402(a)(4) of the act,
as well as section 361 of the Public Health Service Act (PHS Act), 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 22461, (June 19, 1986)), as well as to
prevent the spread of food-borne communicable diseases (44 FR 33239
(June 8, 1979))(See § 110.5(a)). Part 110 also "specifies requirements
that must be met to produce safe and wholesome food" (51 FR 22461 (June
19, 1986)). 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 22462
(June 19, 1986)).

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 (§ 110.10(a)); persons working in contact with food,
food-contact surfaces, and food-packaging materials to follow hygienic
practices (§ 110.10(b)); and that certain personnel have sufficient
education or experience to produce clean and safe food (§ 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 (§ 110.20). Detailed
provisions also require that physical facilities be maintained in
sanitary condition and in sufficient repair to prevent food from being
adulterated (§ 110.35). Any water that contacts food or food-contact
surfaces must be "safe and of adequate sanitary quality" (§ 110.37(a));
plumbing, sewage and other disposal, as well as toilet facilities, must
also protect against contamination (§ 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 (§ 110.40(a)). All operations for receiving,
inspecting, transporting, segregating, preparing, manufacturing,
packaging, and storing food must be conducted using adequate sanitation
principles (§ 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 (§ 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 (§ 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 § 111.10(a)); hygienic practices (final §
111.10(b)); and education, training, or experience (final § 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 §§ 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" (§ 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" (§§ 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 (§ 113.3). Part 113 requires that supervisors
satisfactorily complete training at a school approved by FDA (§ 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 (§ 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) (§§
113.40(a)(13); 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) (§ 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 (§ 113.40(g)(2)(ii)(b)). Regular observations of container
closures are required to be made and recorded (§ 113.60). Each container
must be coded "to enable ready identification of lots during their sale
and distribution" (§ 113.60(c)).

Before using raw materials and ingredients susceptible to
micro-biological contamination, the low-acid food processor must ensure
that they are "suitable for use in processing low-acid food" (§
113.81(a)). Complete records covering all aspects of the establishment
of the scheduled process and of certain confirmation tests must be
maintained permanently (§ 113.83). Scheduled processes must be readily
available to any duly authorized FDA employee (§ 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 (§ 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 (§ 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 (§ 113.89).
Detailed information on processing and production must be entered on
forms (§ 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 (§ 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 (§ 113.100(d)). Records
must be maintained at the processing plant for at least one year after
the date of manufacturing and at a reasonably accessible location for
another two years (§ 113.100(e)).

Similarly, the CGMP regulation for acidified food in part 114 requires
supervision by personnel trained at an FDA-approved school (§ 114.10);
manufacturing in accordance with a scheduled process established by a
qualified person (§§ 114.80 and 114.83); processing sufficient to
destroy the vegetative cells of certain microorganisms (§ 114.80(a)(1));
sufficient control, including frequent testing and recording of results,
to ensure that the finished pH values are not higher than 4.6 (§
114.80(a)(2)); testing and examinations of containers to ensure that the
food is suitably protected from leakage or contamination (§
114.80(a)(4)); and coding to enable ready identification of lots during
their sale and distribution (§ 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 (§ 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 (§ 114.89).

A record must be made of the procedures used in the public health
evaluation and the results of the evaluation (§ 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 (§ 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 (§ 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 (§ 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 (§ 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 (§ 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 § 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
§§ 111.55, 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
§ 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 § 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 § 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 § 111.75(b)(2)).

Rejected dietary supplements must also be held under quarantine (final
§§ 111.370, 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
§ 111.90(c)). Similar to coding low-acid or acidified foods, dietary
supplements must have assigned batch, lot, or control numbers (final §
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 § 111.27). Written procedures for the various
controls are required (*see, e.g.,* final §§ 111.8, 111.25, 111.103),
and required written records (*see, e.g.,* final §§ 111.14, 111.23,
111.35, 111.95) must be kept for 1 year past the shelf life date, if
shelf-life dating is used, or 3 years after the date of distribution of
the last associated batch of dietary supplement (final § 111.605). All
required dietary supplement CGMP records must be readily available for
inspection and copying by FDA (final § 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 at 32563 and 32564
(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" (§ 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 (§ 129.20). All plant equipment and utensils must
be suitable for their intended use (§ 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" (§
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 (§ 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 (§ 129.37(a) and(b)).
Filling, capping, closing, sealing, and packaging of containers must be
done so as to preclude contamination of the water (§ 129.37(d)). All
product water contact surfaces must be nontoxic and in compliance with
section 409 of the act (concerning food additives) (§ 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 (§ 129.80(a)). The treatment processes must be performed with
equipment and substances that will not adulterate the product (§
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 (§ 129.80(a)). Cleaning and
sanitizing solutions must be sampled and tested to assure adequate
performance (§ 129.80(c)).

Each unit package from a batch or segment of continuous production run
must be identified by a production code (§ 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 and labeled (§ 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 (§ 129.80(g)). The methods used
to analyze the samples must be approved by the government agency with
jurisdiction (§ 129.80(g)(3)). Records of the date of sampling, type of
product sampled, production code, and results of analysis must be
maintained (§ 129.80(g)(3)). All required records must be maintained at
the plant for at least 2 years (§ 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 §§ 111.15(e)(2), 111.365(c)). Precautions
that must be taken to prevent contamination of components or dietary
supplements include performing chemical, microbiological, or other
testing (final § 111.365(d)). Filling, assembling, packaging, labeling,
and related operations must be performed to protect the dietary
supplement against adulteration (final § 111.415). Equipment and
utensils must be suitable for their intended use (final § 111.27(a)).
Safe and adequate cleaning compounds and sanitizing agents must be used
(final § 111.15(c)(1)). Representative samples of each batch must be
examined to ensure that the product meets established specifications
(final § 111.415(g)). Each lot of packaged and labeled dietary
supplement must be assigned a batch, lot, or control number (final §
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" (§ 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). 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.

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 (§  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 (49 FR at 12162 and 12163
(March 13, 2003)). 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 of comments regarding
the production and process control system in section X). 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 (i*d.*, at 2.6). 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. 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," 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 sections 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 § 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
(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).

[2. Records Authority]{.underline}

(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 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 § 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" (i*d*. 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 record-keeping 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 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 § 111.70); determines whether the established
specifications are met (final § 111,73); uses the tests it needs to
ensure that those characteristics are consistently met (final §§ 111.75
and 111.315); 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 §§ 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 §§ 111.103 to 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 §§ 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.

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 current good
manufacturing practice 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 record keeping 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, 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)).

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
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 §§ 20.63 and 20.64 contain
provisions for the protection of personal privacy.

[3. Public Health Service Act Authority]{.underline}

(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.

[a. The communicable disease risk posed by dietary
supplements]{.underline}

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 \[1-4%\],
infection spreads from the GI tract into the blood stream, which can be
life-threatening. Persons with immune compromising conditions (such as
cancer, 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.

*E. coli* O157:H7 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*) 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 this section immediately
below, our authority under the PHS Act is not limited to interstate
activities. It also covers intrastate activities.

[b. Activities for which we are asserting legal authority under the PHS
Act]{.underline}

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 hydrogen-ion
concentration (pH), humidity, and water activity (aw), 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.

[c. The interstate commerce nexus for the final rule]{.underline}

i\. 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, 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." (42 U.S.C.
264). 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 PHS Act
§ 361 provides authority.

ii\. The act

The act extends to the sale of a dietary supplement that was
manufactured and 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." 21
U.S.C. 331(k) (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) 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 § 331(k)"); *United States* v.
*Cassaro, Inc.*, 443 F.2d 153, 155-56 (1st Cir. 1971); *United States*
v. *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)).

Number range CHAPTERNor does it matter that the interstate product
component comprises only a minute part of the article, *Number range
CHAPTERUnited 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.

[iii. Commerce Clause]{.underline}

(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.

[iv. Fifth Amendment]{.underline}

(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 § 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
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 (Feb. 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 also* *Boyce
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.

[6. Miscellaneous]{.underline}

(Comment 24) One comment states that the proposed rule violates section
402(f)(1)(A)(i) and (ii) of the act (21 U.S.C. 342 (f)(1)(A)(i) and
(ii)), which deem 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.
Sections 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. 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 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

  § 111.1 Who Is Subject to These Regulations?       § 111.1

  § 111.2 What Definitions Apply to This Part?       § 111.3

  § 111.5 Do Other Statutory Provisions and          § 111.5
  Regulations Apply?                                 
  -------------------------------------------------- --------------------

[B. Who Is Subject to These Regulations?]{.underline}

[(Final § 111.1)]{.underline}

Section 111.1 explains who is subject to the dietary supplement CGMP
requirements. In brief, final § 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 § 111.1(b), however, excludes
certain persons from the rule. Specifically, § 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 §
111.1 immediately below.

(Comment 26) Some comments interpret the proposal as not applying to
persons who perform labeling operations. For example, one comment claims
that proposed § 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 §§ 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 § 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 § 111.1
to include the word "label." Thus, under final § 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 § 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 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 § 111.127(d)), and must approve the release of the
packaged and labeled dietary supplement for distribution (final
§ 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).

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]{.mark} [complaint to us. Reporting a
complaint to us is]{.mark} [not covered by these CGMP
requirements]{.mark} [and would be voluntary, unless the complaint is
subject to the]{.mark} [statutorily mandated]{.mark} [reporting
requirements for "significant adverse events"]{.mark} [pursuant to the
"Dietary Supplement and Non-Prescription Drug Consumer Protection Act"
(Pub. L. 109-462) signed into law on December 22, 2006.]{.mark} [(See
discussion in section XX).]{.mark}

Under the procedures that are set forth in subpart O, Product Complaints
(see section XX), 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 § 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 § 111.3). The
proposed rule, § 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 § 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 §§ 111.70, 111.73, 111.75, and 111.77 (see section X), 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. 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 § 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 § 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 § 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 § 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 § 111.1(b), discussed in this
section. In other words, final § 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 § 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 § 111.1. However, as explained above in the previous
response to comment 29), if a dietary ingredient manufacturer also
supplies or sells a dietary ingredient as a dietary supplement, such
manufacturer would be subject to final § 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 § 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 § 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 distinguish between "holding" dietary supplements for retail sale to
consumers and "holding" dietary supplements in a warehouse for further
distribution, final § 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 § 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:

● These practitioners do not broadly sell products;

● These practitioners make very small quantities of individualized
formulas, and can therefore be very selective as to the quality of
ingredients used;

● 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;

● 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;

● Many states regulate or license these practitioners, so further
federal regulation is unnecessary;

● Some practitioners do not consider themselves to be manufacturers;

● In an analogous situation, compounding pharmacists are not required to
comply with drug CGMPs; and

● 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 1600 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
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 decision making 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 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,
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 rule available when it went on display
and 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 (GATT). 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 § 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 § 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
§ 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 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 § 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?]{.underline}

[(Final § 111.3)]{.underline}

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 with 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 response to comment 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 immediately below.

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.

We discuss the comments on our proposed definition of "batch" and our
changes to the definition in our responses to the comments immediately
below.

(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 one 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 § 111.70, determine whether these
specifications are met under final § 111.73, and ensure that these
component specifications are met using the criteria under final
§ 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 non-substantive,
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.

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.

(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 (i.e. vitamin C ) and you add a
natural product which is intended to supply the Vitamin C (i.e. vitamin
C in the form of rosehips), we would consider the natural product (e.g.
rosehips that contains 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 §
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 with "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 non-substantive,
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 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 non-pathogenic 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 non-substantive, 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 non-substantive, 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, 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 comments immediately below.

(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, 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[.]{.mark}
[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" (Pub. L. 109-462) signed
into law on December 22, 2006.]{.mark} 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 § 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 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
CFSAN CAERS. This final rule has no effect on the [mandatory or]{.mark}
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[.]{.mark} []{.mark} [Such a complaint may be
required to be]{.mark} [reported under the mandatory reporting
requirements of the]{.mark} ["Dietary Supplement and Non-Prescription
Drug Consumer Protection Act" (Pub. L. 109-462) signed into law on
December 22, 2006.]{.mark} 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]{.mark}. 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
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 non-substantive 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, 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 "complaints 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 sections 402(a)(1), (a)(2), (a)(3), and (a)(4) of the Federal
Food, Drug, and Cosmetic 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, 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: § 111.3 (definition of batch); § 111.3 (definition of
lot); § 111.65 (What are the requirements to have quality control
operations?); § 111.70 (What Specifications Must You Establish?); §
111.75 (What must You Do to Determine Whether specifications are met?);
§ 111.80 (What Representative Samples must You Collect?); § 111.95 (What
Records Must You Make and Keep?); § 111.105 (What Must Quality Control
Personnel Do?); § 111.455 (What Requirements Apply to Holding
Components, Dietary Supplements, Packaging, and Labels?); and § 111.515
(When must a Returned Dietary Supplement be Destroyed, 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 commenter 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 §
111.12(b) to require you to identify who is responsible for your quality
control operations. Under final § 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
non-substantive 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 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 comments immediately below in this section. 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 §§ 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 §§ 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).

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 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 § 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.

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*
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 (EPA). 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 § 178.1010 may be used, including the
requirement that they be used in accordance with the EPA-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 § 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 non-binding information is
inconsistent with our current practices for establishing regulations.

We note that EPA 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 (EPA) regulatory authority as pesticide chemicals. EPA recently
codified tolerance exemptions under section 408 of the act for those
food contact surface sanitizing solutions that were previously subject
to our authority at § 178.1010 and transferred to EPA'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 § 178.1010. For an in depth discussion of appropriate
sanitizers for food contact surface use, see the EPA'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)* (Jan
30, 1979) (Ref. 27) (available on the internet at

http://[www.epa.gov/oppad001/](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.

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 § 111.3 the act's definitions and interpretations
"apply to such terms when used in these regulations." Thus, there is no
need for us to define the terms as requested by the comments.

(Comment 56) Proposed § 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
§ 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 § 111.75(b)
(formerly proposed § 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 non-standardized 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 above examples, we 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
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 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).

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 36153 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, 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 § 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 § 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 §
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 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,]{.mark}
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, 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 § 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 § 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, 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 provide clarity
and consistency in interpreting various terms in a rule.

[D. Do Other Statutory Provisions and Regulations Apply?
(Final§ 111.5)]{.underline}

Final § 111.5 states: "In addition to these regulations, you must comply
with other applicable statutory provisions and regulations under the act
related to dietary supplements." Proposed § 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?]{.underline}

The final rule omits sections that were in the proposed rule. Proposed §
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 § 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 §
111.2)

We elected to remove proposed § 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 §
111.2 either disagreed with its general statement or sought to weaken
the provision; the comments' arguments prompted us to reconsider whether
proposed § 111.2 was necessary at all, and, in the end, we decided to
delete the proposed section. We describe the comments on proposed §
111.2 immediately below.

(Comment 63) Several comments argue the proposed rule went beyond the
"minimum standards" mentioned in proposed § 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
§ 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 § 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 § 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 § 111.2 altogether, the change sought by the comment is moot.

2\. "Exclusions" (Proposed § 111.6)

As we stated earlier in this section, proposed § 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 in this section, we decided that the exclusion was not
necessary, given the changes that we made to final § 111.1(a).

Nevertheless, we received several comments on proposed § 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 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 SBA 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 §
111.6, we note that such a change is no longer necessary since we are
deleting § 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 § 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 § 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.

[^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 § 111.1 "Who is subject to these regulations?"
    We also sometimes use the terms to apply to only part of the
    process, i.e., those operations other than labeling, packaging, and
    holding.

[^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.

[^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" (Pub. L. 109-462)
    signed into law on December 22, 2006.]{.mark} [(See discussion in
    section XX).]{.mark}

[^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").

[^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). 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.

[^6]: It is also worth noting that standard references used in many
    industries establish clear expectations for documentation and record
    keeping practices for assuring quality control in manufacturing
    operations. (Ref. 13);(Ref. 9).

[^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))