34752 Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 111 

[Docket No. 1996N–0417] (formerly Docket 

No. 96N–0417) 

RIN 0910–AB88 

Current Good Manufacturing Practice 

in Manufacturing, Packaging, Labeling, 

or Holding Operations for Dietary 

Supplements 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is issuing a final 

rule regarding current good 

manufacturing practice (CGMP) for 

dietary supplements. The final rule 

establishes the minimum CGMPs 

necessary for activities related to 

manufacturing, packaging, labeling, or 

holding dietary supplements to ensure 

the quality of the dietary supplement. 

The final rule is one of many actions 

related to dietary supplements that we 

are taking to promote and protect the 

public health. 

DATES: This rule is effective August 24, 

2007. 

Compliance Dates: The compliance 

date is June 25, 2008; except that for 

businesses employing fewer than 500, 

but 20 or more full-time equivalent 

employees, the compliance date is June 

25, 2009; and except that for businesses 

that employ fewer than 20 full-time 

equivalent employees, the compliance 

date is June 25, 2010. 

FOR FURTHER INFORMATION CONTACT: 

Vasilios H. Frankos, Center for Food 

Safety and Applied Nutrition (HFS– 

810), Food and Drug Administration, 

5100 Paint Branch Pkwy., College Park, 

MD 20740, 301–436–1696. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Background and Related Information 

II. How is the Final Rule Organized? 

III. What Does the Final Rule Do? 

A. Overview of CGMP 

B. Highlights of the Final Rule 

IV. What General Comments Did We 

Receive? 

A. What Comments Did We Receive 

on the Structure and Organization 

of the Rule? 

B. What Comments Did We Receive 

on the Need for Dietary Supplement 

CGMP Requirements? 

C. What Comments Did We Receive 

on Written Procedures? 

1. Overview 

2. Written Procedures That Are 

Required by This Final Rule 

3. Written Procedures That Are Not 

Required by This Final Rule 

D. Other Comments on Written 

Procedures 

E. What Other General Comments Did 

We Receive? 

V. What Legal Authority Comments Did 

We Receive? 

A. Modeled After CGMP for Food 

B. Records Authority 

C. Public Health Service Act 

Authority 

1. The Communicable Disease Risk 

Posed by Dietary Supplements 

2. Activities For Which We Are 

Asserting Legal Authority Under 

the PHS Act 

D. The Interstate Commerce Nexus for 

the Final Rule 

1. The PHS Act 

2. The Act 

3. Commerce Clause 

E. Fifth Amendment 

F. Miscellaneous 

VI. What Comments Did We Receive on 

the General Provisions? (Subpart A) 

A. Organization of Final Subpart A 

B. Who Is Subject to This Part? (Final 

§ 111.1) 

C. What Definitions Apply to This 

Part? (Final § 111.3) 

1. Actual Yield 

2. Batch 

3. Batch Number, Lot Number, or 

Control Number 

4. Component 

5. Contact Surface 

6. Ingredient 

7. In-Process Material 

8. Lot 

9. Microorganisms 

10. Must 

11. Pest 

12. Physical Plant 

13. Product Complaint 

14. Quality 

15. Quality Control 

16. Quality Control Personnel 

17. Representative Sample 

18. Reprocessing 

19. Reserve Sample 

20. Sanitize 

21. Theoretical Yield 

22. Water Activity 

23. We 

24. You 

25. What Other Terms Did the 

Comments Want Defined? 

26. What Definitions Did the 

Comments Want Us to Delete? 

D. Do Other Statutory Provisions and 

Regulations Apply? (Final § 111.5) 

E. What Sections Did We Remove 

From the Rule, and Why? 

1. ‘‘What Are These Regulations 

Intended to Accomplish?’’ 

(Proposed § 111.2) 

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 

1. Revisions 

2. Changes After Considering 

Comments 

C. General Comments on Proposed 

Subpart B 

D. What Are the Requirements Under 

This Subpart for Written 

Procedures? (Final § 111.8) 

E. What Requirements Apply for 

Preventing Microbial 

Contamination From Sick or 

Infected Personnel and for Hygienic 

Practices? (Final § 111.10) 

1. Final § 111.10(a) 

2. Final § 111.10(b) 

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) 

VIII. Comments on Physical Plant and 

Grounds (Final Subpart C) 

A. Organization of Final Subpart C 

B. Highlights of Changes to the 

Proposed Requirements for Physical 

Plant and Grounds 

1. Revisions 

2. Changes After Considering 

Comments 

C. General Comments on Proposed 

Subpart C 

D. What Sanitation Requirements 

Apply to Your Physical Plant and 

Grounds? (Final § 111.15) 

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) 


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G. Under This Subpart, What Records 

Must 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) 

E. What Requirements Apply to the 

Equipment and Utensils That You 

Use? (Final § 111.27) 

1. Final 111.27(a) 

2. Final § 111.27(b) 

3. Final § 111.27(c) 

4. Final § 111.27(d) 

F. Reorganization of Certain 

Paragraphs in Proposed § 111.25 

G. What Requirements Apply to 

Automated, Mechanical, or 

Electronic Equipment? (Final 

§ 111.30) 

1. Comments on the Organization and 

Framework of Proposed § 111.30 

2. Comments Specific to Proposed 

§ 111.30 

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 

D. What Are the Requirements to 

Implement a Production and 

Process Control System? (Final 

§ 111.55) 

E. What Are the Design Requirements 

for the 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) 

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) 

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) 

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. Final § 111.95(a) 

2. Final § 111.95(b) 

XI. Comments on Requirements for 

Quality Control (Final Subpart F) 

A. Organization of Final Subpart F 

B. Highlights of Changes to the 

Proposed Requirements for Quality 

Control Operations 

1. Revisions 

2. Changes Associated With the 

Reorganization 

3. Changes After Considering 

Comments 

C. General Comments on Proposed 

§ 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) 

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) 

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) 

I. What Quality Control Operations 

Are Required for Components, 

Packaging, and Labels Before Use in 

the Manufacture of a Dietary 

Supplement? (Final § 111.120) 

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) 

J. What Quality Control Operations 

Are Required for the Master 

Manufacturing Record, the Batch 

Production Record, and 

Manufacturing Operations? (Final 

§ 111.123) 

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) 

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) 

1. Final § 111.130(a) 

2. Final § 111.130(a)(1) and (a)(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 You Make and 

Keep? (Final § 111.140) 

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 

1. Revisions 

2. Changes After Considering 

Comments 

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) 

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) 

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) 

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, 

and 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) 

1. Final § 111.180(a) 

2. Final § 111.180(b)(1) 

3. Final § 111.180(b)(2) 

4. Final § 111.180(b)(3) 

XIII. Comments on the Production and 

Process Control System: Requirements 

for the Master Manufacturing Record 

(Final Subpart H) 

A. Organization of Final Subpart H 

B. Highlights of Changes to the 

Proposed Requirements for the 

Master Manufacturing Record 

1. Revisions 

2. Changes Associated With the 

Reorganization 

3. Changes After Considering 

Comments 

C. General Comments on Proposed 

§ 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) 

10. Final § 111.260(k) 

11. Final § 111.260(l) 

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 That You Use? 

(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 


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B. Highlights of Changes to the 

Proposed Requirements for 

Manufacturing Operations 

1. Revisions 

2. Changes Made After Considering 

Comments 

3. Revisions Associated With the 

Reorganization 

C. General Comments on 

Manufacturing Operations 

D. What Are the Requirements Under 

This Subpart for Written 

Procedures? (Final § 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 the Production and 

Process Control System: Requirements 

for Packaging and Labeling Operations 

(Final Subpart L) 

A. Organization of Final Subpart L 

B. Highlights of Changes to the 

Proposed Requirements for 

Packaging and Labeling Operations 

1. Revisions 

2. Changes Associated With the 

Reorganization 

3. Changes After Considering 

Comments 

C. General Comments on Proposed 

Requirements for Packaging and 

Labeling Operations 

D. General Comments on 

Requirements for What Must Be on 

the Product Label Rather Than for 

Labeling Operations 

E. What Are the Requirements Under 

This Subpart for Written 

Procedures? (Final § 111.403) 

F. What Requirements Apply to 

Packaging and Labels? (Final 

§ 111.410) 

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) 

J. Under this Subpart, 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) 

A. Organization of Final Subpart M 

B. Highlights of Changes to the 

Proposed Requirements for Holding 

and Distributing 

1. Revisions 

2. Changes Associated With the 

Reorganization 

3. Changes After Considering 

Comments 

C. General Comments on Proposed 

§§ 111.80, 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 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) 

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) 

1. Final § 111.560(a)(1) 

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

F. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.570) 

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) 

XXI. Comments on Records and 

Recordkeeping (Final Subpart P) 

A. Organization of Final Subpart P 

B. Highlights of Changes to the 

Proposed Requirements for Records 

and Recordkeeping 

1. Revisions 

2. Changes After Considering 

Comments 

C. General Comments on Proposed 


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§ 111.125 

D. What Requirements Apply to the 

Records That You Make and Keep? 

(Final § 111.605) 

1. Final § 111.605(a) 

2. Final § 111.605(b) 

3. Final § 111.605(c) 

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 

D. Comments on Implementation and 

Enforcement 

E. Removal of References to Part 112 

XXIII. Paperwork Reduction Act of 1995 

XXIV. Analysis of Impacts 

A. Introduction 

1. Summary of the Economic Analysis 

2. Summary of Comments on the 

Economic Analysis 

B. Final Regulatory Impact Analysis 

1. The Need for the Final Current 

Good Manufacturing Practice Rule 

2. Regulatory Options 

3. Coverage of the Final Rule 

4. Baseline Practices 

5. Baseline Risk 

6. Benefits 

7. Costs 

8. Summary of Benefits and Costs 

9. Benefits and Costs of Regulatory 

Options 

10. Cost Effectiveness Analysis 

11. Uncertainties in the Analysis 

C. Final Regulatory Flexibility 

Analysis 

1. Introduction 

2. Economic Effects on Small Entities 

3. Regulatory Options 

4. Description of Recordkeeping and 

Reporting 

5. Summary 

D. Unfunded Mandates 

XXV. Analysis of Environmental Impact 

XXVI. Federalism 

XXVII. References 

I. Background and Related Information 

On October 25, 1994, the Dietary 

Supplement Health and Education Act 

(DSHEA) (Public Law 103–417) was 

signed into law. DSHEA, among other 

things, amended the Federal Food, 

Drug, and Cosmetic Act (the act) by 

adding section 402(g) of the act (21 

U.S.C. 342(g)). Section 402(g)(2) of the 

act provides, in part, that the Secretary 

of Health and Human Services (the 

Secretary) may, by regulation, prescribe 

good manufacturing practices for dietary 

supplements. Section 402(g) of the act 

also stipulates that such regulations 

shall be modeled after CGMP 

regulations for food and may not impose 

standards for which there are no current 

and generally available analytical 

methodology. The final rule establishes, 

in part 111 (21 CFR part 111), the 

minimum CGMPs necessary for 

activities related to manufacturing, 

packaging, labeling, or holding dietary 

supplements to ensure the quality of the 

dietary supplement. The final rule is 

one of many actions related to dietary 

supplements that we are taking to 

promote and protect the public health. 

In response to DSHEA, we issued an 

Advance Notice of Proposed 

Rulemaking (the 1997 ANPRM) in the 

Federal Register of February 6, 1997 (62 

FR 5700). The 1997 ANPRM contained 

a CGMP outline submitted to us on 

November 20, 1995, by representatives 

of the dietary supplement industry. The 

1997 ANPRM also asked nine questions 

that addressed issues that the industry 

outline did not. For example, we asked 

if there is a need to develop specific 

defect action levels (DALs) for dietary 

ingredients. We also asked whether a 

CGMP rule should require 

manufacturers to establish procedures to 

document, on a continuing or daily 

basis, that they followed pre-established 

procedures for making dietary 

supplements. 

We received more than 100 comments 

in response to the 1997 ANPRM. We 

evaluated these comments before we 

drafted and ultimately issued a 

proposed rule on CGMPs for dietary 

ingredients and dietary supplements 

(which we discuss later in this section 

of this document). 

Additionally, during 1999, we 

conducted a number of outreach 

activities related to dietary 

supplements. We held several public 

meetings to develop our overall strategy 

for achieving effective regulation of 

dietary supplements, which could 

include establishing CGMP regulations. 

We also held public meetings focused 

specifically on CGMPs and the 

economic impact that any CGMP rule 

for dietary ingredients and dietary 

supplements might have on small 

businesses. Further, we toured several 

dietary supplement manufacturing 

facilities to better understand the 

manufacturing processes and practices 

that potentially would be subject to 

CGMP requirements for dietary 

ingredients and dietary supplements 

(Refs. 1 through 6). These activities 

contributed to our knowledge about the 

industry. 

In the Federal Register of March 13, 

2003 (68 FR 12157), we published a 

proposed rule to establish CGMP 

requirements for dietary ingredients and 

dietary supplements (the 2003 CGMP 

Proposal). The preamble to the 2003 

CGMP Proposal addressed the 

comments we had received regarding 

the nine questions in the 1997 ANPRM, 

discussed our legal authority to issue a 

CGMP rule, and described the basis for 

each proposed requirement. 

The 2003 CGMP Proposal specifically 

requested comment on a variety of 

areas, including the need for written 

procedures and recordkeeping 

requirements. Although the proposed 

rule’s comment period was scheduled to 

end on June 11, 2003, in the Federal 

Register of May 19, 2003 (68 FR 27008), 

we extended the comment period to 

August 11, 2003. 

After we published the proposed rule, 

we conducted and/or participated in 

outreach activities related to dietary 

supplements and dietary ingredients. 

We held public stakeholder meetings on 

April 29, 2003, in College Park, MD, and 

on May 6, 2003, in Oakland, CA. We 

also held a public meeting, via satellite 

downlink, on May 9, 2003, with viewing 

sites at our district and regional offices 

throughout the country. These public 

meetings gave an overview of the 

proposed rule, and clarified specific 

points in the proposed rule. Since the 

public stakeholder meetings held as part 

of our outreach efforts, we also have 

participated in several meetings with 

industry and other interested parties 

which are reflected in the public docket. 

We received approximately 400 

comments in response to the proposal. 

The comments came from trade 

associations, government organizations 

and officials, manufacturers of dietary 

supplements and dietary ingredients, 

health care practitioners, consumer 

groups, and individuals. In general, the 

comments supported the idea of 

CGMPs, although many comments 

disagreed with specific aspects of the 

proposal. 

Published elsewhere in this issue of 

the Federal Register we are also issuing 

an interim final rule that sets forth a 

procedure for requesting an exception to 

a CGMP requirement in this final rule. 

The interim final rule allows for 

submission to, and review by, FDA of an 

alternative to the required 100-percent 

identity testing of components that are 

dietary ingredients (as discussed in 

section X of this document (subpart E)), 

provided certain conditions are met. 

The interim final rule also includes a 

requirement for retention of records 

related to the FDA grant of an exception 

request. 


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II. How is the Final Rule Organized? 

The 2003 CGMP Proposal was divided 

into eight subparts, with each subpart 

devoted to a particular topic. For 

example, proposed subpart A was titled 

‘‘General Provisions’’ and contained 

sections describing the rule’s scope, 

purpose, definitions, applicability of 

other statutory and regulatory 

provisions, and exclusions. As another 

example, proposed subpart B was titled 

‘‘Personnel’’ and described microbial 

contamination and hygiene 

requirements, personnel qualification 

requirements, and supervisor 

requirements. 

In response to comments seeking a 

simpler, more ‘‘user-friendly’’ final rule 

or seeking clarification of the rule’s 

applicability to certain persons, items, 

or activities, and to reduce redundant 

provisions or combine similar 

provisions, we have reorganized the 

final rule into 16 subparts, with new 

subparts focusing on specific aspects of 

the manufacturing process or addressing 

specific issues. For example, the 

proposed rule placed all production and 

process control requirements for 

manufacturing, packaging, labeling, and 

laboratory operations in a single subpart 

(proposed subpart E). The final rule 

creates separate subparts for the specific 

operations to make it easier to find the 

relevant production and process control 

requirements for a particular activity. 

Table 1 of this document summarizes 

how we reorganized the rule. We are 

providing this information to help 

readers understand the structural 

changes we made between the proposed 

and final rules. 

TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE

Proposed Subpart and Title Proposed Sections 

in the Subpart 

Final Subpart 

and Title 

Final Sections 

in the Subpart 

A—General Provisions 111.1 

111.2 

111.3 

111.5 

111.6 

A—General Provisions 111.1 

111.3 

111.5 

B—Personnel 111.10 

111.12 

111.13 

B—Personnel 111.8 (new) 

111.10 

111.12 

111.13 

111.14 (new) 

C—Physical Plant 111.15 

111.20 

C—Physical Plant and 

Grounds 

111.15 

111.16 (new) 

111.20 

111.23 (formerly proposed 

§ 111.15(d)(3) and (e)(2)) 

D—Equipment and Utensils 111.25 

111.30 

D—Equipment and Utensils 111.25 (formerly proposed 

§ 111.25(c)(1) and (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)) 


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TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued 

Proposed Subpart and Title Proposed Sections 

in the Subpart 

Final Subpart 

and Title 

Final Sections 

in the Subpart 

E—Production and Process Controls 111.35 

111.37 

111.40 

111.45 

111.50 

111.60 

111.65 

111.70 

111.74 

E—Requirement to Establish 

a Production and Process 

Control System 

111.55 (formerly proposed 

§ 111.35(a)) 

111.60 (formerly proposed 

§ 111.35(b)) 

111.65 (formerly proposed 

§ 111.35(c)) 

111.70 (formerly proposed 

§ 111.35(e), (f), (g), and (k)) 

111.73 (formerly proposed 

§ 111.35(f), (g), and (h) 

111.75 (formerly proposed 

§ 111.35(e) through (i), (k), and 

(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), and 111.85(a) and 

(c)) 

111.90 (formerly proposed 

§§ 111.35(i)(4), 111.50(d)(1), (f), 

and (g), and 111.65(d)) 

111.95 (formerly proposed 

§ 111.35(o)) 


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TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued 

Proposed Subpart and Title Proposed Sections 

in the Subpart 

Final Subpart 

and Title 

Final Sections 

in the Subpart 

F—Production and Process 

Control System: Requirements for Quality Control 

111.103 (new) 

111.105 (formerly proposed 

§ 111.37(a), (b)(1), (b)(11), and 

(b)(12)) 

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) 

and (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) and 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), 

and 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) and 111.37(c) and 

(d) 

G—Production and Process 

Control System: Requirements for Components, 

Packaging, and Labels and 

for Product That You Receive for Packaging or Labeling a Dietary Supplement 

111.153 (new) 

111.155 (formerly proposed 

§§ 111.35(d)(1) through (d)(5) 

and 111.40(a)(1) through (a)(5)) 

111.160 (formerly proposed 

§§ 111.35(e)(4), and 111.40(a)(2) 

and (b)(1) through (b)(4)) 

111.165 (formerly proposed 

§ 111.40(a)(1) through (a)(5)) 

111.170 (formerly proposed 

§ 111.74) 

111.180 (formerly proposed 

§§ 111.35(d)(4), and 

111.40(c)(1)(i) through (c)(1)(iv) 

and (c)(2)) 

H—Production and Process 

Control System: Requirements for the Master Manufacturing Record 

111.205 (formerly proposed 

§ 111.45(a)(1), (a)(2), and (d)) 

111.210 (formerly proposed 

§ 111.45(b)) 


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TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued 

Proposed Subpart and Title Proposed Sections 

in the Subpart 

Final Subpart 

and Title 

Final Sections 

in the Subpart 

I—Production and Process 

Control System: Requirements for the Batch Production Record 

111.255 (formerly proposed 

§ 111.50(a), (b), and (i)) 

111.260 (formerly proposed 

§§ 111.35(i)(2), (j), (m), and 

(o)(2), 111.37(b)(3), (b)(5), (b)(9) 

and 111.50(c)(1) through (c)(11), 

(c)(13), (c)(14), (d)(2), (e), and 

(g), and 111.70(b)(6) and (g)) 

J—Production and Process 

Control System: Requirements for Laboratory Operations 

111.303 (new) 

111.310 (formerly proposed 

§ 111.60(a)) 

111.315 (formerly proposed 

§ 111.60(b)(1)) 

111.320 (formerly proposed 

§ 111.60(c) and (d)) 

111.325 (formerly proposed 

§ 111.60(b)(2) and (b)(3)) 

K—Production and Process 

Control System: Requirements for Manufacturing Operations 

111.353 (new) 

111.355 (formerly proposed 

§ 111.65(a)) 

111.360 (formerly proposed 

§ 111.65(b)) 

111.365 (formerly proposed 

§ 111.65(c)) 

111.370 (formerly proposed 

§ 111.74) 

111.375 (new) 

L—Production and Process 

Control System: Requirements for Packaging and 

Labeling Operations 

111.403 (new) 

111.410 (formerly proposed 

§ 111.70(a), (b)(6), and (f)) 

111.415 (formerly proposed 

§ 111.70(b)) 

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 and Distributing 111.80 

111.82 

111.83 

111.85 

111.90 

M—Holding and Distributing 111.453 (new) 

111.455 (formerly proposed 

§ 111.80) 

111.460 (formerly proposed 

§ 111.82) 

111.465 (formerly proposed 

§ 111.83(b)(1) and (b)(2)) 

111.470 (formerly proposed 

§ 111.90) 

111.475 (new) 


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TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued 

Proposed Subpart and Title Proposed Sections 

in the Subpart 

Final Subpart 

and Title 

Final Sections 

in the Subpart 

N—Returned Dietary Supplements 111.503 (new) 

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 Complaints 111.95 O—Product Complaints 111.553 (new) 

111.560 (formerly proposed 

§ 111.95(a) through (d)) 

111.570 (formerly proposed 

§ 111.95(e) and (f)) 

H—Records and Recordkeeping 111.125 P—Records and Recordkeeping 111.605 (formerly proposed 

§ 111.125((a) and (b)) 

111.610 (formerly proposed 

§ 111.125(b) and (c)) 

1The reference to (d) is the second (d) in the proposed rule in this section due to a misnumbering in the proposed rule. 

We discuss all subparts and sections, 

and our reasons for amending or 

creating subparts and sections, in our 

discussion of the comments to the 

proposal. 

III. What Does the Final Rule Do? 

A. Overview of CGMP 

In considering the specific 

requirements necessary for dietary 

supplement CGMPs, we considered 

information from a variety of sources. 

We considered information from our 

outreach activities, as described in 

section I of this document; comments to 

the 2003 CGMP Proposal; our own 

knowledge and expertise about CGMP 

for foods, including dietary 

supplements; and characteristics of 

CGMP that apply to manufacturing, 

labeling, packaging, and holding 

operations. 

The general food CGMPs in part 110 

(21 CFR part 110) largely address 

practices designed to ensure that food is 

manufactured, processed, packed, and 

held under sanitary conditions and that 

the food is safe, clean, and wholesome. 

Although the general food CGMPs in 

part 110 apply to a variety of food 

products, including dietary 

supplements, they do not address the 

unique characteristics of certain specific 

types of food products. The agency has 

implemented separate, and more 

specific, CGMPs for various types of 

food products to provide for process 

controls in manufacturing that are not 

captured by the more general part 110 

food CGMPs. (See discussion in section 

V of this document (‘‘Legal Authority’’) 

on product specific CGMP 

requirements). At the time DSHEA was 

enacted, there were four such 

additional, specific food CGMP 

regulations: Those for infant formula 

(part 106 (21 CFR part 106)), thermally 

processed low-acid canned food (part 

113 (21 CFR part 113)), acidified food 

(part 114 (21 CFR part 114)), and bottled 

water (part 129 (21 CFR part 129)). 

Dietary supplements are a type of 

food product for which specific food 

CGMPs also are needed. Manufacturing 

process controls are needed to ensure 

that a dietary supplement contains what 

the manufacturer intends. Unlike most 

foods, the majority of dietary 

supplements are packaged into tablets, 

gelcaps, and capsules. Some dietary 

supplements may contain bioactive 

ingredients for which certain, controlled 

amounts are intended to be in each 

tablet or capsule. The process controls 

that must be in place to ensure the tablet 

or capsule contains what it purports to 

contain are different than those that 

must be in place to ensure a food is 

manufactured, processed, packed, and 

held under sanitary conditions. Process 

controls for dietary supplement 

manufacture include establishing and 

meeting specifications to ensure the 

finished dietary supplement contains 

the correct ingredient, purity, strength, 

and composition intended. 

Vitamins can present a concentrated 

source of biologically active 

components. A vitamin, for example, 

that contains too high a concentration, 

such as vitamin D at levels that are 

many times greater than intended, can 

lead to illness and hospitalization (Refs. 

7 and 8). A manufacturer must establish 

a process for manufacturing a dietary 

supplement product in order to produce 

the product consistently and reliably 

each time. In order to achieve 

consistency and reliability, there must 

be process controls in place to ensure, 

for example, that appropriate tests and 

examinations are conducted, a master 

manufacturing record is prepared, each 

batch production follows the master 

manufacturing record, and the finished 

tablet or capsule is placed in the 

intended package with the intended 

label. 

These same types of controls are 

needed for herbal and botanical dietary 

supplements. Botanicals are often 

complex mixtures that can vary in 


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1Throughout 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 this part?’’ We also sometimes use the 

terms to apply to only part of the process, i.e., those 

operations other than labeling, packaging, and 

holding. 

composition depending on factors such 

as the part of the plant used, the 

location of harvesting and growing 

conditions that can vary from year to 

year even in the same location. It can be 

difficult to distinguish between closely 

related species of botanicals, and the 

biological activity of components of an 

incorrectly identified species can lead to 

adverse consequences. In addition, 

different species may be present in 

different ratios or blends in a particular 

product. Various products might 

contain different parts of the plant—

flower, leaf, root, stem, extract—and the 

test methods for each can vary in the 

nature, sensitivity, and specificity of the 

test. 

Well-established principles of CGMP 

require process controls at each step of 

the manufacturing process as early in 

the production process as possible. 

Quality cannot be tested into the 

product only at the end (Ref. 9). Instead, 

the quality of the dietary supplement 

must be built into the product 

throughout the manufacturing process; 

quality begins with the starting material 

and continues with the product being 

manufactured in a reproducible manner 

according to established specifications. 

It is not sufficient, nor effective, to rely 

solely on end product testing to assure 

the quality of the individual dietary 

supplement product sold to the 

consumer. 

CGMPs are intended to establish a 

comprehensive system of process 

controls, including documentation of 

each stage of the manufacturing process, 

that can minimize the likelihood of, or 

detect, problems and variances in 

manufacturing as they occur and before 

the product is in its finished form. 

These process controls that are a part of 

CGMPs are essential to ensure that the 

dietary supplement is manufactured, 

packaged, held, and labeled in a 

consistent and reproducible manner. 

Manufacturing according to CGMP 

means that the manufacturing process 

incorporates a set of controls in the 

design and production processes to 

assure a quality finished product. 

CGMPs specific to dietary supplements 

are necessary to help ensure that these 

products have the identity, purity, 

strength, and composition that meet 

specifications established in the master 

manufacturing record and that they are 

not adulterated. 

Many comments stressed that the 

most critical aspect of a successful 

CGMP system is effective process 

control. Comments asserted that, with 

effective process control, quality is built 

into a product throughout the entire 

production process. The term ‘‘quality’’

came up repeatedly in comments as the 

desired outcome of the dietary 

supplement manufacturing process.1 In 

fact, several comments asked us to 

define ‘‘quality’’ and suggested various 

definitions, each of which related to a 

dietary supplement having the identity, 

purity, strength, and composition 

intended (see comment 49 in section VI 

of this document). Some comments 

distinguished the concept of quality 

from that of preventing adulteration. 

These comments objected to our 

statement that dietary supplement 

CGMP requirements are needed to 

prevent adulteration and stated that 

CGMP is focused on assuring that 

finished products are manufactured 

using quality procedures, but are not 

related to preventing adulteration. Other 

comments asked us to define 

‘‘adulteration.’’

We agree that a critical aspect of 

CGMP is achieving control over 

manufacturing processes. Controls are 

necessary to ensure that you 

manufacture what you intend so that the 

characteristics and/or attributes desired 

in a final product will be consistently 

and reliably achieved. We disagree with 

the comments to the extent that they 

were suggesting that quality is not 

related to preventing contamination in 

the manufacturing process that may 

adulterate the finished product. 

However, we have reconsidered, as 

discussed in this section, what types of 

adulteration and misbranding are 

necessary to control for in this dietary 

supplement CGMP rule. 

To clarify what dietary supplement 

CGMP requirements are intended to 

achieve, we have added a definition of 

quality in the final rule. As defined, 

quality means ‘‘that the dietary 

supplement consistently meets the 

established specifications for identity, 

purity, strength, and composition and 

has been manufactured, packaged, 

labeled, and held under conditions to 

prevent adulteration under section 

402(a)(1), (a)(2), (a)(3), and (a)(4) of the 

Federal Food, Drug, and Cosmetic Act.’’

Ensuring the quality of the dietary 

supplement means that you consistently 

and reliably manufacture what you 

intend and that you establish 

manufacturing controls to prevent the 

dietary supplement from being 

adulterated under section 402(a)(1) of 

the act due to the presence of 

contaminants, under section 402(a)(2) of 

the act, for example, if it bears or 

contains any unintentionally added 

poisonous or deleterious substance, 

under section 402(a)(3) of the act if the 

dietary supplement consists in whole or 

in part of any filthy, putrid, or 

decomposed substance, or if it is 

otherwise unfit for food, or under 

section 402(a)(4) of the act if the dietary 

supplement has been prepared, packed, 

or held under insanitary conditions 

whereby it may have become 

contaminated with filth, or whereby it 

may have been rendered injurious to 

health. The definition of quality limits 

to section 402(a)(1), (a)(2), (a)(3), and 

(a)(4) of the act the types of adulteration 

that you must control for in this CGMP 

final rule. The definition applies to the 

controls that are designed to prevent 

contamination of the product that you 

intend to manufacture. 

In the 2003 CGMP Proposal, we said 

that our purpose was to present a broad 

enough scope to the proposed rule so 

that we could receive the depth and 

breadth of comment needed to develop 

a final rule that would provide the 

proper balance of regulation (68 FR 

12157 at 12161). We asked for comment 

on whether each of the provisions 

proposed was necessary to ensure the 

safety and quality of the dietary 

supplement and was adequate to protect 

the public health (id.). We stated that 

the proposed rule ‘‘would establish the 

minimum CGMPs necessary to ensure 

that, if you engage in activities related 

to manufacturing, packaging, or holding 

dietary ingredients or dietary 

supplements, you do so in a manner 

that will not adulterate and misbrand 

such dietary ingredients or dietary 

supplements’’ (68 FR 12157 at 12158). 

For example, we stated that the 

proposed rule would require the 

manufacturer to test for toxic 

compounds in botanicals that may 

likely be present to ensure that no such 

compounds are present that may 

adulterate the dietary supplement (68 

12157 FR at 12162). Further, we 

included a requirement that the 

ingredients, other than dietary 

ingredients under section 201(ff) of the 

act, be lawful under the applicable food 

additive regulations or be generally 

recognized as safe (GRAS) (proposed 

§ 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 


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2Under 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. 

component, in the manufacture of a 

dietary supplement that would 

adulterate the product under relevant 

provisions of the act, such as section 

402(a)(1) or (a)(2)(C). The manufacturer 

would have been required to establish 

specifications at any point, step, or stage 

in the manufacturing process where 

control is necessary to prevent 

adulteration (proposed § 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 so that 

the dietary supplement label would 

accurately identify the dietary 

supplement (proposed §§ 111.45(b)(7), 

111.50(c)(12), and 111.70(b)(7)). The 

proposed rule also would have required 

the master manufacturing record to 

contain the identity of each ingredient 

that is required to be declared on the 

ingredient list in section 403 of the act 

(21 U.S.C. 343) (proposed 

§ 111.45(b)(4)). 

Several comments seemed to question 

why the dietary supplement CGMP rule 

would require that a manufacturer use 

lawful ingredients when other 

provisions of the act would require such 

use. In fact, some comments objected to 

the proposed requirement in the rule 

that required that a component, other 

than a dietary ingredient, be approved 

for use as a food additive or be GRAS. 

The comments stressed that such a 

provision was not necessary because the 

statute already requires that such an 

ingredient be approved as a food 

additive or be GRAS. In light of these 

comments, we reconsidered our 

interpretation of the scope of ‘‘prevent 

adulteration’’ in the proposed rule and 

whether that interpretation should be 

narrowed. We also considered whether 

to require, as part of a CGMP 

requirement, that the label that 

accurately reflects the ingredients in the 

product be applied or whether such a 

requirement was not necessary, given 

our existing authority in section 403 of 

the act. 

We determined that ensuring quality 

in dietary supplement CGMP, in part, 

means that you produce what you 

intend to produce. As stated in section 

V of this document, manufacturers must 

plan what they intend to produce, 

institute adequate controls to achieve 

the desired outcome, and ensure that 

the controls work so that the desired 

outcome is consistently achieved. Thus, 

for example, the manufacturer decides 

on the identity, purity, strength, and 

composition of the dietary supplement 

it manufactures. The focus of CGMP is 

on process controls to ensure that the 

desired outcome is consistently 

achieved, and not on the inherent safety 

of the ingredients used (which is 

addressed by other statutory 

prohibitions). 

We agree with the comments that the 

safety of a particular ingredient is 

governed by other provisions of the act. 

If you manufacture a dietary 

supplement, you have a responsibility 

as a manufacturer to evaluate the safety 

of the ingredients under, for example, 

section 402(f) of the act.2 Dietary 

supplement CGMP would require you to 

establish the identity, purity, strength, 

and composition specifications for the 

product and ensure that such 

specifications are met in the finished 

batch of dietary supplement. Nothing in 

the dietary supplement CGMPs relieves 

manufacturers from complying with any 

other substantive provisions of the act 

relating to the safety of ingredients and 

other components. 

Quality not only means that you 

produce what you intend, but that you 

prevent contamination in your 

manufacturing process that could 

adulterate your product. Food CGMP 

regulations, after which the dietary 

supplement CGMP rule is modeled, 

require that the manufacturer take 

precautions to ensure that the 

manufacturer does not adulterate the 

product under section 402(a)(1), (a)(2), 

(a)(3), and (a)(4) of the act. For example, 

under § 110.5 (food CGMP), the criteria 

and definitions apply in determining 

whether a food is adulterated under 

section 402(a)(3) and (a)(4) of the act. 

Specifically, § 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 

section 402(a)(1), (a)(2), (a)(3), and (a)(4) 

of the act from contamination during the 

manufacturing, packaging, labeling, and 

holding operations. For example, if you 

are manufacturing a dietary supplement 

that you know is likely to contain a 

contaminant, you would need to 

establish limits on the contaminant in 

your supplement, and you must design 

these limits to prevent the dietary 

supplement from being adulterated 

under section 402(a)(1), (a)(2), (a)(3), 

and (a)(4) of the act. 

Quality, as the term is used for the 

purposes of this final rule, relates both 

to producing what is intended (i.e., 

establishing and ensuring that 

specifications for the identity, purity, 

strength, and composition are met) and 

to ensuring that the dietary supplement 

that you intend to produce has been 

manufactured, packaged, labeled, and 

held under conditions to prevent 

adulteration within the meaning of 

section 402(a)(1), (a)(2), (a)(3), and (a)(4) 

of the act. Thus, this final rule is not 

designed to specifically prevent all 


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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 of this 

document each time it is made. 

Moreover, you have a responsibility 

under CGMP to ensure that the label 

you specify in the master manufacturing 

record is applied to the product. Under 

section 403 of the act, you are required 

to ensure that your label accurately 

reflects the ingredients in the product. 

Because section 403 of the act provides 

that food, including dietary 

supplements, is misbranded if a label 

that does not contain accurate 

statements is applied, we do not need to 

impose the same requirement in this 

final rule. Thus, if the representative 

label in the master manufacturing 

record for the product does not identify 

the correct dietary ingredients and the 

label that lists inaccurate information is 

applied, that dietary supplement would 

be misbranded under section 403 of the 

act. Such labeling would not be a 

violation of dietary supplement CGMP 

unless there is a mixup in your process 

control and you do not put the 

representative label specified in the 

master manufacturing record on the 

product. Such a mixup would be a 

violation of dietary supplement CGMP 

requirements (see e.g., final 

§§ 111.127(d), 111.160(e), 111.410(c), 

111.415). 

Thus, in addition to stating ‘‘ensure 

the quality of the dietary supplement,’’

in the codified instead of ‘‘prevent 

adulteration,’’ we are adding the 

language ‘‘and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record.’’ Such change is intended to 

clarify that the use of the packaging and 

labeling that is stated in the master 

manufacturing record is what is 

required in this final rule. 

A failure to follow the requirements 

in this final rule, including a failure to 

establish required specifications, could 

result in an enforcement action by the 

agency under section 402(g) of the act 

because the dietary supplement is 

adulterated in that it was prepared, 

packed, labeled, or held under 

conditions that do not meet CGMPs for 

dietary supplements. The act establishes 

certain prohibited acts and enforcement 

mechanisms to remove adulterated 

product from the market and prevent 

manufacturers from continuing to 

manufacture adulterated product. 

Enforcement mechanisms currently 

available to us under the act are not 

affected by this final rule. 

Finally, we have included in this final 

rule the existing requirements in part 

110 that we believe are common to 

dietary supplement manufacturing. For 

example, the requirements in subpart C, 

Physical Plant and Grounds, are similar 

to those in § 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 


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of dietary supplements associated with 

those records. 

IV. What General Comments Did We 

Receive? 

We received approximately 400 

comments on the proposed rule. 

Although most comments support 

CGMP requirements for dietary 

supplements and dietary ingredients, 

others question the need for a regulation 

and many sought changes to the rule. 

We describe, in this section, comments 

on general aspects of the final rule. We 

include comments related to the 

structure and organization of the final 

rule, comments we received on why 

CGMP requirements are needed, and 

comments on written procedures. In 

addition, we describe some general 

comments we received on multiple 

sections of the proposed rule that we 

believe are better addressed in one 

response. 

To make it easier to identify 

comments and our responses, the word 

‘‘comment,’’ in parentheses, will appear 

before each comment, and the word 

‘‘response’’ will appear before each 

response. We also have numbered the 

comments to make it easier to 

distinguish between comments; the 

numbers are for organizational purposes 

only and do not reflect the order in 

which we received the comments or any 

value associated with the comment. 

A. What Comments Did We Receive on 

the Structure and Organization of the 

Rule? 

(Comment 1) Several comments seek 

to restructure or reorganize the rule. For 

example, one comment states we should 

simplify the entire section on 

production and process controls. The 

comment asserts it would be more 

logical to list contaminants that may 

adulterate a dietary supplement or lead 

to adulteration as part of the 

requirements for specifications 

(proposed § 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 rewrite the rule to 

be more user friendly. 

Yet another comment says that any 

final rule we issue must clearly set forth 

CGMP requirements. This comment 

seems to suggest the requirements need 

to be more detailed in describing what 

is required. The comment asserts that 

ambiguities in interpretation could 

result in economic disadvantage for 

small businesses because they typically 

do not have in-house legal counsel and, 

thus, must be more conservative in 

interpreting ambiguous regulatory 

provisions. 

(Response) In response to these 

comments, as well as comments on 

specific subparts and provisions, we 

have reorganized the final rule and have 

re-phrased or introduced concepts in a 

‘‘user-friendly’’ or plain language 

format. We also have eliminated certain 

redundant regulatory requirements and 

combined similar requirements. For 

example, rather than put all production 

and process control system 

requirements in a single subpart, we 

have reorganized the final rule to create 

a series of subparts that first describe 

the requirements for the overall design 

and implementation of the production 

and process control system and then 

describe the requirements of the 

individual operations associated with 

that system. We also present each 

requirement as a question rather than as 

a paragraph within a section. This 

question format will help readers focus 

on the subparts or sections that apply to 

specific operations. 

As another example, we reduced the 

redundancy associated with the 

interrelated nature of the proposed rule 

by combining most similar 

requirements. Both proposed 

§§ 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? 

(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 


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are different statutory requirements, 

different regulatory requirements, and 

different safety evaluations for dietary 

supplements and drugs. 

We also disagree that the final rule 

should apply only to manufacturers 

who cannot manufacture dietary 

supplements responsibly. Establishing 

who is or is not a responsible 

manufacturer is not a threshold 

requirement in section 402(g) of the act, 

and it would be impractical to regulate 

dietary supplement CGMP in such a 

manner, because parties may differ as to 

whether a particular manufacturer acted 

‘‘responsibly’’ in a particular situation. 

All dietary supplement manufacturers 

are subject to this final rule, just as all 

dietary supplement manufacturers are 

subject to section 402(g) of the act. We 

therefore are not persuaded that dietary 

supplement CGMP requirements are not 

needed, or should only be applied to 

manufacturers who have not acted 

‘‘responsibly.’’

(Comment 4) Some comments state 

that our authority under the current 

food CGMP regulation in part 110 and 

our authority to take actions against 

adulterated and misbranded products 

generally are sufficient. Other comments 

state that DSHEA gives us the necessary 

legal authority to protect the public 

health and that additional regulatory 

requirements are unnecessary. Several 

comments object to our statement that 

dietary supplement CGMP requirements 

are needed to prevent adulteration. 

These comments suggest dietary 

supplement CGMP is focused on 

ensuring finished products are 

manufactured using quality procedures, 

but are not related to preventing 

adulteration. Other comments state we 

should enforce current food CGMP 

regulations rather than adopt new 

regulations. 

(Response) We disagree that dietary 

supplement CGMP requirements are not 

related to preventing adulteration. In 

fact, under the statutory scheme a 

dietary supplement is deemed to be 

adulterated under section 402(g)(1) of 

the act if it fails to meet CGMP 

requirements we promulgate by 

regulation. As we discussed in section 

III of this document, dietary supplement 

CGMP requirements are necessary to 

ensure the quality of the dietary 

supplement; ensuring quality includes 

ensuring that the dietary supplement 

has been manufactured, packaged, 

labeled, and held under conditions to 

prevent adulteration under section 

402(a)(1), (a)(2), (a)(3), and (a)(4) of the 

act. 

We also disagree with those 

comments stating that the requirements 

in part 110 are adequate and that no 

additional requirements are necessary. 

The comments do not explain why the 

specific requirements set forth in the 

proposed rule that are not also in part 

110 are unnecessary. As discussed in 

greater detail in response to comments 

on our legal authority in section V of 

this document, the particular 

characteristics and hazards of dietary 

supplements call for CGMP 

requirements tailored to dietary 

supplements. Congress specifically 

provided independent authority under 

section 402(g) of the act for us to 

promulgate CGMP requirements for 

dietary supplements. That authority 

would have been unnecessary if 

Congress had concluded that part 110 

was adequate. 

We also disagree that enforcement of 

part 110 would eliminate a need for 

dietary supplement CGMP 

requirements. The dietary supplement 

CGMP requirements include practices 

specifically tailored to the 

characteristics and hazards of dietary 

supplements and their manufacturers. 

The comments asserting that current 

food CGMP requirements in part 110 are 

sufficient provided no persuasive or 

compelling reasons for that assertion, or 

for why we should not implement 

dietary supplement CGMP requirements 

under section 402(g) of the act. For these 

reasons, we are not persuaded by the 

comments that these dietary supplement 

CGMP requirements are not needed. 

(Comment 5) Some comments object 

to the examples of manufacturing 

problems that we used to support the 

need for CGMP requirements. 

Specifically, some comments object to 

the Prevention magazine citation and 

also object to the nine examples we 

presented in the preamble to the 2003 

CGMP Proposal (see 68 FR 12157 at 

12161 through 12163). We cited the 

Prevention magazine survey on 

consumer use of dietary supplements to 

show that only 41 percent of surveyed 

consumers who use vitamins and 

minerals think those products are very 

safe, and only 50 percent think the 

products are somewhat safe; among 

those using herbal products, only 24 

percent thought the products were very 

safe, and only 53 percent thought the 

products were somewhat safe. We noted 

that 74 percent supported increased 

government regulation of dietary 

supplements (see, id.). As one example 

of adulterated dietary supplements 

caused by manufacturing practices, the 

preamble to the 2003 CGMP Proposal 

mentioned an instance where a young 

woman suffered a life-threatening 

abnormal heart function that was traced 

to a mislabeled or contaminated dietary 

ingredient (68 FR 12157 at 12162). 

Another example involved recalls of 

super- and subpotent dietary 

supplements (id.). 

Comments objecting to the Prevention 

survey said it provided no rationale for 

why CGMP requirements are needed. 

Other comments said the nine examples 

we provided represent a failure to 

conform to an existing regulation and do 

not demonstrate a need for a new CGMP 

regulation for dietary supplements. One 

comment disagrees that the CGMP 

requirements would prevent adverse 

reactions, as one example suggested in 

the preamble to the 2003 CGMP 

Proposal (see 68 FR 12157 at 12162) 

because, the comment claims, most 

adverse reactions are not the result of 

manufacturing problems. Another 

comment states the example involving 

plantain (68 FR 12157 at 12162), where 

a raw material was labeled as ‘‘plantain’’

when it was, in fact, Digitalis lanata (a 

plant that can cause life-threatening 

heart reactions), shows that, had there 

been a system in place to test finished 

product for purity and identity or to 

perform identity testing upon receipt, 

the manufacturer could have prevented 

that adulterated product from entering 

the market place. The comment states 

identity testing is necessary in the final 

rule. 

Another comment objects to the 

example of ‘‘non-food grade chemicals’’

(id.) because the reference supporting 

the example involved GammaButyrolactone, 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 


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3Mandatory reporting to FDA of serious adverse 

events is now required as a result of the enactment 

of the ‘‘Dietary Supplement and Non-Prescription 

Drug Consumer Protection Act’’ (Public Law 109–

462) signed into law on December 22, 2006 (see 

discussion in section XX of this document). 

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, and 10; 

see, also, 68 FR 12157 at 12162 through 

12163). These were all examples where 

products were manufactured, labeled, 

and sold to the consumer as dietary 

supplements. We disagree with the 

comments’ assertions that all these 

problems can be adequately dealt with 

by the food CGMP requirements in part 

110, but agree with the comment that, 

had there been a system in place ‘‘to 

perform identity testing upon receipt, 

the manufacturer could have prevented 

that adulterated product from entering 

the market place.’’ Most of these 

examples present situations in which 

the manufacturer could have identified 

these problems through the dietary 

supplement CGMP requirements for 

specifications and testing or 

examination, such as identity 

verification, and could have prevented 

such products from entering the market 

or at least provided a greater assurance 

that such products would not make it 

into the marketplace. The dietary 

supplement CGMP requirements ensure 

adequate controls are in place to 

identify many of these types of 

manufacturing errors before the product 

is in the marketplace and not through 

postmarketing adverse event reports or 

consumers’ illnesses.3

The dietary supplement industry is 

diverse, as are the number and types of 

products marketed as dietary 

supplements. As we stated in the 

preamble to the 2003 CGMP Proposal 

(68 FR 12157 at 12163), given the wide 

range of public health concerns 

presented by the manufacturing 

practices for dietary supplements, a 

comprehensive system of controls is 

necessary. This final rule will set the 

standards for CGMP for dietary 

supplements that, if followed, will help 

ensure the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. The establishment of production 

and process controls and adherence to 

these and other CGMP requirements of 

this final rule will help to prevent the 

types of events (and others) we 

described in the nine examples 

presented in the preamble to the 2003 

CGMP Proposal. 

(Comment 6) Several comments 

suggest that dietary supplements are no 

different in safety or physiologic effect 

and require no different requirements 

than conventional food with respect to 

CGMP. One comment disagrees with us 

that dietary supplements require 

different requirements than 

conventional food because dietary 

supplements are ground up or in 

powder form and may not be easily 

recognized or differentiated; the 

comment says the same is true of many 

food ingredients as well. 

(Response) We disagree with the 

suggestions by these comments that 

dietary supplement CGMP requirements 

need not differ from those for 

conventional foods. By definition, a 

dietary supplement is in a category of 

food separate and distinct from the 

category of conventional food. The 

definition of dietary supplement in 

section 201(ff) of the act, in part, 

essentially describes a dietary 

supplement as a type of food that differs 

from conventional food. The definition 

refers to section 411(c)(1)(B)(i) and 

(c)(1)(B)(ii) of the act (21 U.S.C. 

350(c)(1)(B)(i) and (c)(1)(B)(ii)), which 

describes the forms that dietary 

supplements intended to be ingested 

may take, i.e., tablet, capsule, powder, 

softgel, gelcap, or liquid form, and if not 

in such a form, limitations on how 

dietary supplements can be represented, 

i.e., not as conventional food or as a sole 

item of a meal or the diet. 

Congress included separate additional 

provisions under section 402 of the act 

(see section 402(f) and (g) of the act) for 

when a dietary supplement may be 

adulterated. Congress considered that 

dietary supplements may warrant CGMP 

requirements that are different than 

those for conventional food. Although 

dietary supplements may include 

substances that are used as ingredients 

in conventional foods, the amounts 

consumed as a dietary supplement and 

as a conventional food product may not 

be the same and, in fact, may be more 

concentrated, and in higher amounts, 

when taken as a dietary supplement. 

The forms in which dietary 

supplements are consumed differ (e.g., 

capsule, tablet), as may the frequency, 

when compared to conventional foods. 

The uses of dietary supplements also 

differ from use as conventional food. 

Consequently certain manufacturing 

practices considered to be a part of 

CGMP for dietary supplement 

manufacturing may not be necessary for 

all types of food. 

C. What Comments Did We Receive on 

Written Procedures? 

1. Overview 

In the 2003 CGMP Proposal (68 FR 

12157 at 12165), we stated that written 

procedures were included in the dietary 

supplement CGMP outline submitted to 

us by industry, namely, the National 

Nutritional Foods Association standards 

(NNFA), the NSF International draft 

standards, and the United States 

Pharmacopoeia (USP) draft 

manufacturing practices. We also stated 

that, to limit the burden to 

manufacturers, we were not proposing 

to require written procedures for all the 

requirements. We invited comment on 

whether we should require written 

procedures for a variety of operations; 

specifically, for complying with the 

CGMP requirements, under proposed 

§ 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 


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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 wellrecognized quality systems require 

establishment of written procedures to 

ensure consistent process control, and 

cites examples such as the International 

Organization for Standardization, the 

American National Standards Institute 

(ANSI), and the Malcolm Baldridge 

National Quality Award criteria. Other 

comments state that written procedures 

are necessary for the definition, 

operation, and documentation of a 

process control system, and that without 

such procedures it would be virtually 

impossible for any company, regardless 

of size, to consistently manufacture 

products that meet established 

requirements for identity, purity, 

quality, strength, and composition. The 

comments note that written procedures 

contain the necessary instructions for all 

employees to successfully execute their 

respective functions. Another comment 

supports a requirement for conducting 

key operations using written procedures 

and states that records document that 

operations were performed, but that 

written procedures show how the task is 

to be performed and at what frequency 

it should be performed. One comment 

states effective communication is 

essential to build quality into a process, 

and written procedures provide that 

throughout all levels of an organization. 

Another comment states it is difficult to 

imagine how the quality control unit 

could carry out its obligations under 

proposed § 111.37(b)(1) to ‘‘approve or 

reject all processes, specifications, 

controls, tests, and examinations, and 

deviations from or modifications to 

them * * *’’ if these are not subject to 

written procedures. 

Many comments which present one or 

more of these general reasons for 

requiring written procedures also list 

operations that they believe should be 

conducted using written procedures. 

The operations that one or more 

comments list as key operations are: 

• 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, inprocess 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 crosscontamination. Another comment states 

utility areas such as effluent treatment, 

boilers, cooling towers, and water 


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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 mixups and adulterations will be 

more likely to occur if there are no 

written procedures for control of storage 

locations, manner of storage, and 

container and storage location 

identification codes. 

In response to our request for 

comment on whether written 

procedures should be required for 

complying with the proposed 

requirements for returned dietary 

supplements, one comment states 

written procedures should govern all 

return and salvage operations to create 

a standard for quarantine and salvage 

and to establish parameters for proper 

salvage conditions. 

Responding to our request for 

comment on whether written 

procedures should be required for 

complying with the proposed 

requirements for handling consumer 

complaints, some comments state 

written procedures will encourage 

companies to handle consumer 

complaints in a uniform manner. One 

comment asserts written procedures 

should be required for handling 

consumer complaints because some 

complaints could relate to serious 

illness or injury. The comment states 

that written procedures would set out 

exactly what steps need to be taken 

when complaints are reviewed, and are 

the best way to ensure the essential 

information is captured. 

(Response) We agree with the 

comments that effective process control, 

using written procedures, is an 

important aspect of a successful CGMP 

program. We also agree requiring 

written procedures will help to ensure 

consistent practices in operations i.e., 

help to ensure the operation is 

conducted in the same manner 

regardless of who conducts the 

operation or when the operation is 

conducted. We also agree that written 

procedures provide a sound basis for 

employee training and supervision, are 

an effective communication tool, and 

enable quality control personnel to carry 

out the responsibility to approve or 

reject all processes, specifications, 

controls, tests, and examinations, and 

deviations from or modifications to 

them. In addition, written procedures 

establish expectations for each covered 

operation so the operation does not 

proceed in an ad-hoc manner. Written 

procedures provide specific guidance if 

there is an unanticipated occurrence 

and, thus, can play a key role in 

ensuring a quality product, because 

actions to correct the unanticipated 

occurrence can take place swiftly and 

with confidence in the outcome. 

This final rule establishes the 

minimum CGMPs necessary for 

activities related to manufacturing, 

packaging, labeling, and holding dietary 

supplements to ensure a quality 


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product. The operations required by this 

final rule must be conducted in a 

consistent manner, regardless of who is 

conducting an operation or when the 

operation is conducted. As discussed in 

the following paragraphs, with a few 

exceptions, we are requiring that you 

establish and follow written procedures 

to fulfill the requirements for the 

operations covered by this final rule. 

The exceptions include final subpart A, 

which addresses the scope of the rule, 

rather than operations covered by the 

rule; final subparts E, H, and I, in which 

we conclude that a requirement for 

written procedures would be redundant 

to other requirements; and final subpart 

P, which establishes requirements for 

making and keeping records, rather than 

for conducting operations. 

We believe requiring you to establish 

and follow written procedures to fulfill 

the requirements of subparts B through 

D, F, G, and J through O, when 

combined with other requirements of 

this final rule, justifies reduced 

requirements for testing finished 

batches of product compared to the 

proposed requirements for such testing 

as found in proposed § 111.35. By 

establishing and following written 

procedures, you will focus your 

production and process control system 

on ensuring the quality of the finished 

product at each stage in the production 

process, rather than relying entirely on 

testing at the end of the process. 

2. Written Procedures That Are 

Required by This Final Rule 

a. Written procedures for personnel 

(final subpart B). We believe that 

successful programs for process control 

are directly connected to appropriate 

training programs. Employee training 

must be conducted in a consistent 

manner, regardless of who conducts the 

training or when it is conducted. Failure 

to conduct employee training in a 

consistent manner could lead to a 

failure in ensuring product quality. For 

example, an employee who has not 

received appropriate training on how to 

conduct a specific physical examination 

to verify the identity of a dietary 

ingredient may erroneously report that 

the correct ingredient was received 

when, in fact, the received dietary 

ingredient is related to, but different 

from, the ingredient that is specified in 

the master manufacturing record. 

We also believe the requirements that 

apply to preventing microbial 

contamination due to sick or infected 

personnel and that apply to proper 

hygienic practices must be conducted in 

a consistent manner. For example, it is 

well known that foodborne illness can 

be transmitted by workers who are sick. 

For example, volunteer food workers at 

an outdoor music festival were found to 

be the source of contamination for an 

outbreak of Shigellosis (Ref. 11). 

We include in final subpart B a 

requirement (final § 111.8) that you 

establish and follow written procedures 

for fulfilling the requirements of subpart 

B. 

b. Written procedures for cleaning the 

physical plant, including pest control 

(final subpart C). We agree with the 

comments that written procedures for 

cleaning the physical plant would 

reduce the potential for crosscontamination 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). 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). 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 


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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 of this 

document, the final rule requires you to 

establish and meet specifications for the 

identity, purity, strength, and 

composition of dietary supplements and 

for limits on contamination for dietary 

supplements that you manufacture. 

When considering the specifications 

you must establish to ensure the quality 

of the dietary supplements, you must 

take into account the need to ensure that 

components or dietary supplements are 

not contaminated as a result of using the 

same equipment. Such equipment could 

be a source of contamination if more 

than one product is manufactured using 

the equipment and it is not properly 

cleaned and/or sanitized. 

e. Written procedures for quality 

control operations, including written 

procedures for conducting a material 

review and making a disposition 

decision and written procedures for 

approving or rejecting reprocessing 

(final subpart F). Quality control 

operations must be conducted in a 

consistent manner. Failure to carry out 

quality control operations in a 

consistent and appropriate way could 

lead to failure to ensure product quality 

and to ensure the dietary supplement is 

packaged and labeled as specified in the 

master manufacturing record. For 

example, you could use a component 

that should not have been released for 

use in manufacturing, or you could 

distribute a packaged and labeled 

dietary supplement that should not have 

been released for distribution. 

We include in final subpart F a 

requirement that you establish and 

follow written procedures for quality 

control operations (final § 111.103). We 

agree with the comments that there 

should be written procedures for 

investigating failures in manufacturing 

operations. In the 2003 CGMP Proposal, 

we referred to the process of 

investigating such failures as a ‘‘material 

review’’ and proposed a series of 

requirements related to a material 

review and the disposition decision that 

follows a material review. The review 

must be conducted in a consistent 

manner, and the criteria for making a 

disposition decision must be consistent, 

regardless of who is conducting the 

material review or when it is conducted, 

and regardless of who makes the 

disposition decision and when the 

decision is made. For example, if you do 

not have written criteria for determining 

whether a deviation from specifications 

has resulted in, or could lead to, 

adulteration, different individuals who 

conduct a material review could reach 

different decisions regarding the 

appropriate disposition of the affected 

dietary supplement, including decisions 

that incorrectly result in the release of 

an adulterated product. As discussed 

more fully in sections X and XI of this 

document, the final rule requires that 

quality control personnel conduct all 

required material reviews and make all 

required disposition decisions. 

Therefore, we are requiring that the 

written procedures for quality control 

operations include written procedures 

for conducting a material review and 

making a disposition decision (final 

§ 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). 

We agree with the comments that the 


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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). 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). 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). We agree with the comments that 

written procedures for packaging and 

labeling operations are an effective 

means to hold operators accountable to 

ensure the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. The final provisions for 

packaging and labeling operations 

require that you fill, assemble, package, 

label, and perform other related 

operations in a way that ensures the 

quality of the finished product, 

including practices such as cleaning and 

sanitizing all filling and packaging 

equipment, utensils, and containers; 

protecting manufactured dietary 

supplements against airborne 

contamination, using sanitary handling 

procedures; taking actions to prevent 

mixups; and suitably disposing of 

obsolete packaging and labels. These 

packaging and labeling operations must 

be conducted in a consistent manner, 

regardless of who conducts the 

operation or when it is conducted. 

Failure to perform these operations in a 

consistent way could lead to a failure to 

ensure the quality of the dietary 

supplement and that the dietary 

supplement is labeled and packaged as 

specified in the master manufacturing 

record. For example, if you do not have 

procedures for identifying filled, but 

unlabeled, containers of dietary 

supplements, mixups could occur 

before the labels are applied. The final 

product could contain ingredients other 

than those identified on the label 

specified in the master manufacturing 

record. Therefore, we include in final 

subpart L a requirement that you 

establish and follow written procedures 

for packaging and labeling operations 

(final § 111.403). 

j. Written procedures for holding and 

distributing operations (final subpart 

M). We agree with the comments that 

written procedures for holding and 

distributing operations are an effective 

means to hold operators accountable to 

CGMP standards, and that mixups and 

other problems that affect the final 

product will be more likely to occur if 

there are no written procedures for 

operations such as control of storage 

locations, manner of storage, and 

container and storage location 

identification codes. The final 

provisions for holding and distributing 

operations require, among other things, 

that you hold components and dietary 

supplements under appropriate 

conditions of temperature, humidity, 

and light so that the identity, purity, 

strength, and composition of the 

components and dietary supplements 

are not affected; that you hold 

components, dietary supplements, and 

in-process materials under conditions 

that do not lead to the mixup, 

contamination, or deterioration of 

components or dietary supplements; 

and that you distribute dietary 

supplements under conditions that will 

protect them against contamination and 

deterioration. 

These holding and distributing 

operations must be conducted in a 

consistent manner, regardless of who 

conducts the operation or when it is 

conducted. Failure to follow these 

requirements for holding and 

distributing in a consistent manner 

could lead to a failure to ensure the 

quality of the dietary supplement 

product. For example, if employees do 

not know how to store an in-process 

batch of a botanical dietary supplement 

to control humidity, the growth of mold 

could be promoted. Furthermore, if a 

distributor does not refrigerate a dietary 

supplement that requires refrigeration to 

ensure its strength, the dietary 

supplement may not meet its 

specification for strength. Therefore, we 

include in final subpart M a 

requirement that you establish and 

follow written procedures for holding 


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and distributing operations (final 

§ 111.453). 

k. Written procedures for returned 

dietary supplements (final subpart N). 

We agree with the comments that 

written procedures for returned dietary 

supplements would help to ensure 

appropriate handling of such 

supplements prior to a disposition 

decision. The final rule requires you, 

among other things, to identify and 

quarantine returned dietary 

supplements until quality control 

personnel conduct a material review 

and make a disposition decision. You 

must destroy, or otherwise suitably 

dispose of, any returned dietary 

supplement that quality control 

personnel do not approve for salvage or 

reprocessing. These operations for 

returned dietary supplements must be 

conducted in a consistent manner, 

regardless of who conducts the 

operation or when it is conducted. 

Failure to comply with these 

requirements for quarantine, salvage, 

and disposition in a consistent way 

could lead to a failure to ensure the 

quality of the dietary supplement. For 

example, if an investigation leads to a 

conclusion that a dietary supplement 

requiring refrigeration to ensure its 

strength was not refrigerated while held 

at a customer’s warehouse, and this 

dietary supplement was not quarantined 

while quality control personnel 

conducted a material review, the dietary 

supplement could be inadvertently comixed 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). 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 

a. Written procedures for final subpart 

E (‘‘Requirement to Establish a 

Production and Process Control 

System’’). In the CGMP proposal, we did 

not specifically request comments on 

whether we should require that you 

establish and follow written procedures 

to fulfill the requirements of proposed 

§ 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 


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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). As discussed in 

the 2003 CGMP Proposal (68 FR 12157 

at 12203), a master manufacturing 

record is analogous to a recipe that sets 

forth the ingredients to use, the amounts 

of ingredients to use, the tests to 

perform, and the instructions for 

preparing the quantity the recipe calls 

for. This master manufacturing record 

helps ensure that you manufacture each 

ingredient or dietary supplement in a 

consistent and uniform manner. If you 

neglect to follow the master 

manufacturing record, you might not 

add all of the necessary components in 

the appropriate strength or amount, and 

this could result in a final product not 

consistent with the master 

manufacturing record. Thus, you must 

follow a written master manufacturing 

record in a consistent manner, 

regardless of who conducts the 

operation or when it is conducted. 

However, we agree with the 

comments that the specific requirements 

for what must be in the master 

manufacturing record make it 

unnecessary to require written 

procedures for preparing the master 

manufacturing record. Under final 

subpart H, the master manufacturing 

record must include written 

instructions, including specifications for 

each point, step, or stage in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record; procedures for sampling, testing, 

and examinations; specific actions 

necessary to perform and verify points, 

steps, or stages in the manufacturing 

process where control is necessary to 

ensure the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record; special notations and 

precautions to be followed; and 

corrective action plans for use when a 

specification is not met. With all of this 

detail specified for the written 

instructions the master manufacturing 

record must include, we believe a 

written procedure for developing a 

master manufacturing record can be 

optional. Therefore, we do not require 

you to establish and follow written 

procedures for preparing the master 

manufacturing record. 

A batch is prepared by following the 

written instructions provided in the 

master manufacturing record. The 

master manufacturing record functions 

as a written procedure for the 

production of the batch. Therefore, we 

do not require you to establish and 

follow written procedures for the batch 

production record because such 

practices would be redundant to the 

requirements for the master 

manufacturing record in final subpart H. 

c. Written procedures for records and 

recordkeeping (final subpart P). Final 

subpart P establishes general 

requirements for making and keeping 

records required in other subparts. We 

did not request comments on written 

procedures, nor did we receive any 

comments that supported such a 

requirement. Because we believe that 

requiring written procedures to fulfill 

subpart P requirements would be 

redundant or unnecessary, we do not 

require such written procedures. 

d. Written procedures for product 

recalls. We acknowledge that a product 

recall by persons who manufacture, 

package, label, or hold dietary 

supplements must be conducted in a 

consistent manner, regardless of who 

conducts the operation or when it is 

conducted. However, the final rule does 

not establish any requirements for 

product recalls. Therefore, we do not 

require you to establish and follow 

written procedures for product recalls. 

However, we encourage you to refer to 

our ‘‘Guidance for Industry: Product 

Recalls, Industry Removals and 

Corrections’’ (Ref. 12) (available at 

http://www.fda.gov/opacom/ 

7alerts.html). 

D. Other Comments on Written 

Procedures 

(Comment 9) One comment stresses 

the need for flexibility in requiring 

written procedures, based on differences 

between individual activities and 

companies. The comment suggests 

companies should be required to review 

and determine the need for written 

procedures at each critical step of their 

operations and be prepared to defend 

those determinations as necessary. 

(Response) To the extent the comment 

suggests we do not require any written 

procedures specific to a particular 

function or requirement, and allow 

firms to decide when and when not to 

include them, we disagree. We believe 

that written procedures for the specific 

operations we have identified should 

not be optional. We have no objection 

if firms decide to establish and follow 

additional written procedures, beyond 

those we require in this final rule. 

Although we require written procedures 

for entire subparts, or specific 

requirements within certain subparts, 

we provide flexibility for firms to 

establish those written procedures that 

will ensure the requirements are met. 

(Comment 10) Some comments stress 

the importance of written procedures in 

enabling FDA to ensure compliance 

with the dietary supplement CGMP 

requirements. 

(Response) We believe written 

procedures will help us to ensure 

compliance with these CGMP 

requirements because they will clearly 

communicate the steps the firm must 

take to satisfy the requirements. During 

an inspection, we observe the practices 

that employees follow. However, to 

ensure that a firm is consistently 

complying with CGMP requirements, 

our investigators need access to records 

that both describe a firm’s processes and 

procedures and demonstrate whether 

the firm has been following them. Under 

the final rule, we require you to make 

and keep records of the written 

procedures in each applicable subpart. 

Such records would be available to us 

under the requirements of final subpart 

P, Records and Recordkeeping. 

(Comment 11) Many comments object 

to FDA’s stated reasons for not requiring 

written procedures for most activities, 

including concerns about cost control 

and burden reduction. The comments 

contend that written procedures 


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actually save time and other resources 

because they greatly facilitate employee 

training and ensure that activities are 

performed consistently and correctly. 

Some comments assert most companies 

already have written procedures in 

place, so start-up costs associated with 

such requirements would be minimal. 

One comment notes written procedures 

would be among the least costly of all 

the procedural requirements proposed 

by FDA. 

(Response) We agree that requiring 

that operations be conducted using 

written procedures can save time and 

other resources by facilitating employee 

training and ensuring operations are 

performed consistently and correctly. 

Because following written procedures 

can help ensure uniformity in the 

process and ensure the quality of the 

dietary supplement at every step, 

periodic end product testing can be 

sufficient to determine whether your 

manufacturing process is controlled. 

CGMP is premised upon quality 

assurance at every step of the process. 

It is less costly to establish and follow 

written procedures than it would be to 

test each finished batch for conformance 

with specifications. As suggested by 

these comments, our analysis (section 

XXIV of this document) shows that the 

overall costs are reduced, in part, 

because requiring that certain 

operations be conducted using written 

procedures enables us to reduce 

requirements for testing at the finished 

batch stage. 

(Comment 12) One comment states 

training employees on the required 

hygienic practices prior to their first day 

of handling product is critical to 

ensuring product safety. 

(Response) The requirement to 

establish and follow written procedures 

to fulfill the requirements of subpart B 

does not establish any fixed requirement 

for when an employee must receive 

such training relative to when the 

employee handles product. However, 

final § 111.12(c) requires that any 

person engaged in manufacturing, 

packaging, labeling, or holding, or in 

performing any quality control 

operations, must have the education, 

training, or experience to perform the 

person’s assigned functions. We 

therefore assume that employees will 

have the necessary education, training, 

or experience for each operation that 

they perform before they perform it. 

(Comment 13) Some comments make 

recommendations for what written 

procedures should contain, including 

general parameters that should be 

included in all written procedures and 

specific parameters that should be 

included in specific written procedures. 

The general parameters include 

identification of the company; title that 

reflects the activities to be performed; 

identification or control number with a 

revision level code; effective date; the 

number of pages in the procedure (e.g., 

by a procedure such as listing page 

numbers using a convention such as 

‘‘page 1 of 4’’); approval date and 

signature(s); references to linked or 

related procedures or forms; definitions 

of technical terms and acronyms; list of 

equipment, materials, and supplies 

needed in performing the task; who has 

the responsibility for performing each 

task; when and where a task is to be 

performed; concise step-by-step 

instructions for performing the task; the 

expected results from performing the 

task; what data to collect; and how to 

analyze, file, or report the collected 

data. In the specific case of written 

procedures for cleaning equipment and 

utensils, some comments suggest the 

written procedures include descriptions 

of appropriate cleaning agents, methods 

of cleaning, and the intervals and 

schedules for cleaning equipment. 

(Response) We agree the suggestions 

provided by these comments are useful 

to include in any written procedures. 

However, to provide the flexibility 

necessary to address diverse dietary 

supplement manufacturing processes, 

we are leaving details such as these to 

the judgment of the company rather 

than prescribing them within the final 

rule. 

(Comment 14) Some comments 

request the final rule include 

requirements for managing changes to 

written procedures. One comment states 

changes to written procedures should be 

reviewed, justified, documented, 

approved, and implemented in a 

defined manner. The comments explain 

that ‘‘Change control procedures’’ define 

what is and what is not covered by the 

written procedure and how proposed 

changes will be identified or 

recommended, processed, reviewed, 

and approved. 

(Response) As discussed in final 

subpart F, the final rule requires that 

quality control personnel approve all 

written procedures. ‘‘All’’ written 

procedures includes revisions to written 

procedures. As discussed in this 

section, the final rule requires you to 

establish and follow written procedures 

for quality control operations. We 

believe that procedures for managing 

changes to written procedures can be 

addressed within the written procedures 

for quality control operations. 

(Comment 15) Some comments assert 

the final rule should not require written 

procedures for key operations because 

the rule should stay focused on end 

results and not process. 

(Response) We disagree. The essence 

of good manufacturing practice that is 

established by this final rule is a 

production and process control system 

that is designed to ensure the quality of 

the dietary supplement. 

E. What Other General Comments Did 

We Receive? 

(Comment 16) Some comments say 

any final rule should not require written 

procedures, should not propose a 

definition of appropriate tests, and 

generally should not include 

requirements for procedures better left 

to ‘‘normal business practices.’’ The 

comments cited Executive Order 12866 

and the Small Business Regulatory 

Enforcement Flexibility Act (SBREFA). 

The comment added that there is no 

such requirement in the food CGMPs or 

in the 1997 ANPRM. 

(Response) We disagree the final rule 

violates either Executive Order 12866 or 

SBREFA and discuss this in section 

XXIV of this document. We address 

SBREFA’s regulatory flexibility issues 

by staggering compliance dates so that 

certain businesses would have 24 and 

36 months, respectively, to comply with 

the final rule. As for the assertion that 

food CGMPs do not require written 

procedures, we discuss the 

requirements of food CGMPS in relation 

to the requirements of these dietary 

supplement CGMPs in section V of this 

document. The comment’s assertion that 

the 1997 ANPRM did not contain 

written procedures is incorrect. The 

industry draft that we published in the 

1997 ANPRM had multiple written 

procedures, including written 

procedures for: 

• 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; 


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• 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 5700 at 5704 through 5706). 

(Comment 17) In the analysis of 

impacts in the 2003 CGMP Proposal (68 

FR 12157 at 12222), we stated that we 

had considered imposing fewer CGMP 

requirements for the manufacture of 

vitamins and minerals. Although this 

issue arose as a discussion of regulatory 

options that we had considered and 

rejected, we received several comments 

on this subject. Some comments state 

we should not create different CGMP 

standards based upon the type of dietary 

ingredient. These comments state that 

one set of appropriately flexible 

standards would be more efficient and 

less confusing to industry than separate 

standards for each portion of the 

industry. Some comments say that 

different requirements for vitamins and 

minerals would cause problems because 

most people who use these products 

take a multivitamin/mineral preparation 

as their primary and sole dietary 

supplement, so the risk of adverse 

events arising from adulteration, 

misidentification, or misformulation of 

products would be much higher if 

vitamins and minerals were subject to 

fewer requirements compared to other 

dietary supplements. Other comments 

supported the concept of differing 

standards. Some comments assert, in 

order for the CGMP regulations to set 

minimum quality standards for all 

dietary supplements, we would have to 

regulate each facet of the manufacture, 

packaging, and storage of a dietary 

supplement independently of product 

type. These comments state reducing 

the requirements for vitamin and 

mineral manufacturers would not allow 

the development of minimum quality 

standards across the entire dietary 

supplement industry. 

(Response) The concept of fewer 

requirements for vitamins and minerals 

was simply one regulatory option we 

considered as part of the 2003 CGMP 

Proposal’s analysis of impacts (see 68 

FR 12157 at 12220 through 12223). We 

rejected it (id.). We disagree with the 

comments that there should be fewer 

CGMP requirements for vitamins and 

minerals. Neither the 2003 CGMP 

Proposal, nor this final rule, imposes 

fewer requirements on vitamin or 

mineral firms compared to firms that 

make other types of dietary 

supplements. 

V. What Legal Authority Comments Did 

We Receive? 

Many comments were submitted from 

individuals, companies, and trade 

groups concerning our legal authority 

for this rule. Most of the comments 

question the scope of the rule based on 

the language in section 402(g) of the act 

(21 U.S.C. 342(g)) stating that 

‘‘regulations shall be modeled after 

current good manufacturing practice 

regulations for food.’’ Other comments 

question our authority for records 

access. Some comments assert that 

certain provisions of the proposed rule 

are unconstitutionally vague, and 

therefore violate the Fifth Amendment. 

A few comments disagree with our 

rationale for why dietary supplements 

are different than conventional food and 

need separate CGMP requirements. We 

address these comments immediately 

below in this section. 

A. Modeled After CGMP for Food 

(Comment 18) Some comments 

support our approach of proposing 

requirements that are more 

comprehensive than the CGMP 

requirements for food. One comment 

states that the current requirements for 

food CGMP are less comprehensive than 

the CGMP requirements in current use 

by both the food and dietary 

supplement industries and the current 

‘‘best practices’’ should be incorporated 

into the dietary supplement CGMP rule. 

Several comments state that the 

requirements for dietary supplement 

CGMP do not need to be identical to the 

requirements in existing food CGMP 

regulations, that appropriate 

manufacturing controls are needed for 

dietary ingredients contained in dietary 

supplements to protect the public 

health, that some borrowing of drug 

CGMP concepts may be necessary, and 

that we should balance effective control 

with necessary flexibility in the dietary 

supplement CGMP rule. In addition, one 

comment states that the USP 

manufacturing guidelines, which 

contain wording from the drug CGMP 

requirements, are a model for dietary 

supplement CGMP for many in 

industry. 

Several comments express concern 

about not deviating too drastically from 

the requirements in existing food CGMP 

regulations. Although several comments 

recognize that additional CGMP 

provisions for dietary supplements, 

such as those related to identity, purity, 

strength, quality, and composition, are 

needed, the comments say that we 

should not regulate dietary supplement 

manufacturing in the same manner as 

drug manufacturing because it would 

entail overly burdensome methods for 

production and process controls. Some 

comments contend that some of the 

proposed rule requirements exceed the 

drug CGMP requirements. 

Most of the comments assert that the 

proposed dietary supplement CGMP 

requirements are not modeled after the 

CGMP regulations for food. The reasons 

for this assertion vary. Some assert that 

certain provisions in the proposed rule 

were not found in, or differ from, the 

provisions in part 110. Examples of 

proposed requirements that comments 

indicate exceeded food CGMP included 

batch testing, packaging and labeling, 

recordkeeping, consumer complaints, 

and the use of validated methods. Other 

comments state that the proposed 

requirements exceeded those for food 

because the proposed rule provided for 

finished testing of certain substances 

when used as dietary supplements, such 

as garlic and ginger, whereas no such 

testing is required under existing food 

CGMP regulations when those same 

substances are used as conventional 

food. One comment says the rule was 

modeled after juice hazard analysis and 

critical control point (HACCP) and 

therefore goes beyond existing food 

CGMP regulations. 

Some comments assert that the 

proposed requirements exceed the 

existing food CGMP regulations because 

certain proposed provisions contained a 

level of detail that is not in the food or 

the drug CGMP regulations, or because 

elements of a provision in the proposed 

rule were similar to a provision in part 

210 (21 CFR part 210) (drug CGMP 

regulation). Other comments disagree 

with our rationale that the proposed 

rule was designed on the same 

principles as the existing food CGMP 

regulations to address the characteristics 

and hazards specific to dietary 

supplements, or to prevent adulteration 

in preparing, packaging, or holding 

dietary supplements. The comments 

also disagree that we may include 

provisions in the dietary supplement 

CGMP final rule that were not found in 

the food CGMP regulations at the time 

DSHEA was enacted. 

Several comments state that we 

exceed our legal authority for the 

proposed rule because it used too broad 

a definition of ‘‘modeled after.’’ Some 

comments offer their own definitions of 

‘‘model;’’ others object to the use of the 

noun form ‘‘model’’ and provide 

dictionary definitions of the verb form 

‘‘modeled.’’ A few comments assert that 

the meaning of ‘‘model’’ is clear, despite 

different dictionary meanings, and that 

the statute is not ambiguous under 

Chevron U.S.A. Inc. v. Natural 

Resources Defense Council, 467 U.S. 


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4The 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’’). 

837 (1984) (‘‘Chevron’’). One comment 

states that, even if the language is 

ambiguous and our interpretation merits 

deference, our interpretation is too 

expansive and not based on a 

permissible construction of the statute. 

Another comment states that we did not 

explain why our interpretation was 

consistent with our congressional 

mandate. 

(Response) We agree with the 

comments stating that the dietary 

supplement CGMP requirements in this 

final rule need not be identical to the 

existing food CGMP regulations and that 

a system of manufacturing controls 

specific to dietary supplements is 

needed. We do not agree that we 

exceeded the scope of our authority 

under section 402(g) of the act in issuing 

the proposed requirements for dietary 

supplement CGMP or these final 

requirements. Our interpretation of the 

language in section 402(g) of the act, 

including the ‘‘modeled after’’ language, 

as to what requirements of the act we 

have authority to issue, is based on a 

permissible construction of the statute. 

The comments present the following 

general questions: (1) Whether the 

statute gives us authority to promulgate 

CGMP requirements for dietary 

supplements that are not identical to the 

requirements in existing CGMP 

regulations for food and (2) if so, 

whether the requirements in this final 

rule that differ from those in existing 

CGMP regulations for food are fairly 

encompassed within Congress’ direction 

that the dietary supplement regulations 

shall be ‘‘modeled after’’ food 

regulations and, therefore, are based on 

a permissible construction of the statute. 

Under section 402(g)(1) of the act, a 

dietary supplement is deemed to be 

adulterated if it has ‘‘been prepared, 

packed, or held under conditions that 

do not meet current good manufacturing 

practice regulations, including 

regulations requiring, when necessary, 

expiration date labeling, issued by the 

Secretary under subparagraph (2).’’

Section 402(g)(2) of the act authorizes 

the Secretary, by regulation, to 

‘‘prescribe good manufacturing practices 

for dietary supplements.’’ Congress 

further provided that such regulations 

‘‘shall be modeled after current good 

manufacturing practice regulations for 

food’’ and ‘‘may not impose standards 

for which there is no current and 

generally available analytical 

methodology.’’

In construing the meaning of section 

402(g) of the act, and, in particular, the 

language in that section stating that 

such regulations shall be ‘‘modeled after 

current good manufacturing practice 

regulations for food,’’ we are confronted 

with two questions. First, has Congress 

directly and unambiguously spoken to 

the precise question at issue? (‘‘Chevron 

step one’’) (see Chevron, 467 U.S. at 

842.) To find no ambiguity, Congress 

must have clearly manifested its 

intention with respect to the particular 

issue (see Young v. Community 

Nutrition Institute, 476 U.S. 974, 980 

(1986)). If Congress has spoken directly 

and plainly, we must implement 

Congress’s unambiguously expressed 

intent (see Chevron, 467 U.S. at 842–

843). Second, if the act is silent or 

ambiguous with respect to a particular 

issue in section 402(g) of the act, is our 

interpretation based on a permissible 

construction of the statute (‘‘Chevron 

step two’’) (Chevron, 467 U.S. at 843; 

FDA v. Brown & Williamson Tobacco 

Corp., 529 U.S. 120, 132 (2000))? When 

Congress leaves a gap for the agency to 

fill by regulation, the regulation will 

pass muster so long as it is not 

‘‘arbitrary, capricious, or manifestly 

contrary to the statute’’ (Chevron, 467 

U.S. at 843–844). 

We believe that the language in 

section 402(g) of the act provides an 

express delegation of authority to us to 

promulgate a regulation to ‘‘prescribe 

good manufacturing practices for dietary 

supplements’’ so long as those 

regulations are ‘‘modeled after the 

current good manufacturing practice 

regulations for food.’’ The express 

language in section 402(g) of the act 

contemplates broad, but not unlimited, 

agency discretion as to what to include 

in a dietary supplement CGMP 

regulation. 

Congress has also spoken to the 

precise question of whether the dietary 

supplement CGMP requirements must 

be identical to the requirements in 

existing food CGMP regulations. If 

Congress had wanted dietary 

supplement CGMP to be identical to 

food CGMP, it easily could have 

required that by statute. Indeed, if 

Congress had intended for CGMPs for 

dietary supplements to be the same as 

food CGMPs, there would have been no 

need for Congress to have addressed the 

issue at all; as a type of food, dietary 

supplements would otherwise be 

governed by the food CGMPs. See 

section (ff) of the act (21 U.S.C. 321(ff)). 

Instead, the statute calls for us to issue 

regulations that are ‘‘modeled after’’

CGMP regulations for food. The plain 

meaning of a ‘‘model’’ or ‘‘modeled 

after,’’ as discussed in the 2003 CGMP 

Proposal (68 FR 12157 at 12165) and in 

the comments, relates to a pattern, plan, 

representation, or simulation. The use of 

the term ‘‘modeled after’’ makes it clear 

that the regulations need not be 

identical to the original, but instead are 

contemplated to differ from the original. 

Thus, the additional, independent 

authority to promulgate CGMP 

regulations for dietary supplements that 

Congress provided in section 402(g) of 

the act, without delineating what 

requirements such a regulation could or 

could not include, left us with 

considerable authority to fill in the gaps 

in ways that recognize the differences 

between dietary supplements and other 

foods that warrant different 

manufacturing controls. A contrary 

interpretation, as some comments 

suggested, that the ‘‘modeled after’’

language means the requirements for 

dietary supplement CGMP must be 

precisely found in current part 110, or 

other food CGMP regulations, would so 

narrowly circumscribe our discretion as 

to make it impossible to tailor the 

regulation to fit the products it is 

designed to address. Such an 

interpretation would lead to a rule that 

would ‘‘frustrate the success of the 

regulation undertaken by Congress’’

because it would not take into 

consideration the characteristics, 

hazards, and manufacturing practices 

specific to dietary supplements 

(American Trucking Ass’ns v. U.S., 344 

U.S. 298, 311 (1953)).4

Congress has also spoken to the 

precise question of which requirements 

CGMP ‘‘regulations for food.’’ The plain 

meaning of ‘‘regulations’’ is plural (more 

than one), and the plain meaning of 

‘‘food’’ is as Congress defined in section 

201(f) of the act, including articles 

‘‘used for food or drink.’’ At the time 

DSHEA was enacted, there were five 

food CGMP regulations: Those for infant 

formula (part 106), thermally processed 

low-acid canned food (part 113), 

acidified food (part 114), bottled water 

(part 129), and general food (part 110, 

often referred to as the ‘‘umbrella’’

regulations). All of these regulations 

appear in Subchapter B of Chapter 1 of 

Title 21 of the Code of Federal 

Regulations, entitled ‘‘Food for Human 

Consumption.’’ Nothing in the language 

of section 402(g) or elsewhere suggests 

that Congress meant to limit the term 

CGMP ‘‘regulations for food’’ to only the 

regulation in part 110. Thus, it is 


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consistent with our statutory authority 

for us to look to all of our food CGMP 

regulations—including infant formula, 

low-acid canned foods, acidified foods, 

and bottled water, as well as our general 

food CGMP regulations—after which to 

model our dietary supplement CGMP 

regulations. 

Congress has not spoken to the 

precise question of what specific 

requirements for dietary supplements 

may be imposed under the ‘‘shall be 

modeled after’’ language. Given this 

ambiguity, therefore, under Chevron 

step two, we may determine what 

requirements to include in this final 

rule for dietary supplement CGMP, 

provided that our interpretation is not 

arbitrary, capricious, or manifestly 

contrary to the statute (Chevron, 467 

U.S. at 844). 

Accordingly, we considered the types 

of requirements in the existing food 

CGMP regulations and used those as 

models for the dietary supplement 

CGMP requirements. We considered 

both the objectives and the means of 

achieving the objectives in the existing 

food CGMP regulations. These CGMP 

food regulations include those for infant 

formula (part 106), general food 

(‘‘umbrella’’ regulations) (part 110), 

thermally processed low-acid canned 

food (part 113), acidified food (part 

114), and bottled water (part 129). Each 

of these food CGMP regulations 

provides objectives and means upon 

which we modeled the dietary 

supplement CGMP regulations. Just as 

the precise requirements of the other 

food CGMP regulations are tailored to 

the particular characteristics and 

hazards of the foods and manufacturing 

processes being addressed, the dietary 

supplement CGMP requirements are 

also so tailored. 

For example, the infant formula 

CGMP regulation is intended to ensure 

that the ‘‘safety and nutritional 

potency’’ of a formula are ‘‘built into the 

manufacturing process’’ in order to 

establish a quality control system to 

make sure that infant formula products 

are properly manufactured (47 FR 17016 

at 17017, April 20, 1982). The specific 

criteria in the regulations apply in 

determining whether the infant formula 

meets the safety, quality, and nutrient 

requirements of the act (§ 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 inprocess 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 

§§ 111.95, 111.180(b)(2), 111.260(h), 

111.325(b)(2), and 111.365(d)). Also 

similar to the infant formula CGMP 

regulation, the dietary supplement 

CGMP final rule requires manufacturers 

to maintain procedures for handling 

complaints (final §§ 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 33238 at 33239, 

June 8, 1979). Promulgated primarily 

under the adulteration provisions of 

section 402(a)(3) and (a)(4) of the act, as 

well as section 361 of the Public Health 

Service Act (the PHS Act) (42 U.S.C. 

264), the umbrella CGMP food 

regulation requires a quality control 

operation whose main purpose is ‘‘to 

provide a systematic procedure for 

taking all actions necessary to prevent 

food from being adulterated within the 

meaning of the act’’ (51 FR 22458 at 

22461, June 19, 1986), as well as to 

prevent the spread of food-borne 

communicable diseases (44 FR 33239, 

June 8, 1979) (see § 110.5(a)). Part 110 

also ‘‘specifies requirements that must 

be met to produce safe and wholesome 

food’’ (51 FR 22461). These umbrella 

food CGMP requirements not only 

pertain to food safety, but also are 

‘‘concerned with contamination by filth 

or decomposition which may or may not 

raise safety concerns’’ (51 FR 22458 at 

22462). 

The detailed requirements of the 

umbrella food CGMP regulation 

accomplish these objectives through a 

variety of means. For example, there are 

specific personnel provisions requiring 

employees who may be sources of 

microbial contamination to be excluded 

from certain operations (§ 110.10(a)); 

persons working in contact with food, 

food-contact surfaces, and foodpackaging 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 


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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) and 113.83). 

Observations and measurements of 

certain operating conditions must be 

made and recorded at intervals of 

sufficient frequency to ensure that 

commercial sterility of the food product 

is being achieved (at least every hour) 

(§ 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 

microbiological contamination, the lowacid 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 1 year after the date of 

manufacturing and at a reasonably 

accessible location for another 2 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 hydrogen-ion 

concentration (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 


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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 

and 111.60(a)). Similarly, the ‘‘critical 

factors’’ required to be specified in the 

scheduled process for low-acid and 

acidified foods are akin to the 

‘‘specifications’’ that dietary 

supplement manufacturers must 

establish for certain points in the 

manufacturing process (final § 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 and 111.425); dietary 

supplements which have been 

reprocessed, treated, or which have had 

in-process adjustments must meet all 

established product specifications and 

be approved before release (final 

§ 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, 

and 111.103), and required written 

records (see, e.g., final §§ 111.14, 

111.23, 111.35, and 111.95) must be 

kept for 1 year past the shelf life date, 

if shelf life dating is used, or 2 years 

after the date of distribution of the last 

associated batch of dietary supplement 

(final § 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 32563, November 

26, 1973). The criteria in part 129, as 

well as in part 110, apply in 

determining whether the facilities, 

methods, practices, and controls used to 

process, bottle, hold, and ship bottled 

drinking water conform with good 

manufacturing practice ‘‘to assure that 

bottled drinking water is safe and that 

it has been processed, bottled, held, and 

transported under sanitary conditions’’

(§ 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 watercontact 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 (21 U.S.C. 348) (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 


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5Although the act does not define ‘‘current good 

manufacturing practice,’’ the term is used elsewhere 

in the statute (see, e.g., sections 501(a)(2)(B) (drug 

CGMP) and 520(f)(1)(A) of the act (device CGMP) 

(21 U.S.C. 351(a)(2)(B) and 21 U.S.C. 360j(f)(1)(A), 

respectively). Case law supports the agency’s view 

that ‘‘current’’ does not mean ‘‘actually prevailing 

manufacturing practice’’ in an industry and that 

such a practice need not be accepted by a majority 

of manufacturers (National Ass’n of Pharmaceutical 

Mfr’s v. Department of Health and Human Services, 

586 F. Supp. 740, 752 (S.D.N.Y. 1984)). 

Nevertheless, the requirements of this final rule 

embody current practices of many food and dietary 

supplement manufacturers, as reflected in the 

comments supporting the provisions of the 

proposed rule. 

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) and 111.365(c)). 

Precautions that must be taken to 

prevent contamination of components 

or dietary supplements include 

performing chemical, microbiological, 

or other testing (final § 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, July 9, 1996). The bottled water 

CGMP regulation embodies 

requirements for facilities, methods, 

practices, and controls used in 

processing, bottling, holding, and 

shipping of bottled water to ensure its 

safety and sanitary quality. 

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 (68 FR 

12157 at 12162 and 12163). These 

dietary supplement CGMP requirements 

will help to protect consumers against 

similar types of adulteration and against 

reliance on products that are not 

properly formulated. 

Generally recognized principles 

underlying CGMP also support our 

interpretation of section 402(g) of the 

act. Our interpretation of permissible 

CGMP regulations is reasonable based 

on recognized principles for controlling 

the quality of manufactured products in 

general (Ref. 9). As many comments 

asserted, if the dietary supplement 

CGMP requirements are to be 

meaningful, they must ensure quality in 

the finished product (see, for example, 

the discussion in section X of this 

document of comments regarding the 

production and process control system). 

Controls to ensure quality include 

planning processes to determine desired 

product features or characteristics, a 

system of controls to ensure that the 

desired product will be consistently 

produced, and making necessary 

improvements to the process (section 

2.6 of Ref. 9). Manufacturers must plan 

what they intend to produce, institute 

adequate controls to achieve the desired 

outcome, and ensure that the controls 


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work so that the desired outcome is 

consistently achieved. If the outcome is 

not consistently achieved, corrective 

actions need to be implemented in order 

to reach the desired outcome. 

This final rule, like the other food 

CGMP regulations, embodies the basic 

concepts of controlling quality, i.e., 

planning, control, and improvement. As 

discussed earlier in the ‘‘Overview of 

CGMP’’ (section III.A of this document), 

we have defined the term ‘‘quality’’ for 

this dietary supplement CGMP 

regulation to mean ‘‘that the dietary 

supplement consistently meets the 

established specifications for identity, 

purity, strength, and composition and 

has been manufactured, packaged, 

labeled, and held under conditions to 

prevent adulteration under section 

402(a)(1), (a)(2), (a)(3), and (a)(4) of the 

Federal Food, Drug, and Cosmetic Act.’’

Identifying the desired characteristics of 

identity, purity, strength, and 

composition of a dietary supplement, as 

required in this final rule, is an essential 

part of the planning process to 

manufacture a dietary supplement. 

Without identifying specifications for 

each of these characteristics of a dietary 

supplement, it is not possible to control 

for, and repeatedly and reliably 

produce, the desired end product. 

Similarly, requirements for batch testing 

ensure that there is consistency from 

batch to batch. Packaging and labeling 

requirements ensure that suitable 

packaging is used and that the label 

identified in the master manufacturing 

record for the product is placed on the 

finished product. In addition, 

requirements related to consumer 

complaints help to ensure that 

manufacturers are made aware of 

problems related to their manufacturing 

processes, including those that may 

result in illness or injury, so that they 

can take corrective actions to prevent 

any future problems from occurring. 

The procedures for production and 

process control in this final rule also 

include as key elements measures to 

prevent contamination that could 

adulterate the product. Requirements to 

protect against contamination during 

the manufacturing, packaging, labeling, 

and holding operations help ensure that 

this aspect of ‘‘quality’’ is also achieved 

for dietary supplements. In sum, this 

final rule embodies principles for 

controlling quality through 

requirements designed to ensure both 

that the dietary supplement meets its 

established specifications for identity, 

purity, strength, and composition and 

that it is not adulterated. 

The dietary supplement CGMP 

requirements are also reasonable 

because they take into consideration the 

different product forms in which these 

products will be manufactured. Unlike 

conventional foods, such as fruit, 

vegetables, cereals, and dairy products, 

dietary supplements will be sold in 

tablet, capsule, powder, or softgel form. 

They may also be sold as a concentrate, 

metabolite, constituent, or extract of a 

vitamin, mineral, herb, botanical, or 

dietary substance. Because dietary 

supplements are often sold in different 

forms than conventional foods, different 

processes and controls are needed to 

manufacture dietary supplements than 

to manufacture conventional foods. For 

example, equipment must be able to 

manufacture dietary supplements in 

tablet or softgel form. Therefore, the 

final rule requires that controls be 

established to ensure that the equipment 

functions in accordance with its 

intended use (final § 111.30(e)) and will 

consistently manufacture a product in 

whatever form is desired. Consistent 

with basic CGMP principles, ensuring 

the quality of the dietary supplement 

product requires that the manufacturer 

establish precisely what it will produce 

(specifications for its product), how it 

will make the product (processes), and 

which process controls and tests it will 

use to ensure reliable, reproducible 

results. These CGMP requirements will 

help to achieve these results. 

The dietary supplement CGMP 

requirements are also reasonable when 

viewed in the context of the act as a 

whole. See Brown & Williamson, 529 

U.S. at 133. Our mission is, in part, to 

protect the public health by ensuring 

that foods are safe, wholesome, sanitary, 

and properly labeled (section 

903(b)(2)(A) of the act) (21 U.S.C. 

393(b)(2)(A))). Section 701(a) of the act 

(21 U.S.C 371(a)) gives us the authority 

to promulgate regulations for the 

efficient enforcement of the act in order 

to ‘‘effectuate a congressional objective 

expressed elsewhere in the Act’’

(Association of American, Physicians 

and Surgeons, Inc. v. FDA, 226 F. Supp. 

2d 204 (D.D.C. 2002) (citing Pharm. 

Mfrs. Ass’n. v. FDA, 484 F. Supp. 1179, 

1183 (D. Del. 1980)). The final rule is 

designed to help ensure that dietary 

supplements consistently are 

manufactured to produce the product 

established by the manufacturer, to bear 

the label identified in the master 

manufacturing record, and to prevent 

adulteration. The requirements are 

written to facilitate efficient and 

effective action to enforce their terms 

when necessary. 

Some provisions of the dietary 

supplement CGMP final rule may be 

similar to the existing drug CGMP 

regulations. However, we have not 

modeled these regulations after the drug 

CGMP regulations. Controls that relate 

to certain product forms (e.g., tablets, 

capsules, powder, softgel) are required 

in this final rule based on the specific 

characteristics of dietary supplements 

and the hazards associated with these 

forms, not, as some comments imply, 

based on a desire to emulate drug CGMP 

requirements. The act does not state that 

there may not be similarities between 

the dietary supplement CGMP 

requirements and the CGMP 

requirements for drugs or other nonfood products. Inasmuch as food CGMP 

regulations and other CGMP regulations 

are all based on CGMP principles, it is 

neither surprising nor impermissible 

that there are similarities between the 

dietary supplement CGMP requirements 

and drug or device CGMP requirements. 

Although we do not agree that any of 

the CGMP requirements exceed drug 

GCMP requirements, even if a particular 

requirement did, it is not prohibited 

under the statute. As long as the CGMP 

final rule is ‘‘modeled after’’ the food 

CGMP regulations, we have satisfied the 

statutory requirements. As noted, our 

interpretation of ‘‘modeled after’’ means 

that the dietary supplement CGMP final 

rule provisions share similar objectives 

and/or use similar means as the existing 

food CGMP regulations. To the extent 

that there are similarities to drug CGMP 

regulations, those similarities are 

appropriate and not prohibited by 

section 402(g) of the act. 

Consistent with our role ‘‘to fill in, 

through interpretation, matters of detail 

related to [the statute’s] administration,’’

Barnhart v. Walton, 535 U.S. 212, 225 

(2002), we applied our scientific 

expertise, policy judgment, and 

experience to promulgate dietary 

supplement CGMP requirements that 

will protect the public health and 

effectively implement our statutory 

authority to prescribe dietary 

supplement CGMP. See United States v. 

Mead, 533 U.S. 218, 227–228 (2001); 

Nationsbank of North Carolina v. 

Variable Annuity Life Ins. Co., 513 U.S. 

251, 256–58 (1995); Chevron, 467 U.S. at 

844; Forester v. Consumer Product 

Safety Com., 559 F.2d 774, 783 (D.C. 

Cir. 1977). 

B. Records Authority 

(Comment 19) Some comments state 

that requirements related to record 

keeping and access to such records are 

necessary to allow our inspectors to 

assess the adequacy of a dietary 

supplement manufacturer’s practices. 

Additional comments state that access 

to records is necessary to ensure that 

CGMP requirements are followed and to 

protect the public health. Several 

comments identify specific types of 


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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’’ (id. at 311). In 

this instance, Congress has not 

expressed any specific intent regarding 

recordkeeping for dietary supplements 

but has directed FDA to use other food 

CGMP regulations, which require 

recordkeeping and FDA access to 

records, as models for these regulations. 

Congress has delegated substantial and 

sufficiently specific authority to us to 

promulgate recordkeeping and access 

regulations (Cf. United States v. Storer 

Broadcasting, 351 U.S. 192, 202–03 

(1956) (upholding a rule that established 

limitations on broadcast licensing that 

were ‘‘not specifically authorized by 

statute’’)). As stated earlier in this 

section, the ‘‘modeled after’’ language in 

section 402(g) of the act is ambiguous 

with respect to what specific CGMP 

requirements we are to include in this 

final rule. At the time Congress enacted 

section 402(g) of the act there were 

several food regulations that contained 

recordkeeping and record access 

requirements. We included records 

requirements in the food CGMP 

regulations for infant formula (part 106), 

low acid food (part 113), acidified food 

(part 114), and bottled water (part 129). 

Accordingly, the directive in section 

402(g) of the act is sufficient authority 

for our recordkeeping requirements in 

this final rule. In addition, our authority 

to establish records requirements has 

been upheld under other provisions of 

the act, which lacked explicit 

recordkeeping authority for FDA, where 

we have found records to be necessary 

(National Confectioners Assoc. v. 

Califano, 569 F.2d 690, 693–94 (D.C. 

Cir. 1978) (upholding requirements for 

source coding and distribution records 

based on the statutory scheme as a 

whole)). 

Moreover, records are an 

indispensable component of CGMP. The 

records required by this final rule 

provide the foundation for the planning, 

control, and improvement processes 

that constitute a quality control system. 

Implementation of these processes in a 

manufacturing operation serves as the 

backbone to CGMP. The records will 

show what is to be manufactured; what 

was, in fact, manufactured; and whether 

the controls that the manufacturer put 

in place to control the identity, purity, 

strength, and composition and limits on 

contaminants and to prevent 

adulteration were effective. Further, 

records will show whether and what 

deviations from control processes 

occurred, facilitate evaluation and 

corrective action concerning these 

deviations (including, where necessary, 

whether associated batches of product 

should be recalled from the 

marketplace), and enable a 

manufacturer to assure that the 

corrective action was effective. Written 

procedures also will help ensure that 

personnel follow hygienic practices; 

permit evaluation of whether 

equipment, including software that may 

run the equipment, performs as it is 

intended; and help ensure that the 


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6It is also worth noting that standard references 

used in many industries establish clear expectations 

for documentation and recordkeeping practices for 

assuring quality control in manufacturing 

operations (Refs. 9 and 13). 

7In 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)). 

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); and 

identifies the steps necessary to ensure 

that any necessary tests or examinations 

are completed, reviewed, and recorded 

in a timely fashion before the dietary 

supplement is released for distribution 

to the public (final §§ 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 

through 111.140). The final rule also 

requires that the manufacturer establish 

the ‘‘master recipe(s)’’ for the dietary 

supplement(s) it manufactures so that 

such recipe(s) can be followed for each 

batch produced (final §§ 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 CGMP 

requirements, including the failure to 

have a record that is required by this 

final rule, renders a dietary supplement 

so manufactured to be adulterated as a 

matter of law. The introduction or 

delivery for introduction into interstate 

commerce of an adulterated dietary 

supplement is a prohibited act under 

section 301(a) of the act (21 U.S.C. 

331(a)), and acts done to an ingredient 

in a dietary supplement, or to a dietary 

supplement, while held for sale after 

shipment in interstate commerce that 

result in the ingredient or dietary 

supplement being adulterated violates 

section 301(k) of the act (21 U.S.C. 

331(k)). Thus, in order for us to 

determine whether the dietary 

supplement product is adulterated and 

whether a manufacturer has committed 

a prohibited act, we must have access to 

the manufacturer’s records that we are 

requiring to be kept under section 402(g) 

of the act. 

In light of the foregoing, without 

access to such records, we would not 

know whether a manufacturer was 

complying with the procedures and 

processes required in this final rule. For 

example, our investigator must have 

access to the test results for the identity 

of a dietary ingredient to determine 

whether such ingredient meets the 

manufacturer’s specification for 

identity. The investigator needs to 

understand, by reviewing a record, what 

the software that runs a production 

operation is set up to do and whether it 

performs those functions to achieve the 

desired product characteristics. 

Observation of these processes alone, by 

an investigator, would not allow that 

investigator to evaluate compliance with 

this final rule. Moreover, records often 

cannot be thoroughly evaluated by the 

investigator on site. In such cases, 

records must be readily available to food 

experts at the Center for Food Safety 

and Applied Nutrition (CFSAN) and 

agency consultants. We must have 

accurate, reliable, and objective data 

about the manufacturing specifications 

to be able to achieve an enforceable rule. 

We also disagree with comments 

stating our records inspection authority 

is limited to that provided by section 

306(a) of the Bioterrorism Act. There is 

no basis to conclude that Congress 

intended to limit our authority to 

inspect records, to enforce section 

402(g) of the act, to the records 

inspection authority under the 

Bioterrorism Act. The Bioterrorism Act, 

enacted almost 8 years after section 

402(g), to address credible threats of 

serious adverse health consequences or 

death to humans and animals, required 

recordkeeping to identify the immediate 

previous sources and the immediate 

subsequent recipients of food (21 U.S.C. 

350c). 

There is nothing in the Bioterrorism 

Act that reflects any Congressional 

intent to modify section 402(g) of the 

act. In fact, section 414(d)(1) of the act 

(21 U.S.C. 350c(d)(1)), added by section 

306(a) of the Bioterrorism Act, shows a 

contrary intent. Section 414(d)(1) 

provides that ‘‘This section shall not be 

construed—(1) to limit the authority of 

the Secretary to inspect records or to 

require establishment and maintenance 

of records under any other provision of 

this Act.’’ Moreover, Congress, in the 

legislative history to the Bioterrorism 

Act, supported our general approach of 

requiring recordkeeping pursuant to 

authority in section 701(a) of the act in 

combination with other provisions.7 We 

are not relying on section 704 of the act 

for its underlying authority to require 

recordkeeping and records access in this 

final rule. Those comments asserting 

that we do not have such authority and 

the underlying references, for example, 

to past hearings on records inspection 

authority under section 704 of the act, 

are not controlling with regard to the 

action we are taking under sections 

402(g) and 701(a) of the act. When there 

are other bases for jurisdiction and tools 

to protect the public interest, we may 

use what ‘‘will be the most effective in 

advancing the Congressional objective’’

(U.S. v. Midwest Video Corp., 406 U.S. 

649, 656 (1972)). 

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 


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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. 

C. Public Health Service Act Authority 

(Comment 20) One comment 

acknowledges that we have authority 

under the PHS Act to regulate intrastate 

activities that may cause the spread of 

communicable diseases. The comment 

states that, in any situation in which we 

need to exercise our authority over any 

disease-causing substance within the 

State where a component or dietary 

supplement is manufactured, packed, or 

held, we can and should exercise our 

authority under the PHS Act. However, 

the comment asserts that nothing in the 

preamble clearly states whether we 

believe that the final rule will be, in its 

entirety, binding on manufacturers, 

packers, and holders of dietary 

supplements who are engaged solely in 

intrastate commerce, and that we have 

not requested comment on this specific 

issue. The comment requests that we 

clearly state that the final rule applies 

only to interstate commerce, except for 

activities that may spread 

communicable diseases. 

(Response) We address each of these 

issues in turn. 

1. The Communicable Disease Risk 

Posed by Dietary Supplements 

There are communicable disease risks 

related to the manufacture of dietary 

supplements that are appropriately 

addressed not only under the act, but, 

as the comment acknowledges, also 

under the PHS Act. Microorganisms, 

including Salmonella enterica 

(Salmonella), Campylobacter jejuni, and 

enterohemorrhagic Escherichia coli 

0157:H7 (EHEC), are well-known causes 

of communicable diseases, and may be 

present in dietary supplements and 

their components. There are a number 

of microorganisms that cause 

communicable diseases and that may be 

found in components or dietary 

supplements. These microorganisms 

cause serious effects and symptoms. For 

example, Salmonella causes 

salmonellosis, which affects the 

gastrointestinal (GI) tract and is 

characterized by diarrhea, fever, 

abdominal cramps, headache, nausea, 

and vomiting (Ref. 16). In a small 

portion of healthy people (1 to 4 

percent), infection spreads from the GI 

tract into the blood stream, which can 

be life-threatening. Persons with 

immune compromising conditions (such 

as cancer, Acquired Immunodeficiency 

Syndrome (AIDS), autoimmune 

disorders) are at greater risk of blood 

stream infection (Ref. 16). 

Campylobacteriosis, often due to 

infection with Campylobacter jejuni, is 

characterized by diarrhea, fever, and 

abdominal cramps, which can be severe 

(Ref. 17). These symptoms frequently 

relapse, and the disease may become 

chronic in immune compromised 

persons. People with 

campylobacteriosis are also at increased 

risk of developing certain postinfectious complications, which will 

prolong their recovery. 

EHEC may cause infections with a 

very low infectious dose (as low as 2 to 

45 organisms), and may result in nonbloody and bloody diarrhea, hemolyticuremic 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) 


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humans carry and transmit infections 

through their feces or by direct contact 

with other persons. For other 

microorganisms, domestic and wild 

animals serve as the reservoir, and 

humans become infected when 

contaminated tissues of infected 

animals are used in dietary 

supplements. For both categories of 

microorganisms, dietary supplements 

can also become contaminated 

indirectly by human and animal fecal 

contamination of water or through the 

production or processing environment. 

Dietary supplements may contain a 

variety of components derived from 

domestic and wild animals, such as 

powders prepared from whole or partial 

gecko, deer antler velvet, and organs, 

such as cow liver and brain, pork 

stomach, or sheep spleen from common 

domestic livestock. Each of these tissues 

may be contaminated with 

microorganisms such as Salmonella, 

Campylobacter jejuni, and EHEC. Even 

clinically normal animals obtained from 

safe sources may harbor these 

communicable pathogens and result in 

contaminated products (Ref. 19). 

(Information on these animals and 

potential pathogens can be accessed at 

http://www.fsis.usda.gov/Science/ 

Microbiology/index.asp). Dietary 

supplements also may contain 

crustacean or molluscan shellfish or 

components prepared from them, such 

as glucosamine from shrimp 

exoskeletons and oyster extract, that 

may be contaminated with Vibrio 

species, including V. parahaemolyticus. 

Vibrio species are natural inhabitants of 

shellfish harvest waters, and shellfish 

are commonly naturally contaminated, 

especially during times of the year when 

harvest waters are warm (Refs. 20 

through 23). V. parahaemolyticus most 

often causes gastroenteritis 

characterized by diarrhea, abdominal 

cramps, nausea, vomiting, and fever 

(Ref. 24). 

Dietary supplements may also contain 

botanicals (plants) that may harbor 

microorganisms, including organisms 

from animal feces (Salmonella and 

Shigella spp., Escherichia coli), and 

organisms arising from handling 

(Staphylococcus aureus), harvesting, 

processing, and transportation. 

Components contaminated with 

microorganisms must be treated to 

prevent the finished dietary 

supplements from being contaminated. 

The processes used to manufacture 

dietary supplements do not, by 

themselves, always eliminate the 

microorganisms. Studies show, for 

example, that microorganisms, such as 

EHEC and Salmonella, can even survive 

the tablet production process and 

thereby expose consumers (Ref. 25). 

The industry is aware of the dangers 

of using components contaminated with 

Salmonella and other microorganisms. 

For example, in 2001, a component 

manufacturer recalled 2,400 pounds of 

pepsin contaminated with Salmonella. 

As a result, a number of dietary 

supplement manufacturers issued 

recalls for their dietary supplements 

that contained the pepsin. In the press 

releases accompanying the recalls, the 

dietary supplement manufacturers 

warned consumers of the possible 

dangers of Salmonella contamination, 

and encouraged consumers to either 

destroy or return the supplements (Ref. 

26). 

Therefore, because of the 

communicable disease concerns 

associated with dietary supplements, we 

are asserting legal authority under the 

PHS Act in support of the final rule. As 

discussed in the following section of 

this document, our authority under the 

PHS Act is not limited to interstate 

activities. It also covers intrastate 

activities. 

2. Activities For Which We Are 

Asserting Legal Authority Under the 

PHS Act 

There are many opportunities for 

components and dietary supplements to 

become contaminated with 

microorganisms that spread 

communicable diseases. The final rule 

requires firms to take all the necessary 

precautions during the manufacture of a 

dietary supplement to prevent such 

contamination. 

These precautions, for example, 

include: Performing manufacturing 

operations under conditions and 

controls that protect against potential 

microorganism growth; washing or 

cleaning components that contain soil 

or other contaminants; performing 

microbiological testing, as necessary, to 

prevent the use of contaminated 

components; sterilization, 

pasteurization, freezing, refrigeration, 

and controlling pH, humidity, and water 

activity (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. 

D. The Interstate Commerce Nexus for 

the Final Rule 

1. The PHS Act 

(Comment 21) Several comments 

assert that, although the PHS Act may 

extend to some intrastate activities, its 

reach is very limited. The comments 

appear to conclude that the reach of the 

PHS Act and the act extends only to 

situations in which the finished dietary 

supplement is shipped in interstate 

commerce. 

(Response) We do not agree that this 

view is correct. The PHS Act extends to 

intrastate commerce. Under section 361 

of the PHS Act (42 U.S.C. 264), we may 

‘‘make and enforce such regulations as 

in [our] judgment are necessary to 

prevent the introduction, transmission, 

or spread of communicable diseases 

from foreign countries into the States or 

possessions, or from one State or 

possession into any other State or 

possession.’’

In Louisiana v. Mathews, 427 F. Supp. 

174, 176 (E.D. La. 1977), the court 

upheld FDA’s regulation that banned 

the sale of small turtles to prevent the 

spread of disease caused by turtles 

harboring Salmonella and Arizona 

microorganisms. The ban covered both 

interstate and intrastate sales. The court 

held that the intrastate ban is not only 

authorized by the law, but, under 

modern conditions of transportation and 

commerce ‘‘is clearly reasonable to 

prevent the interstate spread of disease’’

(id.). 

We are authorized under the PHS Act 

to regulate conduct that occurs within a 

State to the extent necessary to prevent 

the interstate spread of communicable 

diseases. Such is the present case with 

respect to the provisions of the dietary 

supplement CGMP final rule for which 

section 361 of the PHS Act provides 

authority. 

2. The Act 

The act extends to the sale of a dietary 

supplement that was manufactured and 


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distributed entirely in one State, if the 

supplement contains any ingredient or 

uses any component that came from 

outside of that State. Such a dietary 

supplement is subject to section 301(k) 

of the act, which prohibits ‘‘[t]he 

alteration, mutilation, destruction, 

obliteration, or removal of the whole or 

any part of the labeling of, or the doing 

of any other act with respect to, a food, 

drug, device, or cosmetic, if such act is 

done while such article is held for sale 

(whether or not the first sale) after 

shipment in interstate commerce and 

results in such article being adulterated 

or misbranded.’’ (emphasis added). See 

also 21 U.S.C. 321(b)(3) (defining food 

to include articles used as components 

of food). 

The interstate commerce prerequisite 

under section 301(k) or section 304(a) 

(21 U.S.C. 334(a)) of the act is 

established when one or more 

components used in the manufacture of 

the product have crossed State lines. 

This principle is known as ‘‘component 

jurisdiction’’ (See, e.g., Baker v. United 

States, 932 F.2d 813, 814–15 (9th Cir. 

1991); United States v. Article of Food 

* * * Coco Rico, Inc., 752 F.2d 11, 14 

(1st Cir. 1985); United States v. 

Dianovin Pharmaceuticals, Inc., 475 

F.2d 100, 103 (1st Cir.), cert. denied, 414 

U.S. 830 (1973) (‘‘appellants’ use of 

components shipped in interstate 

commerce to make vitamin K for 

injection brought their activities within 

§ 331(k)’’); United States v. Cassaro, 

Inc., 443 F.2d 153, 155–56 (1st Cir. 

1971); United Statesv. Detroit Vital 

Foods, Inc., 330 F.2d 78, 81–82 (6th 

Cir.), cert. denied, 379 U.S. 832 (1964); 

United States v. Allbrook Freezing & 

Cold Storage, Inc., 194 F.2d 937, 939 

(5th Cir. 1952); United States v. VarelaCruz, 66 F.Supp.2d 274, 277–281 (D. 

P.R. 1999)). 

Nor does it matter that the interstate 

product component comprises only a 

minute part of the article, United States 

v. Miami Serpentarium Laboratories, 

[1981—1982 Transfer Binder] Food 

Drug Cosm. L.Rep. (CCH) paragraph 

38,164 at 38,930 (S.D. Fla. 1982); United 

States v. 14 Cases * * * Naremco, 374 

F.Supp. 922, 925 (W.D. Mo. 1974), or if 

the interstate ingredient combines with 

others to form a different product. 

Detroit Vital Foods, 330 F.2d at 81; 

United States v. 40 Cases * * * 

Pinocchio Brand * * * Oil, 289 F.2d 

343, 346 (2d Cir.), cert. denied, 368 U.S. 

831 (1961). 

Finally, we note that section 709 of 

the act creates a presumption of 

interstate commerce (see 21 U.S.C. 379a 

(‘‘In any action to enforce the 

requirements of this Act respecting a 

device, food, drug, or cosmetic the 

connection with interstate commerce 

required for jurisdiction in such action 

shall be presumed to exist.’’)). 

In conclusion, the final rule covers 

not only finished products that have 

moved in interstate commerce but also 

products made from ingredients or 

components that have moved in 

interstate commerce. This is true 

regardless of the amount of the 

ingredient or component in the product 

and regardless of whether the finished 

dietary supplement has itself moved in 

interstate commerce. The final rule also 

covers products, components, and 

ingredients that may contribute to the 

spread of communicable disease, 

regardless of whether the component, 

ingredient, or product has itself moved 

in interstate commerce. 

3. Commerce Clause 

(Comment 22) One comment states 

that we must be ‘‘mindful of the limits’’

imposed on the regulation of intrastate 

commerce by the Supreme Court in 

United States v. Lopez, 514 U.S. 549 

(1995). The comment asserts that we 

may only regulate intrastate activity that 

has a ‘‘substantial effect’’ on interstate 

commerce and activity that ‘‘exerts a 

substantial economic effect on interstate 

commerce.’’

(Response) The final rule is consistent 

with the Lopez decision. Among the 

cases cited by the Court in Lopez as 

support for its decision is Wickard v. 

Filburn, 317 U.S. 111 (1942), which 

involved the production and 

consumption of homegrown wheat. In 

that case, the Court explained: 

‘‘although Filburn’s own contribution to 

the demand for wheat may have been 

trivial by itself, that was not enough to 

remove him from the scope of federal 

regulation where, as here, his 

contribution, taken together with that of 

many others similarly situated, is far 

from trivial’’ (Lopez, 514 U.S. at 556). 

The same is true for dietary supplement 

manufacturers. Therefore, the 

requirements of the final rule are 

consistent with the Commerce Clause of 

the Constitution. 

E. Fifth Amendment 

(Comment 23) Several comments 

allege a number of the sections of the 

proposed regulation are 

unconstitutionally vague and violate the 

Administrative Procedure Act (APA) 

because the rule would be ‘‘contrary to 

constitutional right, power, privilege, or 

immunity.’’ The comments express 

concern that if such terms are not 

defined or deleted, there would be no 

fair notice on what conduct is 

prohibited and would result in 

‘‘unbridled discretion’’ in how the rule 

will be enforced. The comments focus 

on provisions containing words such as 

‘‘adequate,’’ ‘‘qualified,’’ ‘‘readily 

accessible,’’ ‘‘convenient,’’ ‘‘suitable,’’

‘‘appropriate,’’ and ‘‘necessary.’’ For 

example, one comment notes that 

proposed § 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. BelMar 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 


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received and published for comment an 

industry draft of a CGMP regulation for 

dietary supplements. The industry draft 

used many of the same terms. For 

example, it provides in part: ‘‘Plumbing 

shall be of adequate size and design and 

adequately installed and maintained’’

(62 FR 5700 at 5703, February 6, 1997). 

Thus, there has been sufficient common 

usage of these terms in the food industry 

and, in particular, the dietary 

supplement industry to enable 

manufacturers, and those who enforce 

the requirements, to comprehend and 

apply such terms ‘‘with a reasonable 

degree of certainty’’ to their particular 

operations (Boyce Motor Lines v. United 

States, 342 U.S. at 340 (‘‘[F]ew words 

possess the precision of mathematical 

symbols, most statutes must deal with 

untold and unforeseen variations in 

factual situations, and the practical 

necessities of discharging the business 

of government inevitably limit the 

specificity with which legislators can 

spell out prohibitions [and therefore] no 

more than a reasonable degree of 

certainty can be demanded.’’)). The 

same reasoning applies here. It 

addresses ‘‘untold and unforeseen 

variations in factual situations’’ and, as 

such, ‘‘no more than a reasonable degree 

of certainty can be demanded.’’

Agencies are permitted to, and indeed 

must, use such qualifying terms to 

address the variety of conditions that 

exist at different companies. We do not 

need to, nor could we, predict with 

mathematical precision how many 

inches or feet, for example, would be 

‘‘adequate space’’ to allow for cleaning 

a particular piece of equipment that 

could be applied to every size of facility 

and every operation (id.). Moreover, 

defining such terms too precisely would 

unduly restrict the application of the 

regulation to a very narrow, limited set 

of circumstances and not provide 

industry with the needed flexibility to 

address the number and variety of types 

of manufacturing operations that 

Congress intended for this rule to cover 

(see Freeman United Coal Mining 

Company v. Federal Mine Safety and 

Health Review Commission, 108 F.3d 

358, 363 (D.C. Cir. 1997) (citations 

omitted) (upholding a regulation that 

required equipment to be ‘‘maintained 

in good repair,’’ the court rejected the 

vagueness challenge: ‘‘specific 

regulations cannot begin to cover all of 

the infinite variety of [conditions at 

firms and that] * * * [b]y requiring 

regulations to be too specific [courts] 

would be opening up large loopholes 

allowing conduct which should be 

regulated to escape regulation.’’); United 

States v. Bel-Mar Laboratories, Inc., 284 

F. Supp. at 883 (rejecting a vagueness 

challenge to the CGMP requirements for 

drugs, noting that ‘‘[a]s a matter of fact, 

there are responsible segments of 

opinion within the industry itself which 

oppose a greater degree of specificity in 

this area.’’). 

Finally, it is important to understand 

that rules are not unconstitutionally 

vague simply because they require 

interpretation by regulated persons. For 

example, courts have held that the term 

‘‘insanitary conditions’’ in the act is not 

unconstitutionally vague (See Golden 

Grain Macaroni Co. v. United States, 

209 F.2d 166, 168 (9th Cir. 1953) (citing 

Boyce Motor Lines, supra); Berger v. 

United States, 200 F.2d 818 (8th Cir. 

1952)). In Berger, the court rejected the 

claim that the term ‘‘insanitary 

condition’’ is unconstitutionally vague 

on the ground that it does not specify 

the ‘‘degree of insanitation’’ required for 

a violation (id. at 822). A law may 

require a person to make ‘‘estimates of 

the degree of dirtiness and lack of 

sanitation’’ which may result in a 

violation (id., see alsoBoyce Motor Lines 

v. United States, 342 U.S. at 340 (It is 

not ‘‘unfair to require that one who 

deliberately goes close to an area of 

proscribed conduct shall take the risk 

that he may cross the line’’)). There are 

sufficient protections under the act to 

overcome any concerns related to how 

it will be criminally enforced. We 

disagree that such terms will lead to 

‘‘unbridled discretion’’ on how the rule 

is enforced. 

In short, we find that the rule is not 

unconstitutionally vague, and does not 

violate section 706(2)(B) of the APA (5 

U.S.C. 706(2)(B)). 

F. Miscellaneous 

(Comment 24) One comment states 

that the proposed rule violates section 

402(f)(1)(A)(i) and (f)(1)(A)(ii) of the act 

(21 U.S.C. 342 (f)(1)(A)(i) and 

(f)(1)(A)(ii)), which deems a dietary 

supplement adulterated if it contains a 

dietary ingredient that presents an 

unreasonable risk of illness or injury 

under conditions of use in labeling or 

ordinary conditions of use, if none are 

suggested or recommended in labeling. 

Under section 402(f) of the act, the 

Government bears the burden of proof to 

show that a dietary supplement is 

adulterated. The comment states that 

the proposed rule reversed the 

presumption under section 402(f) of the 

act, and would revise the rule to require 

us to first show a violation under 

section 402(f) of the act before we could 

take any enforcement action under 

section 402(g). Another comment states 

that, because the rule was intended to 

enable manufacturers to be able to 

detect and avoid adulteration through 

CGMP, the proposed rule created a 

presumption that dietary supplements 

are adulterated until proven otherwise. 

(Response) The final rule does not 

violate section 402(f) of the act. Section 

402(f) and (g) of the act provide two 

independent bases under which we may 

take enforcement action against dietary 

supplements. A dietary supplement may 

be adulterated either because a 

manufacturer has failed to follow a 

CGMP requirement, or because a dietary 

supplement presents an unreasonable 

risk of illness or injury, or both. There 

would be no reason to assert a second 

basis for adulteration under section 

402(g) of the act if one always had to 

demonstrate adulteration under section 

402(f) of the act as a prerequisite. 

We also disagree with the comment 

that the proposed rule creates a 

presumption that the dietary 

supplement is adulterated simply 

because the proposed requirements 

would enable a manufacturer to detect 

and avoid adulteration. The 

requirements for CGMP are prophylactic 

and are designed in part to ensure that 

all aspects of manufacturing, from 

receipt through distribution, provide the 

necessary controls and monitoring to 

ensure the quality of the dietary 

supplement, including that it is 

manufactured, packaged, labeled, and 

held in a manner to prevent 

adulteration. 

(Comment 25) One comment states 

that, if there is reduced competition 

through the enforcement of the rule, 

there will be a secondary effect of 

elimination of speech on dietary 

supplement innovative uses. 

(Response) The comment seems to 

conclude that, if a dietary supplement 

manufacturer is not able to stay in 

business due to adverse enforcement 

actions against it by us, or elects to not 

go into business based on the possibility 

of enforcement action by us, there will 

be reduced competition due to fewer 

products, less labeling, and 

‘‘elimination of speech on innovative 

uses.’’ To the extent that the comment 

is suggesting that the dietary 

supplement CGMP requirements are 

unconstitutionally overbroad, this 

argument is wholly without merit (Cf. 

Wisconsin v. Mitchell, 508 U.S. 476, 

488–89 (1993) (finding no merit to an 

overbreadth argument that the 

possibility of enhanced sentences based 

on prior racially motivated speech or 

associations constitutes an 

impermissible chill on free speech)). 

Manufacturing a dietary supplement in 

a manner that violates the CGMP 

requirements causes the product to be 

adulterated, and therefore, unlawful. 


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The fact that a manufacturer may not 

stay in business, or elects not to enter 

business, due to: (1) Our 

implementation of CGMP requirements 

or (2) our enforcement against a product 

that violates CGMP requirements, does 

not mean that we are somehow 

prohibiting speech. In any event, there 

is no First Amendment protection for 

speech that concerns unlawful activity 

under the first prong of the test set out 

in Central Hudson Gas & Electric Corp. 

v. Public Service Commission, 447 U.S. 

557 (1980). Therefore, the comment’s 

suggestion that there is elimination of 

speech based on the rulemaking is not 

supportable. The requirements in the 

final rule do not infringe on a 

manufacturer’s right to lawfully label 

and market a dietary supplement. 

VI. What Comments Did We Receive on 

the General Provisions? (Subpart A) 

A. Organization of Final Subpart A 

Proposed subpart A contained five 

provisions regarding the scope of the 

proposed rule, definitions, and 

exclusions. Table 2 of this document 

lists the sections in final subpart A and 

identifies the proposed sections that 

form the basis of the final rule. 

TABLE 2.—DERIVATION OF

SECTIONS IN FINAL SUBPART A 

Final Rule 

2003 

CGMP 

Proposal 

§ 111.1 Who is subject 

to this part? 

§ 111.1 

§ 111.3 what definitions 

apply to this part? 

§ 111.3 

§ 111.5 Do other statutory provisions and 

regulations apply? 

§ 111.5 

B. Who Is Subject to This Part? (Final 

§ 111.1) 

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 in the 

following paragraphs. 

(Comment 26) Some comments 

interpret the proposal as not applying to 

persons who perform labeling 

operations. For example, one comment 

claims that proposed § 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 


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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 and 

Grounds). 

In cases where a distributor contracts 

with a manufacturer to manufacture a 

dietary supplement that the distributor 

then distributes under its own label, the 

distributor has an obligation to know 

what and how manufacturing activities 

are performed so that the distributor can 

make decisions related to whether the 

packaged and labeled product conforms 

to its established specifications and 

whether to approve and release the 

product for distribution. 

(Comment 28) Some comments state 

that the proposed rule requirements 

would require the manufacturer to 

report adverse events to us, but would 

not require those who distribute the 

product and whose name is likely to be 

on the product label, to report adverse 

events to us. The comments state that 

reports of adverse events submitted by 

consumers to those who distribute, but 

do not make, dietary supplements could 

be hidden from the public if such 

persons are not required to submit those 

reports to us. 

(Response) The comments may have 

misinterpreted the proposed rule. The 

requirement to review and investigate a 

product complaint is distinct from any 

report about the product complaint to 


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us. Reporting a complaint to us is not 

covered by these CGMP requirements 

and would be voluntary, unless the 

complaint is subject to the statutorily 

mandated reporting requirements for 

‘‘significant adverse events’’ pursuant to 

the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection 

Act’’ (Public Law 109–462), signed into 

law on December 22, 2006 (see 

discussion in section XX of this 

document). 

Under the procedures that are set 

forth in subpart O, Product Complaints 

(see section XX of this document), a 

distributor and a manufacturer are both 

subject to the requirements related to 

the review and investigation of a 

product complaint that they receive. 

(Comment 29) Some comments argue 

against including minimum CGMPs 

necessary for activities related to 

manufacturing, packaging, labeling, or 

holding dietary ingredients in the final 

rule. Several comments argue the 

proposed rule is overly broad and 

inconsistent with congressional intent. 

These comments question whether 

Congress intended that CGMP apply to 

persons involved in the manufacture, 

packaging, labeling, and holding of 

dietary ingredients. The comments also 

argue that, if the rule applies to dietary 

ingredient manufacturers, we would be 

establishing precedent and that we lack 

legal authority to regulate ingredients 

rather than the finished products 

themselves. The comments state that 

neither food CGMP nor drug CGMP 

offers precedent or guidance on 

regulating ingredients. The comments 

argue those who provide dietary 

ingredients should be subject to the 

existing general food CGMP 

requirements in part 110 rather than to 

the dietary supplement CGMP 

requirements. 

Several comments argue that many 

dietary ingredients are used in regular 

foods and in drugs as well as in dietary 

supplements. The comments argue, for 

some dietary ingredients, their use in 

dietary supplements represents a very 

small percentage of the dietary 

ingredient’s worldwide usage. The 

comments say we should allow those 

who deal only with dietary ingredients 

to operate under one set of regulations, 

such as the general food CGMP 

requirements in part 110. According to 

these comments, we have not 

demonstrated either a failure of the 

current system or a compelling need to 

create different regulations for raw 

materials common to both the food and 

dietary supplement industries. The 

comments would revise the title of part 

111 and proposed § 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 nonfood 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 of this document), after 

considering comments about the overall 

production and process control system, 

we revised the final rule’s approach to 

ensuring product quality. This approach 

emphasizes that it is important to 

ensure the quality of the dietary 

supplement throughout the production 

and process control system. This 

approach emphasizes establishing 

specifications for components and 

ensuring those specifications are met. 


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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 in the 

previous response to comment 29, if a 

dietary ingredient manufacturer also 

supplies or sells a dietary ingredient as 

a dietary supplement, such a 

manufacturer would be subject to final 

§ 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 


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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-onone consultation on the premises of the 

practitioner. One comment from a 

practitioner states that she received her 

training from an accredited 4-year 

university and it included didactic and 

clinical training in acupuncture and 

Chinese herbs. Another comment from 

an organization provides detailed 

training guidelines for practitioners, 

including 1,600 hours of training, 400 

hours of which should include clinical 

work. Moreover, many comments also 

assert that the practitioners are different 

from dietary supplement manufacturers 

because they formulate the dietary 

supplements in the course of a one-onone 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 


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comments ask us to follow the example 

of these nations. 

(Response) We intend to consider the 

positions taken by other nations to 

inform us in our decisionmaking in any 

future guidance on how we intend to 

exercise our enforcement discretion on 

the application of this final rule to 

certain practitioners. 

(Comment 35) Many comments say 

we should define when a dietary 

supplement will be said to have entered 

interstate commerce. The comments 

state herbal practitioners (and academic 

institutions) often purchase source 

herbs from outside their State, even if 

they prepare these herbs for their 

specific customers within the State. 

These comments request we clarify that 

the rule does not apply to herbs 

purchased out of State if prepared for 

local use. Other comments request 

clarification regarding clients who have 

moved across State lines, yet maintain 

a relationship with an herbalist 

practitioner. 

(Response) In section V of this 

document we explain the interstate and 

intrastate issue related to the final rule. 

(Comment 36) A few comments assert 

individual practitioners and practitioner 

organizations often are unaware of the 

opportunity to comment on CGMP or 

regulatory issues. Therefore, the 

comments say these practitioners and 

organizations often fail to provide 

comment or otherwise participate in 

rulemaking and say we should give 

these practitioners and practitioner 

organizations a chance to comment. 

(Response) We provided many 

opportunities for comment and, 

therefore, we decline to adopt the 

comments’ suggestion. As we discuss in 

section I of this document, we 

published an ANPRM concerning 

dietary supplement CGMPs on February 

6, 1997 (62 FR 5700); the 1997 ANPRM 

provided an opportunity for public 

comment. On March 7, 2003, we issued 

a Talk Paper, along with other 

background documents, announcing the 

issuance of a proposed dietary 

supplement CGMP rule. We made the 

proposed rule available when it went on 

display (before it published) in the 

Federal Register on March 13, 2003 (68 

FR 12157), and, again, provided an 

opportunity for public comment. We 

also held public meetings on April 29, 

2003, in College Park, MD and on May 

6, 2003, in Oakland, CA. We also held 

a public meeting (via satellite downlink) 

on May 9, 2003, with viewing sites at 

our district and regional offices 

throughout the country. Thus, we 

provided numerous opportunities for 

interested persons to learn about the 

rule and to submit comments or 

otherwise participate in the rulemaking 

process. Consequently, we decline to 

provide yet another opportunity for 

comment. 

(Comment 37) The preamble to the 

2003 CGMP Proposal noted that 

comments submitted in response to our 

1997 ANPRM state we should not 

distinguish between dietary 

supplements made in the United States 

and those made in a foreign country (68 

FR 12157 at 12174). Although we agreed 

with the comments and made no 

distinction between foreign and 

domestic firms in the proposed rule, we 

invited comment on how we might 

ensure dietary ingredients and dietary 

supplements exported to the United 

States have been manufactured, 

packaged, labeled, and held consistent 

with part 111 (68 FR 12157 at 12175). 

Several comments argue the rule 

should apply to foreign firms as well as 

domestic manufacturers to ensure a 

‘‘level playing field’’ and to protect 

American consumers. Some comments 

say we should work with foreign 

countries to harmonize our 

requirements and thus avoid potential 

trade disputes under international trade 

agreements such as the General 

Agreement on Tariffs and Trade. Other 

comments suggest compliance by 

foreign firms could be achieved through 

the use of third party certification 

programs, such as the dietary 

supplement verification program 

administered by USP, or the adoption of 

importer verification provisions similar 

to those used in our HACCP 

requirements for seafood (see § 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 (21 

U.S.C. 381a) authorizes us to refuse 

admission of an imported food if it 

appears from the examination of such 

samples or otherwise that such article 

is, among other things, adulterated. A 

foreign firm’s refusal to allow us to 

obtain records via an inspection for 

CGMP purposes, as required by final 

§ 111.610 (for the dietary supplements 

the foreign firm offers for import into 

the United States), would create the 

appearance that such imported dietary 

supplements are adulterated under 

section 402(g) of the act, and thus, could 

lead to a refusal of admission under 

section 801(a) of the act. 

Foreign firms who ship to the United 

States must operate under conditions 

that satisfy our regulations, including 

the requirement that records be made 

available during the course of an FDA 

inspection. We note that except in 

circumstances where there is a public 

health emergency or we receive 

information that would indicate the 

appearance of adulteration of products 

shipped to the United States, foreign 

inspections are generally scheduled 

well, e.g., weeks, in advance. Thus, we 

believe that taking action under section 

801 of the act is appropriate if 

companies do not accommodate our 

inspectional request. 

C. What Definitions Apply to This Part? 

(Final § 111.3) 

Section 111.3 defines various terms 

that we use in the final rule and notes 

that definitions or interpretations of 

terms in section 201 of the act also 

apply. In general, we adopted the 

definitions that we proposed, although, 

in some cases, we deleted words or 

concepts as a result of other changes we 

made to the final rule. We have added 

a definition of ‘‘quality’’ for purposes 

only of this final rule. 

A recurring change we made is the 

deletion of the words ‘‘dietary 

ingredient’’ in several definitions. In 

some cases, the use of the words 

‘‘dietary ingredient’’ was redundant to 

the use of ‘‘component’’ and thus not 

necessary in the final rule. Because a 

‘‘dietary ingredient’’ is subsumed within 

the definition of ‘‘component,’’ as 

explained in our response to comment 

29, we deleted ‘‘dietary ingredient’’ in 

those definitions where ‘‘component’’

was used to avoid redundancy. 

In other provisions, we deleted 

‘‘dietary ingredient’’ from the definition 

because the use of those words was no 

longer necessary given the narrowing of 

the scope of the rule as it applies to 

dietary ingredient manufacturers 

(explained in the response to comments 


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29 and 30). For example, we deleted 

‘‘dietary ingredient’’ from the proposed 

definition of ‘‘ingredient’’ that referred 

to the ‘‘manufacture of a dietary 

ingredient or dietary supplement’’ and 

the ‘‘finished batch of the dietary 

ingredient or dietary supplement.’’ We 

did not need to state ‘‘manufacture of 

the dietary ingredient’’ or refer to 

‘‘finished batch of dietary ingredient’’

because dietary ingredient 

manufacturers that only supply such 

ingredients to other persons for 

processing into a dietary supplement are 

not subject to the final rule. 

We discuss changes to the definitions, 

other than the changes we have made 

globally such as the deletion of ‘‘dietary 

ingredients,’’ the change from ‘‘include, 

but not limited to’’ to ‘‘includes’’ or 

‘‘include,’’ the addition of labels and 

labeling, and the deletion of the word 

‘‘quality’’ from the phrase ‘‘identity, 

purity, quality, strength, and 

composition,’’ as well as comments 

asking us to define more terms or to 

delete certain definitions, in more detail 

in the following paragraphs. 

1. Actual Yield 

The final rule defines ‘‘actual yield’’

as ‘‘the quantity that is actually 

produced at any appropriate step of 

manufacture or packaging of a particular 

dietary supplement.’’

We received no substantive comments 

to the proposed definition. 

2. Batch 

The final rule defines ‘‘batch’’ as ‘‘a 

specific quantity of a dietary 

supplement that is uniform, that is 

intended to meet specifications for 

identity, purity, strength, and 

composition, and that is produced 

during a specified time period according 

to a single manufacturing record during 

the same cycle of manufacture.’’

This definition differs from the 

proposed definition of ‘‘batch’’ by 

stating that a batch is a specific quantity 

of a dietary supplement that is 

‘‘uniform.’’

We inserted the word ‘‘uniform’’ in 

response to comments asking that we 

define ‘‘lot’’ to be consistent with 

‘‘batch.’’ We explain our reasons for 

harmonizing the definitions and for 

inserting ‘‘uniform’’ into the definition 

of ‘‘batch’’ in the response to comment 

42 of this document. 

We discuss the comments on our 

proposed definition of ‘‘batch’’ and our 

changes to the definition in our 

responses to the following comments. 

(Comment 38) Several comments ask 

us to clarify what the ‘‘same cycle of 

manufacture’’ is in the definition of 

‘‘batch.’’ One comment asks if it meant 

the same product made with the same 

lot(s) of raw materials regardless of how 

many days it took to produce the batch, 

or if it meant a quantity produced in 1 

day. The comment also asks whether 

batches produced on consecutive days, 

using the same formula, can be 

considered to be the same batch with 

respect to the proposed testing 

requirements if the quality control unit 

determined that different lots of raw 

materials are equivalent (e.g., by 

meeting all specifications). 

(Response) The ‘‘same cycle of 

manufacture’’ refers to a process during 

which equipment remains dedicated to 

the manufacture of the batch. The terms 

do not limit you to any particular time 

period or require you to operate 

equipment continuously until you have 

completed the ‘‘same cycle of 

manufacture.’’ The ‘‘same cycle of 

manufacture’’ also does not limit the 

number of lots of components you use. 

You may consider, as one batch, a 

product produced using different lots of 

raw materials where the production of 

the batch is a continuous process on a 

dedicated line. However, for each 

component that you use in the 

manufacture of the batch of dietary 

supplement, you would need to 

establish specifications under final 

§ 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 nonsubstantive, editorial 

revision in the last sentence to put 

parentheses around the reference to 

section 201(ff) of the act and to change 

the word order so that ‘‘component’’

includes ‘‘dietary ingredients * * * and 

other ingredients.’’ (The proposed 

definition had ‘‘components’’ including 

‘‘ingredients and dietary ingredients.’’) 

(Comment 39) Some comments would 

distinguish among ‘‘raw material,’’

‘‘components,’’ and ‘‘starting material’’

because the comments said that defining 

‘‘component’’ to include all these 

materials is confusing. One comment 

adds that many starting materials are 

not food grade or approved food 

ingredients until they have been 

processed. One comment states the term 

‘‘raw material’’ is typically used to 

describe the materials (such as dietary 

ingredients, fillers, and processing aids) 

that will be used to make the final 

product. The comment further states 

‘‘component’’ is typically used to 

describe the specific items used to 

assemble the finished product for the 

end user. The components would 

include packaging components such as 

bottles, caps, and labels, as well as the 

bulk dietary supplement. This comment 

also suggests that we use the term 

‘‘starting material’’ to distinguish 

substances used in the manufacture of 

dietary ingredients from substances 

used in the manufacture of dietary 

supplements. 

(Response) We decline to revise the 

rule as suggested by the comments. 

There may be differences in how 

components are referred to by certain 

manufacturers and how we refer to it in 

this final rule. However, for purposes of 

this final rule we refer to all substances 

used in the manufacture of dietary 

supplements as ‘‘components,’’ whether 

or not those substances appear in the 

finished product. 

Please note that, although ingredients 

are ‘‘components’’ under our definition, 

not all components are ingredients. For 

example, a solvent used to make an 

herbal extract is not an ingredient when 

it is removed from the extract by a 

process such as drying, because the 

solvent was not intended to be present 

in the finished dietary supplement. 

However, the solvent would be a 

‘‘component’’ because it was used in the 

manufacture of the dietary supplement. 


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As for materials that might not be 

food grade or approved food ingredients 

until processing, see the discussion in 

response to comment 240 in section XII 

of this document. 

(Comment 40) Several comments 

express concern that ‘‘component’’

could be interpreted to mean any 

constituent present in a botanical 

extract or other natural product. The 

comments say a single botanical can 

contain tens of thousands of 

constituents or metabolites and that 

chemists have not identified all 

constituents of a single botanical. 

According to the comments, the cost of 

testing for all constituents would exceed 

a product’s total annual revenues. 

(Response) In general, we would 

consider the botanical extract or the 

other natural product to be the 

‘‘component’’ as defined in this final 

rule rather than consider that all the 

various chemical substances contained 

in the botanical extract or other natural 

product are components. Thus, if you 

are manufacturing a dietary supplement 

that is intended to provide a certain 

substance (e.g., vitamin C ) and you add 

a natural product which is intended to 

supply the vitamin C (e.g., vitamin C in 

the form of rosehips), we would 

consider the natural product (e.g. 

rosehips that contain a certain amount 

of vitamin C) to be a component which 

must be listed in the master 

manufacturing record. The component 

specifications for the rosehips must 

include a specification for the strength 

of the substance (e.g., vitamin C) in 

whatever amount you determine is 

necessary to meet the specification for 

the strength of the vitamin C in the 

finished batch of dietary supplement. 

Under final § 111.70, we expect you to 

establish specifications for the natural 

product and ensure that the 

specifications are met. As an example 

relevant to an extract, if you are 

manufacturing a dietary supplement 

that is intended to provide a certain 

amount of vitamin C that derives from 

the natural product rosehips, and the 

substance that you purchase from a 

supplier to add as a component is a 

purified extract of rosehips (rather than 

rosehips themselves), we would 

consider the purified extract to be a 

component (as an ingredient). The 

component specifications for the 

purified extract must include a 

specification for the strength of the 

substance (i.e., vitamin C) in whatever 

amount you determine is necessary to 

meet the specification for the strength of 

the vitamin C in the finished batch of 

dietary supplement. However, in this 

example ‘‘rosehips’’ would not be 

considered a component, because 

‘‘rosehips’’ is not what you added. 

5. Contact Surface 

The final rule defines ‘‘contact 

surface’’ as ‘‘any surface that contacts a 

component or dietary supplement, and 

those surfaces from which drainage onto 

the component or dietary supplement, 

or onto surfaces that contact the 

component or dietary supplement, 

occurs during the normal course of 

operations.’’ The final rule lists 

containers, utensils, tables, contact 

surfaces of equipment, and packaging as 

examples of ‘‘contact surfaces.’’

We did not receive any substantive 

comments on the proposed definition. 

We deleted ‘‘ordinarily’’ from 

‘‘ordinarily occurs during the normal 

course of operations’’ because 

‘‘ordinarily’’ is redundant to ‘‘normal.’’

6. Ingredient 

The final rule defines ‘‘ingredient’’ as 

‘‘any substance that is used in the 

manufacture of a dietary supplement 

and that is intended to be present in the 

finished batch of the dietary 

supplement. An ingredient includes, but 

is not necessarily limited to, a dietary 

ingredient as defined in section 201(ff) 

of the act.’’ We did not receive any 

substantive comments on this 

definition. We made a nonsubstantive, 

editorial change to replace ‘‘finished 

dietary supplement’’ with ‘‘finished 

batch of the dietary supplement.’’

(Comment 41) One comment says we 

should define ‘‘ingredient’’ better to 

ensure consistent interpretation of 

CGMP at all levels throughout the 

dietary supplement industry. 

(Response) We disagree with the 

comment. We believe the definition is 

adequate, including as it does both 

dietary ingredients as described in 

section 201(ff) of the act and other 

ingredients that do not fit that 

description, such as an emulsifier used 

to establish a uniform dispersion in a 

liquid dietary supplement or a color 

additive used to color a capsule. 

Moreover, the comment did not explain 

or specify which aspects of the 

proposed definition should be revised 

or explain why the proposed definition 

would lead to inconsistent 

interpretations of CGMP. 

7. In-Process Material 

The final rule defines ‘‘in-process 

material’’ as ‘‘any material that is 

fabricated, compounded, blended, 

ground, extracted, sifted, sterilized, 

derived by chemical reaction, or 

processed in any other way for use in 

the manufacture of a dietary 

supplement.’’

We did not receive any substantive 

comments on the proposed definition. 

8. Lot 

The final rule defines ‘‘lot’’ as ‘‘a 

batch, or a specific identified portion of 

a batch, that is uniform and that is 

intended to meet specifications for 

identity, purity, strength, and 

composition; or, in the case of a dietary 

supplement produced by continuous 

process, a specific identified amount 

produced in a specified unit of time or 

quantity in a manner that is uniform 

and that is intended to meet 

specifications for identity, purity, 

strength, and composition.’’

The final rule differs from the 

proposed definition in that the proposed 

definition of ‘‘lot’’ would have the batch 

or specific identified portion of a batch 

be intended to have ‘‘uniform identity, 

purity, quality, strength, and 

composition.’’

(Comment 42) One comment agrees 

with the proposed definition for ‘‘lot,’’

but several other comments would 

revise the definition to be more 

consistent with the proposed definition 

of ‘‘batch.’’ Specifically, the comments 

note the proposed definition of ‘‘batch’’

would refer to a quantity of dietary 

supplement that is ‘‘intended to meet 

specifications for identity, purity, 

quality, strength and composition,’’

whereas the proposed definition of ‘‘lot’’

would refer to a batch or specific 

identified portion of a batch that is 

‘‘intended to have uniform identity, 

purity, quality, strength, and 

composition.’’ The comments would 

revise the definition of ‘‘lot’’ by deleting 

the phrase ‘‘intended to have uniform’’

and inserting the phrase ‘‘intended to 

meet specifications for’’ in order to 

make the definitions of ‘‘batch’’ and 

‘‘lot’’ consistent. 

(Response) We agree that the 

definitions for ‘‘batch’’ and ‘‘lot’’ should 

be consistent, but we disagree with the 

comments’ suggestion to delete the term 

‘‘uniform’’ from the definition of ‘‘lot.’’

The attributes of a lot or batch should 

be uniform throughout the lot or batch 

and meet established specifications for 

those attributes. If samples from a lot or 

batch were tested for appropriate 

specifications of identity, purity, 

strength, and composition, the attributes 

should be consistent throughout the 

sample and be uniform from sample to 

sample regardless of whether the test 

samples are taken from the beginning, 

middle, or end of the lot or batch. 

Consequently, we revised the definition 

of ‘‘lot’’ to state, in relevant part, that a 

‘‘lot’’ is a batch or specific identified 

portion of a batch that ‘‘is uniform and 

that is intended to meet specifications 


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for identity, purity, strength, and 

composition’’ or, for dietary 

supplements produced by a continuous 

process, a specific identified amount 

produced in a specified unit of time or 

quantity in a manner that is uniform 

and that is intended to meet 

specifications for identity, purity, 

strength, and composition.’’

Similarly, we revised the definition of 

‘‘batch’’ so that it states, in relevant part, 

that a ‘‘batch’’ is a specific quantity of 

a dietary supplement ‘‘that is intended 

to meet specifications for identity, 

purity, strength, and composition.’’

These revisions make the definitions 

of ‘‘batch’’ and ‘‘lot’’ consistent. 

9. Microorganisms 

The final rule defines 

‘‘microorganisms’’ as ‘‘yeasts, molds, 

bacteria, viruses, and other similar 

microscopic organisms having public 

health or sanitary concern.’’ It adds that 

the definition includes species that: (1) 

May have public health significance; (2) 

may cause a component or dietary 

supplement to decompose; (3) indicate 

that the component or dietary 

supplement is contaminated with filth; 

or (4) otherwise may cause the 

component or dietary supplement to be 

adulterated. 

(Comment 43) One comment would 

revise the definition to identify specific 

microorganisms that have public health 

or sanitary concern (i.e., Salmonella 

species, Escherichia coli, Pseudomonas 

aeruginosa, and Staphylococcus 

aureus). The comment says this would 

be consistent with USP requirements. 

(Response) We disagree with the 

comment. A list of specific 

microorganisms could easily become 

outdated as new pathogens emerge, and 

constantly issuing new rules to revise 

the list would be both inefficient and 

impractical. 

(Comment 44) One comment 

expresses concern that the proposed 

definition for microorganisms would 

include microorganisms that are a 

natural part of the ecology of all natural 

products. The comment says certain 

levels of microorganisms are expected 

on botanical raw materials (i.e., those 

naturally occurring or introduced 

through organic cultivation techniques) 

and that many do not present a public 

health risk. The comment expresses 

concern that nonpathogenic 

microorganisms that are not a public 

health risk would be a ‘‘sanitary’’

concern that would render a product 

adulterated. The comment argues there 

should be little concern about the 

presence of microorganisms that present 

no public health consequence, and so 

we should revise the definition 

accordingly. The comment further 

discusses the difficulties in ‘‘sterilizing’’

botanicals to render them free of 

microorganisms associated with 

insanitary conditions. The comment 

notes that some international 

organizations have established ‘‘upper 

limits’’ for these organisms for botanical 

supplements, which, in the comment’s 

opinion, represent more realistic 

standards than trying to attain a 

‘‘sterile’’ botanical supplement. 

(Response) We disagree with the 

comment. We do not interpret the 

definition of ‘‘microorganism’’ as 

making the presence of nonpathogenic 

microorganisms that are not a public 

health risk a ‘‘sanitary concern’’ that 

would render a product adulterated. 

Instead, we interpret the definition as 

saying that microorganisms of public 

health significance and microorganisms 

presenting sanitary concerns are 

‘‘microorganisms’’ under this rule. 

These are the types of microorganisms 

that may cause a component or dietary 

supplement to become adulterated. 

As for upper limits on microbial 

contamination, the comment offered no 

suggested limits, and we decline to 

establish such limits in this rule. The 

final rule requires manufacturers to 

establish limits for those types of 

contamination that may adulterate or 

lead to adulteration of components or 

dietary supplements. Thus, for example, 

a manufacturer of a botanical dietary 

supplement would have to determine 

what, if any, microorganisms are likely 

or certain to be present and establish 

limits, as appropriate to prevent 

adulteration of the finished batch of the 

dietary supplement. 

We have modified the word ‘‘have’’

with the word ‘‘may’’ to indicate that 

the determination or evaluation of 

whether there is a ‘‘public health 

significance’’ is not made after the fact. 

There does not have to be a factually 

established determination of public 

health significance for you to conclude 

that the microorganisms ‘‘may 

adulterate’’ the dietary supplement. The 

change from ‘‘could cause’’ to ‘‘may 

cause’’ is to be consistent with the 

previous change to ‘‘may have.’’

10. Must 

The final rule explains that the word 

‘‘must’’ is ‘‘used to state a requirement.’’

(Comment 45) One comment would 

revise the definition to say that the term 

‘‘must’’ be used to state mandatory 

requirements ‘‘unless shown to be 

inapplicable or replaced by an 

alternative demonstrated to provide at 

least an equivalent level of quality 

assurance.’’

(Response) We decline to revise the 

rule as suggested by the comment. The 

comment’s revision would undermine 

the reasons for issuing a rule. Rules 

create enforceable requirements. It is not 

clear, nor did the comment discuss, how 

we could enforce the requirements in 

this final rule if firms were able to avoid 

a particular requirement by declaring 

them to be ‘‘inapplicable’’ or 

substituting alternatives which they felt 

they had demonstrated were ‘‘at least an 

equivalent level of quality assurance.’’

There would be inconsistency in the 

general CGMP practices used within the 

dietary supplement industry and 

uncertainty as to whether the process 

and production controls ensure the 

quality of the dietary supplement. 

Consequently, we decline to revise the 

rule as suggested by the comment. 

We have, however, made a 

nonsubstantive, editorial change to the 

definition so that ‘‘must’’ is used to state 

‘‘a requirement.’’ The proposed 

definition had referred to ‘‘mandatory 

requirements.’’ Since a requirement by 

its nature is mandatory, the word 

‘‘mandatory’’ is unnecessary. 

11. Pest 

The final rule defines ‘‘pest’’ as ‘‘any 

objectionable insect or other animal, 

including birds, rodents, flies, mites, 

and larvae.’’

We did not receive any substantive 

comments on this definition. However, 

on our own initiative, we made 

nonsubstantive, editorial changes to 

delete the words, ‘‘but not limited to’’

after ‘‘including’’ and to place the word 

‘‘animals’’ in the singular. 

12. Physical Plant 

The final rule defines ‘‘physical 

plant’’ as ‘‘all or any part of a building 

or facility used for or in connection with 

manufacturing, packaging, labeling, or 

holding a dietary supplement.’’

We received no substantive comments 

on this definition. The final rule is 

substantially similar to the proposed 

rule’s definition of ‘‘physical plant.’’ We 

added ‘‘any’’ and placed ‘‘part’’ in the 

singular to clarify that individual parts 

of a building or facility are subject to the 

CGMP requirements. 

13. Product Complaint 

The final rule defines ‘‘product 

complaint’’ as ‘‘any communication that 

contains any allegation, written, 

electronic, or oral, expressing concern, 

for any reason, with the quality of a 

dietary supplement, that could be 

related to current good manufacturing 

practice. Examples of product 

complaints are: Foul odor, off taste, 

illness or injury, disintegration time, 


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color variation, tablet size or size 

variation, under-filled container, foreign 

material in a dietary supplement 

container, improper packaging, 

mislabeling, or dietary supplements that 

are superpotent, subpotent, or contain 

the wrong ingredient, or contain a drug 

or other contaminant (e.g., bacteria, 

pesticide, mycotoxin, glass, lead).’’

This definition modifies the proposed 

rule’s definition of ‘‘consumer 

complaint,’’ which would define such a 

complaint as any ‘‘communication that 

contains any allegation, written or oral, 

expressing dissatisfaction with the 

quality of a dietary supplement related 

to good manufacturing practices. 

Examples of product quality related to 

good manufacturing practices are: Foul 

odor, off taste, superpotent, subpotent, 

wrong ingredient, drug contaminant, 

other contaminant (e.g., bacteria, 

pesticide, mycotoxin, glass, lead), 

disintegration time, color variation, 

tablet size or size variation, under-filled 

container, foreign material in a dietary 

supplement container, improper 

packaging, or mislabeling. For the 

purposes of this regulation, a consumer 

complaint about product quality may or 

may not include concerns about a 

possible hazard to health. However, a 

consumer complaint does not include 

an adverse event, illness, or injury 

related to the safety of a particular 

dietary ingredient independent of 

whether the product is produced under 

good manufacturing practices.’’

We explain the reasons for revising 

the proposed definition in our response 

to the following comments. 

(Comment 46) Some comments would 

broaden the definition of consumer 

complaint to include complaints from 

dietary ingredient suppliers. One 

comment would change ‘‘consumer 

complaint’’ to ‘‘customer complaint.’’

(Response) As discussed in section VI 

of this document, the final rule does not 

apply to those who only manufacture 

dietary ingredients. However, we 

encourage such firms that receive 

complaints about a dietary supplement 

to share those complaints with those in 

the manufacturing chain associated with 

that dietary supplement’s manufacture 

so others may take corrective action as 

needed. Those who engage in the 

manufacture of a dietary supplement, 

including manufacturing, packaging, 

labeling, and holding operations, are 

responsible for complying with this 

final rule’s product complaint 

requirements. 

Furthermore, we encourage packagers, 

labelers, and distributors who receive a 

product complaint to notify those in a 

dietary supplement’s manufacturing 

chain about product complaints they 

receive or they, themselves, generate 

that may relate to operations outside the 

packagers’, labelers’, or distributors’

control. For example, a distributor who 

purchases a dietary supplement in bulk 

for packaging and labeling may 

complain about product quality to the 

dietary supplement manufacturer. The 

manufacturer who receives the 

complaint must then take appropriate 

action to determine whether the 

complaint involves a possible failure of 

a dietary supplement to meet any CGMP 

requirements. Thus, the final rule 

revises the term ‘‘consumer complaint’’

to ‘‘product complaint’’ to emphasize 

that the complaint is about the product 

regardless of the complaint’s source. 

(Comment 47) One comment 

disagrees that ‘‘disintegration time’’ and 

‘‘tablet size’’ are appropriate examples 

of complaints about product quality 

specifications. 

(Response) We disagree with this 

comment. Complaints about 

disintegration time or tablet size could 

indicate a problem with the production 

and process control system that may 

affect the quality of the dietary 

supplement. 

(Comment 48) Some comments 

disagree with the proposed definition of 

‘‘consumer complaint’’ because it 

excluded an adverse event, illness, or 

injury related to the safety of a 

particular dietary ingredient. The 

comments say there should be a 

consistent approach for handling all 

complaints, including adverse events. 

One comment states consumers will not 

be able to determine whether a product 

quality issue related to CGMP caused an 

adverse event. This comment expresses 

concern that not classifying adverse 

events as consumer complaints could 

lead manufacturers to avoid 

investigating certain adverse events and, 

therefore, prevent them from 

determining the appropriate cause and 

implementing the associated corrective 

action. The comments stress we should 

not treat complaints related to CGMP 

issues differently from other complaints 

and urged us to classify all adverse 

events as consumer complaints, whether 

or not they might have been caused by 

a particular dietary ingredient. 

A few comments state the proposal, 

which did not specifically address 

adverse event reporting, but did address 

the broader category of consumer 

complaints and would require 

companies to investigate ‘‘adverse event 

reports,’’ may simply create more 

confusion and may contradict the 

overall objective of a comprehensive 

adverse event reporting system. The 

comments also state neither the food 

CGMP regulations nor the 1997 ANPRM 

defined ‘‘consumer complaints.’’ The 

comments say we should delete this 

definition and deal with consumer 

complaints separately as part of the new 

CFSAN Adverse Event Reporting 

System (CAERS). 

One comment states we should define 

the term ‘‘serious adverse dietary 

supplement experience.’’ The comment 

would define a ‘‘serious adverse dietary 

supplement experience’’ as ‘‘any 

adverse dietary supplement experience 

occurring at any dose that results in any 

of the following outcomes: death, a lifethreatening 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 lifethreatening, or require hospitalization 

may be considered a serious adverse 

dietary supplement experience and, 

based upon appropriate medical 

judgment, they may jeopardize the 

patient or subject and may require 

medical or surgical intervention to 

prevent one of the outcomes listed in 

this definition.’’

(Response) We decline to include in 

the definition of ‘‘product complaint’’

an adverse event related to the safety of 

a particular dietary ingredient. The final 

rule establishes CGMP requirements for 

dietary supplements and does not focus 

on whether dietary ingredients that 

manufacturers may use in their dietary 

supplements are inherently safe. 

Nevertheless, we encourage firms to 

investigate all complaints, regardless of 

whether the complaints relate to CGMP. 

Furthermore, mandatory reporting to 

FDA of serious adverse events is now 

required as a result of the enactment of 

the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection 

Act’’ (Public Law 109–462), signed into 

law on December 22, 2006. In any event, 

consistent with these CGMP 

requirements, manufacturers must 

establish limits on contamination, as 

needed, for all ingredients or any 

component they use in manufacturing a 

dietary supplement. 

We agree it may be unclear whether 

a particular product complaint is related 

to CGMP. Final § 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 


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comply with the requirements in 

subpart O, unless the firm affirmatively 

determines that the complaint is not 

related to a ‘‘possible failure’’ to meet 

CGMP, and therefore, is not a ‘‘product 

complaint.’’ To make this clear, we 

revised the definition so that it applies 

to any ‘‘communication * * * that 

could be related to good manufacturing 

practice’’ rather than to be any 

‘‘communication * * * that is related to 

good manufacturing practice.’’

We disagree with comments that 

suggested that the requirements for 

product complaints would somehow 

contradict the overall objective of the 

CAERS. This final rule has no effect on 

the mandatory or voluntary reporting of 

adverse events. We agree some adverse 

events may be related to a failure to 

ensure the quality of the dietary 

supplement as required by the final 

rule. To the extent that an adverse event 

is associated with CGMP, it would be 

considered a ‘‘product complaint’’

under the final rule. The fact that it is 

considered a product complaint does 

not mean that such complaint could not 

be voluntarily reported as an adverse 

event through CAERS. Such a complaint 

may be required to be reported under 

the mandatory reporting requirements of 

the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection 

Act’’ (Public Law 109–462), signed into 

law on December 22, 2006. We have 

added ‘‘illness or injury’’ to the final 

rule’s definition of ‘‘product complaint’’

as an example of a product problem 

relating to CGMP to help clarify that 

there may be some overlap in the type 

of complaints related to product quality 

that may also be considered an adverse 

event. 

As for defining ‘‘serious adverse 

dietary supplement experience,’’ we 

decline to add such a definition to the 

final rule. We define certain terms in a 

rule to give those terms a clear and 

consistent meaning. None of the 

provisions in this rule addresses or even 

mentions ‘‘serious adverse dietary 

supplement experiences,’’ so there 

would be no advantage in codifying a 

definition for the term in this final rule. 

If, however, the comment meant to 

narrow the definition of ‘‘consumer 

complaint’’ to ‘‘serious’’ illness, or 

injury, we decline to do so. If a 

consumer reports an illness or injury, 

which he or she attributes to consuming 

a dietary supplement, the report may 

indicate a problem with the production 

and process control system for that 

dietary supplement, even if the injury or 

illness is not ‘‘serious’’ or severe. 

We have, however, decided to delete 

the last two sentences in the proposed 

definition of ‘‘consumer complaint’’

(now ‘‘product complaint’’ in the final 

rule). These sentences explained, in 

part, that a consumer complaint does 

not include an adverse event, illness, or 

injury related to the safety of a 

particular dietary ingredient 

independent of whether the product is 

produced under CGMP. We deleted 

those sentences because they are 

unnecessary to include in the definition 

and can be included as further 

explanation of what the definition of 

‘‘product complaint’’ means in the 

preamble discussion. 

The proposed definition of ‘‘consumer 

complaint’’ used the phrase ‘‘expressing 

dissatisfaction with the quality of a 

dietary * * * supplement;’’ the final 

rule uses the phrase ‘‘expressing 

concern, for any reason, with the quality 

of a dietary supplement.’’ This change is 

to ensure that even if the consumer is 

not actually dissatisfied with the 

product, but has a concern with the 

product, this is still handled as a 

product complaint. 

We made several editorial or 

grammatical changes to the definition of 

product complaint in this final rule for 

simplicity and revised the order of the 

listed examples of product complaints. 

For example, the proposed definition of 

‘‘consumer complaint’’ states the term 

‘‘means communication that contains 

any allegation * * *.’’ The final rule 

defines ‘‘product complaint’’ as 

meaning ‘‘any communication that 

contains any allegation * * *.’’ Another 

nonsubstantive change was to insert the 

words ‘‘dietary supplements that are’’

before ‘‘superpotent, subpotent’’ to give 

the reader a clear understanding as to 

the article that is superpotent or 

subpotent. 

Finally, we added ‘‘electronic’’ as an 

example of how a product complaint 

could be communicated to ensure that 

all forms of communication are 

included and added ‘‘current’’ to modify 

‘‘good manufacturing practice’’ for 

consistency. 

We discuss in section V of this 

document, our general response to the 

comment that stated that neither the 

food CGMP regulations nor the 1997 

ANPRM contains a definition of 

‘‘consumer complaint,’’ is in our 

discussion of whether this final rule 

exceeds our authority or it has to be 

identical to the food CGMP regulations. 

More specifically, we acknowledge that 

the industry draft that we published in 

the 1997 ANPRM did not define 

‘‘consumer complaint.’’ The industry 

draft did contain provisions that would 

be directed to ‘‘complaint files.’’ The 

provisions for complaint files would 

require the use of written procedures to 

handle complaints, retention of records 

of complaints for a certain time period, 

and the inclusion of specific 

information in the record of a 

complaint. 

14. Quality 

For purposes solely of this final rule 

we have decided to define ‘‘quality.’’

Quality means that the dietary 

supplement consistently meets the 

established specifications for identity, 

purity, strength, and composition and 

limits on contaminants and has been 

manufactured, packaged, labeled, and 

held under conditions to prevent 

adulteration under section 402(a)(1), 

(a)(2), (a)(3), and (a)(4) of the act. 

(Comment 49) Some comments asked 

that we define ‘‘quality.’’ Some 

comments claimed the proposal 

described ‘‘quality’’ in terms of 

‘‘identity,’’ ‘‘purity,’’ and 

‘‘composition.’’ One comment would 

define ‘‘quality’’ as ‘‘the total 

characteristics of a product that bear on 

its ability to satisfy stated (i.e., labeled) 

or implied needs of identity, purity, 

strength and composition.’’ Another 

comment would define ‘‘quality’’ as 

‘‘having the appropriate identity, purity, 

and strength for the intended purpose.’’

Another comment would define quality 

using all the other attributes of identity, 

purity, strength and composition. 

(Response) For purposes only of this 

final rule, we have added a definition of 

quality. This definition is not intended 

to apply to CGMP requirements other 

than those that apply to dietary 

supplements. In section III of this 

document, in the overview discussion, 

we discuss the concept of ‘‘quality’’ as 

it applies to these dietary supplement 

CGMP requirements and the distinction 

between the use of the term in the final 

rule and in the proposed rule. 

Because we have defined ‘‘quality’’ as 

encompassing identity, purity, strength, 

and composition, we have revised each 

section with requirements for the 

‘‘identity, purity, quality, strength, and 

composition’’ to remove the word 

‘‘quality.’’ The affected sections in this 

final rule are: § 111.3 (definition of 

batch); § 111.3 (definition of lot); 

§ 111.65 (‘‘What are the requirements for 

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 (‘‘Under this subpart 

E, 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 


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(‘‘When must a returned dietary 

supplement be bestroyed, or otherwise 

suitably disposed of?’’). 

15. Quality Control 

The final rule defines ‘‘quality 

control’’ as ‘‘a planned and systematic 

operation or procedure for ensuring the 

quality of a dietary supplement.’’ The 

proposed rule defined ‘‘quality control’’

as ‘‘a planned or systematic operation 

for preventing a dietary ingredient or 

dietary supplement from being 

adulterated.’’

(Comment 50) One comment suggests 

revising the definition to use more 

positive language. Specifically, the 

comment would define ‘‘quality 

control’’ as ‘‘a planned and systematic 

operation or procedure for ensuring the 

quality of dietary supplement 

products.’’

(Response) We agree that the 

comment’s suggested language conveys 

a positive concept about quality 

control’s role and value and adopt the 

language in part. The final rule’s quality 

control requirements will help ensure 

compliance with other CGMP 

requirements and, therefore, will help 

ensure the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. We have defined the term 

‘‘quality’’ in this final rule as including 

preventing a dietary supplement from 

being adulterated. Consequently, we 

revised the definition of ‘‘quality 

control’’ to state that ‘‘quality control’’

means a planned and systematic 

operation or procedure ‘‘for ensuring the 

quality of a dietary supplement.’’ We 

deleted ‘‘for preventing a dietary 

ingredient or dietary supplement from 

being adulterated’’ in the proposed 

definition since the concept of quality 

includes preventing adulteration. 

16. Quality Control Personnel 

The final rule defines ‘‘quality control 

personnel’’ as ‘‘any person, persons, or 

group, within or outside your 

organization, who you designate to be 

responsible for your quality control 

operations.’’

(Comment 51) Some comments seem 

to suggest that the reference in the 2003 

CGMP Proposal to a ‘‘quality control 

unit’’ mandates a separate unit or 

department with responsibility for all 

quality control operations. One 

comment explains many companies do 

not have one quality control unit with 

oversight of all operations within the 

facility. This comment states companies 

commonly have each separate section of 

an operation perform both its function 

and its own quality control. A few 

comments would clarify the definition 

by indicating that a distinct or separate 

unit need not perform the quality 

control function. These comments say 

the quality control function is best 

performed by a person or persons 

qualified by training, education, or 

experience in the different processing 

areas. 

Many comments say we should 

consider any individual carrying out a 

quality control function to be part of the 

quality control unit for purposes of this 

rule. 

(Response) We agree that the quality 

control function is best performed by a 

person or persons qualified by training, 

education, or experience in relevant 

areas. To the extent that the comments 

interpreted the proposed definition as 

requiring firms to have a separate 

person or group whose sole function in 

the company is to perform quality 

control operations or that the quality 

control functions are limited to those 

who are employed within the firm, we 

disagree. As discussed in the preamble 

to the proposal, the quality control unit 

should consist of as many people as 

necessary to perform the quality control 

operations (68 FR 12157 at 12252). We 

have reconsidered the use of the term 

‘‘unit.’’ In order to clarify that we do not 

intend to require a separate division or 

office be created, we instead use the 

term ‘‘personnel.’’ Although we have 

eliminated references to ‘‘unit,’’ we still 

agree that personnel can be a person, 

persons, or a group, and as many 

persons as necessary, who perform the 

quality control operations. The 

manufacturer must identify the 

appropriate person or persons to be 

responsible for the quality control 

operations associated with a particular 

manufacturing operation. For example, 

the manufacturer may designate one 

individual as a packaging expert who is 

responsible for the quality control 

operations related to packaging, 

designate a second individual as an 

expert in deciding whether to accept or 

reject incoming components, and 

designate a third individual as an expert 

in deciding whether in-process 

specifications are met at certain control 

points. The definition does not limit the 

other activities that these designated 

individuals may perform within the 

manufacturing operations; thus, for 

example, the packaging expert who 

performs the quality control function for 

packaged dietary supplements could 

also have responsibilities in the actual 

packaging operation. Quality control 

responsibilities and specific activities 

are distinct and separate from any other 

responsibilities and specific activities 

that an employee might perform for any 

other operation. In addition, the quality 

control operations may be performed by 

someone outside the organization (such 

as a contractor). 

To clarify these points and to prevent 

potential misinterpretation of quality 

control operations, we revised the 

definition of ‘‘quality control unit.’’

Instead of a unit, quality control 

personnel who perform quality control 

operations may be a person, persons, or 

group and may be ‘‘within or outside of 

your organization.’’ We also added a 

new § 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 nonsubstantive 

grammatical changes to insert ‘‘that are’’

between ‘‘and’’ and ‘‘intended.’’

(Comment 52) Some comments note 

the proposed rule would use the terms 

‘‘representative sample,’’ ‘‘reserve 

sample,’’ and ‘‘representative reserve 

sample’’ but would only define 

‘‘representative sample.’’ The comments 

ask us to clarify the distinction, if any, 

between these terms. 

(Response) A ‘‘reserve sample’’ is a 

sample that is to be held or kept for a 

designated time. It differs from a 

‘‘representative sample’’ in the sense 

that a representative sample is not 

always kept; for example, one might 

take a representative sample to test 

product quality, but one would not 

necessarily keep every tested sample. 

To clarify this distinction, the final 

rule now defines a ‘‘reserve sample’’ as 

‘‘a representative sample of product that 


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is held for a designated period of time.’’

We also revised the rule to refer solely 

to a ‘‘reserve sample’’ rather than use 

both ‘‘reserve sample’’ and 

‘‘representative reserve sample.’’

18. Reprocessing 

The final rule defines ‘‘reprocessing’’

as ‘‘using, in the manufacture of a 

dietary supplement, clean, 

uncontaminated components or dietary 

supplements that have been previously 

removed from manufacturing and that 

have been made suitable for use in the 

manufacture of a dietary supplement.’’

We modified the definition that, in part, 

read ‘‘* * * dietary supplements that 

have been previously removed from 

manufacturing for reasons other than 

insanitary conditions’’ by removing ‘‘for 

reasons other than insanitary 

conditions’’ to expand the scope of what 

may be reprocessed. We explain the 

reason for the latter change in our 

response to the following comments. We 

also changed ‘‘unadulterated’’ to 

‘‘uncontaminated’’ to be consistent with 

the revisions we have made in other 

sections, including the definition of 

quality. 

(Comment 53) Some comments ask us 

to clarify whether components or 

dietary supplements that have been 

successfully treated to reduce microbial 

levels to acceptable levels can be 

reprocessed. Some comments object to 

the proposed definition of 

‘‘reprocessing’’ because it did not 

include components or dietary 

supplements removed for insanitary 

conditions, and several comments object 

to the restrictions to reprocessing 

described in proposed 

§§ 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 of this document). 

19. Reserve Sample 

The final rule contains a new 

definition of ‘‘reserve sample.’’ ‘‘Reserve 

sample’’ is defined as ‘‘a representative 

sample of product that is held for a 

designated period of time.’’ We explain 

our reasons for creating this definition 

in this section under the definition of 

‘‘representative sample.’’

20. Sanitize 

The final rule defines ‘‘sanitize’’ as 

‘‘to adequately treat cleaned equipment, 

containers, utensils, or any other 

cleaned contact surface by a process that 

is effective in destroying vegetative cells 

of microorganisms of public health 

significance, and in substantially 

reducing numbers of other 

microorganisms, but without adversely 

affecting the product or its safety for the 

consumer.’’

The final rule’s definition of 

‘‘sanitize’’ differs from the proposal in 

that the proposed definition would have 

specified a reduction of 5 logs or 99.999 

percent reduction of ‘‘representative 

disease microorganisms of public health 

significance’’ and ‘‘other undesirable 

microorganisms’’ and would have 

specified the use of heat or chemicals. 

The preamble to the 2003 CGMP 

Proposal explained that we based the 

proposed definition of ‘‘sanitize’’ on the 

definition of ‘‘sanitization’’ in the ‘‘Food 

Code’’ (which is a model that gives food 

control authorities a scientifically sound 

technical and legal basis for regulating 

the retail and food service segment of 

the industry) because dietary 

supplements are often consumed 

without further processing, similar to 

foods consumed in retail outlets (68 FR 

12157 at 12179). The preamble to the 

2003 CGMP Proposal also explained 

that, to achieve the reduction levels in 

the proposed definition, one would 

need to validate control measures to 

ensure they are both appropriate to their 

operation and scientifically sound. The 

preamble explained that in many cases, 

manufacturers may rely on a written 

certification from the equipment 

manufacturer or may obtain a written 

scientific evaluation of a process, 

especially in cases where two or more 

control measures are used to accomplish 

the 99.999 percent reduction in the 

target pathogen, to ensure the process is 

adequate to destroy microorganisms of 

public health significance or to prevent 

their growth. 

(Comment 54) Many comments object 

to the proposed text concerning the 

application of heat or chemicals to a 

food contact surface to yield a reduction 

of 5 logs or 99.999 percent of 

representative disease organisms of 

public health significance. The 

comments state the aspect of the 

proposed definition is overly 

prescriptive, beyond our legal authority, 

and would not provide additional 

public health benefits. Many comments 

say it is inappropriate to use the 

definition of sanitization from our Food 

Code because retail and manufacturing 

operations are distinct. A few comments 

assert the process of manufacturing 

dietary supplements shares more in 

common with food or drug 

manufacturing than with retail 

operations. Most comments recommend 

that we define ‘‘sanitize’’ in the manner 

that was presented in the 1997 ANPRM 

and consistent with the current food 

CGMP definition at § 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. 


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Other comments express concern 

about validating control measures to 

ensure that they are scientifically sound 

and appropriate to operations and the 

economic burden to do the testing. A 

few comments state it would be difficult 

to show a 100,000-fold reduction on an 

already cleaned surface, particularly if 

the pre-sanitization level is at or near 

the lower limit of the test method 

employed. 

One comment states the definition 

required the manufacturer to 

demonstrate a 100,000-fold reduction in 

microbial count every time a food 

contact surface is sanitized. A few 

comments express concern that 

processing lines would have to be 

closed down each time they are 

sanitized in order to test them, creating 

a financial hardship especially on 

smaller operations. Other comments ask 

us to give companies the flexibility 

necessary to monitor sanitation needs 

based on individual products and 

manufacturing operations to be 

consistent with existing industry 

practices and food and drug CGMPs. 

One comment requests we clarify that 

a sanitizing agent for use on food 

processing equipment must be approved 

in accordance with part 178, Indirect 

Food Additives: Adjuvants, Production 

Aids, and Sanitizers (21 CFR part 178) 

and our expectations with respect to 

what documentation would be 

necessary to prove the effectiveness of 

the sanitizer used. Two comments say 

the proposed definition of sanitize 

means that manufacturers must perform 

validation studies to demonstrate that 

the sanitizers they are using reduce the 

microbial load on equipment by 

100,000-fold, a requirement for a 

‘‘sanitizer’’ under regulations issued by 

the Environmental Protection Agency. 

The comments say a sanitizer should 

not be held to this standard for the 

purpose of reducing microbial loads on 

food product contact surfaces, and that 

manufacturers of a solid dosage form 

may not need to ‘‘sanitize’’ their 

equipment because the processing 

environment is not suitable for 

microbial growth due to the low water 

activity. One comment recommended 

using the approach in the Food Code, 

which specifies conditions under which 

chemical sanitizers listed in § 178.1010 

may be used, including the requirement 

that they be used in accordance with the 

Environmental Protection Agencyapproved 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 nonbinding information is 

inconsistent with our current practices 

for establishing regulations. 

We note that the Environmental 

Protection Agency has regulatory 

authority over certain uses of sanitizers 

as pesticide chemicals and we have 

regulatory authority over certain uses of 

sanitizers as food additives. Under 

section 201(q)(1)(B) of the act, as 

amended by the Food Quality Protection 

Act (FQPA) (Public Law 104–170) and 

the Antimicrobial Regulation Technical 

Corrections Act (ARTCA) (Public Law 

105–324), certain substances used as 

food contact surface sanitizing solutions 

are subject to the Environmental 

Protection Agency’s regulatory authority 

as pesticide chemicals. The 

Environmental Protection Agency 

recently codified tolerance exemptions 

under section 408 of the act (21 U.S.C. 

346a) for those food contact surface 

sanitizing solutions that were 

previously subject to our authority at 

§ 178.1010 and transferred to the 

Environmental Protection Agency’s 

authority under FQPA and ARTCA (see 

40 CFR 180.940 (69 FR 23113, April 28, 

2004). Such pesticide chemicals must 

comply with the Pesticide Tolerance 

regulations in 40 CFR 180.940. 

Sanitizers used on food packaging must 

comply with our regulations at 

§ 178.1010. For an in depth discussion 

of appropriate sanitizers for food contact 

surface use, see the Environmental 

Protection Agency’s Pesticides; 

Tolerance Exemptions for Active and 

Inert Ingredients for Use in 

Antimicrobial Formulations (Food 

Contact Surface Sanitizing Solutions) 

(69 FR 23113, April 28, 2004) and DIS/ 

TSS–4 Efficacy Data Requirements 

Sanitizing Rinses (for previously 

cleaned food-contact surfaces) (January 

30, 1979) (Ref. 27) (available on the 

Internet at http://www.epa.gov/ 

oppad001/dis_tss_docs/dis-04.htm). 

21. Theoretical Yield 

The final rule defines ‘‘theoretical 

yield’’ as ‘‘the quantity that would be 

produced at any appropriate step of 

manufacture or packaging of a particular 

dietary supplement, based upon the 

quantity of components or packaging to 

be used, in the absence of any loss or 

error in actual production.’’

We received no substantive comments 

on the proposed definition. 

22. Water Activity 

The final rule defines ‘‘water activity’’

as ‘‘a measure of the free moisture in a 

component or dietary supplement and is 

the quotient of the water vapor pressure 

of the substance divided by the vapor 

pressure of pure water at the same 

temperature.’’

We received no substantive comments 

on the proposed definition. 


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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 this part.’’ 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 inprocess 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 

nonstandardized herbals because there 

are no current industry standards for 

these products. This comment suggests 

we clarify the term ‘‘strength’’ so it 

refers to having the correct amount of a 

stated ingredient. One comment notes 

St. Johns wort has a composition of 

approximately 40 different constituents 

in addition to the essential oil that 

contains numerous constituents. The 

comment asks which constituent it 

should use to determine ‘‘strength.’’

Another comment would use the term 

‘‘quantity’’ instead of ‘‘strength.’’

One comment would define 

‘‘composition’’ as ‘‘having the intended 

mix of components or ingredients, 

including dietary ingredients.’’ Another 

comment would delete ‘‘composition’’

from the rule because, the comment 

claimed, an FDA investigator might 

conclude that ‘‘composition’’ refers to 

every constituent of every botanical. 

According to this comment, there are 

many tests that could be used to identify 

the botanical constituents, but that it 

would be economically exhausting 

considering the number of botanical 

constituents, and it would not 

contribute to quality or safety. 

(Response) We decline to revise the 

rule to define identity, purity, strength, 

or composition. The exact way in which 

the dietary supplement industry uses 

these terms may vary, and defining 

these terms could limit the flexibility 

that is needed to accommodate such 

variations. 

Nevertheless, to elaborate on our 

interpretation of identity, purity, 

strength, and composition, and to 

respond to the particular concerns 

raised by some comments, we provide 

the following information. 

a. Identity. The ‘‘identity’’ of a dietary 

supplement refers to the dietary 

supplement’s consistency with the 

master manufacturing record and/or that 

it is the same as described in the master 

manufacturing record. 

b. Purity. The ‘‘purity’’ of a dietary 

supplement refers to that portion or 

percentage of a dietary supplement that 

represents the intended product. For 

example, amino acids generally can 

exist in two forms (i.e., dextro (D-, or 

right) and levo (L-, or left) forms) called 

enantiomers. Enantiomers have the 

same chemical formula and the same 

chemical structure, but differ in their 

three-dimensional orientation. If you 

manufacture a dietary supplement to 

provide the amino acid L-arginine, and 

you determine that 90 percent of the 

manufactured product is L-arginine and 

10 percent of the manufactured product 

is D-arginine, you could describe your 

L-arginine product as ‘‘90 percent 

pure.’’ As another example, if you 

manufacture a mixture of triglycerides 

that provides polyunsaturated fatty 

acids in the diet, the manufactured 

triglycerides may contain small amounts 

of free fatty acids and sterols. The free 

fatty acids and sterols could derive, for 

example, from the source of the 

triglycerides or could be byproducts of 

the manufacturing process. If you 

determine that 95 percent of the 

manufactured product is the mixture of 

the triglycerides that provides the 

polyunsaturated fatty acids, and 5 

percent of the product is free fatty acids 

and sterols, you could describe the 

purity of your product as ‘‘95 percent 

pure.’’

Just as we use the term ‘‘purity’’ to 

refer to the identity and amount of a 

dietary supplement that is the desired 

product, we use ‘‘impurity’’ to refer to 

the identity and amount of a dietary 

supplement that is not the desired 

product. In the previous examples, we 


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view the D-arginine that is present in 

the product that is intended to be Larginine as an ‘‘impurity,’’ and we view 

the free fatty acids and sterols that are 

present in the product that is intended 

to be a mixture of triglycerides that 

provide polyunsaturated fatty acids in 

the diet as ‘‘impurities.’’ For the 

purposes of these examples, we do not 

view these ‘‘impurities’’ as 

‘‘contaminants.’’

If the comments were concerned that 

the dietary supplement CGMP 

requirements regarding a dietary 

supplement’s ‘‘purity’’ mean that we 

expect you to characterize each 

constituent of a natural product to 

determine whether each constituent is 

present in a certain pre-established 

quantity (i.e., purity specification) to 

determine whether it contributes to the 

‘‘purity’’ of the dietary supplement or 

would be considered as an ‘‘impurity,’’

we do not consider such constituents to 

be ‘‘components’’ of a dietary 

supplement (see discussion of the 

definition of component in this section). 

For example, if you manufacture a 

dietary supplement containing fish oil, 

we would not consider the triglycerides, 

which are constituents of the fish oil, to 

be components. Likewise, we would not 

consider particular fatty acids (such as 

the polyunsaturated fatty acids 

docosahexaenoic acid (DHA) and 

eicosapentaenoic acid (EPA)), which are 

constituents of the triglycerides, to be 

components of the dietary supplement. 

In this example, you would be required 

to establish a purity specification for the 

amount of triglycerides in the fish oil. 

(Note that if you are manufacturing fish 

oil to provide the fatty acids DHA and 

EPA in the dietary supplement, the 

component specifications for the fish oil 

must include a strength specification for 

DHA and EPA in whatever amount you 

determine is necessary to meet the 

specification for strength of DHA and 

EPA in the dietary supplement.) We do, 

however, expect you to set appropriate 

limits on contaminants (e.g., toxic 

substances) that are known to be 

constituents of botanical extracts or 

other natural products that are likely or 

certain to contain constituents that are 

harmful. 

c. Strength. The strength of a dietary 

supplement relates to its concentration. 

By concentration, we mean the 

quantitative amount per serving (for 

example, weight/weight, weight/ 

volume, or volume/volume). Therefore, 

for purposes of this final rule, strength 

does not refer simply to the quantity of 

an ingredient, rather it refers to the 

amount of a stated ingredient per a 

specified unit of measure. 

If the comments were concerned that 

the ‘‘strength’’ of a dietary supplement 

meant that you need to establish the 

quantitative amount per unit of measure 

of each constituent in a dietary 

ingredient, such as a botanical extract or 

natural product, we do not consider 

such constituents to be ‘‘components’’

of a dietary supplement, unless you add 

such constituents as components (as in 

an extract) (see discussion of the 

definition of component in this section). 

We do not consider the rule’s 

requirements on dietary supplement 

strength as necessarily relating to the 

individual constituents of such 

products. Whether the requirements 

regarding dietary supplement strength 

apply to one or more constituents of 

dietary ingredients in a dietary 

supplement depends on what you are 

manufacturing. For example, if you are 

manufacturing vitamin C, and your 

source of vitamin C is rosehips, you 

would establish a strength specification 

for vitamin C in the finished batch of 

the dietary supplement (e.g., ‘‘x 

milligrams (mg) of vitamin C per 

tablet’’). You are required to ensure that 

the dietary supplement does in fact 

contain ‘‘x mg of vitamin C per tablet.’’

Alternatively, if you are manufacturing 

rosehips and not vitamin C from 

rosehips, the strength specification that 

you establish for the finished batch of 

the dietary supplement is the strength of 

the rosehips themselves (i.e., the 

concentration of rosehips in the final 

product, such as ‘‘x mg of rosehips per 

tablet’’). You are required to ensure that 

the product does in fact contain ‘‘x mg 

of rosehips per tablet.’’

We discuss the requirements to 

establish and meet specifications in our 

discussion of subpart E (see section X of 

this document). 

d. Composition. A dietary 

supplement’s ‘‘composition’’ refers to 

the specified mix of product and 

product-related substances in a dietary 

supplement. For example, a dietary 

supplement manufactured to provide 

vitamin C may contain, in addition to 

vitamin C, a tablet coating agent and 

substances used as binders. The 

composition could be described as the 

percent of the dietary supplement that 

is vitamin C, the tablet-coating agent, 

and each binder. 

e. Other terms. 

(Comment 58) Several comments 

would revise the rule to define 

‘‘manufacturer.’’ Many comments ask 

whether the rule applies to certain types 

of companies or professionals and said 

a definition of ‘‘manufacturer’’ would 

clarify the rule’s applicability. 

Some comments suggest specific text 

for a definition. For example, one 

comment would define ‘‘manufacturer’’

as ‘‘a person who formulates or changes 

the composition or physical 

characteristics of a dietary supplement 

or who packages or labels the product 

in a container for distribution’’ to clarify 

that a company that does not 

manufacture a specific dietary 

supplement, but purchases a dietary 

supplement in bulk and then packages 

or labels the bulk dietary supplement 

for sale to consumers, is still subject to 

dietary supplement CGMP 

requirements. The comment cites our 

proposed definition of ‘‘manufacturer’’

in our infant formula CGMP proposal 

(see 61 FR 36154 at 36209, July 9, 1996 

(proposing to define a ‘‘manufacturer’’

as ‘‘a person who prepares, reconstitutes or otherwise changes the 

physical or chemical characteristics of 

an infant formula or packages or labels 

the product in a container for 

distribution’’)). 

Other comments would define 

‘‘manufacturer’’ to exclude a health care 

practitioner or herbalist and noted the 

Canadian Natural Health Product 

regulations do not apply to health care 

practitioners. 

(Response) We decline to define 

‘‘manufacturer’’ in the final rule. In 

section III, footnote 1 of this document, 

we explain that ‘‘manufacture’’ is a 

broad term and is not limited to 

production, packaging, or labeling 

activities. Consequently, we prefer to 

explain our interpretation of the final 

rule in this preamble and to have the 

codified provisions state general 

principles rather than attempt to capture 

subtleties in a definition of 

‘‘manufacturer.’’

(Comment 59) Proposed § 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 inprocess 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 


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results published in, for example, 

scientific journals, references, text 

books, or proprietary research (68 FR 

12157 at 12198). 

Several comments agree that 

scientifically valid analytical methods 

are those that are based on scientific 

data or results published in scientific 

journals, references, textbooks, or 

proprietary research. However, several 

comments ask us to define or better 

explain the terms ‘‘test’’ or 

‘‘scientifically valid analytical method’’

as used in the dietary supplement 

CGMP final rule. One comment argues 

that, because of the evolving nature of 

methodology for ingredients used in 

dietary supplements, we should give the 

industry more guidance as to what can 

be considered authoritative for the 

purpose of compliance with CGMP. 

Some comments state we should 

acknowledge methods from the Institute 

for Nutraceutical Advancement (INA), 

American Herbal Pharmacopoeia (AHP), 

European Pharmacopoeia, and the 

World Health Organization (WHO) as 

scientifically valid analytical methods. 

One comment notes the USP establishes 

scientifically valid procedures in its 

compendia and encouraged us to 

designate compendial procedures as 

‘‘scientifically valid’’ by defining 

‘‘scientifically valid’’ to include 

compendial procedures. The comment 

further argues that failure to 

acknowledge compendial procedures as 

scientifically valid would be 

inconsistent with section 403(s)(2)(D) of 

the act, which acknowledges the role of 

compendia, by considering a dietary 

supplement misbranded if the 

supplement is covered by the 

specifications of an official 

compendium, is represented as 

conforming to the specifications of an 

official compendium, and fails to so 

conform. 

Other comments would define 

‘‘validation’’ and ‘‘verification’’ and 

directed us to ‘‘ANSI Standard A8402–

1994’’ (a description of validation and 

verification standards). 

(Response) We decline to define 

‘‘test,’’ ‘‘scientifically valid analytical 

method,’’ or ‘‘scientifically valid 

method’’ in this final rule. As the 

comments recognized, the analytical 

methods for components are evolving. A 

regulatory definition for ‘‘test,’’

‘‘scientifically valid analytical method,’’

or ‘‘scientifically valid method’’ could 

become obsolete if we based it on 

specific sources such as INA, AHP, or 

USP that may or may not themselves 

stay current or that may be modified in 

a manner that did not enjoy widespread 

support. 

The preamble to the 2003 CGMP 

Proposal acknowledged that compendia 

can have a role in establishing tests used 

to determine whether specifications are 

met. For example, we noted that 

compendial standards may be 

appropriate reference materials for use 

in conducting tests or examinations (68 

FR 12157 at 12208). However, we did 

not list specific compendia that would 

be suitable sources or scientifically 

valid analytical tests, and are not listing 

such compendia in this final rule. The 

compendia identified in the comments, 

i.e., INA, ANSI, AHP, and USP, may 

include some methods that are based on 

scientific data or results published in 

scientific journals, references, textbooks, 

or proprietary research, but also contain 

some methods that are not based on 

such data or results. Thus, whether or 

not a method is scientifically valid is 

not determined solely by its inclusion in 

a compendium. Rather, it is the 

responsibility of quality control 

personnel to approve the use of those 

scientifically valid tests that will ensure 

a product’s identity, purity, strength, 

and composition whether or not such 

tests are contained in a particular 

compendium. 

We also decline to define ‘‘validation’’

and ‘‘verification’’ because the final rule 

does not establish any requirements that 

use these terms. 

(Comment 60) One comment asks us 

to define the terms ‘‘adequate,’’

‘‘sufficient,’’ and ‘‘qualified’’ and argues 

that, without these definitions, an FDA 

investigator may assert that something 

or someone is not adequate, sufficient, 

or qualified. 

(Response) We decline to define 

‘‘adequate,’’ ‘‘sufficient,’’ or ‘‘qualified’’

in this final rule. Deciding what is 

‘‘adequate’’ or ‘‘sufficient,’’ or who is 

‘‘qualified’’ must be done on a case-bycase basis, depending on the operations 

and the particular facts. As explained in 

section V of this document, we do not 

need to, nor could we, predict with 

mathematical precision how many 

inches or feet, for example, would be 

‘‘adequate space’’ to allow for cleaning 

a particular piece of equipment that 

could be applied to every size of facility 

and every operation. Furthermore, 

defining ‘‘adequate,’’ as defined in part 

110, as ‘‘that which is needed to 

accomplish the intended purpose in 

keeping with good public health 

practice’’ would still require context to 

determine whether, in a particular 

operation and based on a particular set 

of facts the particular practice was 

‘‘adequate.’’ Moreover, for terms such as 

‘‘adequate,’’ ‘‘sufficient,’’ and 

‘‘qualified,’’ where there has been 

common usage in the food industry to 

enable manufacturers and FDA 

investigators to comprehend and apply 

such terms to a particular operation, we 

do not believe a definition for these 

terms is necessary. 

(Comment 61) Several comments 

would define the terms ‘‘certificate of 

analysis,’’ ‘‘certificate of compliance/ 

conformance,’’ and ‘‘continuing product 

guarantee.’’ Most comments include 

these terms in a list of terms that they 

want us to define to ensure consistent 

interpretation of the rule throughout the 

industry. One comment says a standard 

for documentation, such as a certificate 

of analysis, would put greater emphasis 

on the firm’s responsibility to comply 

with CGMP. 

(Response) We decline to define these 

terms as suggested by the comments. We 

have included, in the codified, the use 

of a certificate of analysis as an option 

to determine whether certain 

specifications have been met. The final 

§ 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 of 

this document, Congress did not require 

dietary supplement CGMP requirements 

to be identical to the food CGMP 

requirements, so the mere fact that a 

definition may not appear in a food 

CGMP regulation does not mean we 

must delete that definition from this 

final rule, especially when the 

comments offered no other justification 

for deleting the definition. Definitions 


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provide clarity and consistency in 

interpreting various terms in a rule. 

D. Do Other Statutory Provisions and 

Regulations Apply? (Final § 111.5) 

Final § 111.5 states: ‘‘In addition to 

this part, you must comply with other 

applicable statutory provisions and 

regulations under the act related to 

dietary supplements.’’ Proposed § 111.5 

stated that, in addition to the dietary 

supplement CGMP requirements, ‘‘you 

must comply with other applicable 

statutory provisions and regulations 

under the act related to the 

manufacturing, packaging or holding of 

dietary ingredients or dietary 

supplements.’’

Section 111.5 reminds you that other 

statutory or regulatory requirements, not 

included in the dietary supplement 

CGMP requirements, may apply to your 

particular products, operations, or 

activities. In our further review of this 

provision, we determined that we do 

not need to elaborate on the individual 

operations and have shortened the 

provision to eliminate the references to 

particular operations. You are required 

to comply with other applicable 

statutory and regulatory requirements, 

and we have retained this provision to 

ensure you understand that this final 

rule does not relieve you of your 

responsibilities to comply with other 

applicable statutory and regulatory 

requirements related to dietary 

supplements. 

E. What Sections Did We Remove From 

the Rule, and Why? 

The final rule omits sections that were 

in the proposed rule. Proposed § 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 in the following paragraphs. 

(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 of this document, 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 


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businesses comply with dietary 

supplement CGMPs, we are giving 

businesses with fewer than 500 

employees but 20 or more employees a 

compliance date of 24 months after the 

date of publication of this final rule, and 

we are giving businesses with fewer 

than 20 employees a compliance date of 

36 months after the date of publication 

of this final rule. 

We carefully considered the size of a 

business when developing these 

regulations. The most common Small 

Business Association size standard 

applicable to manufacturers covered by 

this final rule is 500 employees. Based 

on comments and our knowledge of the 

dietary supplement industry, we know 

that there are a number of dietary 

supplement manufacturers who fall 

significantly below the standard of 500 

employees. To accommodate these 

manufacturers, we have established 

different compliance dates as noted. 

(Comment 66) One comment would 

exempt ‘‘consolidators’’ (whom it 

described as individuals who purchase 

raw agricultural commodities for sale to 

raw ingredient manufacturers) from the 

rule. Some comments suggest expanding 

the exclusion pertaining to harvesting, 

storage, and distribution of raw 

agricultural commodities to include 

other common and basic raw botanical 

processing activities, such as drying, 

chopping, cutting, size reduction, 

sifting, grinding, and storage. One 

comment would delete the word 

‘‘solely’’ to make the rule more flexible 

and make it possible to exclude 

producers, who do not manufacture a 

distinct product, from the CGMP rule. 

Another comment expresses concern 

about potential safety issues that can 

arise from the early stages of 

manufacturing, such as the use of 

improper handling of agricultural 

commodities and the risk of 

adulteration; the comment says 

businesses involved in producing or 

distributing raw agricultural 

commodities should be subject to some 

requirements under the rule. A few 

comments ask us to draft guidance 

documents to address activities such as 

wildcrafting, plant identification, good 

agricultural practices, and good 

hygienic practices for wildcrafters 

(persons who harvest plants grown in 

the wild), and growers and brokers and 

specific service providers (millers, 

extractors). Some comments would 

exempt individual wildcrafters because 

wildcrafters deal in relatively small 

amounts of material at a time and sell 

their material to larger brokers who 

combine materials from different 

pickers together. 

(Response) As explained in our 

responses to comments 29 and 30, 

persons who only manufacture or 

supply a component that will be further 

processed as a dietary supplement by 

another person are not within the scope 

of this final rule. Thus, a ‘‘consolidator’’

who simply buys raw agricultural 

commodities and then sells them to 

dietary ingredient manufacturers would 

not be subject to this final rule. 

Similarly, persons engaged in drying, 

chopping, cutting, size reduction, 

sifting, and grinding of raw agricultural 

commodities which they then sell to 

others for processing into a dietary 

supplement would not be subject to this 

final rule. We note, however, that such 

persons are not exempt from other 

regulatory requirements. We remind 

readers that a dietary ingredient is a 

food under section 201(f)(3) of the act. 

Consequently, a raw agricultural 

commodity that is a dietary ingredient 

is still subject to the umbrella food 

CGMP requirements in part 110, and 

activities such as drying, chopping, and 

cutting are what we have long 

considered to be types of food 

processing. 

As for ‘‘wildcrafters,’’ if they package 

and label raw agricultural commodities 

as dietary supplements or sell them to 

consumers for use as a dietary 

supplement, we would consider them to 

be manufacturers of a dietary 

supplement and subject to the rule. If, 

however, the wildcrafter simply sells 

the raw agricultural commodity to 

another for incorporation into a dietary 

supplement, it would not be subject to 

this final rule, but might be subject to 

the CGMP requirements in part 110. 

Persons engaged in the harvesting, 

storage, or distribution of raw 

agricultural commodities, whether for 

distribution as a dietary supplement or 

for distribution as a dietary ingredient to 

a dietary supplement manufacturer, may 

want to read our guidance entitled 

‘‘Guide to Minimize Microbial Food 

Safety Hazards for Fresh Fruits and 

Vegetables’’ available at http:// 

www.cfsan.fda.gov/~dms/ 

prodguid.html (Ref. 28). This guidance 

addresses common areas of food safety 

concern in the growing, harvesting, 

sorting, packing, and distribution of 

fresh produce, and contains principles 

that would apply to raw agricultural 

commodities, such as herbs and 

botanicals. 

As for the comment that would delete 

the word ‘‘solely’’ from proposed 

§ 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. 

VII. Comments on Personnel (Final 

Subpart B) 

A. Organization of Final Subpart B 

Proposed subpart B contained three 

provisions regarding personnel. Table 3 

of this document lists the sections in 

final subpart B and identifies the 

proposed sections that form the basis of 

the final rule. 

TABLE 3.—DERIVATION OF

SECTIONS IN FINAL SUBPART B 

Final Rule 

2003 

CGMP 

Proposal 

§ 111.8 What are the requirements under this 

subpart B for written 

procedures? 

N/A 

§ 111.10 What requirements apply for preventing microbial contamination from sick or 

infected personnel and 

for hygienic practices? 

§ 111.10 


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TABLE 3.—DERIVATION OF SECTIONS IN FINAL SUBPART B—

Continued 

Final Rule 

2003 

CGMP 

Proposal 

§ 111.12 What personnel 

qualification requirements apply? 

§ 111.12 

§ 111.13 What supervisor requirements 

apply? 

§ 111.13 

§ 111.14 Under this subpart B, what records 

must you make and 

keep? 

N/A 

B. Highlights of Changes to the 

Proposed Requirements for Personnel 

1. Revisions 

The final provisions in subpart B 

include revisions that clarify that the 

final rule applies only to persons who 

manufacture, package, label, or hold 

dietary supplements unless subject to an 

exclusion in § 111.1. 

The final provisions also include 

revisions that clarify the applicability of 

the rule to persons who perform 

labeling operations for dietary 

supplements. 

2. Changes After Considering Comments 

The final rule: 

• Requires you to establish and 

follow written procedures to fulfill the 

requirements of subpart B; 

• Provides flexibility regarding the 

requirement to exclude personnel who 

might be a source of microbial 

contamination (e.g., due to illness or 

open lesions) so that such personnel 

must be excluded only from operations 

where such contamination may occur; 

• Clarifies that the qualification of 

personnel and supervisors may be done 

through education, training, or 

experience; 

• Sets forth a new requirement that 

you identify qualified personnel to 

perform quality control operations and 

requires that such personnel have 

distinct and separate responsibilities 

related to performing quality control 

operations from those responsibilities 

that the person otherwise has when not 

performing quality control operations; 

and 

• Sets forth a new requirement to 

make and keep records that document 

training of personnel. 

C. General Comments on Proposed 

Subpart B 

(Comment 67) Some comments assert 

one or more proposed requirements are 

unconstitutionally vague under the Fifth 

Amendment and arbitrary and 

capricious under section 706(2)(B) of 

the Administrative Procedure Act (APA) 

and therefore should be deleted. The 

comments focus on: 

• Proposed § 111.12(a) which would 

require ‘‘qualified employees’’ and 

• Proposed § 111.13(a) which would 

require ‘‘qualified personnel to 

supervise.’’

In general, these comments say the 

proposal’s failure to define the term 

‘‘qualified’’ means that persons who are 

subject to the rule could not discern the 

meaning of the term. These comments 

also say the proposal imposes no limits 

on enforcement officers as to what 

would satisfy the requirements and, 

thus would represent an exercise of 

unbridled discretion and disparate 

decisionmaking. These comments argue 

proposed § 111.12(b), which would 

require employees to have ‘‘the training 

and experience to perform the person’s 

duties,’’ and proposed § 111.13(b), 

which would require supervisors to be 

‘‘qualified by training and experience to 

supervise,’’ would suffice. 

(Response) We are not deleting 

§§ 111.12(a) and 111.13(a) as requested 

by these comments. As discussed in 

section V of this document, we disagree 

that the terms in question are 

unconstitutionally vague, need to be 

defined, or may result in discriminatory 

enforcement. There has been sufficient 

common usage of these terms in the 

food industry to enable manufacturers, 

and those who enforce the 

requirements, to comprehend and apply 

such terms ‘‘with a reasonable degree of 

certainty’’ to their particular operations 

(see Boyce Motor Lines v. United States 

342 U.S. at 340). Further, agencies are 

permitted to use qualifying terms to 

enable them to address a wide variety of 

conditions at companies. For these 

reasons, we have retained the use of the 

terms in the final rule. The provisions 

at issue also give firms the flexibility to 

determine how to comply with the 

regulations. We also explain in section 

V of this document that the final rule 

does not violate the APA. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.8) 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV. We also respond to 

individual comments on specific 

provisions in the same section. Final 

§ 111.8 requires you to establish and 

follow written procedures to fulfill the 

requirements of subpart B. Additionally, 

to ensure that we can evaluate firms’

compliance with their written 

procedures, final § 111.14 requires that 

a person who manufactures, packages, 

labels, or holds dietary supplements 

make and keep records of such 

procedures. Such records would be 

available to us under subpart P. 

E. What Requirements Apply for 

Preventing Microbial Contamination 

From Sick or Infected Personnel and for 

Hygienic Practices? (Final § 111.10) 

The title of this provision has been 

changed from proposed § 111.10 to 

clarify that the requirements are related 

to the prevention of microbial 

contamination due to the health 

condition of personnel and not other 

sources. 

1. Final § 111.10(a) 

Final § 111.10(a) requires you to take 

measures to exclude from any 

operations any person who might be a 

source of microbial contamination, due 

to a health condition, where such 

contamination may occur, of any 

material including components, dietary 

supplements, and contact surfaces used 

in the manufacture, packaging, labeling, 

or holding of a dietary supplement. This 

provision is similar to proposed 

§ 111.10. We added ‘‘due to a health 

condition’’ for clarity. 

(Comment 68) Several comments 

suggest that employees who are sick 

should be allowed to work in areas 

where they will not come into contact 

with components, dietary supplements, 

or contact surfaces, and that the 

requirements of proposed § 111.10 are 

too strict. These comments say proposed 

§ 111.10(a) is too broad in stating that 

such persons be excluded ‘‘from 

working in any operation.’’ These 

comments explain that such persons 

may be suitable for performing other 

tasks, such as warehouse functions or 

administrative work. These comments 

would revise proposed § 111.10(a) so 

that it is acceptable for such persons to 

work so long as they will not be a vessel 

for microbial contamination. 

Other comments agree with proposed 

§ 111.10(a), and state that employees 

who are sick should be excluded from 

the plant, even from areas where 

products are not processed. These 

comments state excluding such 

personnel should be mandatory as the 

microbes from an open sore, wound, or 

other source of contamination could 

contaminate the surrounding air, 

personnel, etc. For example, if the 

production area is a closed loop air 

handling system, then contamination 

could spread to the other areas through 

the common air handling units/ducts. 


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(Response) We agree that some tasks 

may be suitable for a person who might 

be a source of microbial contamination. 

Certain warehouse functions or 

administrative tasks may be appropriate 

for such a person to do, provided that 

these functions or tasks do not expose 

components, dietary supplements, or 

contact surfaces to microbial 

contamination from the person, and 

provided that the person would not 

infect others who would then expose 

components, dietary supplements, or 

contact surfaces to microbial 

contamination. 

A requirement to exclude employees 

from being present at work would limit 

potential microbial contamination, 

which is the basis of the point made by 

some comments that employees who are 

sick should be excluded from the plant. 

However, the comments do not 

persuade us to deny firms the flexibility 

to determine whether it would be 

appropriate for an employee who may 

be a source of microbial contamination 

to work in some areas of the physical 

plant that are sufficiently separated 

from areas where product 

contamination could occur. When 

considering whether an employee may 

be permitted to work and whether he/ 

she represents a potential source of 

microbial contamination, one should 

look beyond the obvious potential 

sources of contamination, and consider 

possibilities such as the forms of 

indirect contamination discussed by the 

comments. Therefore, we are revising 

proposed § 111.10(a) to require you to 

take measures to exclude ‘‘from any 

operations any person who might be a 

source of microbial contamination, due 

to a health condition, where such 

contamination may occur, of any 

material including components, dietary 

supplements, and contact surfaces used 

in the manufacture, packaging, labeling, 

or holding of a dietary supplement.’’

As one measure to reduce potential 

microbial contamination, final 

§ 111.10(a)(1) requires you to exclude, 

from working in any operations that 

may result in contamination, any person 

who, by medical examination, the 

person’s acknowledgement, or 

supervisory observation, is shown to 

have, or appears to have an illness, 

infection, open lesion, or any other 

abnormal source of microbial 

contamination, that may result in 

microbial contamination of components, 

dietary supplements, or contact 

surfaces, until the health condition no 

longer exists. Final § 111.10(a)(1) is 

similar to proposed § 111.10(a)(1). We 

have added that the person can 

acknowledge that he or she may be a 

source of microbial contamination. We 

are moving and modifying the 

prepositional phrase concerning 

‘‘working in any operation.’’ We also 

have added the word ‘‘infection’’ to 

clarify the sources of potential abnormal 

contamination. 

(Comment 69) Several comments 

suggest employees who may be the 

source of microbial contamination 

should be permitted to work in areas of 

the plant where they pose no risk of 

contamination, and therefore should not 

be excluded unless they pose such a 

risk. 

(Response) We agree with the 

comments and are revising proposed 

§ 111.10(a)(1) accordingly. Therefore, 

you may allow persons with certain 

health conditions to work in areas of a 

plant where they pose no risk of 

contamination even though they must 

be excluded from other areas where they 

would pose such a risk. 

Final § 111.10(a)(2) requires you to 

instruct your employees to notify their 

supervisor(s) if they have, or if there is 

a reasonable possibility that they have, 

a health condition stated in 

§ 111.10(a)(1) that could contaminate 

any components, dietary supplements, 

or any contact surface. 

We did not receive comments specific 

to proposed § 111.10(a)(2). 

2. Final § 111.10(b) 

Final § 111.10(b) requires, if you work 

in an operation during which 

adulteration of the component, dietary 

supplement, or contact surface may 

occur, you to use hygienic practices to 

the extent necessary to protect against 

contamination of components, dietary 

supplements, or contact surfaces. Final 

§ 111.10(b) lists nine hygienic practices, 

such as wearing outer garments in a 

manner that protects against 

contamination, washing hands 

thoroughly, and wearing, where 

appropriate, hair nets, caps, beard 

covers, or other effective hair restraints. 

We did not receive any comments 

concerning proposed § 111.10(b)(1) 

(wearing outer garments in a manner 

that protects against contamination), 

§ 111.10(b)(2) (maintaining adequate 

personal cleanliness), § 111.10(b)(3) 

(washing hands thoroughly), 

§ 111.10(b)(4) (removing all unsecured 

jewelry and other objects that might fall 

into components, dietary supplements, 

equipment, or packaging and removing 

hand jewelry that cannot be adequately 

sanitized), § 111.10(b)(6) (wearing, 

where appropriate, hair nets, caps, 

beard covers, and other effective hair 

restraints), § 111.10(b)(7) (not storing 

clothing or other personal belongings 

where components, dietary 

supplements, or contact surfaces are 

exposed or where contact surfaces are 

washed), and § 111.10(b)(9) (taking any 

other precautions necessary to protect 

against contamination). 

Proposed § 111.10(b)(5) would require 

the hygienic practices that you use to 

include maintaining gloves used in 

handling components, dietary 

ingredients, or dietary supplements in 

an intact, clean, and sanitary condition 

and ensuring that gloves be of an 

impermeable material. 

(Comment 70) One comment asks us 

to clarify the requirements for the use of 

gloves in proposed § 111.10(b)(5). The 

comment says there are situations in 

which gloves are ineffective or 

cumbersome. The comment provides as 

an example, if a person is packaging a 

bulk material in fiber packs with metal 

ring lids, bulky gloves can interfere with 

the finer work such as attaching security 

tabs, and thin, flexible gloves can be 

easily damaged by the sharp edges of 

the metal rings on the lid. 

(Response) Final § 111.10(b)(5) 

requires you to maintain gloves in an 

intact, clean, and sanitary condition; it 

does not require you to use gloves in 

any specific situation. Although there is 

no requirement for wearing gloves while 

performing specific operations, you 

must wear gloves when they are 

necessary to protect against 

contamination of any components, 

dietary supplements, or contact 

surfaces. 

(Comment 71) Proposed § 111.10(b)(8) 

would require that the hygienic 

practices that you use, to the extent 

necessary to protect against 

contamination, include not eating food, 

chewing gum, drinking beverages, or 

using tobacco products in areas where 

components, dietary ingredients, dietary 

supplements, or any contact surfaces are 

exposed, or where contact surfaces are 

washed. 

One comment would substitute the 

word ‘‘processed’’ for the word 

‘‘exposed’’ in proposed § 111.10(b)(8). 

The comment says, although areas 

where components, dietary 

supplements, and contact surfaces are 

exposed pose the greatest risk, 

adulteration is also possible where these 

items are held (i.e., stored in containers 

and, thus, not exposed). Furthermore, 

the comment explains the use of the 

word ‘‘processed,’’ rather than 

‘‘exposed,’’ would cover all areas 

intended to be covered by CGMPs and 

would alleviate the need to specify that 

the requirement applies to areas where 

contact surfaces are washed. 

(Response) We decline to revise the 

rule as suggested by the comment. We 

believe the word ‘‘exposed’’ covers all 

areas intended to be covered by the 


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requirement, including areas where 

contact surfaces are washed. We 

consider an area where contact surfaces 

are washed to ‘‘expose’’ the contact 

surface. To avoid any confusion, we are 

modifying § 111.10(b)(8) to say ‘‘* * * 

any contact surfaces are exposed, or 

where contact surfaces are washed.’’ As 

written, the requirement to not eat, 

chew gum, drink, or use tobacco 

products in areas where components, 

dietary supplements, and contact 

surfaces are exposed gives firms 

appropriate flexibility to determine 

areas where employees may or may not 

eat, chew gum, drink, or use tobacco 

products. 

F. What Personnel Qualification 

Requirements Apply? (Final § 111.12) 

Final § 111.12(a) requires you to have 

qualified employees who manufacture, 

package, label, or hold dietary 

supplements. Final § 111.12(a) is similar 

to proposed § 111.12(a), except that the 

final rule includes an editorial change to 

clarify that the requirement is to have 

the qualified employees do the work 

rather than merely to have qualified 

employees. 

(Comment 72) The 2003 CGMP 

Proposal invited comment on whether 

there is a minimum number of 

employees needed to manufacture 

dietary supplements (68 FR 12157 at 

12183). Several comments state the final 

rule should not include such a 

minimum number because firms should 

be able to decide for themselves how 

many qualified personnel they need. 

(Response) The final rule does not 

stipulate a minimum number of 

employees. However, there should be 

enough employees to manufacture, 

package, label, and hold dietary 

supplements to ensure compliance with 

the final rule. In general, CGMP suggests 

the need for a minimum of two persons: 

One to perform the work, and a second 

to check the work performed to ensure 

that a manufacturing deviation or an 

unanticipated occurrence is not 

overlooked. 

(Comment 73) Some comments about 

the proposed definition of ‘‘quality 

control unit’’ say the quality control 

function need not be performed by a 

distinct or separate unit. These 

comments say the quality control 

function is best performed by a person 

or persons qualified by training, 

education, or experience in the different 

processing areas. 

(Response) As discussed, we have 

revised the proposed definition and 

substituted the term ‘‘personnel’’ for 

‘‘unit.’’ (For the definition of quality 

control personnel, see section VI of this 

document.) We agree the quality control 

functions do not need to be performed 

by a distinct or separate unit or person 

and that a person who is qualified by 

training, education, or experience can 

serve a quality control function. 

Therefore, we are adding a new 

§ 111.12(b) to clarify that you must 

identify who is responsible for quality 

control operations. Under final 

§ 111.12(b) each person identified must 

be qualified to perform such operations, 

and must have distinct and separate 

responsibilities related to performing 

such operations from those 

responsibilities that the person 

otherwise has when not performing 

such operations. The quality control 

personnel can have dual functions 

within the facility but should separately 

perform the different responsibilities. 

Final § 111.12(c) requires that each 

person engaged in manufacturing, 

packaging, labeling, or holding, or in 

performing any quality control 

operations, have the education, training, 

or experience to perform the person’s 

assigned functions. Final § 111.12(c) 

includes a revision associated with final 

§ 111.12(b) by including persons who 

perform quality control operations as 

persons who also need to have the 

education, training, or experience for 

the assigned functions. 

(Comment 74) Several comments state 

we should revise the rule to allow for 

any combination of ‘‘training or 

experience.’’ These comments explain it 

is not always possible for an employee 

to have both ‘‘training and experience.’’

These comments would revise proposed 

§ 111.12(b) to read, ‘‘each person 

engaged in the manufacture of a dietary 

product should have the proper 

education, training, and experience (or 

any combination thereof) needed to 

perform the assigned functions. 

Training should be in the particular 

operations(s) that the employee 

performs as they relate to the 

employee’s functions.’’ Another 

comment asks for guidance as to what 

type of education, training, or 

experience is required for an employee 

to be considered qualified. 

(Response) We agree with the point 

made by the comments. We 

acknowledge that some positions will 

require an appropriate educational 

background in addition to any on-thejob training. In the preamble to the 2003 

CGMP Proposal (68 FR 12157 at 12183) 

we noted ‘‘training’’ may be considered 

a form of ‘‘education’’ and elected to 

require that employees be qualified by 

‘‘training and experience’’ rather than 

‘‘education, training, and experience.’’

The 2003 CGMP Proposal used the 

conjunction ‘‘and’’ because we 

considered ‘‘experience’’ to be different 

from training, in that ‘‘experience’’ is 

knowledge that a person gains over 

time, e.g., as he or she becomes 

increasingly familiar with a particular 

action or piece of equipment. 

These comments persuade us that the 

rule would be clearer if we added 

‘‘education’’ to the list of attributes that 

are used to qualify an employee. We 

also agree there are some employees 

who could be qualified based solely on 

their education or experience and other 

employees who would become qualified 

through, for example, on-the-job 

training before they are left on their own 

to perform their assigned duties. Rather 

than revise the rule to list all three 

attributes and then explain that an 

employee can be qualified by any 

combination of the attributes, we have 

changed the conjunction from ‘‘and’’ to 

‘‘or.’’ Additionally, on our own 

initiative, we have replaced ‘‘person’s 

duties’’ with ‘‘person’s assigned 

functions.’’ This change reinforces the 

principle that the employee’s training 

relates to the functions that he or she is 

assigned to perform. 

We will consider whether it would be 

useful to provide guidance on what type 

of education, training, or experience 

would be sufficient for an employee to 

be properly qualified. We believe that 

such education, training, or experience 

may vary by job function and that it 

would be difficult to provide generic 

guidance that would be sufficient for all 

specific job tasks. We decline to suggest 

that training should be limited, as the 

comments suggest, to the particular 

operation(s) that the employee performs 

as they relate to the person’s functions. 

These CGMP requirements apply to 

many types of manufacturing operations 

of various size and complexity, so the 

training may vary depending on the 

circumstances and may include more 

than the employee’s assigned functions. 

(Comment 75) One comment states we 

should provide training materials such 

as texts, videos, Internet training, or 

seminars, to help companies properly 

train their employees. 

(Response) We have no plans at this 

time to provide companies with training 

materials for their employees. We 

expect that most companies already 

have trained or will train their 

employees and that where additional 

training is needed to comply with these 

regulations, companies will develop the 

training materials that are appropriate 

for the functions their employees 

perform. We may consider providing 

guidance in the future if circumstances 

warrant such guidance. 


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G. What Supervisor Requirements 

Apply? (Final § 111.13) 

Final § 111.13(a) requires you to 

assign qualified personnel to supervise 

the manufacturing, packaging, labeling, 

or holding of dietary supplements. Final 

§ 111.13(a) derives from proposed 

§ 111.13(a). 

We did not receive comments specific 

to proposed § 111.13(a). 

Final § 111.13(b) requires each 

supervisor you use to be qualified by 

education, training, or experience to 

supervise. Final 111.13(b) derives from 

proposed § 111.13(b) which would 

require you and your supervisors to be 

qualified by training and experience to 

supervise. 

(Comment 76) Several comments ask 

us to revise the rule so that supervisors 

may be qualified by any combination of 

training or experience. These comments 

would revise proposed § 111.13(b) to 

read, ‘‘supervisors must be qualified by 

education, training, and experience (or 

any combination thereof) to supervise 

the manufacturing, packaging, or 

holding of dietary ingredients and 

dietary supplements in compliance with 

this rule.’’ One comment, however, 

would make an exception for quality 

control and sanitation supervisors, 

stating we should require these 

supervisors to have both training and 

experience. 

(Response) Consistent with the 

change we made to proposed 

§ 111.12(c), we are revising proposed 

§ 111.13(b) to require the supervisors 

you use to be qualified by ‘‘education, 

training, or experience.’’ We 

acknowledge that some supervisory 

personnel may need a different range of 

education, training, or experience than 

others, and expect firms to determine 

the appropriate balance of education, 

training, and experience. 

(Comment 77) Several comments say 

our use of the phrase ‘‘you and the 

supervisors you use’’ in proposed 

§ 111.13(b) was unclear. According to 

these comments, the term ‘‘you’’ as 

defined in the proposal, is quite 

expansive and could be read so broadly 

as to require the Chief Executive Officer 

(CEO) of a company be ‘‘qualified’’ to 

supervise. 

(Response) We agree that the phrase 

‘‘you and the supervisors you use’’

could be clearer. Therefore, we are 

revising proposed § 111.13(b) to say that 

‘‘each supervisor whom you use’’ must 

be qualified to supervise. Section 

111.13(b) applies to any person who 

supervises the manufacturing, 

packaging, labeling, or holding of 

dietary supplements, even if that person 

also is an executive such as the CEO. 

Thus, final § 111.13(b) states, ‘‘Each 

supervisor whom you use must be 

qualified by education, training, or 

experience to supervise.’’

(Comment 78) Several comments say 

the term ‘‘to supervise’’ is ambiguous 

and would revise the rule to clarify 

what a supervisor must be qualified to 

supervise: The manufacture, packaging, 

or holding of dietary ingredients and 

dietary supplements. Another comment 

would revise proposed § 111.13(b) to 

clarify what type of training and 

experience are required so that firms 

would have more guidance as to what 

is expected to confirm that personnel 

are qualified. 

(Response) We decline to revise the 

rule as suggested by the comments. We 

disagree that the term ‘‘to supervise,’’

which is commonly used in the 

industry, is ambiguous. These CGMP 

requirements apply to many types of 

manufacturing operations of various 

size and complexity, and the training 

must be suited to the circumstances. 

H. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.14) 

As discussed in this section, the final 

rule contains a new § 111.8 requiring 

you to establish and follow written 

procedures to fulfill the requirements of 

subpart B. Those written procedures are 

records. Therefore, we are adding a new 

§ 111.14(a) requiring you to make and 

keep records in accordance with subpart 

P. Final § 111.14(b)(1) requires you to 

make and keep a record of the written 

procedures for fulfilling the 

requirements of subpart B. 

The preamble to the 2003 CGMP 

Proposal invited comment on whether 

we should require documentation and 

records regarding each employee’s 

training (68 FR 12157 at 12183). After 

considering comments and for the 

reasons discussed in the following 

paragraphs, § 111.14(b)(2) requires you 

to make and keep documentation of 

training, including the date of training, 

the type of training, and the person(s) 

trained. 

We also invited comment on whether 

the final rule should contain 

requirements for documentation about 

consultants that you use (68 FR 12157 

at 12183). We specifically suggested any 

such requirement include the 

consultant’s name, address, 

qualifications, and a description of 

services provided. After considering the 

comments and for the reasons discussed 

in the following paragraphs, the final 

rule does not include any requirements 

to make and keep records regarding 

consultants. 

(Comment 79) Several comments state 

employee training records are critical 

and should be required under the final 

rule. The comments explain that these 

records should show the content of the 

training, the date of the training, and the 

signature of the employee trained. These 

comments assert that a formal (written) 

GMP training program is necessary to 

track which employees have been 

trained in the CGMP requirements. 

These comments add, without a written 

and documented training program, it is 

likely that some employees may not 

receive sufficient training, or in some 

cases, any CGMP training at all. These 

comments say successful quality control 

programs are inextricably connected to 

appropriate training programs, and 

written documentation of employee 

training is an important safeguard to 

ensuring safe and accurately labeled 

dietary supplements. These comments 

also state it is already an industry 

standard to document training. 

Other comments question our ability 

to evaluate whether a firm’s employees 

have been adequately trained without 

written documentation of the training. 

(Response) As discussed more fully in 

the discussion of subpart E in section X 

of this document, the final rule focuses 

on ensuring the quality of the dietary 

supplement at every stage of the 

production and process control system. 

Such a system begins with the proper 

training. We agree that documentation 

of employee training is necessary to 

track which employees have been 

trained in which operations. Therefore, 

final § 111.14(b)(2) requires you to keep 

documentation of training, including 

the date of the training, the type of 

training, and the person(s) trained. 

(Comment 80) One comment says we 

should not require manufacturers to 

document and keep records regarding 

each employee’s training. The comment 

says the rule should focus on end 

results and not on process. 

(Response) We disagree with the 

comment. As we have explained in this 

section, each person engaged in an 

activity covered by these CGMP 

regulations must have the education, 

training, or experience to perform the 

person’s assigned functions. Some 

employees will be considered qualified 

based in part on training taken as 

company employees. To show that such 

training is appropriate to the employee’s 

functions and has in fact occurred, the 

training must be properly documented. 

This documentation is an important 

aspect of ensuring adequate training 

and, therefore, helping to ensure the 

result of having qualified employees 

who perform their functions properly. 


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(Comment 81) Several comments state 

the documentation of the training 

program should include the title of the 

person doing the training, an evaluation 

of the employee’s understanding of the 

training, and recommendations for the 

frequency of refresher training. One 

comment describes a specific method 

for training and for tracking training. 

The comments state an evaluation of the 

employee’s understanding of the 

training would ensure that employees 

who receive training understand what 

they have been taught. 

(Response) We decline to require 

specific additional documentation of 

employee training. We believe a firm 

should have some flexibility in how it 

wants to document training. 

(Comment 82) Several comments 

respond to our question as to whether 

the final rule should require 

documentation about consultants, 

including each consultant’s name, 

address, qualifications, and a 

description of services provided. 

Several comments say that documenting 

this information is useful and could be 

done on a voluntary basis, but that such 

information is not necessary to ensure 

safe and accurately labeled supplements 

and, thus, should not be required. One 

comment notes that recommendations 

from consultants may or may not be 

used, and that a company should not 

have to explain at a later date why such 

decisions were made. Another comment 

asserts that we and the company may 

have different opinions on whether a 

consultant is qualified and that the 

consultant’s qualification is not our 

concern if a product is not adulterated. 

One comment says documenting the 

name and services of the GMP 

consultants should be required to 

facilitate contact in case of need. 

(Response) The proposal noted 

documentation of the name, address, 

qualifications, and services rendered for 

each consultant may help you know 

whom to contact and if questions arise 

concerning the advice that the 

consultant has given. Thus, our intent in 

suggesting such documentation was to 

help you rather than to make the 

information available for us to 

determine whether we agreed with you 

that a particular individual was 

qualified to be a consultant. However, 

the comments persuade us that such 

information is not necessary to help 

ensure dietary supplement quality. 

Therefore, the final rule does not require 

documentation regarding consultants. 

VIII. Comments on Physical Plant and 

Grounds (Final Subpart C) 

A. Organization of Final Subpart C 

Proposed subpart C contained two 

provisions regarding physical plants. 

Table 4 of this document lists the 

sections in final subpart C and identifies 

the corresponding proposed sections 

that form the basis of the final rule. 

TABLE 4.—DERIVATION OF

SECTIONS IN FINAL SUBPART C 

Final Rule 2003 CGMP 

Proposal 

§ 111.15 What sanitation 

requirements apply to 

your physical plant 

and grounds? 

§ 111.15 

§ 111.16 What are the 

requirements under 

this subpart C for written procedures? 

N/A 

§ 111.20 What design 

and construction requirements apply to 

your physical plant? 

§ 111.20 

§ 111.23 Under this subpart C, what records 

must you make and 

keep? 

§ 111.15(d)(3) 

and (e)(2) 

B. Highlights of Changes to the 

Proposed Requirements for Physical 

Plant and Grounds 

1. Revisions 

The final rule: 

• Reflects that the rule applies to 

persons who manufacture, package, 

label, or hold dietary supplements 

unless subject to an exclusion in 

§ 111.1. 

• Requires you to have 

documentation or otherwise be able to 

show that water that is used in a manner 

such that the water may become a 

component of the dietary supplement, 

e.g., when such water contacts 

components, dietary supplements, or 

any contact surface, meets applicable 

Federal, State, and local requirements 

and does not contaminate the dietary 

supplement. 

2. Changes After Considering Comments 

The final rule: 

• Includes requirements similar to the 

food CGMP requirements in § 110.20(a) 

for keeping the grounds bordering your 

physical plant in a condition that 

protects against contamination. 

• Clarifies that sanitation supervisors 

can be qualified by education, training, 

or experience. 

• Modifies the minimum 

requirements for water that is used in a 

manner such that the water may become 

a component of the dietary supplement, 

e.g., when such water contacts 

components, dietary supplements, or 

any contact surface. Such water must, at 

a minimum, comply with applicable 

Federal, State, and local requirements 

and not contaminate the dietary 

supplement. 

• Simplifies the sanitation 

requirements for toxic materials, 

bathroom facilities, and hand-washing 

facilities. 

• Simplifies and clarifies the design 

requirements for floors, walls, and 

ceilings; fans and other air-blowing 

equipment; equipment that controls 

temperature and humidity; and the use 

of safety-type glass or glass-like 

materials. 

• Requires written procedures for 

cleaning the physical plant and for pest 

control. 

• Requires that you make and keep 

records of the written procedures. 

C. General Comments on Proposed 

Subpart C 

(Comment 83) Several comments say 

we should have different sanitation 

requirements for dietary ingredient 

manufacturers than for dietary 

supplement manufacturers. These 

comments state that the manufacture of 

synthetic or highly processed dietary 

ingredients includes extensive 

purification steps, especially toward the 

end of the manufacturing process, and 

that these steps remove contaminants 

that may have been introduced at earlier 

stages in the manufacturing process. 

These comments consider some stages 

of the dietary ingredient manufacturing 

process to not be subject to the same 

strict controls as those used for 

manufacturing finished dietary 

supplements. 

(Response) As discussed in section VI 

of this document (subpart A), the final 

rule applies to persons who 

manufacture, package, label, or hold 

dietary supplements and who are not 

subject to an exclusion in § 111.1, and 

does not apply to establishments that 

only manufacture dietary ingredients. 

We addressed this comment in the 

response to comment 29. 

(Comment 84) Some comments assert 

that one or more proposed requirements 

are unconstitutionally vague under the 

Fifth Amendment and are arbitrary and 

capricious under section 706(2)(B) of 

the APA. The comments would delete 

the following proposed requirements: 

• § 111.15(e), which would require 

plumbing to be ‘‘of an adequate size and 


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design and be adequately installed and 

maintained;’’

• § 111.15(g), which would require 

bathrooms to be ‘‘adequate’’ and 

‘‘readily accessible; ’’

• § 111.15(h), which would require 

hand-washing facilities ‘‘to be adequate, 

convenient, and furnish running water 

at a suitable temperature;’’

• § 111.15(h)(i), which would require 

hand-washing and, where appropriate, 

hand-sanitizing facilities ‘‘at each 

location in your physical plant’’ where 

good hygienic practices require 

employees to wash or to sanitize or both 

wash and sanitize their hands; 

• § 111.20(a), which would require 

your physical plant to ‘‘be suitable in 

size, construction, and design to 

facilitate maintenance, cleaning, and 

sanitizing operations;’’ and 

• § 111.20(d)(6), which would require 

aisles or working spaces between 

equipment and walls to be adequately 

unobstructed and of adequate width. 

In general, these comments assert the 

2003 CGMP Proposal did not define 

terms or phrases (such as ‘‘adequately’’

or ‘‘at each location’’) in a way that 

persons who are subject to the rule can 

discern the meaning of the term or 

phrase. These comments argue that the 

proposed rule imposes no limitations on 

enforcement officers on the exercise of 

their discretion and, thus, invites 

exercise of unbridled discretion and 

disparate decisionmaking. 

(Response) As discussed in section V 

of this document, we disagree that the 

terms that the comments objected to in 

the 2003 CGMP Proposal are 

unconstitutionally vague, need to be 

defined, or may result in discriminatory 

enforcement. We are retaining the terms 

in the final rule. 

D. What Sanitation Requirements Apply 

to Your Physical Plant and Grounds? 

(Final § 111.15) 

1. Final § 111.15(a) 

The preamble to the 2003 CGMP 

Proposal (68 FR 12157 at 12184) stated 

that we were not proposing 

requirements similar to the food CGMP 

requirements found in § 110.20(a) for 

keeping the grounds bordering your 

physical plant in a condition that 

protects against contamination of 

components or dietary supplements in 

order to limit the burden to 

manufacturers. However, we invited 

comment on whether we should include 

such requirements in a final rule. After 

considering the comments, we have 

drafted final § 111.15(a) to require you 

to keep the grounds of your physical 

plant in a condition that protects against 

the contamination of components, 

dietary supplements, or contact 

surfaces. The methods for adequate 

ground maintenance include: 

• Properly storing equipment, 

removing litter and waste, and cutting 

weeds or grass within the immediate 

vicinity of the physical plant so that it 

does not attract pests, harbor pests, or 

provide pests a place for breeding; 

• Maintaining roads, yards, and 

parking lots so that they do not 

constitute a source of contamination in 

areas where components, dietary 

supplements, or contact surfaces are 

exposed; 

• Adequately draining areas that may 

contribute to the contamination of 

components, dietary supplements, or 

contact surfaces by seepage, filth or any 

other extraneous materials, or by 

providing a breeding place for pests; 

• Adequately operating systems for 

waste treatment and disposal so that 

they do not constitute a source of 

contamination in areas where 

components, dietary supplements, or 

contact surfaces are exposed; and 

• If your plant grounds are bordered 

by grounds not under your control, and 

if those other grounds are not 

maintained in the manner described in 

this section, you must exercise care in 

the plant by inspection, extermination, 

or other means to exclude pests, dirt, 

and filth or any other extraneous 

material that may be a source of 

contamination. 

(Comment 85) Several comments say 

the final rule should require the 

maintenance of external areas similar to 

the food CGMP requirement at 

§ 110.20(a) for keeping the grounds 

outside the facility adequately 

maintained. These comments state that 

such a requirement is basic, is equally 

important to facilities that manufacture 

conventional foods and to facilities that 

manufacture dietary supplements, and 

that there is no reason why this 

requirement should differ from food 

CGMPs. One comment asserts such a 

requirement is basic to the industry and 

it should not be dismissed as a burden 

to the industry. Some comments also 

assert that a provision similar to 

§ 110.20(a) would help train staff and 

would explain to plant maintenance 

personnel what is required and why. 

One comment says there should be 

some minimum requirement for 

sanitation and cleanliness in the area 

surrounding the plant and that 

requirements for drainage and trash 

removal should be adequate. 

(Response) We agree that a 

requirement to maintain grounds is 

equally important for facilities that 

manufacture conventional foods and for 

facilities that manufacture dietary 

supplements. Although some 

requirements in § 110.20(a) are not 

strictly limited to drainage and trash 

disposal, the comment suggesting the 

requirements to maintain grounds be 

limited to drainage and trash disposal 

did not explain why, for example, it 

would not be as important for a facility 

that manufactures dietary supplements 

to maintain roads, yards, and parking 

lots so that they do not become a source 

of contamination as it already is for 

facilities that manufacture conventional 

foods. Therefore, the final rule is adding 

§ 111.15(a), which is similar to 

§ 110.20(a) with editorial revisions 

consistent with the rest of this final rule. 

2. Final § 111.15(b)(1) 

Final § 111.15(b)(1) (proposed 

§ 111.15(a)) requires you to maintain 

your physical plant in a clean and 

sanitary condition. Final § 111.15(b)(2) 

requires you to maintain your physical 

plant in repair sufficient to prevent 

components, dietary supplements, or 

contact surfaces from becoming 

contaminated. 

We did not receive comments specific 

to proposed § 111.15(a). 

3. Final § 111.15(c) 

Final § 111.15(c) (proposed 

§ 111.15(b)) sets forth requirements for 

cleaning compounds, sanitizing agents, 

pesticides, and other toxic materials. 

Final § 111.15(c) includes changes 

that we are making for clarity and 

consistency. We added other ‘‘toxic’’

materials because some paragraphs 

within final § 111.15(c) simply refer to 

the cleaning compounds, sanitizing 

agents, and pesticides as ‘‘toxic 

materials,’’ and because proposed 

§ 111.15(b)(2) addressed the use and 

storage of toxic materials that are not 

within the general category of cleaning 

compounds, sanitizing agents, or 

pesticides. 

Final § 111.15(c)(1) requires you to 

use cleaning compounds and sanitizing 

agents that are free from microorganisms 

of public health significance and that 

are safe and adequate under the 

conditions of use. Final § 111.15(c)(1) is 

similar to proposed § 111.15(b)(1), 

except that we inserted ‘‘that are’’ before 

‘‘safe and adequate.’’ We consider this 

to be a nonsubstantive, editorial change. 

Proposed § 111.15(b)(1) was, itself, 

patterned after § 110.35(b)(1), which: (1) 

Requires cleaning compounds and 

sanitizing agents used in cleaning and 

sanitizing procedures to be free from 

undesirable microorganisms and safe 

and adequate under the conditions of 

use and (2) provides that compliance 

may be verified by any effective means 

including purchase of these substances 


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under a supplier’s guarantee or 

certification or examination of these 

substances for contamination. 

(Comment 86) Several comments ask 

us to clarify our expectations with 

respect to substantiating that a cleaning 

compound or sanitizing agent is free 

from microorganisms of public health 

significance and is safe and adequate 

under conditions of use. Some 

comments suggest proposed 

§ 111.15(b)(1) provide for the use of 

certifications or guarantees from a 

supplier because our investigators 

otherwise may not recognize such 

documents as evidence of compliance. 

Several comments say it is not necessary 

for a manufacturer to test these types of 

products, and that a continuing product 

guarantee, combined with a statement of 

intended use from the manufacturer of 

the cleaning compound or sanitizing 

agent, should satisfy the requirements. 

(Response) When assessing 

compliance with final § 111.15(c)(1), we 

would not treat a firm that 

manufactures, packages, labels, or holds 

a dietary supplement differently than 

we would treat a facility that 

manufactures, packages, labels, or holds 

conventional foods. Therefore, we 

intend to accept, as the comments 

request, a supplier’s guarantee or 

certification that a cleaning compound 

or sanitizing agent is free from 

microorganisms of public health 

significance and is safe and adequate 

under the conditions of use for the 

purpose of determining compliance 

with final § 111.15(c)(1). 

Final § 111.15(c)(2) requires you to 

not use or hold toxic materials in a 

physical plant in which components, 

dietary supplements, or contact surfaces 

are manufactured or exposed, unless 

those materials are necessary: (1) To 

maintain clean and sanitary conditions, 

(2) for use in laboratory testing 

procedures, (3) for maintaining or 

operating the physical plant or 

equipment, or (4) for use in the plant’s 

operations. 

We did not receive comments specific 

to proposed § 111.15(b)(2). We have 

made a nonsubstantive edit to 

§ 111.15(c)(2) by moving ‘‘contact 

surfaces’’ to be the last item on the list. 

Final § 111.15(c)(3) requires you to 

identify and hold cleaning compounds, 

sanitizing agents, pesticides, pesticide 

chemicals, and other toxic materials in 

a manner that protects against 

contamination of components, dietary 

supplements, or contact surfaces. Final 

§ 111.15(c)(3) is similar to proposed 

§ 111.15(b)(3). 

We did not receive comments specific 

to proposed § 111.15(b)(3), but replaced 

‘‘toxic cleaning compounds’’ with 

‘‘cleaning compounds,’’ and added 

‘‘other toxic materials.’’

4. Final § 111.15(d) 

Final § 111.15(d) (proposed 

§ 111.15(c)) sets forth requirements for 

pest control. Section § 111.15(d) is 

almost identical to proposed § 111.15(c). 

Final § 111.15(d)(1) requires you to 

not allow animals or pests in any area 

of your physical plant. Final 

§ 111.15(d)(1) allows guard or guide 

dogs in some areas of your physical 

plant if the presence of the dogs will not 

result in contamination of components, 

dietary supplements, or contact 

surfaces. Final § 111.15(d)(2) requires 

that you take effective measures to 

exclude pests from your physical plant 

and to protect against the contamination 

of components, dietary supplements, 

and contact surfaces on the premises by 

pests. Final § 111.15(d)(3) requires that 

you not use insecticides, fumigants, 

fungicides, or rodenticides unless you 

take precautions to protect against the 

contamination of your components, 

dietary supplements, or contact 

surfaces. 

(Comment 87) Several comments 

claim proposed § 111.15(c) would 

require that sealed equipment outside of 

the plant (e.g. storage tanks, vessels, 

piping) be enclosed to prevent pests 

from roaming around these areas. The 

comments say there is no need to shelter 

outdoor equipment if it is properly 

sealed. These comments state that 

dietary supplements are sometimes 

manufactured in extensive, highly 

automated facilities in which large tanks 

and vessels are interconnected via 

piping, and that in these cases ‘‘the 

physical plant’’ and ‘‘the equipment in 

the plant’’ converge so that some or 

much of the equipment is effectively 

located outdoors. Thus, the comments 

ask us to revise proposed § 111.15(c) to 

clarify that it applies only to interior 

areas of the physical plant. 

(Response) Equipment such as that 

described by the comments, if properly 

sealed, should protect components, 

dietary supplements, and contact 

surfaces from contamination with pests. 

Final § 111.15(d) does not require that 

sealed equipment outside of the plant, 

such as storage tanks, vessels, or piping, 

be enclosed, e.g., inside a building. 

Final § 111.15(d)(2) requires that you 

take effective measures to exclude pests 

from your physical plant and to protect 

against the contamination of 

components, dietary supplements, or 

contact surfaces on the premises by 

pests. Moreover, final § 111.15(a) 

includes several requirements designed 

to limit or exclude pests around all parts 

of the exterior of your physical plant. 

Therefore, although you do not have to 

enclose your outside equipment, you 

must take measures to exclude pests 

from areas outside of the plant. 

5. Final § 111.15(e) 

Final § 111.15(e) (proposed 

§ 111.15(d)) sets forth requirements for 

the water supply of your physical plant. 

Final § 111.15(e)(1) requires that you 

must provide water that is safe and 

sanitary at suitable temperatures and 

under pressure as needed for all uses 

where water does not become a 

component of the dietary supplement. 

We did not receive comments specific 

to proposed § 111.15(d)(1). We have 

modified the phrase ‘‘safe and of 

adequate sanitary quality’’ to read ‘‘safe 

and sanitary.’’ To avoid confusion with 

the definition of ‘‘quality’’ we have 

adopted solely for purposes of this final 

rule, we deleted the references to 

‘‘quality’’ as it applies to water 

standards. We consider this change to 

be nonsubstantive and still require 

water that is not a component of a 

dietary supplement to meet a safe and 

sanitary standard. 

Final § 111.15(e)(2) requires that 

water used in a manner such that the 

water may become a component of the 

dietary supplement, e.g., when such 

water contacts components, dietary 

supplements, or any contact surface, 

must, at a minimum, comply with 

applicable Federal, State, and local 

requirements and not contaminate the 

dietary supplement. Final § 111.15(e)(2) 

derives from proposed § 111.15(d)(2) 

which would require that water that 

contacts components, dietary 

supplements, or any contact surfaces 

must, at a minimum, comply with the 

applicable National Primary Drinking 

Water (NPDW) regulations and any State 

and local government requirements. 

Final § 111.15(e)(2) includes changes we 

are making after considering comments 

discussed in the following paragraphs. 

(Comment 88) Several comments state 

the water quality that is required for 

conventional foods is sufficient for 

dietary supplements. The comments 

argue that no additional water standards 

are listed in the CGMPs for low-acid 

canned foods in part 113 or in the 

CGMPs for acidified foods in part 114. 

These comments argue that, if ‘‘safe and 

of adequate sanitary quality’’ is 

sufficient to ensure the quality of the 

water used in most food products, then 

it is also adequate to ensure the quality 

of the water used in dietary 

supplements. 

Other comments would revise the 

final rule to allow different standards 

and requirements for water that contacts 

or is used in dietary supplements 


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compared to water that contacts 

components, including dietary 

ingredients. These comments state 

current food CGMP regulations require 

only that water supplies that contact 

food (defined to include ingredients and 

raw materials) be ‘‘safe and of adequate 

sanitary quality.’’ These comments say 

that this would be consistent with the 

act’s basis for CGMP requirements for 

foods, i.e., that food is not prepared 

‘‘under unsanitary conditions whereby 

it may have become contaminated with 

filth, or whereby it may have been 

rendered injurious to health’’ (section 

402(a)(4) of the act). Several comments 

state the final rule should adopt a 

similar rationale for components, 

including dietary ingredients. These 

comments explain that components, 

including dietary ingredients, are not in 

a form in which they will be consumed 

and are subject to further processing 

prior to consumption. 

Several comments say that requiring 

water used for cleaning contact surfaces 

to meet Environmental Protection 

Agency regulations is an unnecessary 

burden for companies that do not have 

access to municipal water. According to 

these comments, potable water should 

be sufficient. 

(Response) In the preamble to the 

2003 CGMP Proposal (68 FR 12157 at 

12185), we stated that water should, at 

a minimum, be potable and that water 

that is ‘‘safe and of adequate sanitary 

quality’’ should be potable. We also said 

water that contacts components, dietary 

supplements, or contact surfaces 

should, at a minimum, meet the 

Environmental Protection Agency’s 

NPDW regulations and State, and local 

requirements. We proposed to require 

that water used in operations where 

water contacts components, dietary 

supplements, or any contact surfaces 

meet the NPDW regulations because of 

the potential for contamination if water 

were used that did not adhere to the 

microbial standards, for example, in the 

NPDW regulations. Finally, we stated 

these requirements were minimum 

requirements and that water that is more 

pure than that required under the 

NPDW regulations may be desired. 

The comments stated some 

manufacturers may not have access to 

municipal water, and therefore, that 

meeting the NPDW regulations for 

cleaning contact surfaces would be too 

burdensome. These comments asserted 

that potable water would be sufficient. 

The comments do not provide a 

definition of ‘‘potable water.’’ We have 

defined ‘‘potable water,’’ in the 

regulations on interstate conveyance 

sanitation in 21 CFR part 1250 to be, in 

part, water that meets the standards 

prescribed in the Environmental 

Protection Agency’s NPDW regulations 

in 40 CFR part 141. 

We would consider it to be a rare 

situation where a dietary supplement 

manufacturer uses well water and has 

no access to municipal water. 

Nonetheless, to the extent that a 

manufacturer uses water that is not 

subject to Federal oversight, the 

manufacturer would have to comply 

with any State or local regulations that 

apply to food manufacturing facilities 

using such water in food processing. 

Manufacturers that use water from a 

municipal source, which is subject to 

the Environmental Protection Agency 

NPDW regulations, should not be 

subject to a lesser standard in this final 

rule than what is already required of 

them by the Environmental Protection 

Agency. Thus, to accommodate 

manufacturers subject to the 

Environmental Protection Agency’s 

NPDW regulations for the water that 

they use in the manufacture of dietary 

supplements, as well as those dietary 

supplement manufacturers who are not 

subject to the Environmental Protection 

Agency’s NPDW regulations, we are 

modifying the rule to state water that is 

used in a manner such that the water 

may become a component of the dietary 

supplement, e.g., when such water 

contacts components, dietary 

supplements, or any contact surface, 

must, at a minimum, comply with 

applicable Federal, State, and local 

requirements and not contaminate the 

dietary supplement. We decline to use 

‘‘safe and of adequate safety’’ that some 

comments state is sufficient because it 

is for conventional foods. We believe 

that requiring that water comply with 

Federal, State and local requirements 

and not contaminate dietary 

supplements provides a clear standard 

as to what is required. 

(Comment 89) Some comments assert 

that water that is used to manufacture 

components or dietary ingredients 

where such components or dietary 

ingredients are subject to further 

processing prior to consumption, should 

be subject to the ‘‘safe and of adequate 

sanitary quality’’ standard in § 110.37. 

(Response) We acknowledge that such 

components and dietary ingredients are 

subject to the requirement in § 110.37. If 

the manufacturers do not fall within the 

scope of final § 111.1, such 

manufacturers would be subject to the 

CGMP requirements in part 110. 

To the extent that such comments 

request the ‘‘safe and of adequate 

sanitary quality’’ language apply to 

water used in the manufacture of a 

dietary supplement, we decline to make 

that change. Water that is safe and 

sanitary would not necessarily comply 

with, for example, the NPDW 

regulations. A requirement stating ‘‘safe 

and of adequate sanitary quality’’ or, as 

stated in the final rule, the requirement 

of ‘‘safe and sanitary’’ could be seen as 

a lesser standard than water that 

complies with ‘‘applicable Federal, 

State, and local requirements.’’ We want 

to make clear that you must comply 

with applicable Federal, State, and local 

requirements related to the water that 

you use for food processing that would 

otherwise be required of you, and not to 

some lesser standard that you may 

consider is ‘‘safe and sanitary’’ when 

water is used in a manner such that the 

water may become a component of the 

dietary supplement, e.g., when such 

water contacts a component, dietary 

supplement, or any contact surface. 

Foreign manufacturers would need to 

comply with the water standard 

required in this final rule and achieve 

the same level of performance as is 

required of domestic manufacturers. 

The water used in domestic or foreign 

manufacturing must not contaminate 

the dietary supplement. To clarify that 

the water used, whether by a domestic 

or foreign manufacturer, must not be a 

source of contamination, we are adding 

the words ‘‘and not contaminate the 

dietary supplement’’ in final 

§ 111.15(e)(2). We also want to make it 

clear that water includes what is in the 

water, e.g., any of its contaminants in 

addition to H2O. For example, when we 

speak of drinking water, we do not just 

mean the H2O, we mean the iron, lead, 

sulfur, and any other contaminants 

contained in the water. 

(Comment 90) Several comments 

suggest water should meet some or all 

standards of the USP monograph for 

sterile, purified water and say that the 

standard in the USP monograph is a 

higher, and presumably safer, standard 

than the NPDW standard. The 

comments state the USP’s water 

deionization and purification systems 

requirements are already common in the 

industry. 

(Response) We do not discourage 

firms from using water in dietary 

supplement manufacturing that meets 

USP standards, including deionized or 

purified water, but we do not require, as 

a CGMP, the use of USP standards. This 

final rule sets forth minimum 

requirements for persons who 

manufacture, package, label, or hold a 

dietary supplement. Thus, firms may 

use water that exceeds our minimum 

requirements. 

(Comment 91) The preamble to the 

2003 CGMP Proposal recognized that 

foreign firms might not be subject to 

Environmental Protection Agency water 


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requirements or adhere to such 

requirements, but also stated that water 

quality is an important part of CGMP 

(68 FR 12157 at 12185). Thus, in the 

preamble to the 2003 CGMP Proposal, 

we invited comment on how we might 

ensure that foreign firms meet the same 

water quality requirements as domestic 

firms. Several comments respond to our 

request for comments specific to the 

applicability of the water standards to 

foreign firms. Several comments 

recommend we not distinguish between 

domestic and foreign firms with regard 

to water quality. The comments claim 

all firms must compete on a ‘‘level 

playing field.’’ These comments state 

water quality standards vary from 

country to country, and many countries 

do not have requirements that are 

comparable to those in the United 

States. The comments say foreign 

manufacturers should not be permitted 

to import products into the United 

States that do not meet the same safety 

standards as domestic goods. 

Other comments ask us to consider 

the water quality requirement to be met 

if the water complies with the NPDW 

standard or any equivalent water quality 

standard that is ensured by a foreign 

public agency. 

(Response) We agree that foreign firms 

should be required to meet the water 

safety and sanitary requirements 

required of domestic firms and achieve 

the same level of performance of 

domestic firms. As discussed in this 

section, foreign firms are required to 

meet all requirements and would need 

to comply with their own national or 

local water safety requirements and not 

contaminate the dietary supplement. 

(Comment 92) One comment would 

combine proposed § 111.15(d)(1) and 

(d)(2) into a single paragraph. The 

comment says the two proposed 

paragraphs are redundant. Proposed 

§ 111.15(d)(1) would require that you 

provide water that is safe and of 

adequate sanitary quality, at suitable 

temperatures, and under pressure as 

needed, in all areas where water is 

necessary for: (1) Manufacturing dietary 

ingredients or dietary supplements; (2) 

making ice that comes in contact with 

components, dietary ingredients, dietary 

supplements, or contact surfaces; (3) 

cleaning any surface; and (4) employee 

bathrooms and hand-washing facilities. 

Proposed § 111.15(d)(2) would require 

that water that contacts components, 

dietary ingredients, dietary 

supplements, or any contact surface 

must at a minimum comply with the 

NPDW regulations prescribed by the 

Environmental Protection Agency under 

40 CFR part 141 and any State and local 

government requirements. 

(Response) We disagree that proposed 

§ 111.15(d)(1) and (d)(2) were 

redundant. For example, as described in 

the proposed sections, nonpotable water 

that would have been ‘‘safe and of 

adequate sanitary quality’’ for use in 

flushing toilets may not have been ‘‘safe 

and of adequate sanitary quality’’ for use 

in the manufacture of a liquid dietary 

supplement. 

Final § 111.15(e)(1) requires that you 

provide water that is safe and sanitary, 

at suitable temperatures, and under 

pressure as needed, for all uses where 

water does not become a component of 

the dietary supplement. Final 

§ 111.15(e)(2) requires that water that is 

used in a manner such that the water 

may become a component of the dietary 

supplement, e.g., when such water 

contacts components, dietary 

supplements, or any contact surface, 

must, at a minimum, comply with 

applicable Federal, State, and local 

requirements and not contaminate the 

dietary supplement. As an example of 

how the requirements would apply, 

water that contains lead at a level that 

is 20 times higher than the maximum 

accepted level in the Environmental 

Protection Agency’s NPDW standards 

for lead may not be safe for use in the 

manufacture of dietary supplement that 

is consumed in four 2-ounce portions 

per day, but may be safe for use in 

cleaning the floors of the physical plant. 

Therefore, to emphasize that water that 

is ‘‘safe and sanitary’’ may be different 

depending on its use, the final rule 

continues to separate § 111.15(e)(1) and 

(e)(2) (formerly proposed § 111.15(d)(1) 

and (d)(2)). 

Additionally, to emphasize the 

importance of the water that is used in 

the manufacture of a dietary 

supplement, where the water is used in 

a manner such that the water may 

become a component of the dietary 

supplement, final § 111.23(c) (proposed 

§ 111.15(d)(3)) requires you to have 

documentation and keep records that 

such water meets the requirements of 

final § 111.15(e)(2). In contrast, there is 

no corresponding requirement for 

documentation in final § 111.23 that 

other water, such as water that is used 

to clean floors or used in employee 

bathrooms, meets requirements of final 

§ 111.15(e)(1). 

(Comment 93) Several comments 

state, if we retain a water standard 

requirement based on the 

Environmental Protection Agency 

NPDW standard, then it is important to 

include provisions recognizing the 

acceptability of municipal water sources 

and the frequency of testing required for 

other water sources. Some comments 

recommend water should meet the USP 

standard for purified water and point 

out that the USP standard provides an 

assurance of the water’s consistency and 

provides a system that can be 

monitored. 

Several comments suggest we include 

timetables for water testing or describe 

water testing frequency requirements. 

These comments state we should apply 

something analogous to the proposed 

requirements for infant formula which 

would require manufacturers to conduct 

the tests with sufficient frequency to 

ensure that the water meets the 

Environmental Protection Agency’s 

NPDW standard, but not less frequently 

than annually for chemical 

contaminants, every 4 years for 

radiological contaminants, and weekly 

for bacteriological contaminants. Other 

comments refer to the amendments to 

the bottled water regulations at 

§ 165.110 which require a minimum 

yearly monitoring of source water and 

finished bottled water products for 

chemical contaminants for which 

allowable levels have been established 

in the bottled water quality standard. 

(Response) Final § 111.23(c) requires 

you to have documentation that water, 

when used in a manner such that the 

water may become a component of the 

dietary supplement, e.g., when such 

water contacts a component, dietary 

supplement, or contact surface, meets 

the requirements of final § 111.15(e)(2). 

You must meet the requirement for final 

§ 111.15(e)(2) at the point of use, rather 

than at the point of delivery, i.e., at the 

point the water may become a 

component of the dietary supplement, 

such as when the water contacts 

components, dietary supplements, or 

any contact surface (such as when the 

water comes out of the faucet or comes 

out of a spigot from a holding tank 

where you store water). Thus, you must 

ensure that the water used in a manner 

such that the water may become a 

component of the dietary supplement, 

not the water source before it enters 

your facility, meets the NPDW 

regulations, or if not subject to the 

NPDW regulations, that it meets any 

other applicable Federal, State, and 

local requirements and does not 

contaminate the dietary supplement. 

For example, if the water that enters 

your facility is subject to the 

Environmental Protection Agency 

NPDW regulations, then the water must 

comply with such requirements at the 

point of use, i.e., when it contacts the 

components, dietary supplement, or any 

contact surface (such as when the water 

comes out of the faucet or out of a spigot 

from a holding tank where you store 

water). You could rely on a certificate of 

analysis under final § 111.75(a)(2)(ii) 


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from the supplier of the water (e.g., the 

municipality) to ensure that the water 

entering your facility complies the 

applicable Federal, State, and local 

requirements. However, you must 

ensure that nothing happens to the 

water that may contaminate the water 

once it enters your facility and before 

the water may become a component of 

the dietary supplement at the point of 

use. Certain contaminants or 

microorganisms may be introduced into 

the water from the facility. Thus, you 

may need to establish specifications and 

procedures to prevent contamination 

from pipes through which the water 

travels in the facility or from vessels in 

which the water is held in the facility 

prior to use. You may need to test for 

certain contaminants, e.g., lead or 

microorganisms, at point of use to 

ensure there is no contamination of the 

water within your facility. Such tests 

may not need to include all of the 

chemical, microbiological, or 

contaminant testing already certified by 

the supplier to determine whether the 

water entering your facility complies 

with Federal, State and local 

requirements. Rather, you would need 

to evaluate what, if any, introductions of 

contaminants are likely to occur within 

your facility and determine whether 

additional tests are needed to verify that 

the water, at point of use, will comply 

with Federal, State, and local 

requirements and not contaminate the 

dietary supplement. Alternatively, you 

may decide not to rely on a certificate 

of analysis and instead conduct your 

own testing at point of use to determine 

if the water complies with applicable 

Federal, State, and local requirements. 

We decline to set out testing 

requirements or frequency of testing in 

this final rule in lieu of giving 

manufacturers the flexibility to decide 

on the appropriate testing and frequency 

of such testing to ensure that the water 

meets the requirements in final 

§ 111.15(e)(2). We may consider issuing 

guidance, as needed, on our 

recommendation for testing based on 

water sources and the purposes for 

which the water is used. If you rely on 

a certificate of analysis from the 

supplier of the water, we recommend 

that you qualify your facility by 

conducting appropriate tests at the point 

of use to verify that no other tests are 

necessary or that any additional tests 

you have chosen are sufficient to 

establish that the water that is used in 

a manner such that the water may 

become a component of the dietary 

supplement, e.g., when such water 

contacts components, dietary 

supplements or any contact surface, 

meets the requirements of final 

§ 111.15(e)(2). We also recommend that 

you requalify your facility at the point 

of use at appropriate intervals. 

If you use water from a private source, 

you must use water that complies with 

any State and local requirement and 

does not contaminate the dietary 

supplement. You may need to perform 

appropriate water treatment procedures, 

including filtration, sedimentation, and 

chlorination to satisfy final 

§ 111.15(e)(2). 

(Comment 94) Several comments 

would delete proposed § 111.15(d)(2), 

arguing that it is unnecessary to state a 

requirement that water meet the 

Environmental Protection Agency’s 

NPDW standards. These comments state 

that if water is used in processing or at 

critical points in the cleaning process, 

then a manufacturer will already have 

established specifications for its 

appropriate use. 

(Response) We agree that a 

manufacturer will need to establish 

specifications, under final § 111.70(a), 

for any point, step, or stage in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement, and for water that 

is used in a manner such that the water 

may become a component of the dietary 

supplement. For reasons set forth in 

response to comment 88, final 

§ 111.15(e)(2) establishes the minimum 

standards for water that will be used in 

a manner such that the water may 

become a component the dietary 

supplement, e.g., when such water 

contacts components, dietary 

supplements, or any contact surface. 

Thus, we disagree that proposed 

§ 111.15(e)(2) be eliminated. 

6. Final § 111.15(f) 

Final § 111.15(f) (proposed 

§111.15(e)) sets forth requirements for 

the plumbing of your physical plant. 

Final § 111.15(f) requires your 

plumbing to be of an adequate size and 

design and be adequately installed and 

maintained to: (1) Carry sufficient 

amounts of water to required locations 

throughout the physical plant; (2) 

properly convey sewage and liquid 

disposable waste from your physical 

plant; (3) avoid being a source of 

contamination to components, dietary 

supplements, water supplies, or any 

contact surface, or creating an 

unsanitary condition; (4) provide 

adequate floor drainage in all areas 

where floors are subject to flooding-type 

cleaning or where normal operations 

release or discharge water or other 

liquid waste on the floor; and (5) not 

allow backflow from, or crossconnection between, piping systems 

that discharge waste water or sewage 

and piping systems that carry water 

used for manufacturing dietary 

supplements, for cleaning contact 

surfaces, or for use in bathrooms and 

hand-washing facilities. 

We did not receive comments specific 

to proposed § 111.15(e), other than 

comments arguing that certain text was 

unconstitutionally vague and arbitrary 

and capricious. We address those 

comments in section V of this 

document. 

7. Final § 111.15(g) 

Final § 111.15(g) (proposed 

§ 111.15(f)) sets forth requirements for 

sewage disposal and requires you to 

dispose of sewage into an adequate 

sewage system or through other 

adequate means. 

We did not receive comments specific 

to proposed § 111.15(f). 

8. Final § 111.15(h) 

Final § 111.15(h) (proposed 

§ 111.15(g)(1)) sets forth requirements 

for the bathrooms of your physical 

plant. Final § 111.15(h) requires you to 

provide your employees with adequate, 

readily accessible bathrooms, and that 

the bathrooms be kept clean and not be 

a potential source of contamination to 

your components, dietary supplements, 

or contact surfaces. 

(Comment 95) Several comments state 

companies should be given flexibility in 

designing their bathrooms. These 

comments assert the food CGMP 

requirements allow flexibility in 

bathroom design, so the dietary 

supplement CGMP rule should do the 

same. The comments would delete 

proposed § 111.15(g)(1) through (g)(3), 

which pertained to: (1) Keeping the 

bathrooms in good repair at all times; (2) 

providing self-closing doors; and (3) 

providing doors that do not open into 

areas where components, dietary 

ingredients, dietary supplements, or 

contact surfaces are exposed to airborne 

contamination, except where alternate 

means have been taken to protect 

against contamination. 

(Response) We agree that it is 

unnecessary to require specific 

bathroom features such as those in 

proposed § 111.15(g)(1) through (g)(3) 

because you may be able to achieve 

compliance through other means better 

suited to your operations. Accordingly, 

we are revising the rule by deleting 

proposed § 111.15(g)(1) through (g)(3) as 

requested by the comments. However, 

we continue to believe that mechanisms 

such as self-closing doors and doors that 

do not open onto areas where 

components, dietary supplements, or 

contact surfaces are exposed to 


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contamination will help protect against 

contamination. 

9. Final § 111.15(i) 

Final § 111.15(i) (proposed § 111.5(h)) 

sets forth requirements for the handwashing facilities of your physical 

plant. Final § 111.15(i) requires you to 

provide hand-washing facilities that are 

designed to ensure that an employee’s 

hands are not a source of contamination 

of components, dietary supplements, or 

any contact surface, by providing 

facilities that are adequate, convenient, 

and furnish running water at a suitable 

temperature. 

Final § 111.15(i) differs from the 

proposal in that the proposal would list 

six specific features of a hand-washing 

facility, such as effective hand-cleaning 

and sanitizing preparations (proposed 

§ 111.15(h)(2)), air driers, sanitary towel 

service, or other suitable drying devices 

(proposed § 111.15(h)(3)), and trash bins 

that are constructed to protect against 

recontamination (proposed 

§ 111.15(h)(4)). 

(Comment 96) Several comments state 

we should give firms the flexibility to 

design their hand-washing facilities. 

According to these comments, 

substituting the word ‘‘may’’ for the 

word ‘‘must’’ would accomplish this. 

The comments argue that, as with 

bathrooms, an overall sanitation 

requirement should be sufficient, and 

that, as long as there is a strong and 

enforceable standard, firms should have 

the flexibility to adopt only those 

measures that are needed to meet the 

underlying requirement. 

(Response) We agree that it is 

unnecessary to require specific handwashing mechanisms because you may 

be able to achieve compliance through 

other means better suited to your 

operations. However, we disagree that 

an overall sanitation requirement would 

be sufficient, because such a 

requirement would not clearly state the 

purpose of the requirement, which is to 

ensure that an employee’s hands are not 

a source of contamination of 

components, dietary supplements, or 

any contact surface. 

We are revising proposed § 111.15(h) 

(final § 111.15(i)) in the final rule in two 

respects. First, the final rule states that 

the hand-washing facilities are to be 

designed to ensure that an employee’s 

hands are not a source of contamination. 

Second, final § 111.15(i) states that the 

hand-washing facilities are to be 

adequate, convenient, and furnish 

running water at suitable temperatures 

but does not provide the specific handwashing mechanisms detailed in the 

2003 CGMP Proposal. 

10. Final § 111.15(j) 

Final § 111.15(j) (proposed § 111.15(i)) 

sets forth requirements for trash 

disposal at your physical plant. Final 

§ 111.15(j) requires that you convey, 

store, and dispose of trash to: (1) 

Minimize the development of odors; (2) 

minimize the potential for trash to 

attract, harbor, or become a breeding 

place for pests; (3) protect against 

contamination of components, dietary 

supplements, any contact surface, water 

supplies, and grounds surrounding your 

physical plant; and (4) control 

hazardous waste to prevent 

contamination of components, dietary 

supplements, and contact surfaces. 

(Comment 97) One comment suggests 

deleting proposed § 111.15(i)(1) 

concerning minimizing the 

development of odors, because, the 

comment claimed, minimizing odors is 

not a ‘‘true’’ CGMP requirement. 

(Response) We disagree that 

minimizing the development of odors is 

not part of CGMP. Odor from trash is 

often an indication of problems with 

microbial contamination, such as 

decomposition, decay, and the growth 

of harmful bacteria. In addition, odor 

from trash can attract pests. By 

conveying, storing, and disposing of 

trash to minimize the development of 

odors, you will help reduce the 

potential for problems with microbial 

contamination and pests. 

11. Final § 111.15(k) 

Final § 111.15(k) (proposed 

§ 111.15(j)) sets forth requirements for 

sanitation supervisors at your physical 

plant. Final § 111.15(k) requires that you 

assign one or more employees to 

supervise overall sanitation. Each 

supervisor must be qualified by 

education, training, or experience to 

develop and supervise sanitation 

procedures. Final § 111.15(k) differs 

from proposed § 111.15(j) in that the 

proposal would require that each 

supervisor be qualified by training and 

experience. 

(Comment 98) Several comments 

suggest revising proposed § 111.15(j) to 

state that sanitation supervisors may be 

qualified by education, training, or 

experience (or any combination thereof) 

to develop and supervise sanitation 

procedures. In contrast, several 

comments say that sanitation 

supervisors should be qualified by both 

training and experience. 

(Response) Consistent with our 

response to comment 76 in section VII 

of this document, final § 111.15(k) 

provides that sanitation supervisors, 

like other supervisors, must be qualified 

by education, training, or experience to 

develop and supervise sanitation 

procedures. As we also stated in 

response to comment 76, we 

acknowledge that some supervisory 

personnel may need a different range of 

education, training, or experience than 

others. However, we have decided to 

give firms the flexibility to decide the 

appropriate amount of education, 

training, or experience for a given job 

function. If that includes a combination 

of attributes, the firm should select and 

train employees accordingly. 

E. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.16) 

We received many comments that 

recommend written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to comments on specific 

provisions in the same section. 

We are adding a new final § 111.16 

entitled ‘‘What Are the Requirements 

Under This Subpart for Written 

Procedures?,’’ to require you to establish 

and follow written procedures for 

fulfilling certain requirements of 

subpart C. You must establish and 

follow written procedures for cleaning 

the physical plant and for pest control. 

F. What Design and Construction 

Requirements Apply to Your Physical 

Plant? (Final § 111.20) 

Final § 111.20 addresses physical 

plant design and construction 

requirements. 

1. Final § 111.20(a) and (b) 

Final § 111.20(a) and (b) require that 

any physical plant that you use in the 

manufacturing, packaging, labeling, or 

holding of dietary supplements: (1) Be 

suitable in size, construction, and 

design to facilitate maintenance, 

cleaning, and sanitizing operations and 

(2) have adequate space for the orderly 

placement of equipment and holding of 

materials as is necessary for 

maintenance, cleaning, and sanitizing 

operations and to prevent 

contamination and mixups of 

components and dietary supplements 

during manufacturing, packaging, 

labeling, or holding. 

We did not receive comments specific 

to proposed § 111.20(a) or (b), other than 

comments arguing that certain text in 

proposed § 111.20(b) was 

unconstitutionally vague and arbitrary 

and capricious. We address those 

comments in this section and section V 

of this document. 


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2. Final § 111.20(c) 

Final § 111.20(c) requires that any 

physical plant you use in the 

manufacturing, packaging, labeling, or 

holding of dietary supplements provide 

for the use of proper precautions to 

reduce the potential for mixups or 

contamination of components, dietary 

supplements, or contact surfaces, with 

microorganisms, chemicals, filth, or 

other extraneous material. 

Under final § 111.20(c) your physical 

plant must have, and you must use, 

separate or defined areas of adequate 

size or other control systems, such as 

computerized inventory controls or 

automated systems of separation, to 

prevent contamination and mixups of 

components and dietary supplements 

during the following operations: (1) 

Receiving, identifying, holding, and 

withholding from use, components, 

dietary supplements, packaging, and 

labels that will be used in or during the 

manufacturing, packaging, labeling, or 

holding of dietary supplements; (2) 

separating, as necessary, components, 

dietary supplements, packaging, and 

labels that are to be used in 

manufacturing from components, 

dietary supplements, packaging, or 

labels that are awaiting material review 

and disposition decision, reprocessing, 

or are awaiting disposal after rejection; 

(3) separating the manufacturing, 

packaging, labeling, and holding of 

different product types including 

different types of dietary supplements 

and other foods, cosmetics, and 

pharmaceutical products; (4) performing 

laboratory analyses and holding 

laboratory supplies and samples; (5) 

cleaning and sanitizing contact surfaces; 

(6) packaging and label operations; and 

(7) holding components or dietary 

supplements. 

(Comment 99) Several comments 

would change ‘‘computerized inventory 

controls’’ to ‘‘adequate inventory 

controls’’ in proposed § 111.20(c). The 

comments say that a requirement to use 

a computerized system is too 

prescriptive and that inventory controls 

that are not computerized may be 

equally effective in achieving 

compliance with proposed § 111.20(c). 

(Response) These comments may have 

misinterpreted proposed § 111.20(c). 

Computerized inventory controls are an 

example of the type of system that may 

be appropriate; § 111.20(c) does not 

require you to have a computerized 

system in the first instance. Thus, final 

§ 111.20(c) continues to use 

computerized inventory controls as an 

example of a central system. 

(Comment 100) Several comments ask 

us to clarify the degree of separation 

that is intended under proposed 

§ 111.20(c) when it referred to ‘‘separate 

or defined areas’’ of a physical plant. 

These comments state that it is unclear 

if we expect a firm not to manufacture 

multiple products in a single room or 

area. The comments state that, if this is 

the case, this would be equivalent to the 

drug CGMP requirements and would be 

excessive. The comments argue that, if 

the proper controls are in place, 

manufacturing and packaging of 

multiple products is possible in a single 

room or area without compromising 

product identity, quality, strength, 

purity, and composition. 

(Response) Final § 111.20(c) states 

that you must have and use separate or 

defined areas of adequate size or other 

control systems, such as computerized 

inventory controls or automated systems 

of separation. The preamble of the 2003 

CGMP Proposal explained that if your 

physical plant does not allow for 

physically separate areas, you could 

develop an alternative approach for 

segregating components and dietary 

supplements at points when they are 

received, stored, and rejected (68 FR 

12157 at 12188). We interpret the 

comments as asking whether alternative 

approaches for segregating products 

could be used, even if physically 

separate areas were available in a 

facility, so that different materials could 

be processed in the same area. Final 

§ 111.20(c) allows you to use ‘‘separate 

or defined areas of adequate size or 

other control systems;’’ thus, you can 

comply with this requirement by 

manufacturing multiple products in the 

same room or area instead of using a 

physically separate location, as long as 

you have systems in place to prevent 

contamination and mixups of 

components and dietary supplements. 

3. Final § 111.20(d) 

Final § 111.20(d) requires that any 

physical plant you use in the 

manufacturing, packaging, labeling, or 

holding of dietary supplements be 

designed and constructed in a manner 

that prevents contamination of 

components, dietary supplements, or 

contact surfaces. 

Final § 111.20(d)(1) requires the 

design and construction to include: (1) 

Floors, walls, and ceilings that can be 

adequately cleaned and kept clean and 

in good repair; (2) fixtures, ducts, and 

pipes that do not contaminate 

components, dietary supplements, or 

contact surfaces by dripping or other 

leakage or condensate; (3) adequate 

ventilation or environmental control 

equipment, such as air flow systems, 

including filters, fans, and other airblowing equipment, that minimize 

odors and vapors (including steam and 

noxious fumes) in areas where they may 

contaminate components, dietary 

supplements, or contact surfaces; (4) 

equipment that controls temperature 

and humidity, when such equipment is 

necessary to ensure the quality of the 

dietary supplement; and (5) aisles or 

working spaces between equipment and 

walls that are adequately unobstructed 

and of adequate width to permit all 

persons to perform their duties and to 

protect against contamination of 

components, dietary supplements, or 

contact surfaces with clothing or 

personal contact. 

Final § 111.20(d)(1)(i) through 

(d)(1)(v) is similar to proposed 

§ 111.20(d)(1), (d)(2), (d)(3), (d)(5), and 

(d)(6), respectively. Additionally, as 

explained in the following paragraphs, 

we have made other changes to 

proposed § 111.20(d)(1) (final 

§ 111.20(d)(1)(i)) and proposed 

§ 111.20(d)(5) (final § 111.20(d)(1)(iv)). 

(Comment 101) Several comments 

argue that the requirement of proposed 

§ 111.20(d)(1) that floors, walls, and 

ceilings be made of ‘‘smooth and hard 

surfaces,’’ if read literally, could be 

interpreted to prohibit the use of 

ceilings with drop-in tiles. These 

comments assert that, while there may 

be areas in a manufacturing plant where 

drop-in ceilings are inappropriate given 

the height of the ceiling, the nature of 

the product, or the type of operation 

conducted in that area, such ceilings are 

adequate in many areas of a 

manufacturing facility, and certainly are 

appropriate in places where product is 

labeled or stored. The comments argue 

that replacing such ceilings with 

surfaces that are ‘‘smooth and hard’’ is 

unnecessary. Several other comments 

argue that they could find no precedent 

in any food CGMP regulations for a 

provision specifying ‘‘smooth and hard 

surfaces’’ for ceilings, but did identify a 

precedent in the section of drug CGMP 

requirements relating to ‘‘aseptic 

processing.’’ The comments state that 

adopting such a drug CGMP 

requirement is inappropriate for dietary 

supplements. 

The comments say the overall 

purpose of proposed § 111.20(d)(1) 

should be to ensure that facilities can be 

kept in a clean and sanitary condition. 

The comments would revise proposed 

§ 111.20(d)(1) to require physical plants 

to have surfaces that can be adequately 

cleaned, but would give manufacturers 

the flexibility to use appropriate 

surfaces in different parts of a plant. 

The comments also argue that the 

rule’s specificity establishes a 

conundrum for certain manufacturers to 

conform to other Federal regulations, 


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e.g., Occupational Safety and Health 

Administration (OSHA) noise levels. 

The comments argue that firms should 

be allowed to simultaneously conform 

to both OSHA and FDA requirements. 

(Response) We agree that a smooth 

and hard surface may not be necessary 

in every case to prevent contamination 

of the dietary supplement. However, 

you may need floors, walls, and ceilings 

that are constructed of smooth and hard 

surfaces to prevent contamination of the 

dietary supplement when, for example, 

physical attributes of components (e.g., 

particle size or electrostatic charge) 

would make it difficult to keep floors, 

walls, and ceilings clean. Consequently, 

we conclude that a requirement that the 

physical plant have floors, walls, and 

ceilings that can be adequately cleaned 

and kept clean and in good repair to 

prevent contamination of the dietary 

supplement is sufficient. We are 

revising final § 111.20(d)(1) to remove 

the language concerning smooth and 

hard surfaces. The final rule gives you 

the flexibility to determine how best to 

construct your facility in order to 

prevent contamination and to ensure the 

quality of the dietary supplements you 

manufacture, package, label, or hold. 

Section 111.20(d)(1)(ii) of the final 

rule (proposed § 111.20(d)(2)) requires 

your physical plant design and 

construction to have fixtures, ducts, and 

pipes that do not contaminate 

components, dietary supplements, or 

contact surfaces by dripping or other 

leakage, or condensate. Final 

§ 111.20(d)(1)(iii) (proposed 

§ 111.20(d)(3)) pertains to adequate 

ventilation or environmental control 

equipment. We added ‘‘or other 

leakage’’ to clarify that the requirement 

relates to ‘‘leakage’’ regardless of 

whether the leakage is in the form of 

‘‘dripping.’’

(Comment 102) Proposed 

§ 111.20(d)(5) would require your 

physical plant design and construction 

to include equipment that controls 

temperature and humidity. Several 

comments suggest adding a qualifier to 

the temperature and humidity control 

requirements so that controls are only 

required as necessary to prevent 

adulteration. The comments state there 

is adequate evidence that temperature 

and humidity do not stimulate 

reproduction of microorganisms and 

pests in dietary supplements. The 

comments also argue that retesting older 

ingredients stored in an uncontrolled 

environment and subjected to heat, 

cold, and ambient humidity produced 

no evidence of reproduction of 

microorganisms. According to the 

comments, temperature and humidity 

may present issues with raw, 

unprocessed botanical ingredients or 

animal-derived ingredients, but there is 

no proven issue with the powdered 

botanical and animal derived 

ingredients used by the dietary 

supplement industry. 

Several comments argue against 

requiring temperature and heat controls, 

asserting that most equipment used to 

manufacture dietary supplements is 

often cleaned with large amounts of hot 

water, and therefore temperature and 

humidity controls are not practical. 

(Response) We agree that controls for 

temperature and humidity should only 

be required when necessary to ensure 

the quality of the dietary supplement, 

and we are revising final § 111.20(d) 

accordingly. However, we disagree that 

there is adequate evidence that 

temperature and humidity do not 

stimulate reproduction of 

microorganisms in dietary supplements. 

It is well-recognized that 

microorganisms such as bacteria will 

grow in a warm environment and that 

microorganisms, such as molds, will 

grow in a moist environment. In 

addition, if the comments are suggesting 

that this final rule should only include 

requirements that derive from specific, 

already known examples that the 

absence of a requirement directly led to 

a problem with a dietary supplement, 

we disagree. CGMP requirements can 

help prevent products from becoming 

adulterated during the manufacturing 

process, and, in certain cases, 

controlling temperature and humidity 

may be necessary to ensure the quality 

of the dietary supplement. 

With respect to the comments stating 

that using hot water to clean equipment 

makes control of temperature and 

humidity impractical, we advise that a 

firm unable to control temperature and 

humidity in those parts of its facility 

where control is necessary to ensure the 

quality of the dietary supplement 

because it uses hot water to clean 

equipment would not be in compliance 

with final § 111.20(c). The provision 

requires that your physical plant have, 

and that you use, separate and defined 

areas of adequate size, or other control 

systems, to prevent contamination 

during operations such as cleaning 

contact surfaces (final § 111.20(c)(5)). 

Final § 111.20(d)(2) (proposed 

§ 111.20(d)(4)) requires that, when fans 

and other air-blowing equipment are 

used, such fans and equipment be 

located and operated in a manner that 

minimizes the potential for 

microorganisms and particulate matter 

to contaminate components, dietary 

supplements, or contact surfaces. 

(Comment 103) Several comments 

interpret proposed § 111.20(d)(4) as 

requiring fans and air-blowing 

equipment. These comments state this 

type of equipment is not always needed 

and may, in some instances, be more 

likely to cause adulteration than prevent 

it. The comments ask us to clarify that 

fans and other air-blowing equipment 

are only required when they are 

necessary to prevent adulteration. 

(Response) Proposed § 111.20(d)(4) 

was intended to require that any fans 

and other air-blowing equipment you 

use be located and operated in a manner 

that minimizes the potential for 

microorganisms and particulate matter 

to contaminate components, dietary 

supplements, or contact surfaces. 

Nevertheless, given the comments’

misinterpretation, we are revising 

proposed § 111.20(d)(4) (final 

§ 111.20(d)(2)) to state that, ‘‘When fans 

and other air-blowing equipment are 

used,’’ those fans and equipment must 

be located and operated in a manner 

that minimizes the potential for 

contamination by microorganisms and 

particulate matter. This should clarify 

that the rule does not mandate the use 

of fans and air-blowing equipment. 

(Comment 104) Some comments state 

that exhaust and venting equipment 

can, under certain circumstances, be a 

source of microbial contamination. The 

comments would revise proposed 

§ 111.20(d)(4) to read: ‘‘Fans and other 

air-blowing or exhaust and venting 

equipment located and operated in a 

manner that minimizes the potential for 

microorganisms and particulate matter 

to contaminate components, dietary 

ingredients, dietary supplements, or 

contact surfaces.’’

(Response) We decline to revise the 

rule as suggested by these comments as 

there is no need to do so. We consider 

exhaust equipment and venting 

equipment to be types of fans or airblowing equipment and therefore 

covered by the term ‘‘fans and other airblowing equipment.’’

4. Final § 111.20(e) 

Final § 111.20(e) (proposed 

§ 111.20(e)) requires that any physical 

plant that you use in the manufacturing, 

packaging, labeling, or holding of 

dietary supplements provide adequate 

light in: (1) All areas where components 

or dietary supplements are examined, 

processed, or held; (2) all areas where 

contact surfaces are cleaned; and (3) 

hand-washing areas, dressing and locker 

rooms, and bathrooms. 

We did not receive any comments 

specific to proposed § 111.20(e). 

5. Final § 111.20(f) 

Final § 111.20(f) (proposed 

§ 111.20(f)) requires that any physical 


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plant you use in the manufacturing, 

packaging, labeling, or holding of 

dietary supplements use safety-type 

light bulbs, fixtures, skylights, or other 

glass or glass-like materials when the 

light bulbs, fixtures, skylights, or other 

glass or glass-like materials are 

suspended over exposed components or 

dietary supplements in any step of 

preparation, unless your physical plant 

is otherwise constructed in a manner 

that will protect against contamination 

of components or dietary supplements 

in case of breakage of glass or glass-like 

materials. 

We did not receive any comments 

specific to proposed § 111.20(f). On our 

own initiative, we are making clarifying 

changes to final § 111.20(f) by: 

• Adding ‘‘or glass-like materials’’

after the word ‘‘glass.’’ Although 

proposed § 111.20(f) only specified 

glass, its intent was to cover any 

material that could shatter and 

contaminate components, dietary 

supplements, or contact surfaces. 

Therefore, we are adding glass-like 

material to final § 111.20(f) to cover 

fixtures and skylights that use non-glass 

materials (such as acrylic and 

polycarbonate materials) but could still 

contaminate components, dietary 

supplements, or contact surfaces if 

shattered or broken. 

Further, we are stating that the 

requirement applies when the light 

bulbs, fixtures, skylights, or other glass 

or glass-like materials are suspended 

over exposed components or dietary 

supplements in any step of preparation. 

We made this change to prevent the rule 

from being misinterpreted as requiring 

firms to suspend light bulbs, fixtures, 

skylights, or other glass over 

components or dietary supplements in 

every step of preparation. 

6. Final § 111.20(g) 

Final § 111.20(g) (proposed 

§ 111.20(g)) requires that any physical 

plant you use in the manufacturing, 

packaging, labeling, or holding of 

dietary supplements provide effective 

protection against contamination of 

components and dietary supplements in 

bulk fermentation vessels. Such 

protection includes: (1) Use of 

protective coverings; (2) placement in 

areas where you can eliminate 

harborages for pests over and around the 

vessels; (3) placement in areas where 

you can check regularly for pests, pest 

infestation, filth or any other extraneous 

materials; and (4) use of skimming 

equipment. 

We did not receive comments specific 

to proposed § 111.20(g). We have made 

nonsubstantive, grammatical changes to 

the provision by replacing ‘‘by any 

effective means’’ with ‘‘effective’’ before 

the word protection and ‘‘including 

consideration of’’ with ‘‘by, for 

example:’’. 

7. Final § 111.20(h) 

Final § 111.20(h) (proposed 

§ 111.20(h)) requires that any physical 

plant you use in the manufacturing, 

packaging, labeling, or holding of 

dietary supplements use adequate 

screening or other protection against 

pests, where necessary. 

(Comment 105) One comment argues 

that proposed § 111.20(h) should be 

deleted because it is redundant when 

compared to proposed § 111.15(c) which 

would require you to not allow animals 

or pests in any area of your physical 

plant, except for guard or guide dogs in 

certain circumstances. 

(Response) We disagree that final 

§ 111.20(h) is redundant to proposed 

§ 111.15(c) (final § 111.15(d)). Although 

both paragraphs deal with pests, final 

§ 111.20(h) establishes a design 

requirement (i.e., a specific requirement 

to use adequate screening or other 

protection), while final § 111.15(d) sets 

forth a sanitation requirement (i.e., to 

not allow animals or pests in your 

physical plant). Therefore, we are 

retaining § 111.20(h) in the final rule. 

G. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.23) 

Final § 111.23(a) requires you to make 

and keep records required under this 

subpart in accordance with subpart P. 

Final § 111.23(b) requires that you 

make and keep records of the written 

procedures for cleaning the physical 

plant and for pest control. This 

provision was added to ensure that the 

written procedures now required under 

final § 111.16 are maintained as 

required under subpart P. 

Final § 111.23(c)(1) (proposed 

§ 111.15(d)(3)) requires that you make 

and keep records that water, when used 

in a manner such that the water may 

become a component of the dietary 

supplement, meets the requirements of 

final § 111.15(e)(2). 

(Comment 106) Several comments 

state there is no documentation 

requirement for water in the food or 

drug CGMPs. The comments, therefore, 

say there should be not be such a 

requirement in this final rule for dietary 

supplements. 

(Response) To the extent that the 

comments assert we cannot include 

such a requirement for documentation 

in the dietary supplement CGMP 

because there is no corollary 

requirement in part 110, we have 

responded to this issue in section V of 

this document. The absence of a 

provision in drug CGMP requirements 

does not preclude us from requiring it 

in this final rule establishing CGMP 

requirements for dietary supplements 

for which we have no pre-approval 

scheme for ingredients used in such a 

product. 

(Comment 107) Several comments ask 

us to clarify that, if a municipal water 

supply is used in a facility, the 

municipal water report is acceptable 

documentation of water quality. These 

comments say that a city’s yearly report 

of its municipal water quality should be 

sufficient documentation, and that 

independent testing should not be 

required. Several comments claim that 

our officials made statements to this 

effect during a public meeting held on 

May 6, 2003. 

The comments also assert that water 

quality in a community is typically well 

known due to public notification that is 

required by the Environmental 

Protection Agency or due to other 

resources. These comments say that 

municipal water supplies are also well 

controlled as a result of Environmental 

Protection Agency regulations, and that, 

if water quality in a community or 

country is suspect, we can move 

aggressively to enforce the standards. 

The comments argue that, overall, our 

enforcement burden would be less than 

requiring every company in the industry 

to maintain and produce documentation 

related to water quality. 

(Response) A yearly municipal report 

is a good starting point for documenting 

water meets the requirements of final 

§ 111.15(e), however, such a report 

cannot stand on its own as the only 

assurance that the water of the regulated 

body (such as persons subject to this 

final rule) complies with these 

regulations. A municipal water report 

offers reasonable assurance that the 

water entering your plant satisfies the 

requirements of the Environmental 

Protection Agency’s NPDW regulations. 

However, as discussed previously, the 

requirement to show that the water that 

is used in a manner such that the water 

may become a component of the dietary 

supplement, e.g., when such water 

contacts components, dietary 

supplements, or any contact surface, 

meets the requirements of § 111.15(e)(2), 

applies to water at the point of use, i.e., 

after it has passed through your 

plumbing system. 

If you use a municipal water supply, 

you should take steps to ensure that you 

are at all times aware of problems, such 

as an acute problem with microbial 

contamination or a long-term problem 

associated with lead pipes that are 

present in some parts of the city water 


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supply, that may not be reflected in the 

municipal water report. 

IX. Comments on Requirements Related 

to Equipment and Utensils (Subpart D) 

A. Organization of Final Subpart D 

Proposed subpart D contained two 

provisions regarding equipment, 

utensils, and automatic, mechanical, or 

electronic equipment. Table 5 of this 

document lists the sections in the final 

rule and identifies the corresponding 

sections in the 2003 CGMP Proposal 

that form the basis of the final rule. 

TABLE 5.—DERIVATION OF SECTIONS

IN SUBPART D 

Final Rule 2003 CGMP 

Proposal 

§ 111.25 What are the 

requirements under 

this subpart D for written procedures? 

§ 111.25(c)(1) 

§ 111.25(e)(1) 

§ 111.27 What requirements apply to the 

equipment and utensils that you use? 

§ 111.25(a), (b), 

(d), and (e) 

§ 111.30 What requirements apply to automated, mechanical, or 

electronic equipment? 

§ 111.30 

§ 111.35 Under this subpart D, what records 

must you make and 

keep? 

§§ 111.25(c)(1), 

(c)(2), (d), 

and (f), 

§ 111.30(b)(2), 

(b)(5), and (c) 

§ 111.50(c)(4) 

B. Highlights of Changes to the 

Proposed Requirements for Equipment 

and Utensils 

1. Revisions 

The final rule includes revisions that 

reflect the final rule applies to persons 

who manufacture, package, label, or 

hold dietary supplements unless subject 

to an exclusion in § 111.1. 

2. Revisions Associated With the 

Reorganization 

The revisions associated with the 

reorganization include: 

• Renumbering proposed § 111.25 as 

final § 111.27 and correcting the 

numbering of the sections misnumbered 

in the 2003 CGMP Proposal; 

• Requiring documentation and 

backup files in a separate section for 

recordkeeping requirements; and 

• A nonsubstantive editorial change 

to refer to ‘‘automated equipment’’

rather than ‘‘automatic equipment.’’

Although there is no practical difference 

between these two terms, the term 

‘‘automated’’ is the customary term. 

3. Changes After Considering Comments 

The final rule: 

• Requires you to establish and 

follow written procedures to fulfill the 

requirements of subpart D, including 

written procedures for: 

Æ Calibrating instruments and 

controls; 

Æ Calibrating, inspecting, and 

checking automated, mechanical, 

and electronic equipment; and 

Æ Maintaining, cleaning, and 

sanitizing, as necessary, equipment, 

utensils, and other contact surfaces; 

• Requires you to keep records of the 

maintenance, cleaning, and sanitizing of 

equipment either in equipment logs or 

in batch records; 

• Requires that quality control 

personnel periodically review records of 

calibrations, inspections, or checks of 

automated, mechanical, or electronic 

equipment rather than approve such 

records when they are made; 

• Specifies that software for a 

computer controlled process is included 

under automated, mechanical, or 

electronic equipment; and 

• Clarifies that the requirement to 

retain backup files of software programs 

and of data entered into computer 

systems is for computer systems that 

you use in the manufacture, packaging, 

labeling, or holding of dietary 

supplements. 

C. General Comments on Proposed 

Subpart D 

(Comment 108) Some comments 

claim one or more proposed 

requirements are unconstitutionally 

vague under the Fifth Amendment and 

arbitrary and capricious under 

§ 706(2)(B) of the APA. These proposed 

requirements include: 

• § 111.25(a)(1), which would require 

that equipment and utensils be ‘‘of 

appropriate design, construction, and 

workmanship to enable them to be 

suitable for their intended use and to be 

adequately cleaned and properly 

maintained’’; and 

• § 111.25(a)(2), which would require 

you to ‘‘use equipment and utensils of 

appropriate design and construction so 

that use will not result in the 

contamination of components, dietary 

ingredients, or dietary supplements.’’

In general, these comments assert the 

proposed sections did not define terms 

or phrases (such as ‘‘suitable’’ or 

‘‘appropriate design’’) in a way that 

persons who are subject to the rule can 

discern the meaning of the term. These 

comments also assert the proposed 

sections do not limit enforcement 

officers’ exercise of their discretion as to 

what will satisfy the requirements and, 

thus, invite exercise of unbridled 

discretion and disparate 

decisionmaking. 

(Response) As discussed in section V 

of this document, we disagree that the 

terms are unconstitutionally vague, 

need to be defined, may result in 

discriminatory enforcement, or violate 

the APA. There has been sufficient 

usage of these terms in the food industry 

to enable manufacturers, and those who 

enforce the requirements, to 

comprehend and apply such terms. 

Agencies are permitted to use qualifying 

terms to enable them to address a wide 

variety of conditions at companies. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.25) 

We received many comments that 

recommend written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to comments on specific 

provisions in the same section. We are 

adding final § 111.25 that requires you 

to establish and follow written 

procedures for certain requirements. 

E. What Requirements Apply to the 

Equipment and Utensils That You Use? 

(Final § 111.27) 

Final § 111.27 (proposed § 111.25) 

sets forth various requirements for 

equipment and utensils. 

1. Final § 111.27(a) 

a. Final § 111.27(a). Final § 111.27(a) 

(proposed § 111.25(a)(1)) requires you to 

use equipment and utensils that are of 

appropriate design, construction, and 

workmanship to enable them to be 

suitable for their intended use and to be 

adequately cleaned and properly 

maintained. In order to correct the 

misnumbering of this provision in the 

2003 CGMP Proposal, this general 

requirement has been broken out from 

the remaining requirements of final 

§ 111.27(a). 

Final § 111.27(a)(1)(i) through (a)(1)(v) 

provide examples of such equipment, 

such as equipment used to hold or 

convey (§ 111.27(a)(1)(i)), equipment 

using compressed air or gas 

(§ 111.27(a)(1)(iii)), and equipment used 

in automated, mechanical, or electronic 

systems (§ 111.27(a)(1)(v)). 

Final § 111.27(a)(1) is similar to 

proposed § 111.25(a)(1) except for two, 

nonsubstantive editorial changes. The 

first change replaces ‘‘automatic 

equipment’’ with ‘‘automated 

equipment’’ in what is now 

§ 111.27(a)(1)(v) (proposed 

§ 111.25(a)(1)(5)). Although there is no 

practical difference between 


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‘‘automatic’’ and ‘‘automated,’’ the latter 

is the customary term. 

(Comment 109) Some comments argue 

that the proposal’s use of terms such as 

‘‘appropriate design, construction, and 

workmanship to enable them to be 

suitable for their intended use’’ and 

‘‘adequately cleaned and properly 

maintained’’ are unconstitutionally 

vague under the Fifth Amendment and 

arbitrary and capricious under the APA. 

(Response) We discuss those 

comments generally in section V of this 

document and, because we disagree that 

the final rule violates either the Fifth 

Amendment of the Constitution or the 

APA, we have not revised § 111.27(a)(1) 

except for the changes mentioned in the 

previous paragraphs. 

b. Final § 111.27(a)(2). Final 

§ 111.27(a)(2) (proposed § 111.25(a)(2)) 

requires you to use equipment and 

utensils of appropriate design and 

construction so that use will not result 

in the contamination of components or 

dietary supplements with: (1) 

Lubricants, (2) fuel, (3) coolants, (4) 

metal or glass fragments, (5) filth or any 

other extraneous material, (6) 

contaminated water, or (7) any other 

contaminants. 

(Comment 110) Several comments 

state we should recognize that 

lubricants are an integral part of the 

encapsulation of gelatin-enrobed 

products and other dosage forms. These 

comments state lubricants are not 

potential contaminants, and in fact, help 

move gelatin ribbons through 

encapsulating machines. The comments 

would revise proposed § 111.25(a)(2) to 

read, ‘‘lubricants not intended for 

product contact,’’ to clarify the rule’s 

intent. 

(Response) We decline to revise the 

final rule as suggested by the comments. 

Final § 111.27(a)(2) states that the use of 

equipment and utensils must not result 

in the contamination of components or 

dietary supplements with lubricants. If 

a lubricant used for encapsulation does 

not result in contamination of the 

components or dietary supplements 

then the encapsulating machine 

complies with final § 111.27(a)(2). 

c. Final § 111.27(a)(3). Final 

§ 111.27(a)(3) (proposed § 111.25(a)(3)) 

requires all equipment and utensils you 

use to be: (1) Installed and maintained 

to facilitate cleaning the equipment, 

utensils, and all adjacent spaces; (2) 

corrosion-resistant if the equipment or 

utensils contact components or dietary 

supplements; (3) made of nontoxic 

materials; (4) designed and constructed 

to withstand the environment in which 

they are used, the action of components 

or dietary supplements, and, if 

applicable, cleaning compounds and 

sanitizing agents; and (5) maintained to 

protect components and dietary 

supplements from being contaminated 

by any source. 

We did not receive comments specific 

to proposed § 111.25(a)(3). We have 

substituted the phrase ‘‘in which they 

are used’’ for ‘‘of their intended use’’ to 

make clear the requirement applies to 

equipment actually used in the 

manufacture, packaging, labeling, or 

holding of dietary supplements. 

d. Final § 111.27(a)(4). Final 

§ 111.27(a)(4) (proposed § 111.25(a)(4)) 

requires that the equipment and utensils 

you use have seams that are smoothly 

bonded or maintained to minimize 

accumulation of dirt, filth, organic 

material, particles of components or 

dietary supplements, or any other 

extraneous materials or contaminants. 

Final § 111.27(a)(4) is similar to 

proposed § 111.25(a)(4) and is analogous 

to § 110.40(b) which requires that seams 

on food-contact surfaces be smoothly 

bonded or maintained so as to minimize 

accumulation of food particles, dirt, and 

organic matter and thus minimize the 

opportunity for growth of 

microorganisms. We have deleted the 

phrase ‘‘to minimize the opportunity for 

growth of microorganisms’’ as 

unnecessary in this context as the 

remaining wording of the provision 

encompasses this concept. In 

nonsubstantive editorial changes to final 

§ 111.27(a)(4) we substitute ‘‘particles of 

components or dietary supplements’’ for 

‘‘component or dietary supplement 

particles’’ to improve clarity, and reorder the list of extraneous materials or 

contaminants. 

(Comment 111) Several comments 

argue that proposed § 111.25(a)(4) is 

overly restrictive by requiring 

equipment and utensils to ‘‘have seams 

that are smoothly bonded or 

maintained’’ to minimize 

contamination. The comments would 

revise the rule as follows: ‘‘Equipment 

and utensils you use must be of proper 

design and maintained to minimize 

accumulation * * *.’’

(Response) We disagree that proposed 

§ 111.25(a)(4) (final § 111.27(a)(4)) is 

overly restrictive or that it requires a 

particular design. Final § 111.27(a)(4) 

requires seams that are smoothly 

bonded or maintained to minimize 

accumulation of dirt and gives firms the 

flexibility to use any design they 

choose, provided that the seams, by 

design or maintenance, minimize 

accumulation of contaminants. 

e. Final § 111.27(a)(5). Final 

§ 111.27(a)(5) (proposed § 111.27(a)(5)) 

requires that each freezer, refrigerator, 

and other cold storage compartment you 

use to hold components or dietary 

supplements: (1) Be fitted with an 

indicating thermometer, temperaturemeasuring device, or temperaturerecording device that indicates, and 

records, or allows for recording by hand, 

the temperature accurately within the 

compartment and (2) have an automated 

device for regulating temperature or an 

automated alarm system to indicate a 

significant temperature change in a 

manual operation. 

(Comment 112) The preamble to the 

2003 CGMP Proposal invited comment 

as to whether we should require specific 

target temperatures for dietary 

ingredients or dietary supplements held 

in freezers or cold storage (68 FR 12157 

at 12190). Several comments assert there 

is no need for us to specify storage 

temperatures for dietary ingredients or 

dietary supplements. The comments 

state most dietary supplements and 

dietary ingredients are shelf stable based 

on their low water activity control, 

which limits and slows chemical 

degradation and microbiological growth. 

Other comments say target temperatures 

are not required where freezing is used 

only to enhance the milling properties 

(fracturing) of dried botanicals and not 

to prevent microbial contamination. 

(Response) We have not included any 

specific target temperature requirements 

in the final rule. Consequently, firms 

should determine for themselves what 

temperatures are needed to ensure that 

the their dietary supplements are not 

adulterated (see final § 111.70 regarding 

the specifications you must establish). 

f. Final § 111.27(a)(6). Final 

§ 111.27(a)(6) (proposed § 111.25(a)(6)) 

requires the instruments or controls you 

use in the manufacturing, packaging, 

labeling, or holding of a dietary 

supplement, and instruments or 

controls that you use to measure, 

regulate, or record temperatures, pH, aw, 

or other conditions, to control or 

prevent the growth of microorganisms 

or other contamination, be accurate and 

precise, adequately maintained, and 

adequate in number for their designated 

uses. 

(Comment 113) One comment states 

that proposed § 111.25(a)(6)(i)’s 

requirements that instruments and 

controls be ‘‘accurate and precise’’ goes 

beyond ‘‘typical’’ calibration, and would 

require full validation of all instruments 

and controls. The comment argues that 

it is unnecessary to require both 

accuracy and precision for all 

instruments and controls, and would 

require precision only when necessary 

to prevent contamination. The comment 

states calibration to ensure accuracy of 

instruments and controls is usually 

sufficient to ensure control or 

prevention of the growth of 


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microorganisms or other contaminants 

in most situations. The comment gives 

an example where thermometers are 

used to monitor temperature in a 

warehouse where dietary supplements 

are stored. 

(Response) We disagree that proposed 

§ 111.27(a)(6) requires full validation of 

all equipment and controls. As 

discussed in the preamble to the 2003 

CGMP Proposal (68 FR 12157 at 12190), 

accuracy means that the recorded 

measurements are equal to the (true 

value) of the thing being measured and 

precision means that individual 

measurements should be close to each 

other when made under the same 

conditions. 

We also disagree that instruments 

need not be precise. An instrument that 

gives widely varying readings from one 

use to the next cannot ensure product 

quality over time. The degree of 

accuracy and precision is determined by 

the nature of the instrument or control 

and the process to which it relates. We 

have, however, made several 

nonsubstantive, editorial changes to 

§ 111.27(a)(6) as well as other edits to 

conform to changes made throughout 

the final rule. These are the 

nonsubstantive editorial changes: 

• Inserting a hyphen between 

‘‘hydrogen’’ and ‘‘ion’’ and 

• Revising the end of the paragraph 

so that it discusses ‘‘instruments and 

controls that you use * * * to control 

or prevent the growth of 

microorganisms or other contamination 

* * *.’’ The proposal stated 

‘‘instruments and controls that you use 

* * * that control or prevent the growth 

of microorganisms or other 

contamination * * *’’. (In other words, 

the final rule replaces ‘‘that’’ with ‘‘to’’.) 

g. Final § 111.27(a)(7). Final 

§ 111.27(a)(7) (proposed § 111.25(a)(7)) 

requires that the compressed air or other 

gases you introduce mechanically into 

or onto a component, dietary 

supplement, or contact surface or you 

use to clean any contact surface be 

treated in such a way that the 

component, dietary supplement, or 

contact surface is not contaminated. 

We received no comments specific to 

proposed § 111.25(a)(7). 

2. Final § 111.27(b) 

Final § 111.27(b) (proposed 

§ 111.25(b)(1)) requires you to calibrate 

instruments and controls that you use in 

manufacturing or testing a component 

or dietary supplement. In order to 

correct the misnumbering of this 

provision in the 2003 CGMP Proposal, 

this general requirement has been 

broken out from the remaining 

requirements of final § 111.27(b) and 

now has paragraphs (b) and (b)(1) 

through (b)(3). 

Final § 111.27(b)(1) through (b)(3) 

(proposed § 111.25(b)(1) and (b)(2)) 

requires you to calibrate before first use, 

and at the frequency specified in writing 

by the manufacturer of the instrument 

or control, or at routine intervals, or as 

otherwise necessary to ensure the 

accuracy and precision of the 

instrument and control. 

(Comment 114) Several comments 

object to the level of detail regarding the 

proposed calibration. Specifically, the 

comments object to requiring that 

manufacturers calibrate instruments and 

controls ‘‘as specified in writing by the 

manufacturer of the instrument and 

control.’’ The comments say this 

requirement is more prescriptive than 

drug CGMP requirements. The 

comments acknowledge that following 

manufacturer specifications is likely to 

be part of the calibration procedure, but 

state that firms should have the 

flexibility to modify their procedures as 

necessary. These comments would 

couple proposed § 111.25(b) with a 

requirement to establish and follow 

written procedures for calibrating 

instruments and controls and redraft 

proposed § 111.25(b) to mirror the drug 

CGMP requirements, using language 

such as ‘‘You must routinely calibrate 

instruments and controls that control or 

monitor critical parameters that you use 

in manufacturing or testing a 

component or dietary supplement.’’

(Response) We disagree that proposed 

§ 111.25(b) is overly prescriptive, 

exceeds drug CGMP requirements, or 

requires what is claimed by the 

comments. We discuss, generally, the 

issue of whether this final rule ‘‘exceeds 

drug CGMPs’’ in section V of this 

document. It is standard practice to 

calibrate an instrument before using it 

for the first time. A requirement that 

you calibrate as specified by the 

manufacturer of the equipment, or at 

routine intervals, or as otherwise 

necessary to ensure the accuracy and 

precision of the instrument and control, 

provides ample flexibility. Calibration, 

whether for instruments and controls 

used in manufacturing or testing drugs, 

devices, conventional foods, or dietary 

supplements, helps ensure the accuracy 

and precision of the instrument and 

control. We do not prescribe how 

frequently such calibration must be 

done, but it must be done often enough 

to ensure that instruments and controls 

are operating within the correct 

parameters. We are revising the 2003 

CGMP Proposal (at § 111.27(b)(2)) to 

clarify that the requirement relates to 

the frequency of calibration. 

(Comment 115) Several comments 

claim requirements relating to 

calibration of instruments and controls 

should be limited to those instruments 

and controls that directly affect the 

identity, purity, quality, strength, and 

composition of a dietary supplement. 

According to the comments, in most 

manufacturing facilities, there are many 

instruments and controls that do not 

directly affect identity, purity, quality, 

strength, and composition, and that 

calibrating all instruments and controls 

could easily become unduly 

burdensome. The comments also would 

limit the requirement for periodic 

calibration of instruments and controls 

to those instruments and controls 

directly involved in the critical control 

parameters of the process, i.e., those 

parameters needed to meet 

specifications or to ensure identity, 

purity, quality, strength, and 

composition. The comments suggest 

that critical control parameters would 

have to be established. 

(Response) We decline to revise the 

rule as suggested by the comments. The 

requirement to calibrate instruments 

and controls is limited to those 

instruments and controls that you use in 

testing a component or dietary 

supplement or in manufacturing a 

dietary supplement. Any such 

equipment has the potential to affect, 

directly or indirectly, the quality of the 

dietary supplement. 

(Comment 116) Some comments 

would revise proposed § 111.25(b)(1) to 

state that ‘‘calibration should be done, 

where standards are available or where 

it is necessary to meet product 

specifications.’’

(Response) We decline to revise the 

rule as suggested by the comments. It 

would be customary for an equipment 

manufacturer to have standards that can 

be used to calibrate the equipment, 

irrespective of the specific composition 

of the dietary supplement that is 

manufactured using that equipment. 

Equipment that is not or cannot be 

calibrated is unlikely to be in 

compliance with the requirement of 

final § 111.27(a)(6)(i) which requires 

instruments used in the manufacturing, 

packaging, labeling, and holding of 

dietary supplements, and instruments 

and controls that you use to perform 

certain operations, be accurate and 

precise. 

(Comment 117) Some comments 

would revise proposed § 111.25 from 

the active voice to the passive voice. 

These comments claim that the active 

voice—i.e., requiring that ‘‘you’’

calibrate instruments and controls—

requires that the dietary supplement 

manufacturer perform the calibration, 


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when in fact such calibrations are often 

performed by an outside service. 

(Response) You may use an outside 

service. We would not consider that 

calibration done for you by an outside 

service is any different than calibration 

done by your employees, and it is you 

(rather than an outside service) whom 

we will hold responsible to ensure that 

the calibration is performed. 

Accordingly, we decline to revise the 

provisions as suggested. 

(Comment 118) Several comments say 

calibration before first use should not be 

required for certified, precalibrated 

instrumentation. The comments state 

precalibrated instrumentation is much 

more expensive than noncalibrated 

instrumentation, with the additional 

expense attributed to the precalibration. 

Several comments would revise 

proposed § 111.25(b)(2) to read, ‘‘you 

must calibrate, or be able to verify that 

the calibration has been completed, 

before first use,’’ instead of ‘‘you must 

calibrate before first use.’’ The 

comments state that performance test 

results could be made available for this 

verification. 

(Response) As written, the 

requirement that equipment be 

calibrated before first use includes 

calibration performed by a third party as 

a precalibration because we would 

consider that calibration performed by a 

third party as no different from 

calibration performed by one of your 

own employees. Under final 

§ 111.35(b)(3) you must have 

documentation of the calibration. 

If you purchase a precalibrated 

instrument, we strongly recommend 

that the vendor conduct the certification 

onsite after installation. If not, we 

strongly recommend that you verify that 

the instrument remains calibrated after 

it has been installed. 

(Comment 119) Several comments ask 

whether the proposed requirement to 

calibrate ‘‘before first use’’ refers to the 

first use after installation or the first use 

after each start-up. 

(Response) Final § 111.27(b)(1) refers 

to the first use after installation and 

does not require calibration after each 

start-up. 

(Comment 120) Some comments 

would require that instruments and 

controls be calibrated, but argue that the 

final rule should not include detailed 

procedures specifying calibration 

methods. The comments said the rule 

should stay focused on end results and 

not process. 

(Response) We disagree that the 

regulations should not focus on process. 

The essence of the CGMP requirements 

established by these regulations is a 

production and process control system, 

i.e., a process, that is designed to ensure 

the quality of the dietary supplement. 

The final rule gives firms the flexibility 

to use different calibration methods as 

long as the method used is established 

in a written procedure. 

3. Final § 111.27(c) 

Final § 111.27(c) (proposed 

§ 111.25(d)) requires that you repair or 

replace instruments or controls that 

cannot be adjusted to agree with the 

reference standard. 

We received no comments specific to 

proposed § 111.25(d). 

4. Final § 111.27(d) 

Final § 111.27(d) (proposed 

§ 111.25(e)) requires you to maintain, 

clean, and sanitize, as necessary, all 

equipment, utensils, and any other 

contact surfaces used to manufacture, 

package, label, or hold components or 

dietary supplements. In order to correct 

the misnumbering of this provision in 

the 2003 CGMP Proposal, this general 

requirement has been broken out from 

the remaining requirements of final 

§ 111.27(d) and now has paragraphs (d) 

and (d)(1) through (d)(7). 

a. Final § 111.27(d)(1). Final 

§ 111.27(d)(1) requires that the 

equipment and utensils be taken apart 

as necessary for thorough maintenance, 

cleaning, and sanitizing. 

(Comment 121) Some comments argue 

that individual manufacturing 

operations will determine when 

sanitizing agents are needed after 

cleaning because of the wide variety of 

processes in the industry. The 

comments also say widespread use of 

sanitizing agents is creating resistant 

microbial strains, and incorporating 

unnecessary sanitization processes 

would contribute to this health concern. 

Some comments recommend 

manufacturers calibrate sanitizing 

procedures to the particular process in 

a declared fashion depending upon the 

risk factors of their process and 

materials. The comments set out several 

standards for sanitation procedures. 

(Response) Final § 111.27(d) requires 

you to maintain, clean, and sanitize, as 

necessary, equipment, utensils, and any 

other contact surfaces, used to 

manufacture, package, label, or hold 

dietary supplements. The final rule thus 

gives you discretion to decide when 

sanitizers or sanitizing treatments, such 

as heat, are necessary and does not 

mandate the incorporation of 

unnecessary sanitization processes. 

Additionally, under final § 111.27(d) 

you have flexibility to determine when 

sanitizing is appropriate and to sanitize 

only as necessary. We note that this 

flexibility was also present in proposed 

§ 111.25(e)(1). Some comments 

suggested calibrating sanitation 

operations based on risk. The final rule 

largely leaves it up to firms to decide 

whether to sanitize or to just clean 

without sanitizing, based on the risks 

associated with the materials and 

process used. However, under final 

§ 111.27(d)(3), if you use wet 

processing, if you determine that it is 

necessary to clean a contact surface, you 

must also sanitize that surface. 

(Comment 122) Several comments 

state the final rule should include a 

requirement for validating cleaning 

procedures. The comments argue that 

testing requirements for finished dietary 

supplements might not test for certain 

contaminants that could arise as a result 

of cleaning. One comment asserts these 

potential contaminants would be 

discovered in a properly designed and 

executed cleaning validation protocol, 

and that including these written 

cleaning procedures in the final rule 

would help prevent adulteration and 

help ensure the identity, purity, quality, 

strength, and composition of dietary 

supplements. 

(Response) We decline to require 

specific cleaning validation procedures 

in the final rule. Final § 111.27(d) and 

the requirements for written procedures 

under final § 111.25(c) are sufficient to 

ensure the use of cleaning procedures to 

ensure the quality of the dietary 

supplement. 

b. Final § 111.27(d)(2). Final 

§ 111.27(d)(2) (proposed § 111.25(e)(2)) 

requires you to ensure that all contact 

surfaces, used for manufacturing or 

holding low-moisture components or 

dietary supplements, are in a dry and 

sanitary condition when in use. When 

the surfaces are wet-cleaned, you must 

sanitize them, when necessary, and 

allow them to dry thoroughly before you 

use them again. 

We received no comments specific to 

proposed § 111.25(e)(2). We have 

substituted the phrase ‘‘when in use’’

for ‘‘at the time of use’’ for clarity. 

c. Final § 111.27(d)(3). Final 

§ 111.27(d)(3) (proposed § 111.25(e)(3)) 

requires you, if you use wet processing 

during manufacturing, to clean and 

sanitize all contact surfaces, as 

necessary, to protect against the 

introduction of microorganisms into 

components or dietary supplements. 

Final § 111.27(d)(3) also requires that: 

• When cleaning and sanitizing is 

necessary, you clean and sanitize all 

contact surfaces before use and after any 

interruption during which the contact 

surface may become contaminated and 

• If you use contact surfaces in a 

continuous production operation or in 

consecutive operations involving 


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different batches of the same dietary 

supplement, you must adequately clean 

and sanitize the contact surfaces, as 

necessary. In this provision, we 

substituted ‘‘consecutive’’ for ‘‘back-toback,’’ a nonsubstantive change. We also 

inserted ‘‘adequately’’ to make clear that 

cleaning and sanitizing must be 

adequate. 

(Comment 123) Several comments 

argue against using the term ‘‘sanitize’’

in proposed § 111.25(e)(3). The 

comments state that, based on the 

proposed definition of ‘‘sanitize,’’

§ 111.25(e)(3) would require evaluation 

of any sanitation steps to ensure that the 

level of log reduction is reached, for 

example, by taking ‘‘before and after’’

swab samples. The comments would 

revise proposed § 111.25(e)(3) to state 

that equipment, utensils, etc. shall be 

cleaned and sanitized in a manner that 

keeps microorganisms and other 

adulterants from contaminating all 

components, ingredients, in-process 

materials, and finished goods. 

(Response) The final rule now defines 

‘‘sanitize’’ as ‘‘to adequately treat 

cleaned equipment, containers, utensils, 

or any other cleaned product contact 

surface by a process that is effective in 

destroying vegetative cells of 

microorganisms of public health 

significance, and in substantially 

reducing numbers of other 

microorganisms, but without adversely 

affecting the product or its safety for the 

consumer.’’ The definition no longer 

specifies a level of log reduction, so the 

revised definition should eliminate the 

comments’ concern as to any possible 

need for ‘‘before and after’’ samples. 

d. Final § 111.27(d)(4). Final 

§ 111.27(d)(4) (proposed § 111.25(e)(4)) 

requires you to clean surfaces that do 

not come into direct contact with 

components or dietary supplements as 

frequently as necessary to protect 

against contamination. Final 

§ 111.27(d)(4) relates to final 

§ 111.27(d)(2) and (d)(3). For example, 

you would not have to clean your 

ceilings as often as you clean your 

contact surfaces because your ceilings 

normally do not touch components or 

dietary supplements. However, you 

would have to clean your ceilings as 

frequently as necessary to prevent dust 

or other contaminants from falling onto 

your components, dietary supplements, 

and contact surfaces. 

We received no comments specific to 

proposed § 111.25(e)(4). We substituted 

‘‘do not come into direct contact with’’

for ‘‘do not touch’’ as a nonsubstantive 

editorial revision. 

e. Final § 111.27(d)(5). Final 

§ 111.27(d)(5) (proposed § 111.25(e)(5)) 

requires that single-service articles 

(such as utensils intended for one-time 

use, paper cups, and paper towels) be: 

(1) Stored in appropriate containers and 

(2) handled, dispensed, used, and 

disposed of in a manner that protects 

against contamination of components, 

dietary supplements, or any contact 

surface. 

We received no comments specific to 

proposed § 111.25(e)(5). 

f. Final § 111.27(d)(6). Final 

§ 111.27(d)(6) (proposed § 111.25(e)(6)) 

requires your cleaning compounds and 

sanitizing agents to be adequate for their 

intended use and safe under their 

conditions of use. 

(Comment 124) One comment would 

delete proposed § 111.25(e)(6), stating it 

is redundant to proposed § 111.15(b), 

which would require you to use 

cleaning compounds and sanitizing 

agents that are free from microorganisms 

of public health significance and safe 

and adequate under the conditions of 

use. 

(Response) We disagree with this 

comment. Proposed §§ 111.15(b)(1) and 

111.25(e)(6) (now final §§ 111.15(b)(1) 

and 111.27(d)(6), respectively) differed 

in their requirements and their 

applicability. Proposed § 111.15(b)(1) 

would apply to cleaning compounds 

and sanitizing agents used in the 

physical plant and would require them 

to be ‘‘safe and adequate under the 

conditions of use.’’ In contrast, 

proposed § 111.25(e)(6) would apply to 

cleaning compounds and sanitizing 

agents used on equipment, utensils, and 

contact surfaces used to manufacture, 

package, or hold components, dietary 

ingredients, or dietary supplements, and 

it would require such cleaning 

compounds or sanitizing agents to be 

‘‘adequate for intended use and safe 

under condition [sic] of use.’’ By using 

the phrase ‘‘adequate for intended use,’’

proposed § 111.25(e)(6) would have you 

consider whether a particular cleaning 

compound or sanitizing agent was 

appropriate for the particular use to 

which it was being applied. 

Furthermore, depending on the 

situation, a cleaning compound or 

sanitizing agent that is appropriate for 

use on a physical plant may be 

inappropriate for use on equipment, 

utensils, and contact surfaces. For 

example, a powdered cleaning 

compound might be suitable for 

cleaning your physical plant’s floors, 

but inappropriate for cleaning 

equipment that mixes components. In 

other words, the ‘‘conditions of use’’ can 

also vary between final §§ 111.15(e)(1) 

and 111.27(d)(6) and lead to different 

conclusions regarding use of the same 

cleaning compound. 

Additionally, on our own initiative, 

we have made two editorial, 

nonsubstantive changes to final 

§ 111.27(d)(6). The final rule now states 

that the cleaning compounds and 

sanitizing agents must be adequate for 

‘‘their’’ intended use and safe under 

‘‘their conditions’’ of use. 

g. Final § 111.27(d)(7). Final 

§ 111.27(d)(7) (proposed § 111.25(e)(7)) 

requires you to store cleaned and 

sanitized portable equipment and 

utensils that have contact surfaces in a 

location and in a manner that protects 

them from contamination. We received 

no comments specific to proposed 

§ 111.25(e)(7). 

F. Reorganization of Certain Paragraphs 

in Proposed § 111.25 

Proposed § 111.25 would impose 

certain requirements relating to written 

procedures for calibrating instruments 

and controls (proposed § 111.25(c) and 

(d)) and keeping calibration records 

(proposed § 111.25(f)). The final rule 

now contains a new recordkeeping 

section (§ 111.35) that combines 

elements of proposed § 111.25(c), (d), 

and (f), as well as other sections. We 

discuss comments on proposed 

§ 111.25(c), (d), and (f) and describe 

final § 111.35 in this section. 

G. What Requirements Apply to 

Automated, Mechanical, or Electronic 

Equipment? (Final § 111.30) 

Final § 111.30 sets forth requirements 

for automated, mechanical, or electronic 

equipment that you use to manufacture, 

package, label, or hold a dietary 

supplement. 

1. Comments on the Organization and 

Framework of Proposed § 111.30 

(Comment 125) Some comments 

would revise proposed § 111.30(a) to 

replace ‘‘equipment to manufacture, 

package, label, and hold’’ with 

‘‘equipment to manufacture, package, 

label, or hold.’’ The comments said that 

the same piece of equipment will not 

serve to manufacture, package, label, 

and hold components or dietary 

supplements. 

(Response) We agree, and have 

revised § 111.30 accordingly. Final 

§ 111.30 also contains the following 

changes: 

• ‘‘Automatic’’ (as in ‘‘automatic 

equipment’’) is replaced with 

‘‘automated’’ as an editorial, 

nonsubstantive change; 

• The phrase ‘‘determine the 

suitability of your equipment’’ has been 

revised to read ‘‘determine the 

suitability of the equipment * * *’’ in 

§ 111.30(b) and has no substantive 

impact; and 


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• We have substituted the word 

‘‘met’’ for ‘‘achieved’’ to comply with 

‘‘plain language’’ initiatives and to be 

consistent with other provisions. 

We describe other changes to 

proposed § 111.30 in the following 

paragraphs. 

(Comment 126) Several comments 

support proposed § 111.30 particularly 

with respect to computers. The 

comments state computers are 

susceptible to erroneous data input, are 

subject to malfunctions and software 

problems, and thus should be regulated 

under the final rule. 

One comment questions why we 

organized proposed § 111.30 into two 

paragraphs (a) and (b). The comment 

claims there was no meaningful 

difference between the two paragraphs. 

Other comments say some proposed 

requirements for automatic, mechanical, 

and electronic equipment, such as the 

proposed requirement for maintaining 

backup files of data entered into 

computer systems, would apply to 

automatic, mechanical, and electronic 

equipment that are not related to 

CGMPs. The comments argue that 

proposed § 111.30(b) would apply to 

computers on which payroll records are 

maintained, and that such a requirement 

does not belong in these CGMPs. 

(Response) We agree, in part, and 

disagree, in part, with the comments. 

We agree that computers used in the 

manufacture, packaging, labeling, or 

holding of dietary supplements should 

be, and are, subject to final § 111.30. 

We disagree, however, with those 

comments that interpreted proposed 

§ 111.30(a) and (b) as being the same or 

interpreted proposed § 111.30 as 

applying to equipment that has no 

direct bearing on dietary supplements. 

Proposed § 111.30(a) differed from 

proposed § 111.30(b) in that paragraph 

(a) would pertain to the operation and 

suitability of your equipment within 

your manufacturing process. In contrast, 

proposed § 111.30(b) would apply to 

calibration of your equipment and 

controls you establish for your 

equipment. 

We disagree with those comments 

that would interpret proposed 

§ 111.30(b) as applying to payroll 

computers or other equipment that has 

no CGMP function. To prevent 

misinterpretations of final § 111.30, we 

have revised it to apply to equipment 

‘‘that you use to manufacture, package, 

label, or hold a dietary supplement’’ and 

renumbered proposed § 111.30(a)(1), 

(a)(2), (b)(1), (b)(3), and (b)(4) as 

§ 111.30(a) through (e), respectively. 

Proposed § 111.30(b)(2) which would 

require you to make and keep written 

records of equipment calibrations, 

inspections, and checks, and proposed 

§ 111.30(b)(5) which would require you 

to make and keep backup files of 

software programs and data, are now 

incorporated into final § 111.35, and we 

discuss these provisions later in this 

section. 

(Comment 127) Several comments 

would limit proposed § 111.30(a) and 

(b) to automatic, mechanical, or 

electronic equipment that actually 

affects product specifications. The 

comments argue that, in a modern 

manufacturing facility, most, if not all, 

equipment used to manufacture, 

package, label, or hold any food product 

is automatic, mechanical, or electronic. 

The comments say that equipment, such 

as forklifts, should not be required to be 

designed or selected in a manner that 

ensures that product specifications are 

met, as would be required in proposed 

§ 111.30(a)(1), or to be calibrated, as 

would be required in § 111.30(b)(1). 

(Response) As we stated previously, 

we have revised § 111.30 so that it 

applies to equipment ‘‘that you use to 

manufacture, package, label, or hold a 

dietary supplement.’’ This revision 

should prevent the rule from being 

interpreted as applying to forklifts or 

other equipment that have no bearing on 

the manufacture, packaging, labeling, or 

holding of dietary supplements. 

(Comment 128) Several comments 

argue that proposed § 111.30 is 

redundant to proposed § 111.25 and 

could be removed without meaningful 

effect. One comment argues that 

proposed § 111.30(a) and (b) (i.e., that 

all automatic, mechanical, and 

electronic equipment be designed or 

selected to ensure that product 

specifications are consistently achieved 

and operate satisfactorily within 

operating limits required by the process) 

are redundant to proposed § 111.25(a)(1) 

(which would require that all 

equipment be of appropriate design, 

construction, and workmanship to 

enable them to be suitable for their 

intended use) and proposed 

§ 111.25(a)(1)(v) (which would state that 

‘‘equipment’’ includes automatic, 

mechanical, or electronic systems). The 

comment states that, for equipment to 

be suitable for its intended use, the 

equipment must operate satisfactorily 

within operating limits and, by 

extension, ensure that product 

specifications are consistently achieved. 

The comment states the separate 

regulations for automatic equipment in 

the drug CGMPs is less detailed despite 

our efforts to present the 2003 CGMP 

Proposal in ‘‘simplified language.’’

(Response) We disagree that proposed 

§ 111.30 is redundant to proposed 

§ 111.25 (final § 111.27). Although both 

proposed §§ 111.25 and 111.30 

pertained to equipment, they differed in 

their focus. Proposed § 111.25 would 

focus on equipment design, 

construction, maintenance, cleaning, 

sanitizing, and calibration. In contrast, 

proposed § 111.30 would focus on the 

equipment’s operation or suitability 

within your manufacturing process. For 

example, proposed § 111.30(a)(2) would 

require you to determine the suitability 

of your equipment by ensuring that your 

equipment is capable of operating 

satisfactorily ‘‘within the operating 

limits required by the process.’’ In 

contrast, proposed § 111.25 had no 

comparable suitability requirement 

insofar as your manufacturing processes 

were concerned. Thus, the proposed 

sections are not redundant, and the final 

rule retains both § 111.27 (proposed 

§ 111.25) and § 111.30. 

2. Comments Specific to Proposed 

§ 111.30 

a. Final § 111.30(a) and (b). Final 

§ 111.30(a) (proposed § 111.30(a)(1)) 

requires you, for any automated, 

mechanical, or electronic equipment 

you use to manufacture, package, label, 

or hold a dietary supplement, to design 

or select the equipment to ensure that 

dietary supplement specifications are 

consistently met. 

Final § 111.30(b) (proposed § 111.30 

(a)(2)) requires you, for any automated, 

mechanical, or electronic equipment 

that you use to manufacture, package, 

label, or hold a dietary supplement, to 

determine the suitability of the 

equipment by ensuring that the 

equipment is capable of operating 

satisfactorily within the operating limits 

required by the process. 

(Comment 129) Some comments argue 

that the requirements of proposed 

§ 111.30(a) might be impossible to meet 

because, in many instances, dietary 

supplement manufacturers cannot 

predict, at the time of purchase, the 

entire range of ingredients and products 

for which a particular piece of 

equipment might be used. The 

comments argue that a particular piece 

of equipment’s suitability for a 

particular ingredient or product must be 

evaluated at the time the need arises. 

The comments would revise proposed 

§ 111.30(a)(1). The words ‘‘Design and 

select equipment to ensure’’ would be 

replaced with the words ‘‘Use 

equipment that ensures;’’ and proposed 

§ 111.30(a)(2) would be revised to 

replace the words ‘‘is capable of 

operating’’ with the word, ‘‘operates.’’

(Response) We disagree with the 

comments. Although a company may 

not know the entire range of products 

that a machine may be used for, 


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proposed § 111.30(a)(1) and (a)(2) would 

neither require you to determine all uses 

of equipment at the time of purchase 

nor prevent you from evaluating an old 

machine for a new use (these provisions 

are renumbered as final § 111.30(a) and 

(b), respectively). Thus, even if you 

chose to use old equipment for a new 

use, you still must select that equipment 

to ensure that dietary supplement 

specifications are consistently met with 

the new equipment use and determine 

the suitability of the new equipment use 

by ensuring that the equipment is 

capable of operating satisfactorily 

within the operating limits required by 

the new process. 

(Comment 130) Several comments 

express concern that facilities and much 

equipment in the industry are old and 

lack historical documentation. These 

comments ask us to clarify whether 

manufacturers would have to establish 

baseline information for old facilities 

and equipment. 

(Response) All equipment that you 

use, regardless of whether it is old or 

new, must be capable of doing what you 

intend it to do. Just as you could 

evaluate old equipment for a new use, 

you can demonstrate that old equipment 

does, in fact, do what you intend it to 

do for uses that you developed before 

these CGMP requirements were 

established, and thereby comply with 

final § 111.30(a) and (b). 

(Comment 131) Several comments 

argue that our statement in the preamble 

to the 2003 CGMP Proposal that 

‘‘systems need to be installed in a 

manner that takes into account the 

inherent limitations of the system, 

tested under conditions that reflect 

actual conditions of use’’ (68 FR 12157 

at 12193) is vague and subject to 

multiple interpretations. 

(Response) We disagree with the 

comment. The statement in question 

should be read in context because the 

preamble to the 2003 CGMP Proposal 

described several conditions for 

consideration. The preamble to the 2003 

CGMP Proposal stated, in relevant part: 

‘‘Some systems may work properly only 

within a narrow range of environmental 

conditions, such as temperature and 

humidity, and some might be 

particularly sensitive to electromagnetic 

interference. The actual conditions of 

use of a system should be considered as 

early as possible in its design and 

development. Systems need to be 

installed in a manner that takes into 

account the inherent limitations of each 

system, tested under conditions of use, 

and properly maintained to ensure that 

they continue to function as expected 

during their lifetime’’ (68 FR 12157 at 

12193.) Thus, suitability under final 

§ 111.30(b) involves considerations of 

how the equipment would be affected 

by environmental conditions, whether 

the equipment is appropriate for its 

intended use, and whether the 

equipment can be maintained properly 

to ensure satisfactory operation. 

(Comment 132) Several comments 

argue that the requirement of proposed 

§ 111.30(a)(2) to ‘‘determine the 

suitability of your equipment by 

ensuring that your equipment is capable 

of operating satisfactorily within the 

operating limits required by the 

process’’ is vague and subject to many 

interpretations. These comments assert 

that this may cause an uneven playing 

field among companies as they apply 

differing standards to this requirement. 

The comments also argue that the 

vagueness of this requirement could 

potentially cause uneven enforcement, 

depending on the experience and 

understanding of individual inspectors. 

(Response) We disagree that proposed 

§ 111.30(a)(2) (final § 111.30(b)) is vague 

or may result in uneven enforcement. 

There has been sufficient common usage 

of terms such as ‘‘suitable,’’ ‘‘capable,’’

and ‘‘satisfactorily’’ in the industry to 

enable firms, and those who enforce the 

requirements, to comprehend and apply 

such terms to particular operations. 

Agencies may use qualifying terms to 

enable them to address a wide variety of 

conditions, and such terms provide the 

flexibility needed for various 

operations. 

(Comment 133) Several comments 

assert that proposed § 111.30(a)(2) is 

without justification and overly 

prescriptive when compared to 

conventional food CGMPs. 

(Response) As discussed in section V 

of this document, the mere fact that a 

dietary supplement CGMP requirement 

has no counterpart in the food CGMP 

regulations, or has more detail than a 

counterpart in such regulations, does 

not mean that it is overly prescriptive. 

Rather, what is important is whether 

proposed § 111.30(a)(2) (final 

§ 111.30(b)) is necessary to ensure the 

quality of the dietary supplements. For 

example, the preamble to the 2003 

CGMP Proposal (68 FR 12157 at 12193) 

discussed how the incorporation of 

software into the operation of automatic 

equipment has both increased the 

complexity of such equipment and 

resulted in a process that may operate 

differently for each execution, because a 

software-based control system can be 

configured at will by the operator or by 

the system itself. Therefore, it is 

essential that you ensure that automated 

equipment is capable of operating 

satisfactorily within the operating limits 

required by the process. 

(Comment 134) Several comments 

urge us to develop a separate guidance 

document with respect to determining 

the suitability and capability of 

equipment used in the manufacture of 

dietary supplements. 

(Response) We believe that firms have 

sufficient experience to determine 

whether equipment is suitable and 

capable of performing its intended 

function. However, if we find that 

guidance will be helpful, we will 

consider whether to issue guidance at a 

later date. 

b. Final § 111.30(c). Final § 111.30(c) 

(proposed § 111.30(b)(1)) requires you, 

for any automated, mechanical, or 

electronic equipment you use to 

manufacture, package, label, or hold a 

dietary supplement, to routinely 

calibrate, inspect, or check the 

equipment to ensure proper 

performance. Final § 111.30(c) also 

requires quality control personnel to 

periodically review these calibrations, 

inspections, or checks. 

(Comment 135) Several comments 

claim the requirement for the quality 

control unit to approve calibrations, 

inspections, or checks of equipment is 

too prescriptive and that qualified 

persons outside of the quality control 

unit should be able to approve these 

calibrations, inspections, or checks. The 

comments also state the quality control 

unit should perform audits of the 

records generated to ensure the 

appropriate calibrations, inspections, or 

checks are being adequately performed 

at the required intervals. 

Other comments refer to related 

requirements in proposed § 111.37(b)(8) 

that the quality control unit review all 

records for equipment calibrations, 

inspections, or checks. The comments 

state the requirements for oversight by 

the quality control unit in proposed 

§ 111.37(b)(8) are excessive and go 

beyond requirements for both the drug 

CGMPs and food CGMPs. One comment 

would revise proposed § 111.37(b)(8) to 

require a review of all records when 

there is a negative impact on the dietary 

supplement due to a calibration failure. 

(Response) Final § 111.12(b) requires 

that you identify who is responsible for 

your quality control operations, and 

each person who is designated to 

perform quality control operations must 

be qualified to do so and have distinct 

and separate responsibilities related to 

performing such operations from those 

responsibilities that the person 

otherwise has when not performing 

such operations. Thus, you may identify 

any person whom you believe is 

qualified to approve calibrations, 

equipments, or checks to perform 

quality control operations. 


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We disagree that the review by quality 

control personnel should be limited to 

circumstances when there has been a 

calibration failure. One function of 

quality control personnel is to provide 

oversight to prevent problems with the 

product that you distribute by finding 

any problems with the equipment that 

you use to produce the product rather 

than to investigate the cause of a 

problem with a product that you already 

distributed. However, we agree that it is 

sufficient to periodically review the 

records of calibrations, inspections, or 

checks of automated, mechanical, or 

electronic equipment, for example, on 

an annual basis, rather than to approve 

each record when it is made. A periodic 

review can uncover trends in the 

performance of the equipment that have 

the potential to adversely affect the 

quality of the dietary supplement and 

that may not be obvious by merely 

approving each record when it is made. 

Seeing such trends would enable quality 

control personnel to recommend 

corrective actions. This periodic review 

is consistent with proposed 

§ 111.37(b)(8) which would require the 

quality control unit to ‘‘review’’ all 

records for equipment calibration, 

inspections, or checks rather than 

‘‘approve’’ these records. Therefore, we 

have revised the requirement that the 

quality control unit approve 

calibrations, inspections, or checks of 

automatic, mechanical or electronic 

equipment so that final § 111.30(c) 

requires that quality control personnel 

periodically review such operations 

rather than approve them when they are 

made. 

Additionally, we have made a minor 

change to § 111.30(c). The change 

inserts the words ‘‘the equipment’’ after 

‘‘Routinely calibrate, inspect, or check 

* * *.’’ This insertion simply reiterates 

that ‘‘the equipment’’ must be routinely 

calibrated, inspected, or checked. 

c. Final § 111.30(d). Final § 111.30(d) 

(proposed § 111.30(b)(3)) requires you, 

for any automated, mechanical, or 

electronic equipment you use to 

manufacture, package, label, or hold a 

dietary supplement, to establish and use 

appropriate controls for the equipment 

(including software for a computercontrolled process) to ensure that any 

changes to the manufacturing, 

packaging, labeling, holding, or other 

operations are approved by quality 

control personnel and instituted only by 

authorized personnel. 

(Comment 136) The preamble to the 

2003 CGMP Proposal invited comment 

on whether we should regulate 

computerized systems separately from 

other automatic equipment, given the 

broad range in sophistication, 

complexity, and computerization in 

manufacturing equipment (68 FR 12157 

at 12194). 

Several comments state that 

computers are susceptible to erroneous 

data input and subject to malfunctions 

and software problems and, thus, 

should be regulated under the final rule. 

(Response) We agree that computers 

used in the manufacturing processes 

should be regulated under the final rule. 

As the preamble to the 2003 CGMP 

Proposal stated the incorporation of 

software into the operation of automatic 

equipment has increased the complexity 

of such equipment and resulted in a 

process that may operate differently for 

each execution, because a softwarebased control system can be configured 

at will by the operator or by the system 

itself (68 FR 12157 at 12193). 

Additionally, final § 111.35(b)(5) 

requires you to make and keep backup 

files of software programs and data to 

keep them secure from alterations, 

inadvertent erasures, or loss. The issue 

in the preamble to the 2003 CGMP 

Proposal, however, was whether 

computerized systems should be 

regulated separately from other 

equipment; in the absence of comments 

supporting separate treatment for 

computerized systems, we have 

included computerized systems as 

‘‘equipment’’ in final § 111.30(d). 

We are, however, revising final 

§ 111.30(d) in the following manner: 

• We are inserting the words ‘‘for 

automated, mechanical, and electronic 

equipment (including software for a 

computer controlled process)’’ after 

‘‘Establish and use appropriate 

controls.’’ This change simply reiterates 

the types of equipment for which 

appropriate controls must be established 

and used, and makes it clear that 

software is included under the rule and 

• We are rephrasing the purpose of 

§ 111.30(d). The proposal stated that 

you must establish and use appropriate 

controls ‘‘to ensure that your quality 

control unit approves changes in the 

master manufacturing record batch 

control records, packaging operations, 

and label operations, or changes to other 

operations related to the equipment that 

you use and that only authorized 

personnel institute the changes.’’ The 

final rule states that you must establish 

and use appropriate controls for your 

equipment ‘‘to ensure that any changes 

to the manufacturing, packaging, 

labeling, holding, or other operations 

are approved by quality control 

personnel and instituted only by 

authorized personnel.’’

As revised, final § 111.30(d) shifts its 

emphasis from the person(s) who must 

approve or institute the changes to the 

types of changes that must be approved 

and instituted. This shift in emphasis is 

appropriate given that the final rule 

addresses responsibilities of the quality 

control personnel elsewhere. 

d. Final § 111.30(e). Final § 111.30(e) 

(proposed § 111.30(b)(4)) requires you, 

for any automated, mechanical, or 

electronic equipment you use to 

manufacture, package, label, or hold a 

dietary supplement, to establish and use 

appropriate controls to ensure that the 

equipment functions in accordance with 

its intended use. Quality control 

personnel must approve these controls. 

We did not receive comments specific 

to proposed § 111.30(b)(4). 

3. Reorganization of Certain Paragraphs 

in Proposed § 111.30 

As we explained earlier in this 

section, proposed § 111.30 would 

impose certain requirements relating to 

written records of equipment 

calibrations, inspections, or checks 

(proposed § 111.30(b)(2)) and making 

and keeping backup files of software 

programs and data (proposed 

§ 111.30(b)(5)). The final rule now 

contains a new recordkeeping section, 

final § 111.35, that combines elements 

of proposed § 111.30(b)(2) and (b)(5), as 

well as other sections. 

Additionally, proposed § 111.30(c) 

would require you to keep records in 

accordance with the written procedure 

and recordkeeping requirements in 

proposed § 111.125. Section 111.35 of 

the final rule now incorporates 

proposed § 111.30(c) as well. We 

discuss final § 111.35 in the following 

paragraphs. 

H. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.35) 

Final § 111.35 describes the 

recordkeeping requirements. It 

represents a combination of proposed 

§§ 111.25(c)(1) through (c)(2), (d)(1) 

through (d)(7), and (f); 111.30(b)(2), 

(b)(5), and (c); and 111.50(c)(4). 

1. Final § 111.35(a) 

Final § 111.35(a) states that you must 

make and keep records required under 

subpart D in accordance with subpart P. 

Subpart P deals with records and 

recordkeeping. 

Final § 111.35(a) is broader than 

proposed § 111.25(f), which stated that 

you ‘‘must keep calibration records as 

required by this section in accordance 

with’’ the 2003 CGMP Proposal’s 

recordkeeping section, and compared to 

proposed § 111.30(c), which stated that 

you must keep ‘‘automatic, mechanical, 

or electronic equipment records 

required by this section in accordance 


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8Although the preamble to the 2003 CGMP 

Proposal discussed this issue in relation to 

proposed § 111.25 (‘‘What Requirements Apply to 

the Equipment and Utensils You Use?’’), the same 

principle applies to proposed § 111.50(c)(4). 

with’’ the 2003 CGMP Proposal’s 

recordkeeping section. However, final 

§ 111.35(a) has the same effect as 

proposed §§ 111.25(f) and 111.30(c). 

We did not receive any substantive 

comments on proposed §§ 111.25(f) or 

111.30(c). 

2. Final 111.35(b)(1) and (b)(2) 

Final § 111.35(b) combines the 

various recordkeeping requirements that 

were in proposed §§ 111.25(c) (written 

procedures for calibrating instruments 

and controls and documentation that 

those procedures were followed and 

that the calibration was performed), 

111.25(d) (written procedures or 

documentation for calibration, such as 

the instrument or control calibrated and 

the calibration date), 111.30(b)(2) and 

(b)(5) (written records of equipment 

calibrations, inspections, or checks, and 

backup files of software and data, 

respectively), and 111.50(b)(4) 

(inclusion of date and time of 

maintenance, cleaning, and sanitizing of 

equipment and processing lines in the 

batch record). 

Specifically, final § 111.35(b)(1) states 

that you must make and keep records of 

‘‘written procedures for fulfilling the 

requirements of this subpart,’’ including 

written procedures for: 

• Calibrating instruments and 

controls that you use in manufacturing 

or testing a component or dietary 

supplement. This paragraph is similar to 

proposed § 111.25(c). Although we did 

not receive any substantive comment on 

proposed § 111.25(c), we are rephrasing 

the paragraph due to its reorganization 

as part of final § 111.35. Additionally, 

although proposed § 111.25(c) would 

require you to document that the 

written procedures for calibration were 

followed each time a calibration is 

performed, we are moving the 

documentation requirement to final 

§ 111.35(b)(3) which we discuss later in 

this section. 

• Calibrating, inspecting, and 

checking automated, mechanical, and 

electronic equipment. This paragraph is 

similar to proposed § 111.30(b)(2), 

although we are rephrasing the 

paragraph due to its reorganization as 

part of final § 111.35. 

• Maintaining, cleaning, and 

sanitizing, as necessary, all equipment, 

utensils, and any other contact surfaces 

that are used to manufacture, package, 

label, or hold components or dietary 

supplements. This paragraph relates to 

final § 111.25(c) which requires you to 

establish and follow written procedures 

for such activities. 

We did not receive any comments 

specific to proposed §§ 111.25(c) or 

111.30(b)(2). 

Final § 111.35(b)(2) (proposed 

§ 111.50(c)(4)) requires you to make and 

keep documentation, in individual 

equipment logs, of the date of the use, 

maintenance, cleaning, and sanitizing of 

equipment, unless such documentation 

is kept with the batch record. 

(Comment 137) Proposed 

§ 111.50(c)(4) would require that the 

batch record include the date and time 

of the maintenance, cleaning, and 

sanitizing of the equipment and 

processing lines used in producing the 

batch. The preamble to the 2003 CGMP 

Proposal also invited comment on 

whether the person performing the 

maintenance, cleaning, and sanitizing of 

portable equipment and utensils should 

document at the time of performance 

the maintenance, cleaning, and 

sanitizing (68 FR 12157 at 121928). 

Several comments argue that the final 

rule should require documentation at 

the time of performance of equipment, 

utensil, and contact surface 

maintenance, cleaning, and sanitation 

and should also require this 

documentation to be kept as records. 

The comments explain that such 

recordkeeping is common practice in 

the industry, is an important part of 

batch history, and omitting such a 

requirement would diminish the 

industry standard. In addition, the 

comments state that written records are 

an effective way to ensure that there is 

consistency in how employees are 

trained and to assess compliance. 

Several comments agree that 

equipment maintenance, cleaning, and 

sanitizing records should be kept and 

state that this information should be 

kept with individual pieces of 

equipment, rather than in the batch 

record as proposed § 111.50(c)(4) would 

require. The comments say it is easier 

and more efficient for some companies 

to maintain equipment logs that can be 

referenced when necessary. 

Other comments say manufacturers 

should have flexibility to design a 

recordkeeping program suited to their 

operations, and should have the option 

of using an equipment log as it provides 

an efficient way to document, trace, and 

review equipment use, maintenance, 

cleaning, and sanitization of equipment. 

According to these comments, because 

the 2003 CGMP Proposal would require 

batch production records to identify all 

equipment used during production, this 

will allow for cross-referencing with the 

equipment log, should the need occur. 

The comments argue that the proposed 

approach will be awkward for some 

companies to comply with and would 

not result in collection of information in 

a logical order or location where it can 

be easily referenced and reviewed, such 

as on the production floor, or to provide 

data for trend analysis. The comments 

also contend requiring all information to 

be maintained in the batch record will 

be difficult in practice and place an 

enormous burden on companies. 

(Response) We agree that 

documenting the cleaning, sanitizing, 

and maintenance of equipment is 

important. However, we have revised 

the provision so that these records need 

not be part of the batch record. Instead, 

final § 111.35(b)(2) requires you to make 

and keep documentation of the date of 

use, maintenance, cleaning, and 

sanitizing of equipment in individual 

equipment logs, unless such 

documentation is kept with the batch 

record. By ‘‘equipment log,’’ we mean a 

written record that includes information 

about the history of a piece of 

equipment. This history includes items 

such as date of installation, routine 

maintenance, repairs, and cleaning. 

Additionally, final § 111.260 requires 

you to identify the equipment and 

processing lines used in producing the 

batch and either provide a crossreference that will make it possible to 

find the applicable equipment log as 

needed or include documentation that 

equipment was cleaned, sanitized, or 

maintained (we discuss final § 111.260 

in section XIV of this document). For 

example, you may keep records 

documenting that you cleaned 

containers you will use for holding a 

finished batch either in records 

associated with the equipment you use 

for cleaning, or with the applicable 

batch record, depending on what is 

most convenient and practical for your 

operations. 

(Comment 138) Several comments 

state documenting the cleaning of 

contact surfaces would be unnecessarily 

labor-intensive because the term is so 

broadly defined. Other comments argue 

that documenting the cleaning of 

utensils is unnecessary and 

inappropriate. These comments support 

requiring documentation for the 

cleaning of large equipment, but claim 

that requiring manufacturers to 

uniquely identify each spoon, spatula, 

container, and hose (or other general 

cleaning) in order to document each 

cleaning would be inappropriate and 

create an enormous burden on the 

manufacturer. According to these 

comments, such a requirement would 

slow and complicate the cleaning 

process, making proper cleaning more 

cumbersome. The comments assert that 


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contamination from these sources has 

not caused any recalls and is not 

justified. 

(Response) We disagree with these 

comments. The final rule requires you 

to document the work that was done, 

but gives you the flexibility to decide 

how to document that work was done. 

For contact surfaces such as containers 

you use to hold a finished batch, you 

could, for example, record the cleaning 

either on a single line that you provide 

in your batch record, or as a line entry 

in the log of the equipment that you use 

to clean the containers, or in some other 

way that suits your needs. These are not 

labor-intensive requirements. 

It is important that you have 

procedures in place to know that small 

items, such as spatulas, are clean when 

you use them. For example, if you have 

a log where you designate equipment 

that has been cleaned, your batch record 

could simply have a place to check that 

you used equipment designated as 

clean. 

3. Final § 111.35(b)(3) 

Final § 111.35(b)(3) (proposed 

§ 111.25(d)(1) through (d)(7)) requires 

you to make and keep documentation of 

any calibration, each time the 

calibration is performed, for instruments 

and controls that you use in 

manufacturing or testing a component 

or dietary supplement. In the 

documentation you must: (1) Identify 

the instrument or control calibrated; (2) 

provide the calibration date; (3) identify 

the reference standard used, including 

the certification of accuracy of the 

known reference standard and a history 

of recertification of accuracy; (4) 

identify the calibration method used, 

including appropriate limits for 

accuracy and precision of instruments 

and controls when calibrating; (5) 

provide the calibration reading or 

readings found; (6) identify the 

recalibration method used, and reading 

or readings found, if accuracy or 

precision or both accuracy and 

precision limits for instruments and 

controls were not met; and (7) include 

the initials of the person who performed 

the calibration and any recalibration. 

(Comment 139) Some comments 

support proposed § 111.25(d). However, 

other comments argue that the 

documentation requirements are unduly 

prescriptive. Some comments would 

revise proposed § 111.25(d) to more 

closely mirror the requirements in drug 

CGMPs. Some comments suggest the 

requirement to maintain written records 

of calibrations should simply state ‘‘You 

must maintain written records of 

calibrations according to Sec. 111.125.’’

Other comments suggest detailed 

calibration requirements would not be 

needed if the final rule included 

requirements to establish and follow 

written procedures. 

(Response) The information required 

under final § 111.35(b)(3) (proposed 

§ 111.25(d)) is the minimum amount 

necessary to provide sufficient 

information concerning equipment 

calibration. For example, some firms 

may have more than one machine to 

perform a given function; in those 

situations, documentation that 

identified the exact machine that was 

calibrated would distinguish it from 

other, seemingly identical, but 

noncalibrated machines. Likewise, if the 

maintenance instructions for a machine 

called for calibration checks every 

month, documenting the date of 

calibration would show you whether 

calibrations were done on schedule. As 

another example, if a machine required 

calibration according to a particular 

standard, identifying the reference 

standard would help verify that the 

calibration was done correctly. 

Thus, we disagree with those 

comments claiming that proposed 

§ 111.25(d) was too prescriptive. If, for 

example, the final rule simply directed 

you to document calibration, without 

specifying what information should be 

contained in that documentation, then 

the resulting documentation could have 

little or no value. For example, assume 

that you have two identical pieces of 

equipment, but only one had been 

calibrated. If the documentation simply 

said, ‘‘machine was calibrated,’’ you 

would not know which machine had 

been calibrated. As another example, if 

you had a machine that had to be 

recalibrated every year, and the 

documentation merely said, 

‘‘recalibration completed,’’ you would 

not know whether the machine had 

been recalibrated yesterday, last month, 

last year, or 4 years ago. 

With respect to the argument that 

proposed § 111.25(d) should be revised 

to resemble the drug CGMPs, we 

disagree. We recognize that the drug 

CGMPs are less detailed with respect to 

documentation; for example, 21 CFR 

211.68(a), ‘‘Automatic, mechanical, and 

electronic equipment,’’ simply states, in 

relevant part, ‘‘If such equipment is so 

used, it shall be routinely calibrated, 

inspected, or checked according to a 

written program designed to assure 

proper performance’’ and ‘‘Written 

records of those calibration checks and 

inspections shall be maintained.’’

However, the comments overlook the 

fact that, from 1993 to 2003, the Center 

for Drug Evaluation and Research 

(CDER) issued periodic guidance, in the 

form of ‘‘Human Drug CGMP Notes,’’

and those guidances offered advice on 

various drug CGMP issues. With respect 

to calibration, for example, the 

December 1997 edition dealt with the 

question of whether the drug CGMP 

regulations require equipment to be 

labeled with calibration dates. The 

guidance identified various regulations 

that would be applicable and also said 

that: ‘‘During an inspection a firm 

should be able to document when a 

specific piece of equipment was last 

calibrated/maintained, the results or 

action, and when its next calibration/ 

maintenance is scheduled. The absence 

of such documentation is a CGMP 

deviation’’ (see CDER, ‘‘Human Drug 

CGMP Notes,’’ December 1997, at page 

3 (Ref. 29)). 

This advice is comparable, in several 

respects, to the information required by 

final § 111.35(b)(3). For example, it 

refers to a ‘‘specific piece of 

equipment,’’ which is similar to final 

§ 111.35(b)(3)(i)’s requirement to 

identify the instrument or control 

calibrated. It refers to the time when 

calibration occurred; this is similar to 

final § 111.35(b)(3)(ii)’s requirement to 

provide the calibration date. Although 

public distribution of ‘‘Human Drug 

CGMP Notes’’ ended in 2003, and the 

document was circulated only within 

FDA from 2001 to 2003 (but was 

available through FOIA), the guidances 

offered the drug industry advice on 

complying with the drug CGMPs, and 

we have retained the guidances on our 

Internet site. In other words, the drug 

CGMP regulations did not have to be as 

‘‘prescriptive’’ because the drug 

industry learned about our 

interpretations or expectations of the 

drug CGMPs through guidance. 

Here, in contrast, there is no 

comparable history of issuing periodic 

guidance to inform the dietary 

supplement industry about specific 

CGMP issues. 

Yet, even if final § 111.35 is more 

‘‘prescriptive’’ than the drug CGMPs, 

that difference does not mean that we 

must revise the rule to ‘‘mirror’’ the 

drug CGMPs. The dietary supplement 

industry is more diverse compared to 

the drug industry, and so, at least with 

respect to documenting calibration, 

more—rather than less—detail is 

appropriate. 

We do note, however, that final 

§ 111.35(b)(3) differs from proposed 

§ 111.25(d) in the following respects: 

• § 111.25(d) would require you to 

identify specific calibration-related 

information ‘‘in any written procedure 

or at the time of performance,’’ final 

§ 111.35(b)(3) requires documentation 

‘‘each time the calibration is 

performed.’’ Final section 111.35(b)(1) 


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requires you to have records of the 

written procedures for calibrating 

instruments and controls, but does not 

specify the contents of such written 

procedures; 

• § 111.25(d) would refer to 

‘‘instruments and controls.’’ Final 

§ 111.35(b)(3) now refers to 

‘‘instruments and controls that you use 

in manufacturing or testing a 

component or dietary supplement.’’

This change clarifies the instruments 

and controls that are subject to final 

§ 111.35(b)(3) and is consistent with 

final § 111.27(b), which requires you to 

calibrate instruments and controls; 

• The type of information that must 

be documented under § 111.35(b)(3)(i) 

through (b)(3)(vii) is essentially 

identical to that in proposed 

§ 111.25(d)(1) through (d)(7), but we 

revised the sentence structure due to the 

manner in which we reorganized final 

§ 111.35; 

• § 111.25(d)(6) would have you 

identify the recalibration method used. 

Final § 111.35(b)(3)(vi) requires you to 

identify the recalibration method used 

‘‘and reading or readings found.’’ The 

addition of ‘‘reading or readings found’’

is consistent with the remainder of 

proposed § 111.25(d)(6) (final 

§ 111.35(b)(3)(vi)) which is a 

simplification of the phrase ‘‘accuracy 

or precision or both accuracy and 

precision limits for instruments and 

controls were not met.’’ One would only 

know that limits were not met based on 

a reading or readings; and 

• § 111.25(d)(7) would require the 

initials of the person who performed the 

calibration. Final § 111.35(b)(3)(vii) 

requires the initials of the person who 

performed the calibration and any 

recalibration. Arguably, recalibration is 

a type of calibration, but we have added 

‘‘any recalibration’’ to final 

§ 111.35(b)(3)(vii) to ensure that 

recalibrations are included in the rule. 

(Comment 140) Several comments 

would revise proposed § 111.25(d) to 

read, ‘‘The following must be identified 

***’’, rather than ‘‘you must 

identify.’’ The comments explain that 

calibrations and recalibrations are often 

performed by the equipment 

manufacturer, vendor, or other outside 

service, rather than by the dietary 

supplement manufacturer. The 

comments argue that the proposal 

requires that the calibration or 

recalibration must be performed onsite 

(i.e., at the plant manufacturing the 

dietary ingredient or supplement) when 

in fact many calibrations can, or even 

must, be performed offsite. 

(Response) We decline to revise the 

paragraph as requested. As we discuss 

in section VI of this document, the term 

‘‘you’’ can refer to someone with whom 

you contract, but you are responsible for 

ensuring that the calibration 

requirements are met, and to have 

documentation of the calibration, even 

though the steps may be performed 

offsite. 

4. Final § 111.35(b)(4) 

Final § 111.35(b)(4) (proposed 

§ 111.30(b)(2)) requires you to make and 

keep written records of calibrations, 

inspections, and checks of automated, 

mechanical, and electronic equipment 

that is used to manufacture, package, 

label, or hold a dietary supplement. 

We did not receive comments specific 

to proposed § 111.30(b)(2). We have 

made nonsubstantive editorial changes 

to the rule. For example, proposed 

§ 111.30(b)(2) would require you to 

‘‘make and keep’’ written records; final 

§ 111.35(b)(4) omits the words ‘‘ make 

and keep’’ because that requirement 

appears earlier in § 111.35. 

5. Final § 111.35(b)(5) 

Final § 111.35(b)(5) (proposed 

§ 111.30(b)(5)) requires you to make and 

keep backup file(s) of current software 

programs (and of outdated software that 

is necessary to retrieve records that you 

are required to keep in accordance with 

subpart P, when current software is not 

able to retrieve such records) and of data 

entered into computer systems that you 

use to manufacture, package, label, or 

hold dietary supplements. Under final 

§ 111.35(b)(5)(i), your backup file (e.g., a 

hard copy of data you have entered, 

diskettes, tapes, microfilm, or compact 

disks) must be an exact and complete 

record of the data you entered. Under 

final § 111.35(b)(5)(ii), you must keep 

your backup software programs and data 

secure from alterations, inadvertent 

erasures, or loss. 

(Comment 141) Several comments 

would limit the requirement for 

maintaining backup files of data entered 

into computer systems to those data 

entered into computer systems that are 

relied upon for compliance with 

CGMPs. These comments argue that the 

paragraph, as written, calls for a firm to 

make and keep backup files of data 

entered into computers on which 

personnel payroll records are 

maintained, and state that no such 

requirement should be imposed. 

Therefore, these comments would 

replace the words ‘‘your computer 

system’’ with the words ‘‘any of your 

computer systems that are relied upon 

for compliance with this part.’’

(Response) We have modified the 

provision to clarify that the requirement 

is for computer systems that you use to 

manufacture, package, label, or hold 

dietary supplements. 

(Comment 142) Several comments 

argue that many software programs are 

in a near constant state of revision and 

that it is not a common business 

practice for a firm in any industry to 

maintain records of outdated software 

programs, at least if the firm is still able 

to use a revised program to access data 

it entered using an outdated program. 

The comments assert that, although the 

drug CGMPs require the maintenance of 

certain backup files of data entered into 

computer systems, they do not require 

the maintenance of backup files of 

software programs. 

(Response) Keeping backup copies of 

software helps ensure that data can be 

retrieved if the primary software 

develops a problem. When we use the 

term ‘‘backup,’’ we mean a second copy 

of the software in question rather than 

a copy of previous versions of the 

software that are outdated, provided 

that data can be retrieved. However, if 

the data collected using outdated 

software cannot be retrieved by the 

newer software, there would still be a 

need to maintain a primary copy and a 

backup copy of the outdated software 

used to collect or manage the data. 

We have narrowed the requirement to 

retain backup files of software to current 

software and of outdated software that 

is necessary to retrieve records that you 

are required to keep in accordance with 

subpart P, when current software is not 

able to retrieve such records. 

(Comment 143) Some comments 

claim that, although the drug CGMPs 

require the maintenance of certain 

backup files of data entered into 

computer systems, they do not require 

the maintenance of backup files of 

software programs. Several comments 

also assert that it is not always possible 

to keep backup files of the software 

programs used in certain pieces of 

equipment, because the equipment 

manufacturer may be the only one 

having access to the programming of its 

equipment. The comments would delete 

the words ‘‘software programs and’’

from proposed § 111.30(b)(5). 

(Response) In most cases, we 

anticipate that firms will have access to 

backup copies of their software 

programs. We acknowledge that in rare 

instances, backup copies may not be 

available and in these situations, we 

will take that into account in reviewing 

compliance with this provision. We 

decline to revise the provision as 

suggested. 

6. Final § 111.35(b)(6) 

Final § 111.35(b)(6) states that you 

must make and keep ‘‘documentation of 


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the controls that you use to ensure that 

equipment functions in accordance with 

its intended use.’’

The preamble to the 2003 CGMP 

Proposal stated that we were not 

proposing verification requirements for 

automatic, mechanical, or electronic 

equipment (68 FR 12157 at 12194). 

However, we invited comment on 

whether the final rule should require 

such verification (id.). Verification 

would ensure that the processes using 

automatic, mechanical, and electronic 

equipment consistently produce an 

outcome that meets a predetermined 

specification and any predetermined 

quality characteristics. Verification 

would show whether your automatic, 

mechanical, or electronic processes will 

consistently operate as they should. 

(Comment 144) Several comments 

argue against including equipment 

verification requirements. The 

comments argue that the verification 

discussion in the preamble to the 2003 

CGMP Proposal is difficult to 

distinguish from drug validation. The 

comments argue that validation should 

be allowed to evolve in the dietary 

supplement industry as it evolved in 

drug CGMPs. According to these 

comments, the dietary supplement 

industry, being largely self regulated in 

CGMPs to date and not generally 

practicing verification, would be more 

readily adaptable to, and better 

controlled by, strict operating controls 

and quality control checks including 

sufficient input and output checks on 

computer operated systems, than having 

to digest the concept of verification and 

implement verification processes. The 

comments state that, in the future, 

verification may be a means of offsetting 

some of the extensive testing of finished 

products. 

Other comments state we should not 

require verification of processes that use 

automatic, mechanical, or electronic 

equipment given the different processes 

that dietary supplement manufacturers 

use. The comments argue that although 

dietary supplement manufacturers, 

depending on the unique circumstances 

of a particular manufacturing process, 

may choose to verify processes using a 

sound verification system, we should 

not require verification. 

Several comments ask us to clarify 

whether we intended to require full 

validation of equipment used to process 

dietary supplements because terms such 

as ‘‘suitability’’ and ‘‘capable,’’ which 

we used in proposed § 111.30(a)(1) and 

(a)(2), might be interpreted to require 

validation. These comments state 

validation is unnecessary and overly 

burdensome for equipment used in 

manufacturing dietary supplements. 

Several comments argue that 

proposed § 111.30(a)(1) and (a)(2) have 

the effect of establishing unnecessarily 

formal, stringent, and expensive 

validation requirements on equipment 

design, selection, and capability. The 

comment states that this language 

represents a de facto ‘‘IQ/OQ/PQ’’

(installation qualification/operational 

qualification/performance qualification) 

requirement. According to these 

comments, emphasis should instead be 

directed to actual use and operation. 

In contrast, several comments argue 

we should require manufacturers to 

develop and maintain data that 

demonstrate that equipment is suitable 

and that the production process 

consistently delivers expected results. 

The comments argue that one key CGMP 

element is the requirement for systems 

to operate consistently and to produce 

an outcome that meets a predetermined 

specification. According to these 

comments, demonstration of system 

capability is best achieved through 

systems verification. The comments 

explain that, in an industry where the 

complexity of finished products often 

precludes finished product testing, the 

capability of the systems employed is of 

paramount importance. The comments 

state if the processes used fail to 

produce a product meeting 

predetermined specifications and 

quality characteristics, then the product 

should not be sold. The comments add 

that, although verification imposes 

additional costs on manufacturers, 

frequently rejected product, adequate 

rework procedures, and extensive inprocess and finished product testing 

also would be costly. 

Several comments also claim the use 

of an appropriate verification system 

may, under certain circumstances, allow 

for lot testing as opposed to batch 

testing. These comments state that, with 

process verification and an appropriate 

testing scheme, a manufacturer could 

demonstrate that lot testing provides 

sufficient assurance of quality and lack 

of adulteration. The comments ask us to 

address these alternatives in the final 

rule. Many comments said written 

records of verification should be 

maintained. The comments offer several 

suggestions on how this could be 

accomplished, including using 

statistical process control techniques or 

other appropriate statistical tools. 

(Response) We used the term 

‘‘verification’’ rather than ‘‘validation’’

to signal that we did not expect that a 

final rule would include requirements 

for formal process validation 

requirements, such as an IQ/OQ/PQ 

requirement, for equipment. Regardless, 

several comments interpreted our 

request for comments as a suggestion 

that we were considering such formal 

validation requirements. At this time, 

we are not requiring formal process 

validation for equipment. However, we 

will monitor the development of 

systems that evolve within this diverse 

industry. 

We disagree that proposed 

§ 111.30(a)(1) and (a)(2) would have the 

effect of establishing unnecessarily 

formal, stringent, and expensive 

validation requirements on equipment 

design, selection, and capability, and 

that the language would represent a de 

facto ‘‘IQ/OQ/PQ’’ requirement for 

equipment. Final § 111.30(e) requires 

you to ensure equipment operates in 

accordance with its intended use. We 

agree with the comments that argued 

that data demonstrating that equipment 

is suitable, and that the production 

process consistently delivers expected 

results, are a key element of CGMP. 

Therefore, final § 111.35(b)(6) requires 

you to make and keep documentation of 

the controls that you use to ensure that 

the equipment functions in accordance 

with its intended use. Examples of such 

controls include temperature settings, 

fill rates, and blending times that must 

be set, checked, and adjusted as 

necessary. 

X. Comments on Requirement to 

Establish a Production and Process 

Control System (Final Subpart E) 

A. Reorganization of Proposed § 111.35 

Into Final Subpart E 

In the 2003 CGMP Proposal, the 

requirements for a production and 

process control system were set forth in 

§ 111.35. As shown in table 6 of this 

document, we are reorganizing 

proposed § 111.35 into subpart E. Table 

6 lists the sections in final subpart E and 

identifies the sections in the 2003 

CGMP Proposal that form the basis of 

the final rule. 

TABLE 6.—DERIVATION OF SECTIONS

IN FINAL SUBPART E 

Final Rule 2003 CGMP 

Proposal 

§ 111.55 What are the 

requirements to implement a production and 

process control system? 

§ 111.35(a) 

§ 111.60 What are the 

design requirements 

for the production and 

process control system? 

§ 111.35(b) 


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TABLE 6.—DERIVATION OF SECTIONS

IN FINAL SUBPART E—Continued 

Final Rule 2003 CGMP 

Proposal 

§ 111.65 What are the 

requirements for quality control operations? 

§ 111.35(c) 

§ 111.70 What specifications must you establish? § 111.35(e), (f), 

(g), and (k) 

§ 111.73 What is your 

responsibility for determining whether established specifications 

are met? 

§ 111.35 (f), (g), 

and (h) 

§ 111.75 What must you 

do to determine 

whether specifications 

are met? 

§ 111.35(e), (f), 

(g), (h), (i), 

(k), and (l) 

§ 111.37 

(b)(11)(iv) 

§ 111.40(a)(2) 

§ 111.77 What must you 

do if established specifications are not met? 

§ 111.50(d)(2), 

(f), and (g) 

§ 111.35(i)(4)(i) 

and (i)(4)(ii) 

§111.80 What representative samples must 

you collect? 

§ 111.37(b)(11) 

§ 111.83 What are the 

requirements for reserve samples? 

§ 111.37(b)(12) 

§ 111.50(h) 

§ 111.83(b)(2) 

§ 111.87 Who conducts 

a material review and 

makes a disposition 

decision? 

§ 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 What requirements apply to treatment, 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? 

§ 111.35(i)(4) 

§ 111.50(d)(1), 

(f), and (g) 

§ 111.65(d) 

§ 111.95 under this subpart E, what records 

must you make and 

keep? 

§ 111.35(m) and 

(o) 

B. General Comments on Proposed 

§ 111.35 

(Comment 145) Several comments 

emphasize the first step in ensuring 

safe, high quality products is to use high 

quality components that meet welldefined specifications. Some of these 

comments assert the 2003 CGMP 

Proposal does not encourage 

development of such specifications. 

Several comments assert that a more 

appropriate balance is needed between 

an effective process control system and 

a reasonable testing scheme that is 

calculated to confirm the quality of 

dietary supplements, and that it is 

important to provide companies with 

more flexibility in developing a specific 

CGMP program that satisfies the 

requirements. The comments stress it is 

important to build quality into a 

product throughout the entire 

production process by relying on strong 

process controls rather than by testing at 

the finished batch stage. One comment 

asserts that, in an appropriate process 

control system, testing is a means to 

monitor and ensure that the control 

system is functioning as intended. Many 

comments recommend the final rule 

include rigorous in-process controls 

plus a requirement for one identity test 

of incoming components to ensure 

quality and safety. 

Many comments assert a certificate of 

analysis can be a key element of the 

manufacturing process provided that a 

manufacturer certifies that a vendor 

consistently supplies suitable product 

through a combination of vendor audits 

and product testing. (A certificate of 

analysis is a document, provided by the 

supplier of a component prior to or 

upon receipt of the component, that 

documents certain characteristics and 

attributes of the component.) Comments 

also assert that, with use of a certificate 

of analysis from a properly qualified 

supplier, the amount of required testing 

could be reduced. One comment notes 

that, although a certificate of analysis 

may not be relied upon completely to 

forgo testing of a received ingredient, 

the extent of testing could be reduced to 

take into account the history of the 

supplier in providing quality 

ingredients. This and other comments 

recommend the dietary supplement 

manufacturer conduct identity tests to 

ensure that the correct component has 

been received. A few comments note 

that the drug CGMP regulations permit 

the use of a supplier’s certificate of 

analysis based upon certification of the 

supplier by a program of complete 

testing for conformance with the 

certificate of analysis. 

Several comments support the use of 

a qualified supplier’s certificate of 

analysis in lieu of testing at the finished 

batch stage. One comment recommends 

testing be strategically employed to 

verify that other control procedures 

have accomplished their intended 

result; if other controls are adequate, a 

statistically-based testing program 

should be permitted for finished batches 

rather than the proposed requirement 

for testing every batch for every 

specification. 

Many comments note that section 

402(g)(2) of the act directs us to develop 

dietary supplement CGMP requirements 

that are modeled after the CGMP 

regulations for food. These comments 

point out that, because the food CGMPs 

allow the use of a verified certificate of 

analysis, it is unfair and illogical to 

disallow a certificate of analysis in the 

dietary supplement CGMP final rule. 

One comment states the proposed 

requirements for production and 

process controls are more stringent than 

the requirements for drug products. 

Several comments stress that the most 

critical aspect of a successful CGMP 

system is effective process control, 

which includes a requirement for 

written procedures and documentation 

for all key processing operations. Many 

comments argue that effective process 

control, including extensive written 

procedures, should allow for a 

decreased testing burden with respect to 

the finished product. One comment 

suggests we exempt manufacturers from 

the requirement to test each batch of 

finished product if they have a qualified 

manufacturing process that meets 

certain basic criteria, including a 

requirement for written procedures for 

each stage of the process and a written 

plan for qualifying this process. 

Several comments urge us to build 

more flexibility into the testing 

requirements, in both the type and 

number of tests required and the 

point(s) in the supply chain at which 

they would be required. Some 

comments recommend that the 

frequency of testing be established 

under a statistically valid method to 

ensure that in-process controls are 

adequate to guarantee production of a 

safe and effective dietary supplement or 

ingredient. Several comments 

recommend we require manufacturers to 

test incoming ingredients and raw 

materials, in lieu of testing each 

finished batch of product. These 

comments state it is more prudent to 

test to ensure that the materials used in 

formulating a product are appropriate 

and safe than to risk making an 

adulterated product and, in so doing, 

contaminate manufacturing equipment. 

Several comments recommend we 

allow manufacturers to employ skip-lot 

testing as an alternative to testing each 

finished batch of product. One comment 

states that, with adequate process 

controls in place, periodic or skip-lot 

testing is sufficient, and notes that skiplot testing is acceptable under the 

regulatory frameworks for herbal 


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products in other countries, including 

Canada and countries in the European 

Union. 

In summary, the comments suggest an 

approach that stresses the importance of 

establishing specifications for 

components, relying on a certificate of 

analysis from a qualified supplier for 

certain specifications with qualification 

of the suppliers, and establishing and 

following written procedures. This 

overall approach would focus on 

building quality into a dietary 

supplement throughout the production 

and process control system. The role of 

testing at the finished batch stage would 

become a check on whether the overall 

manufacturing process is, in fact, under 

control. 

(Response) Based upon a review of 

the comments, we have reconsidered 

the approach taken in the 2003 CGMP 

Proposal. The 2003 CGMP Proposal 

would require that all finished batches 

of dietary supplements be tested at the 

finished batch stage to ensure that the 

products met specifications for identity, 

purity, strength, and composition. The 

2003 CGMP proposal recommended, but 

would not require, testing of incoming 

components to ensure that component 

specifications, including identity, were 

met. However, if a specification (such as 

identity) could not be tested at the 

finished batch stage, the proposed rule 

would require a firm to test incoming 

components for that specification and to 

test for that specification at the inprocess stage as necessary to ensure that 

products met specifications. We are 

persuaded that, as an alternative to 

testing each finished batch of product, 

we can allow for the use of a statistically 

sound sampling and testing program for 

finished batches of dietary supplements 

unless a manufacturer chooses to test 

every batch. Such a sampling and 

testing program is feasible when 

controls are implemented earlier than 

the final product stage in the 

manufacturing process. Controls include 

the use of a certificate of analysis from 

a qualified supplier for specifications 

other than the identity of a dietary 

ingredient, and the establishment and 

monitoring of in-process manufacturing 

controls. We agree with the comments 

that if we reduce the requirements for 

testing at the finished batch stage, then 

it is critical that you determine whether 

components meet specifications. We 

address this issue in the following two 

ways: (1) Each manufacturer must 

confirm the identity of each component 

prior to use (you must test or examine 

dietary ingredients to verify the identity, 

but may rely on a certificate of analysis 

to confirm the identify of components 

other than dietary ingredients) and (2) 

each company must confirm other 

required specifications for components 

prior to use, either by relying upon a 

certificate of analysis or by testing or 

examining the component. 

As the comments have suggested, 

specifications for the ‘‘identity’’ of 

components of dietary supplements are 

critically important. These comments 

included references to industry 

proposals that supported identity 

testing. The 1997 ANPRM (62 FR 5700) 

included an industry proposed outline 

of CGMP provisions which contained a 

provision that required identity testing 

as follows: ‘‘(iv) Each lot of raw material 

shall undergo at least one test by the 

manufacturer to verify its identity. Such 

tests may include any appropriate test 

with sufficient specificity to determine 

identity, including chemical and 

laboratory tests, gross organoleptic 

analysis, microscopic identification, or 

analysis of constituent markers.’’ (60 FR 

5700 at 5705). 

In January 2004, a group of trade 

associations representing dietary 

supplement manufacturers and others 

submitted text of proposed CGMP 

requirements to the docket as an 

alternative to the 2003 CGMP Proposal. 

This submission also included a 

provision which required identity 

testing as follows: 

(1) For components, dietary ingredients, or 

dietary supplements that you receive, you 

must: 

(i) conduct at least one test or examination 

to verify that the specifications for identity 

are met; * * * 

(1996N–0417, EMC000261–02 at 20). 

Both the 1997 ANPRM industry 

outline and the January 2004 industry 

docket submission included provisions 

that allowed certificates of analysis to 

establish specifications other than for 

identity for ingredients and 

components. 

In the preamble to the 2003 CGMP 

Proposal (68 FR 12157 at 12162) we 

discussed a case in which Digitalis 

lanata was labeled as plantain and, as 

a result, a young woman experienced a 

life-threatening abnormal heart function 

after consuming a dietary supplement 

containing D. lanata in lieu of plantain. 

The problem occurred notwithstanding 

the fact that certificates of analysis 

furnished by the supplier provided 

assurances that the component was 

indeed plantain. 

Because of the critical importance of 

ensuring the proper identity of dietary 

ingredients—they are the central 

defining ingredients of a dietary 

supplement—we are requiring each firm 

that uses a dietary ingredient to perform 

its own testing or examination for 

identity of each dietary ingredient prior 

to use. This requirement is similar to the 

proposed requirement set forth by 

industry in both the 1997 ANPRM and 

in the January 2004 industry comment 

to the proposed rule. Firms may not rely 

upon a certificate of analysis provided 

by suppliers to determine the identity of 

a dietary ingredient before use. We 

recognize, however, that it may be 

possible for a manufacturer to 

demonstrate, through various methods 

and processes in use over time for its 

particular operation, that a system of 

less than 100 percent identity testing 

would provide no material diminution 

of assurance of the identity of the 

dietary ingredient as compared to the 

assurance provided by 100 percent 

identity testing. To provide an 

opportunity for a manufacturer to make 

such a showing and reduce the 

frequency of identity testing of 

components that are dietary ingredients 

from 100 percent to some lower 

frequency, we decided to provide, in an 

interim final rule published elsewhere 

in this issue of the Federal Register, a 

procedure that allows for submission to, 

and review by, FDA of an alternative to 

the required 100 percent identity testing 

of components that are dietary 

ingredients, provided certain conditions 

are met. 

In the preamble to the 2003 CGMP 

Proposal (68 FR 12157 at 12198), we 

explained that we would not permit 

firms to rely upon supplier 

certifications. The decision was based, 

in large part, on problems that have 

occurred with faulty certificates in the 

past. We have, however, reconsidered 

our position on certificates for 

specifications, other than for the 

identity of the dietary ingredients, based 

on comments discussing how firms have 

taken steps to ensure that their 

certificates are reliable. We believe that 

the minimum criteria that we are 

establishing for a certificate of analysis, 

together with the requirement that a 

firm relying on a certificate of analysis 

must qualify a supplier and periodically 

repeat that qualification process, can 

prevent the problems that have occurred 

with faulty certificates in the past. 

Therefore, for component specifications, 

other than the identity of a dietary 

ingredient, including confirming the 

identity of components that are not 

dietary ingredients, we are permitting 

firms to rely upon certificates of 

analysis provided by suppliers, if the 

certificates meet the requirements of the 

final rule. Under final § 111.75(a), a firm 

may rely upon a certificate of analysis 

from its supplier of a component, 

provided that certain criteria are met 

which include the following: (1) The 


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firm first qualifies the supplier by 

establishing the reliability of the 

supplier’s certificate of analysis through 

confirmation of the results of the 

supplier’s tests or examinations; (2) the 

certificate of analysis includes a 

description of the test or examination 

method(s) used, limits of the test or 

examinations, and actual results of the 

tests or examinations; (3) the firm 

maintains documentation of how it 

qualified the supplier; (4) the firm 

periodically reconfirms the supplier’s 

certificate of analysis; and (5) the firm’s 

quality control personnel review and 

approve the documentation setting forth 

the basis for qualification (and 

requalification) of any supplier. 

As we discussed in the preamble to 

the 2003 CGMP Proposal, in-process 

controls are necessary to ensure that 

dietary supplements are manufactured 

in accordance with their specifications 

(68 FR 12157 at 12197). Under final 

§ 111.75(b), firms must monitor the inprocess points, steps, or stages where 

control is necessary to ensure the 

quality of the finished batch of the 

dietary supplement to: (1) Determine 

whether the in-process specifications 

are met and (2) detect any deviation or 

unanticipated occurrence that may 

result in a failure to meet specifications. 

In addition, we have strengthened the 

requirements for in-process controls by 

requiring that quality control personnel 

conduct all required material reviews 

and make all required disposition 

decisions using written procedures to 

ensure that deviations or unanticipated 

occurrences that occur are consistently 

handled. 

Because of the strengthened 

requirements regarding component and 

in-process specifications, the final rule 

permits testing of a subset of finished 

batches rather than requiring testing of 

each finished batch. Consistent with 

several suggestions in the comments, we 

built more flexibility into the testing 

requirements so that a firm may test a 

subset of finished dietary supplement 

batches that the firm identifies through 

a sound statistical sampling plan for 

selected specifications rather than test 

every batch of the finished dietary 

supplement for every specification. 

Finally, quality control personnel must 

review and approve any exceptions 

from testing requirements that are 

allowed under the rule and the basis for 

such exceptions. This approach is 

consistent with the comments that we 

received and will achieve a high degree 

of integrity in the manufacturing 

process, while at the same time provide 

flexibility to the industry. 

Additional discussion on the 

requirements for identity testing of 

dietary ingredients and the appropriate 

reliance on a certificate of analysis for 

components other than dietary 

ingredients is found in this section in 

response to comment 174. 

C. Final Subpart E and Highlights of 

Changes to the Proposed Regulations 

The provisions in final subpart E 

reflect that the final rule applies only to 

persons who manufacture, package, 

label, or hold a dietary supplement 

unless subject to an exclusion in final 

§ 111.1. The approach that we are 

incorporating into the final rule requires 

changes in most of the individual 

paragraphs of proposed § 111.35. 

D. What Are the Requirements to 

Implement a Production and Process 

Control System? (Final § 111.55) 

Final § 111.55 requires you to 

implement a system of production and 

process controls that covers all stages of 

manufacturing, packaging, labeling, and 

holding of the dietary supplement to 

ensure the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. Final § 111.55 derives from 

proposed § 111.35(a). 

(Comment 146) A few comments say 

the production and process controls 

outlined in proposed § 111.35 are 

critical in ensuring that dietary 

supplements meet specifications for 

identity, purity, quality, strength, and 

composition. One comment 

recommends proposed § 111.35(a) be 

revised to state ‘‘* * * that covers all 

stages of manufacturing, packaging, 

labeling, and holding of * * * dietary 

supplements that occur in your facility 

or for which you otherwise have 

responsibility.’’ This comment explains 

that the production of dietary 

supplements is often broken up into 

several stages which are under the 

control of different entities. The 

comment gives the following examples: 

A marketing company may manufacture 

and package a product itself; or it may 

contract with one company to 

manufacture and package the product; 

or it may contract with one company to 

manufacture the product and another 

company to package the product; and 

contract manufacturers and packagers 

may subcontract portions of the 

manufacturing or packaging. 

(Response) We decline to revise the 

rule as suggested by the comments. As 

we discussed in response to comment 

37 in section VI of this document, you 

must comply with the CGMP 

requirements that apply to your 

operations related to the manufacturing, 

packaging, labeling, and holding of 

dietary supplements. We decline to 

include codified language that may not 

capture all of the possible relationships 

that exist in a given operation. 

E. What Are the Design Requirements 

for the Production and Process Control 

System? (Final § 111.60) 

Final § 111.60(a) requires that your 

production and in-process control 

system be designed to ensure that the 

dietary supplement is manufactured, 

packaged, labeled, and held in a manner 

that will ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. Final § 111.60(b) requires that 

the production and in-process control 

system include all requirements of 

subparts E through L of part 111 and be 

reviewed and approved by quality 

control personnel. Final § 111.60(a) and 

(b) derive from proposed § 111.35(b). 

As discussed in section III of this 

document, we are clarifying a number of 

provisions that did not explicitly 

identify labeling as an operation that is 

covered by the rule. Final § 111.60 is 

one such provision. Under proposed 

§ 111.35(a) we would require that you 

implement a system of production and 

process controls that covers all stages of 

manufacturing, packaging, labeling, and 

holding of the dietary supplements. In 

an oversight, proposed § 111.35(b) 

would require your production and inprocess control system to be designed to 

ensure that the dietary supplement is 

manufactured, packaged, and held—but 

not labeled—in a manner that would 

prevent adulteration of the dietary 

supplement. To correct this oversight, 

final § 111.60 explicitly identifies 

labeling as an operation that the design 

of your production and process control 

system must address. 

(Comment 147) A few comments 

recommend that the phrase ‘‘designed to 

ensure’’ in proposed § 111.35(b) be 

deleted because it requires that formal, 

prospective studies (similar to a process 

validation) must be performed and such 

a requirement would be unduly 

burdensome. 

(Response) We disagree with the 

comments’ interpretation of the 

proposed regulation and decline the 

request. Final § 111.60(a) relates to the 

overall design of your production and 

process control system. It does not 

require validation based on scientific 

studies, but rather that your process 

contain all the controls necessary to 

ensure the quality of your dietary 

supplements and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. The process, for example, must 


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ensure that the dietary supplement 

meets all specifications established 

under § 111.70(e). 

F. What Are the Requirements for 

Quality Control Operations? (Final 

§ 111.65) 

Final § 111.65 requires that you 

implement quality control operations in 

your manufacturing, packaging, 

labeling, and holding operations for 

producing the dietary supplement to 

ensure that these operations are 

performed in a manner that ensures the 

quality of the dietary supplement and 

that the dietary supplement is packaged 

and labeled as specified in the master 

manufacturing record. Final § 111.65 

derives from proposed § 111.35(c). 

Proposed § 111.35(c) referred to the 

role of the quality control unit in 

manufacturing, packaging, and label 

operations—but not in holding 

operations. This was an oversight. We, 

therefore, revised proposed § 111.35(c) 

to include ‘‘holding’’ as an operation 

that is subject to the oversight of quality 

control personnel for consistency with 

final § 111.105 (proposed § 111.37(a)), 

which provides for the performance of 

quality control operations to ‘‘ensure 

that your manufacturing, packaging, 

label, and holding operations ensure the 

quality of the dietary supplement and 

that the dietary supplement is packaged 

and labeled as specified in the master 

manufacturing record.’’

(Comment 148) One comment 

recommends proposed § 111.35(c) be 

revised to state ‘‘ensures that the * * * 

dietary supplement meets 

manufacturing specifications for 

identity, purity, quality, strength, and 

composition.’’

(Response) We are not making this 

change because it is unnecessary in the 

context of the provisions of final 

§ 111.65. 

(Comment 149) One comment argues 

that proposed § 111.35(c) is too wordy 

and needs clarification. The comment 

recommends it be revised to state ‘‘You 

must use a quality control unit to ensure 

that the dietary supplement meets 

specifications for identity, purity, 

quality, strength, and composition.’’

(Response) We disagree with this 

comment. The change requested by the 

comment would emphasize a single 

responsibility of quality control 

personnel (i.e., releasing final product) 

and would obscure the fact that quality 

control personnel have a role in the 

design and conduct of most of your 

operations. 

(Comment 150) One comment 

recommends proposed § 111.35(c) be 

revised to state ‘‘ensures that the * * * 

dietary supplement meets specifications 

for identity, purity, quality, strength, 

and composition as appropriate to 

protect the public health; and quality, 

strength, and composition as 

appropriate for the * * * product.’’

This comment states it is confusing and 

unnecessary to require that all five of 

these attributes be addressed for all 

dietary supplements. The comment also 

states the term ‘‘purity’’ requires 

explanation because not all ingredients 

or supplements are subject to the same 

types of contamination. 

(Response) We are not making any 

changes in the provision as suggested by 

this comment. The comment provides 

no basis for the assertion that the 

proposed requirement to use a quality 

control unit to ensure that a dietary 

supplement meets specifications for 

identity, purity, strength, and 

composition is confusing and 

unnecessary. In section VI of this 

document, we explain that purity means 

that portion or percentage of a dietary 

supplement that represents the intended 

product. 

G. What Specifications Must You 

Establish? (Final § 111.70) 

Final § 111.70 derives from proposed 

§§ 111.35(e), (f), (g), and (k), 

111.37(b)(11)(iv), and 111.70(c). 

(Comment 151) Some comments state 

proposed § 111.35(k), which would 

require that you test or examine 

components and dietary supplements 

for those types of contamination that 

may adulterate or lead to adulteration, 

is more appropriate for, and should be 

incorporated into, proposed § 111.35(e) 

which would require, in part, that you 

establish specifications for the identity, 

purity, quality, strength, and 

composition of components that you 

receive and of dietary supplements that 

you manufacture. The comments note 

this suggestion would help simplify and 

eliminate some redundancy in proposed 

§ 111.35. One comment would revise 

proposed § 111.35(k) to state ‘‘Purity 

specifications for purchased or 

manufactured components and dietary 

supplements must be established for 

those types of contamination which can 

reasonably be expected to affect the 

component, ingredient, or supplement 

in question * * *.’’ According to the 

comment not all ingredients or 

supplements are subject to the same 

types of contamination, and it would be 

unduly burdensome to require that all 

ingredients and supplements be tested 

for all possible contaminants (as 

opposed to all likely contaminants). 

(Response) We agree that not all 

ingredients or dietary supplements are 

subject to the same types of 

contamination. It would not be 

practicable or necessary to require 

testing for all possible contaminants for 

every dietary supplement, or for every 

component used to manufacture a 

dietary supplement. As we explained in 

the 2003 CGMP Proposal (68 FR 12157 

at 12199 through 12200), the 

manufacturer has the responsibility to 

determine what types of contamination 

are likely or certain to contaminate a 

given product and to determine what 

types of tests to conduct and when to 

test for such contamination. We 

explained that botanicals are likely or 

certain to contain filth and 

microorganisms of public health 

significance based on the areas in which 

they are harvested (id.). As another 

example, fungal growth on a botanical 

component can provide the 

environment for mycotoxin production, 

especially aflatoxin (id.). If fungal 

growth is present, the manufacturer 

would need to perform an appropriate 

test that can detect the toxic substance. 

We stated that the manufacturer must be 

aware of potential contamination, 

regardless of whether due to filth, 

insects, microorganisms, or toxins and 

to test or examine, as appropriate, the 

components and dietary supplements 

for those types of contamination that 

may adulterate or that may lead to 

adulteration (id.). Thus, the types of 

contamination that we were referring to 

in proposed § 111.35(k) are those that 

are likely or certain to be present in or 

on components received, based on the 

nature of the product, its source, 

handling prior to receipt by the facility, 

or other reason, and not due to poor 

manufacturing practices that resulted in 

their presence in the first instance. 

It is the responsibility of the 

manufacturer to identify those 

contaminants and to establish limits to 

prevent adulteration under section 

402(a)(1), (a)(2), (a)(3), and (a)(4) of the 

act. For example, if you manufacture a 

polysaccharide that derives from 

seaweed, it is likely that you would 

include a limit on cadmium, because 

cadmium is a common contaminant that 

can be present in marine-derived 

ingredients. If you manufacture a 

polysaccharide that has a composition 

similar to seaweed-derived 

polysaccharide, but derives from a landbased plant, it is not likely that you 

would include a limit on cadmium, 

because cadmium is not a common 

contaminant of land-based plants. 

Likewise, if you manufacture a mineral 

that contains phosphates, it is likely that 

you would include a limit on arsenic, 

because phosphates are generally mined 

and arsenic is a common contaminant 

that can be present in ingredients that 


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are mined. If you manufacture a mineral 

that does not include ingredients that 

are mined, it is not likely that you 

would include a limit on arsenic. 

We agree that controlling 

contamination is critical to the quality 

of the dietary supplement. However, we 

do not agree that the types of 

contamination addressed by proposed 

§ 111.35(k) should be considered as a 

purity specification. We have described 

purity in this final rule to mean 

something that you intend to be present 

in the final product. As explained in 

section VI of this document, purity 

means that portion or percentage of a 

dietary supplement that represents the 

intended product. For example, you 

may manufacture a dietary supplement 

that uses a natural product such as fish 

oil to provide triglycerides that are a 

source of the polyunsaturated fatty acids 

DHA and EPA. The purity refers to the 

percent of the fish oil that is 

triglycerides. (Note that if you are 

manufacturing fish oil to provide the 

fatty acids DHA and EPA in the dietary 

supplement, the component 

specifications for the fish oil must 

include a strength specification for DHA 

and EPA in whatever amount you 

determine is necessary to meet the 

specification for strength of DHA and 

EPA in the dietary supplement.) If the 

natural product also contains lead, or 

other unwanted ingredients that may 

adulterate or may lead to adulteration, 

you would have to establish limits for 

such contaminants. Thus, to distinguish 

the proposed requirement in § 111.35(k), 

which relates to contaminants that may 

be present on or in the components that 

you receive, from the requirements 

related to specifications for desired 

characteristics of identity, purity, 

strength, and composition, we are 

including a separate requirement on 

establishing limits on such 

contaminants for components that you 

receive (final § 111.70(b)). We also 

include a requirement for establishing 

an in-process specification for any 

point, step, or stage in the master 

manufacturing record where control is 

necessary to help ensure that 

specifications are met, as necessary, for 

limits on contamination. In addition, we 

are including a requirement for such 

limits on contaminants in the finished 

batch of dietary supplement (or subset 

of finished batches) (final § 111.70(e)) to 

ensure that the manufacturing process 

has not adversely affected such levels, 

e.g., has not contributed an additional 

source of such contaminant or failed to 

remove the contaminant, when 

necessary. Such limits would need to 

ensure the quality of the dietary 

supplement, i.e., to ensure that the 

dietary supplement has been 

manufactured, packaged, labeled, and 

held under conditions to prevent 

adulteration under section 402(a)(1), 

(a)(2), (a)(3), and (a)(4) of the act. 

Thus, in addition to the presence of 

contaminants that may be in or on 

components that you receive, there may 

be sources of contamination that you 

need to control for in your facility. As 

discussed in this section, you must 

establish specifications under final 

§ 111.70(a) and (c) to prevent 

adulteration from such sources. The 

specifications established under final 

§ 111.70(a) and (c) may or may not 

include limits on such contaminants. By 

‘‘limits on those types of 

contamination’’ in final § 111.70, we do 

not mean contamination from, for 

example, the presence of rodent pellets 

or other filth that would constitute an 

insanitary condition under section 

402(a)(3) or (a)(4) of the act, if such filth 

was present in your facility. You are not 

allowed to establish specifications for 

limits on contaminants that would 

otherwise adulterate your product under 

the act if such contaminants were 

present. 

Further, in proposed § 111.35(k), we 

included a listing of the types of 

contamination we considered to be 

applicable to dietary supplements (68 

12157 FR at 12258). We stated that the 

types of contamination include: (1) 

Filth, insects, or other extraneous 

material; (2) microorganisms; and (3) 

toxic substances. We have deleted the 

listing of the types of contamination in 

the final rule because the listing is 

simply informative and establishes no 

independent requirement. We received 

several comments, discussed in the 

following paragraphs, on the types of 

contamination that may be present, 

some which were solicited by us in the 

2003 CGMP Proposal (68 FR 12157 at 

12179 through 12181). 

In the 2003 CGMP Proposal, we 

solicited comment on whether we 

should include in the final rule specific 

requirements for manufacturing, 

packaging, or holding animal-derived 

dietary ingredients, because animalderived dietary ingredients present 

important public health and safety 

issues. 

In the 2003 CGMP Proposal, the 

example we used was an animal-derived 

dietary ingredient potentially 

contaminated with the agent that causes 

bovine spongiform encephalopathy 

(BSE), which is a type of transmissible 

spongiform encephalopathy (TSE). TSEs 

are fatal, neurodegenerative disorders, 

which have been identified in humans 

and a number of animal species (e.g., 

cattle, sheep, goats, elk, deer, cats, and 

mink), but primarily in ruminants 

(cattle, sheep, elk, deer) (69 FR 42256, 

July 14, 2004). Most scientists believe 

that variant Creutzfeldt Jakob Disease 

(vCJD), a progressive neurological 

disease in humans, is caused by 

consumption of cattle products 

contaminated with the agent that causes 

BSE (69 FR 42256 at 42257). 

In the 2003 CGMP Proposal (68 FR 

12157 at 12180), we stated that we had 

communicated with the public and 

manufacturers of FDA-regulated 

products about appropriate steps to 

increase product safety and minimize 

the risk of products contaminated with 

the BSE agent. We referenced a notice 

in the Federal Register of August 29, 

1994 (59 FR 44591), entitled ‘‘BovineDerived Materials; Agency Letters to 

Manufacturers of FDA-Regulated 

Products.’’ We sent letters to dietary 

supplements manufacturers to alert 

them to the developing concern about 

TSEs in animals and Creutzfeldt-Jakob 

Disease in humans. We recommended 

they investigate the source of any 

bovine and ovine material used in their 

products. We suggested that 

manufacturers develop plans to ensure, 

with a high degree of certainty, that 

bovine and ovine materials used in their 

products were not from BSE countries 

or from sheep flocks (foreign or 

domestic) infected with scrapie. We 

stated that our Center for Biologics 

Evaluation and Research (CBER) had 

developed guidances for industry that 

describe steps manufacturers should 

take to ensure the safety and suitability 

for human use of animal-derived 

biologics. We also stated that we were 

considering whether the procedures that 

CBER recommends for a product with 

animal-derived materials, substances, or 

tissues would be appropriate for dietary 

ingredients and dietary supplements 

that contain animal-derived materials, 

substances, or tissues. We believed that 

the use of an animal-derived material, 

substance, or tissue in a dietary 

supplement may raise many of the same 

serious public health and safety issues 

as animal-derived materials, substances, 

or tissues, in a biologic. We invited 

comment on whether there is a 

scientific basis for us to treat animalderived dietary ingredients in a manner 

different from, or that would offer less 

protection than, what is recommended 

for animal-derived biologics when the 

same public health and safety risks may 

be present. 

(Comment 152) Several comments 

state there should not be specific 

requirements for manufacturing, 

packaging, or holding animal-derived 

dietary ingredients because BSE issues 


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are not specific to dietary supplements, 

and because other guidance and 

regulations, issued by FDA and by the 

U.S. Department of Agriculture (USDA), 

already address BSE and public health. 

Other comments state it would be 

appropriate to include specific CGMP 

requirements for BSE as long as the 

requirements reflect the thinking in 

currently existing regulations and 

guidance. 

Several comments do not support the 

need for additional provisions regarding 

the handling of imported animalderived ingredients because the 

industry has already taken steps to 

comply with the requirements or 

recommendations issued by either 

USDA or FDA. The comments state that 

the regulations issued by USDA for meat 

related products in the food industry 

provide adequate control over the use of 

animal tissues that might contain 

microorganisms, specifically viruses, of 

public health concern. 

One comment argues that if purchases 

of domestic raw tissues have been 

inspected by USDA, it is unfair to 

impose additional regulations simply 

because these tissues are included in 

dietary supplements. This comment 

asserts it would be unfair to require 

testing of animal-derived products given 

the fact that there are no tests for BSE 

available, and that reliance on USDA 

and FDA is the best way to stop the 

spread of BSE. 

Another comment states that industry 

trade associations have been working 

actively with their member companies 

to ensure adherence to the requirements 

set forth in our various letters regarding 

the need to develop plans ‘‘that ensure, 

with a high degree of certainty’’ that 

animal-derived ingredients are used 

only in accordance with FDA and USDA 

policies designed to protect against BSE. 

The comment states that a summary of 

industry procurement and handling 

practices regarding animal-derived 

ingredients (submitted to us) contains 

lists of animal-derived ingredients used 

by various companies, with examples of 

the certificates of origin and other 

documentation required for import of 

any animal-derived materials. One 

comment states that industry members 

who handle animal-derived ingredients 

already have implemented many of the 

controls that originated either from 

USDA or the dietary ingredient 

suppliers in response to demands by 

various governments or consumers, and 

that such matters should remain with 

USDA to avoid duplication of effort. 

Some comments oppose any 

recommendation that guidance issued 

by CBER for ensuring the safety and 

suitability for human use of animalderived biologics apply to dietary 

supplement products. One comment 

includes a review of literature on BSE 

and claims the review justifies not 

applying the CBER guidances on BSE to 

dietary supplement products under part 

111. 

(Response) For cattle derived 

materials, you must comply with the 

requirements of the interim final rule on 

BSE set forth in § 189.5 (see 70 FR 

53063, September 7, 2005) and any 

subsequent modifications. Under the 

interim final rule, no human food, 

including dietary supplements, shall be 

manufactured from, processed with, or 

otherwise contain, prohibited cattle 

materials as defined in the rule. In 

addition, manufacturers and processors 

of such food that is manufactured from, 

processed with, or otherwise contains, 

cattle material must make existing 

records relevant to compliance available 

to us for inspection and copying. For 

both cattle-derived and other animalderived materials, you must comply 

with all applicable provisions of this 

final rule. For example, under final 

§ 111.70, you must establish 

specifications for any point, step, or 

stage in the manufacturing process 

where control is necessary to ensure the 

quality of the dietary supplement. Thus, 

you must establish specifications for 

your animal-derived materials that are 

necessary to ensure the quality of the 

dietary supplement. Ensuring quality 

includes preventing contamination that 

may adulterate the product under 

section 402(a)(1), (a)(2), (a)(3), or (a)(4) 

of the act. In addition, you must take 

actions to determine whether the 

specifications are met (final § 111.73). 

Therefore, if you used animal-derived 

materials other than prohibited cattle 

materials subject to the BSE interim 

final rule, you would need to establish 

specifications necessary to ensure the 

quality of the dietary supplement. 

The guidances issued by CBER are 

still in effect for animal-derived 

biologics, and we continue to 

recommend that you use them as 

appropriate for your products that 

contain animal-derived ingredients. 

(Comment 153) One comment agrees 

with the provisions of proposed 

§ 111.35(k) but requests that we provide 

guidance to the industry on allowable 

limits for the types of contamination 

listed. Another comment asks us to 

develop specific defect action levels 

(DALs) for dietary supplements as more 

information becomes available, rather 

than rely on existing DALs from the 

food industry. 

(Response) In the 2003 CGMP 

Proposal (68 FR 12157 at 12163), we 

stated that we were not identifying 

DALs for the types of contaminants for 

dietary ingredients because there are not 

enough data available to identify an 

appropriate DAL for most dietary 

ingredients. These comments do not 

provide data, or evidence that data are 

available, to enable us to issue guidance 

for DALs for specific contamination. 

Therefore, we are not taking the action 

requested by these comments. We 

discuss DALs in this section in response 

to comment 156. 

(Comment 154) Some comments 

suggest the provisions in proposed 

§ 111.35(k), testing for contamination 

that could adulterate a product, would 

be more appropriate to include in 

proposed § 111.35(e), which concerns 

the establishment of specifications. 

(Response) We agree with these 

comments and are including 

requirements to include limits on 

contamination in final § 111.70. The 

requirements set forth in final §§ 111.70 

and 111.75 are consistent with this 

comment. Under final § 111.70(b) you 

must establish limits on those types of 

contamination that may adulterate or 

may lead to adulteration of the finished 

batch of the dietary supplement to 

ensure the quality of the dietary 

supplement. Under final § 111.70(c) you 

must establish in-process specifications 

for any point, step, or stage in the 

master manufacturing record where 

control is necessary to help ensure that 

specifications are met for the identity, 

purity, strength, and composition of the 

dietary supplements, and as necessary, 

limits on contamination for those types 

of contamination that may adulterate or 

may lead to adulteration of the finished 

batch of the dietary supplement. Under 

final § 111.70(e), you must establish 

product specifications for the identity, 

purity, strength, and composition of the 

finished batch of the dietary 

supplement, and for limits on those 

types of contamination that may 

adulterate, or that may lead to 

adulteration of, the finished batch of the 

dietary supplement to ensure the quality 

of the dietary supplement. As we 

explained in the response to comment 

151, by ‘‘limits on those types of 

contamination’’ in final § 111.70, we do 

not mean contamination from, for 

example, the presence of rodent pellets 

or other filth that would constitute an 

insanitary condition under section 

402(a)(3) or (a)(4) of the act, if such filth 

was present in your facility. You are not 

allowed to establish specifications for 

limits on contaminants that would 

otherwise adulterate your product under 

the act if such contaminants were 

present. 

(Comment 155) Several comments 

object to proposed § 111.35(k) because 


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9The Food Chemicals Codex (FCC) project is an 

activity of the Food and Nutrition Board of the 

Institute of Medicine. The FCC was intended to 

provide standards for the purity of food chemicals 

and thus promote uniform quality and ensure safety 

in the use of such chemicals. The First Edition of 

the resulting FCC, published in 1966, was limited 

to chemicals added directly to foods to achieve a 

desired technological function. Succeeding editions 

upgraded the specifications for these substances 

and added specifications for substances that come 

into contact with foods and some that are regarded 

as foods, rather than as additives. The FCC is 

available for purchase at 1–800–624–6242 or at 

http://www.nap.edu. 

the provision would be more stringent 

than the food or drug CGMP 

requirements. Some point out that the 

consumption levels for food are higher 

than for dietary supplements. A few 

comments argue that proposed 

§ 111.35(k) is too broad as it requires 

testing or examination for those 

contaminants that ‘‘may’’ adulterate or 

‘‘may lead to’’ adulteration, which could 

be interpreted to mean testing for 

unknown contaminants of every 

description. The comments suggest that 

this provision be revised to require 

testing or examination for those types of 

contamination that ‘‘may be present in 

an amount or at a level’’ that may 

adulterate or lead to adulteration or that 

‘‘may reasonably be expected’’ to 

adulterate or lead to adulteration. Other 

comments agree that to test for all 

possible contaminants would be 

burdensome. 

Several comments state that 

manufacturers should be allowed to rely 

on a supplier’s certificate of analysis 

and that testing should not be required 

for every potential contaminant. One 

comment recommends that CGMPs 

should be specific to the source and that 

testing should depend on the nature of 

the material. 

Some comments note that for 

botanicals it is sometimes nearly 

impossible to identify and analyze all 

naturally occurring substances. 

(Response) The final rule does not 

include any specific requirements to test 

or examine components or dietary 

supplements for contamination. Rather, 

under final § 111.70(b), (c), and (e), you 

are required to establish specifications 

for limits on those types of 

contamination that may adulterate or 

may lead to adulteration of the finished 

batch of the dietary supplement. Under 

final § 111.73, you must determine 

whether the specifications established 

under § 111.70 are met. Final § 111.75(a) 

through (d) sets forth the criteria you 

must use to determine whether the 

specifications that you establish under 

final § 111.70(b), (c), and (e) are met. 

Consistent with these comments, under 

final § 111.75(a) you may rely on a 

certificate of analysis (other than for the 

identity of a dietary ingredient) from a 

qualified supplier of components to 

ensure that specifications that include 

limits on contamination are met, 

provided you satisfy the criteria set 

forth in final § 111.75(a). This would 

include, for example, relying on a 

certificate of analysis to ensure that the 

level of lead in each of your components 

would not adulterate the dietary 

supplement. 

In determining compliance with the 

requirements to set limits for those 

types of contamination that may 

adulterate the dietary supplement or 

lead to adulteration for received 

components, we would not expect you 

to set limits for every potential 

contaminant or for every naturally 

occurring constituent of a botanical. 

Rather, we agree with the comments 

that the substances you would consider 

when determining whether to set limits 

for particular types of contamination 

would vary depending on the source of 

a component, such as a plant source, an 

animal source, a microbial source, or a 

marine source. 

(Comment 156) Some comments point 

out that some compounds, such as 

mycotoxins, that are toxic at higher 

levels are detectable in nearly all plant 

ingredients and are found in the food 

supply. A few comments assert that 

dietary ingredients should not contain 

levels of certain toxic compounds that 

are higher than reasonable or higher 

than recognized maximum allowable 

limits as opposed to the zero tolerance 

for toxic compounds contained in the 

2003 CGMP Proposal. 

One comment requests clarification of 

the term ‘‘toxic substances.’’ One 

comment points out that information for 

identifying potential adulterants is 

provided in monographs. Another 

comment requests clarification on 

whether dietary supplement 

manufacturers will be required to test 

for toxins while food manufacturers, 

who may use some of the same 

ingredients, will not. 

(Response) As the comments point 

out, the food supply does contain some 

degree of contaminants such as 

mycotoxins that can be found, for 

example, in certain grain. We do not 

have a ‘‘zero tolerance’’ policy for such 

unavoidable contaminants but we have 

issued some regulations and guidance to 

address certain common contaminants. 

We also have issued a booklet entitled 

‘‘Action Levels For Poisonous Or 

Deleterious Substances In Human Food 

And Animal Feed’’ (Ref. 30; available at 

http://www.cfsan.fda.gov). The booklet 

is a useful resource for manufacturers 

who seek information about common 

contaminants that may adulterate a 

dietary supplement product or lead to 

adulteration. Another resource is the 

Foods Chemical Codex,9 which includes 

monographs on many substances, such 

as salts that are used as sources of 

minerals used in both dietary 

supplements and conventional food. 

These monographs include limits on 

common contaminants, such as lead or 

other heavy metals. In addition, the 

regulations in 21 CFR part 109 provide 

information about certain contaminants. 

(Comment 157) One comment 

recommends that all finished products 

be tested for microorganisms. Another 

comment contends the manufacturer 

should be allowed to restrict testing to 

the raw material if the facility and 

equipment are monitored for 

contamination. Some comments point 

out that contaminants may be detectable 

in raw materials but not in the finished 

product. 

(Response) We disagree that all 

finished products must, as a matter of 

course, be tested for contamination with 

microorganisms. Whether it is necessary 

to test the finished product for 

microorganisms would depend, for 

example, on the characteristics of your 

product, the nature and source of your 

components, the specifications you 

establish for microbial contaminants in 

your components and whether these 

specifications are addressed in a 

certificate of analysis, the in-process 

specifications you establish, and the 

nature of your manufacturing process. 

However, these comments raise an 

important point—i.e., that microbial 

contamination could occur at your 

facility even if an incoming component 

is free of microorganisms. Final subpart 

K discussed in section XVI of this 

document, sets forth requirements for 

your manufacturing operations. Many of 

these requirements are designed to limit 

the potential for contamination with 

microorganisms. 

(Comment 158) Some comments 

would revise the requirements for 

establishment of specifications for inprocess controls (proposed 

§ 111.35(e)(2)) and the finished batch of 

dietary supplements (proposed 

§ 111.35(e)(3)), so that specifications for 

attributes of quality, strength, and 

composition are not required for a 

product that does not purport to possess 

such attributes. 

(Response) We decline to reword the 

provision as requested by these 

comments. The requirement to establish 

specifications for strength and 

composition relate to the manufacturers’

responsibility to know what their 

finished dietary supplement is 


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composed of so that their products are 

consistently manufactured. Establishing 

specifications and following these 

CGMP requirements will help ensure 

the quality of the dietary supplement. 

The requirement to establish 

specifications is not limited to when a 

manufacturer purports that its product 

possesses attributes of strength and 

composition on the label. As discussed 

in the 2003 CGMP Proposal (68 FR 

12157 at 12162), the absence of 

minimum standards has contributed to 

the adulteration and misbranding of 

dietary supplements because of 

contaminants or because manufacturers 

do not set and meet specifications for 

their products, including specifications 

for identity, purity, strength, and 

composition and do not set and meet 

limits on contaminants, when 

necessary. The comment does not 

persuade us otherwise. We note, 

however, that the final rule’s 

requirements to establish specifications 

for components do, in fact, provide 

flexibility so that you are not required 

to establish a component specification 

for certain attributes, such as the 

strength of a tablet coating agent (see the 

discussion of final § 111.70(b) in this 

section). 

(Comment 159) One comment asks for 

guidance as to what constitutes an 

official or scientifically valid standard 

for specifications. 

(Response) We are not aware of any 

officially recognized standard for 

specifications. Specifications are critical 

standards that are proposed and 

justified by the manufacturer for each 

product that the manufacturer produces. 

The manufacturer establishes the set of 

criteria to which a product should 

conform to be considered acceptable for 

its intended use. In general, a 

specification may include a list of tests, 

references to analytical procedures, and 

appropriate acceptance criteria that are 

numerical limits, ranges, or other 

criteria for the tests described. 

(Comment 160) One comment asks 

that we clarify whether every 

specification sheet must include 

separate, specific qualitative or 

quantitative standards, and tests to be 

established for each attribute, or 

whether a specification sheet can be 

modeled after a compendial monograph. 

Some comments state that product 

specification sheets should be modeled 

after pharmacopoeia monographs other 

than those listed in the preamble to the 

2003 CGMP Proposal. 

(Response) These CGMP requirements 

do not establish any requirements to 

have a ‘‘specification sheet.’’ Rather, the 

final rule (final § 111.70(a)) requires you 

to establish a specification for any point, 

step, or stage in the manufacturing 

process where control is necessary to 

ensure the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. We require that you establish 

specifications for components (final 

§ 111.70(b)), in-process production 

(final § 111.70(c)), labels and packaging 

(final § 111.70(d)), the finished batch of 

dietary supplement (final § 111.70(e)), 

product that you receive from a supplier 

for packaging and labeling (final 

§ 111.70(f)), and the packaging and 

labeling for the finished packaged and 

labeled dietary supplement (final 

§ 111.70(g)). The general requirement for 

establishing specifications in final 

§ 111.70(a) includes specifications, not 

otherwise required in final § 111.70(b) 

through (g), that the manufacturer 

determines are necessary to achieve 

quality, i.e., that are necessary to meet 

the identity, purity, strength, or 

composition of the dietary supplement 

or that are necessary to prevent 

adulteration under section 402(a)(1), 

(a)(2), (a)(3), and (a)(4) of the act. 

Requirements to establish 

specifications to control for 

contamination are included in final 

§ 111.70(a), (b), (c), and (e). As 

discussed earlier, the specifications for 

contaminants in final § 111.70(b) refer to 

those types of contamination of a 

component or dietary supplement that 

may adulterate or that may lead to 

adulteration that are due to 

contaminants that may be present in or 

on the components that you receive, 

based on the nature of the product, its 

source, its handling prior to receipt, or 

other reason. Limits are established by 

the manufacturer for such contaminants 

at receipt. 

The requirement to establish 

specifications to control for 

contamination under final § 111.70(a) 

and (c) include specifications necessary 

to prevent adulteration under section 

402(a)(1), (a)(2), (a)(3), and (a)(4) of the 

act as a result of what the manufacturer 

may do or fail to do in its manufacturing 

operation, and not as a result of 

contaminants that are in or on the 

components received. For example, it 

may be critical that a certain piece of 

equipment be cleaned and/or sanitized 

after handling certain raw materials to 

ensure that there is no microbial 

contamination from microorganisms of 

public health significance to 

components processed on the 

equipment. If the manufacturer failed to 

establish a specification for cleaning 

and/or sanitizing after handling those 

raw materials before processing 

components, the manufacturer would 

have failed to establish a specification 

required by final § 111.70(a) or (c) 

necessary to prevent a type of 

contamination that may lead to 

adulteration under section 402(a)(4) of 

the act. We would consider it a failure 

to follow CGMP requirements if a 

manufacturer allowed conditions in the 

manufacture of a dietary supplement 

that would not ensure the quality of the 

dietary supplement. 

We have specified in final § 111.70(b) 

that you must establish certain types of 

specifications that are critical to 

ensuring that you know what the 

components are that you use in 

manufacturing a dietary supplement 

and that are necessary to ensure that the 

dietary supplements you manufacture 

meet their specifications for identity, 

purity, strength, composition, and do 

not exceed their limits for contaminants. 

The identity, purity, strength, and 

composition, and the limits that you 

establish for contaminants, for a 

finished batch of dietary supplement are 

what we call ‘‘product specifications’’ in 

final § 111.70(e). These product 

specifications must be met in order for 

you to ensure the quality of your 

finished batch of dietary supplement. A 

specification may include a list of tests, 

references to analytical procedures, and 

appropriate acceptance criteria that are 

numerical limits, ranges, or other 

criteria for the tests described. For 

example, a specification for a 

component may include information 

about the test used to verify the identity 

of the component and the range of test 

results that are acceptable. Under final 

§ 111.70(c), a specification for an inprocess control may include 

information about the viscosity that 

must be achieved during a batch 

production of a liquid product and 

information about the test or equipment 

used to measure the viscosity. Under 

final § 111.70(d), a specification for 

packaging may include the specific type 

or grade of plastic. Under final 

§ 111.70(e), a specification for the 

finished batch may include the 

quantitative amount of a dietary 

ingredient, such as vitamin C. 

Under this final rule, the 

manufacturer has the flexibility—and 

the responsibility—to develop 

specifications that are appropriate to the 

circumstances, including whether 

information in any particular 

monograph is an appropriate model for 

a given dietary supplement. 

1. Final § 111.70(a) 

Final § 111.70(a) requires you to 

establish a specification for any point, 

step, or stage in the manufacturing 

process where control is necessary to 


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ensure the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. Final § 111.70(a) derives from 

the opening statement in proposed 

§ 111.35(e). 

As we discussed in the preamble to 

the 2003 CGMP Proposal (68 FR 12157 

at 12196), the points, steps, or stages 

where specifications must be 

established may include heating steps, 

cooling steps, points where specific 

sanitation procedures are needed, 

product formulation control steps, 

points where cross-contamination may 

occur, and steps where employee and 

environmental hygiene are necessary to 

ensure the quality of the dietary 

supplement. These specifications are 

regulatory specifications addressed by 

these CGMP regulations. The final rule 

does not prevent you from establishing 

additional, nonregulatory specifications 

that are not at points, steps, or stages 

where control is necessary to ensure the 

quality of the dietary supplement. For 

example, you could establish 

specifications that largely address the 

appearance of the dietary supplement in 

an aesthetic sense. Such nonregulatory 

specifications are not addressed by the 

final rule. 

(Comment 161) One comment notes 

that labelers would not be subject to 

proposed § 111.35(e). 

(Response) Consistent with final 

§ 111.1, persons who perform labeling 

operations are, in fact, subject to the 

final rule, including the requirements to 

establish specifications. As discussed in 

this section, the final rule includes an 

explicit requirement that, if you receive 

a product from a supplier for packaging 

or labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier), you must establish 

specifications to ensure that the product 

that you receive is adequately identified 

and is consistent with your purchase 

order (final § 111.70(f)). 

(Comment 162) One comment asks 

whether the manufacturer determines 

where control is ‘‘necessary’’ to prevent 

adulteration. 

(Response) In accordance with the 

changes made to the section, the 

manufacturer does determine where 

control is necessary to ensure the 

quality of the dietary supplement. 

(Comment 163) Some comments 

express concern that manufacturers who 

must confirm the validity of subjective 

criteria established as specifications 

may set the specifications as low as 

possible or set meaningless 

specifications. 

(Response) The specifications you 

must establish under this final rule are 

designed to ensure the quality of the 

dietary supplement that you 

manufacture. It is not meaningless to 

establish requirements that will ensure, 

for example, the product meets the 

established specifications for identity, 

purity, strength, and composition, and 

is within specified limits on 

contaminants to prevent adulteration. 

(Comment 164) Some comments 

express concern that the language of 

proposed § 111.35(e) may require 

specifications beyond those already 

required in the master manufacturing 

record, as stated in proposed 

§ 111.45(a)(1), to identify specifications 

for the points, steps, or stages in the 

manufacturing process where control is 

necessary to prevent adulteration, or 

may require specifications for attributes 

that are not present at all stages. These 

comments urge us to be flexible during 

inspections as to what specifications are 

appropriate. 

(Response) Final § 111.70(a) provides 

the manufacturer with flexibility in 

determining what specifications may be 

necessary for its operation. Moreover, 

final § 111.70(a) through (g) provide the 

manufacturer with flexibility to 

determine what the specifications 

require in order to ensure the quality of 

the dietary supplement. 

2. Final § 111.70(b) 

Final § 111.70(b) requires you to 

establish component specifications for 

each component you use in the 

manufacture of a dietary supplement. 

Under final § 111.70(b)(1), you must 

establish an identity specification for 

each component that you use in the 

manufacture of a dietary supplement. A 

specification for identity may include 

more than one attribute. For example, a 

specification for the identity of a salt 

used in the manufacture of a vitamin 

and mineral supplement may include 

the physical characteristics of the solid 

(e.g., as a crystal or as a powder), the 

color, and the state of hydration (e.g., 

with two or three molecules of water). 

A specification for the identity of a 

botanical may include the part of the 

plant (e.g., roots or leaves), the color, 

and whether the part of the plant is in 

a native state or has been ground. Under 

final § 111.70(b)(2), you must establish 

component specifications that are 

necessary to ensure that specifications 

for the purity, strength, and composition 

of dietary supplements manufactured 

using the components are met. Under 

final § 111.70(b)(3) you must establish 

limits on those types of contamination 

that may adulterate or may lead to 

adulteration of the finished batch of the 

dietary supplement to ensure the quality 

of the dietary supplement. Final 

§ 111.70(b) derives from proposed 

§ 111.35(e)(1) and (k). Final § 111.70(b) 

is consistent with comments, already 

discussed, that recommended the 

provisions of proposed § 111.35(k), 

regarding contaminants that could 

adulterate a product, be incorporated 

into proposed § 111.35(e). In addition, 

as discussed previously with respect to 

final § 111.55, final § 111.70(b) provides 

that the required component 

specifications you must establish for a 

dietary supplement include identity, 

purity, strength, and composition. 

(Comment 165) A few comments state 

it is appropriate and acceptable to 

establish a requirement for a 

specification for the identity and purity 

of components, insofar as such 

specifications are necessary to ensure 

that components are not contaminated 

with substances having public health 

significance. However, these comments 

argue that specifications for quality, 

strength, and composition of 

components should only be required for 

the quality, strength, and composition 

that a component is purported to 

possess. One comment notes this would 

provide the same requirement that is 

currently established for drug products 

and processing. Some comments 

recommend that specifications should 

be established ‘‘as appropriate’’ or 

‘‘where control is necessary to assure 

production of a quality product.’’

(Response) After considering the 

comments that questioned the need to 

establish specifications for the identity, 

purity, quality, strength, and 

composition of components, as well as 

the general comments that led to the 

overall approach that focuses on 

building quality into a dietary 

supplement at every stage of the 

production and process control system 

(see discussion in section IV of this 

document), we are requiring in final 

§ 111.70(b)(1) that you establish an 

identity specification for components 

that you use. This identity specification 

is necessary to ensure that the finished 

dietary supplement meets its 

specification for identity because you 

could not know what your final product 

contains if you do not know what you 

put into it. In addition, final 

§ 111.70(b)(2) requires you to establish 

those component specifications for 

purity, strength, and composition that 

are necessary to ensure that 

specifications for the purity, strength, 

and composition of dietary supplements 

manufactured using the components are 

met. 

Final § 111.70(b)(2) provides 

flexibility for you to determine which 

component specifications other than 

identity are, or are not, necessary to 


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ensure that the final dietary supplement 

meets its specifications. For example, it 

is likely that you will need to establish 

a specification for the strength of 

vitamin C added as a component, that 

you use to make a multivitamin 

supplement, so that you will know how 

much vitamin C to add to satisfy the 

specification for the strength of the 

vitamin C in the final product. Thus, if 

you are manufacturing a vitamin C 

tablet with a strength of 50 milligrams 

(mg) per tablet, you must determine 

how much vitamin C, of a given 

strength, you must add in order to 

produce tablets that will contain 50 mg, 

after accounting for the theoretical yield 

at each step in the manufacturing 

process. However, you may not need to 

establish a specification for the strength 

of the tablet coating agent for that 

multivitamin supplement, if your final 

specifications include the amount of the 

tablet coating agent as part of the 

specifications for the composition, but 

not the strength of the multivitamin 

supplement. In most cases, a 

specification for the composition of the 

dietary supplement would be sufficient 

to ensure that the tablet coating agent is 

used within the established level. 

(Comment 166) A few comments 

express concern about how to determine 

certain specifications for botanicals, 

such as the strength of peppermint leaf. 

The comments explain that a 

specification for strength of peppermint 

leaf could be based on a number of 

different attributes. One comment 

argues that establishing specifications 

for all dietary ingredients may not 

contribute to any assurance of product 

quality and will not protect public 

health. Some comments assert that 

‘‘quality, strength, and composition’’ are 

subjective with respect to botanical 

ingredients for which no potency claim 

is made, and, thus, these attributes 

should not be included in the rule. 

Another comment asserts proposed 

§ 111.35(e)(1) goes beyond either food or 

drug CGMPs and that the composition 

of approximately 1,200 botanicals used 

in the industry will be impossible to 

determine in an economically feasible 

manner. 

(Response) To the extent that these 

comments assert that this final rule 

should not require you to establish 

specifications for the strength and 

composition of botanical ingredients, 

we disagree. As explained in response 

to comment 145, it is fundamental to 

CGMPs that you know what 

components are used to manufacture 

your dietary supplement and to ensure 

that the finished batch of dietary 

supplement contains the established 

identity, purity, strength, and 

composition. As explained in response 

to comment 40, this final rule does not 

require that you establish specifications 

for the identity, purity, strength, or 

composition of the various constituents 

that are inherently present in a natural 

product such as a botanical. However, 

as previously discussed in section VI of 

this document, depending on what you 

are manufacturing, the product 

specifications for the finished batch of 

a dietary supplement may include a 

specification, for example, of the 

strength of a substance that is present in 

the dietary supplement because it is a 

constituent of a natural product that you 

add as a component. For example, you 

may establish a specification for the 

amount of vitamin C in a dietary 

supplement that you manufacture by 

adding the component rose hips. If this 

is the case, then the component 

specifications for the natural product 

must include a specification for the 

strength of the constituent (e.g., vitamin 

C) in whatever amount you determine is 

necessary to meet the specification for 

the constituent (vitamin C) in the 

finished batch of dietary supplement. 

(Comment 167) One comment asserts 

it would be more appropriate for 

proposed § 111.35(e)(1) to address 

components ‘‘that you purchase’’ than 

to address components ‘‘that you 

receive,’’ because customers sometimes 

provide the ingredient or product to be 

processed and the customer, rather than 

the manufacturer, establishes the 

specifications. 

(Response) Final § 111.70(b) (derived 

from proposed § 111.35(e)(2)) requires 

that component specifications be 

established for each component that you 

use in the manufacture of a dietary 

supplement. Thus, the firm must 

establish specifications for the 

components it uses to manufacture a 

dietary supplement, regardless of 

whether it manufactures the 

components itself or contracts with 

another firm to manufacture the 

components. The firm that conducts the 

manufacturing operations, as explained 

in section VI of this document, would 

be responsible for complying with all 

relevant CGMP requirements in this 

final rule related to its operations. 

(Comment 168) One comment asserts 

that proposed § 111.35(e)(1) is 

unnecessary because the requirements 

for testing to meet the manufacturer’s 

specifications are described elsewhere. 

(Response) We disagree. The 

requirements to establish specifications 

are distinct from what you must do to 

determine whether specifications are 

met. Under the final rule (§ 111.73), you 

have a responsibility to determine 

whether the established specifications 

are met. What criteria you must use in 

order to determine whether 

specifications are met are set forth in 

final § 111.75. 

3. Final § 111.70(c) 

Final § 111.70(c)(1) requires you, for 

in-process production, to establish inprocess specifications for any point, 

step, or stage in the master 

manufacturing record where control is 

necessary to help ensure that 

specifications are met for the identity, 

purity, strength, and composition of the 

dietary supplements and, as necessary, 

for limits on those types of 

contamination that may adulterate or 

may lead to adulteration of the finished 

batch of the dietary supplement. Final 

§ 111.70(c)(1) derives from proposed 

§ 111.35(e)(2). Final § 111.70(c)(1) 

includes a nonsubstantive, editorial 

change that we are making for 

consistency with other regulations in 

part 111. This change is to refer to ‘‘inprocess specifications for any point, 

step, or stage in the master 

manufacturing record where control is 

necessary’’ rather than ‘‘in-process 

controls in the master manufacturing 

record where control is necessary.’’

We also have added that you must 

establish in-process specifications, as 

necessary, for limits on those types of 

contamination that may adulterate or 

may lead to adulteration of the finished 

batch of the dietary supplement. This 

clarifies that if it is necessary to 

establish limits on contaminants inprocess, due to contamination that may 

occur in the facility you do so under 

final § 111.70(c)(1). With a requirement 

to set, as necessary, limits on 

contamination in-process, aspects of the 

production and process system from 

receipt to finished product are covered 

with respect to contamination. For 

example, under final § 111.70(e) you 

may determine that you need to 

establish a microbiological specification 

that the aerobic plate count of your 

finished batch of the dietary supplement 

will not exceed a certain number of 

colony forming units per gram of 

product. Under the written instructions 

in your master manufacturing record 

(final § 111.210(h)) and your written 

procedures for manufacturing 

operations (final § 111.353), you would 

establish controls to prevent microbial 

contamination at each point, step, or 

stage in the manufacturing process 

where control is necessary to prevent 

microbial contamination. To ensure that 

you will meet the microbiological 

specification that you set for the 

finished batch of the dietary 

supplement, you may determine that it 

is necessary to establish a specification 


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for the aerobic plate count at an 

intermediate stage of the in-process 

production. 

Final § 111.70(c)(2) requires you, for 

in-process production, to provide 

adequate documentation of your basis 

for why meeting the in-process 

specifications, in combination with 

meeting component specifications, will 

help ensure that the specifications are 

met for identity, purity, strength, and 

composition of the dietary supplements 

and for limits on those types of 

contamination that may adulterate or 

may lead to adulteration of the finished 

batch of the dietary supplement. Final 

§ 111.70(c)(3) requires that quality 

control personnel review and approve 

the documentation you provide under 

final § 111.70(c)(2). Final § 111.70(c)(3) 

also derives in part from proposed 

§ 111.37(b)(1) which would require the 

quality control unit to approve or reject 

all processes that may affect the 

identity, purity, strength, or 

composition of a dietary supplement. 

In final § 111.70(c)(2), we are 

requiring documentation that includes 

the basis for why meeting the in-process 

specifications, in combination with 

meeting the component specifications 

will help ensure the specifications for 

the identity, purity, strength, and 

composition of the dietary supplement 

and limits on contamination are met. 

Meeting in-process specifications alone 

may not ensure the identity, purity, 

strength, or composition of the dietary 

supplement, but information about the 

component specification may be needed 

in order to put the results from the inprocess specification in perspective. For 

example, if the manufacturer establishes 

a component specification for lead that 

it not be greater than ‘‘x’’ mg and 

establishes a specification that all 

piping that comes into contact with the 

component be lead free in the facility, 

and there are no other components or 

equipment that would be a source of 

lead, then there should be no added 

lead from processing, provided that the 

material only came in contact with the 

lead-free pipes and only the other leadfree components and equipment are 

used. Thus, we would not know by 

looking solely at the in-process 

specification whether the lead in the 

final product is not greater than ‘‘x’’ mg. 

We would need to evaluate the 

component specification, in addition to 

the in-process specification, to ensure 

that the final product contains no 

greater than ‘‘x’’ mg lead. To emphasize 

the interplay of the specifications and 

component specifications in ensuring 

the specifications are met for the 

identity, purity, strength, and 

composition of dietary supplements, 

and, as necessary, for limits on 

contamination, final § 111.70(c)(1) and 

(c)(2) state ‘‘help ensure’’ rather then 

‘‘ensure’’ the identity, purity, strength, 

and composition of dietary supplements 

and for limits on contamination. 

(Comment 169) One comment asserts 

monitoring and process controls are 

more practical and effective than the 

proposed requirements for in-process 

testing, which the comment asserts are 

overly broad and could impose an 

undue burden on small businesses. 

(Response) The comment’s objection 

is unclear. The final rule requires that 

you establish in-process specifications 

for any point, step, or stage in the 

master manufacturing record where 

control is necessary in the 

manufacturing process to help ensure 

that specifications are met for the 

identity, purity, strength, and 

composition of the dietary supplement 

and, as necessary, for limits on 

contamination. You must monitor the 

in-process points, steps, or stages, where 

control is necessary to ensure the 

quality of the finished batch of dietary 

supplement, to determine whether the 

in-process specifications are met and to 

detect any deviation or unanticipated 

occurrence that may result in a failure 

to meet specifications (see final 

§ 111.75(b)). The final rule does not 

establish specific requirements for inprocess monitoring. The manufacturer 

must determine any in-process 

monitoring that is necessary to ensure 

that the specifications are met for the 

finished batch. Examples of such 

monitoring include measuring pH or 

viscosity. 

4. Final § 111.70(d) 

Final § 111.70(d) requires you to 

establish specifications for dietary 

supplement labels (label specifications) 

and for packaging that may come in 

contact with dietary supplements 

(packaging specifications). Final 

§ 111.70(d) derives from proposed 

§ 111.35(e)(4). Further, § 111.70(d) 

requires that packaging that may come 

into contact with dietary supplements 

must be safe and suitable for its 

intended use and must not be reactive 

or absorptive or otherwise affect the 

safety or quality of the dietary 

supplements, consistent with proposed 

§ 111.35(e)(4). We deleted the phrase 

‘‘comply with other statutory and 

regulatory provisions’’ from proposed 

§ 111.35(e)(4) because the requirement 

was redundant to final § 111.5. 

5. Final § 111.70(e) 

Final § 111.70(e) requires you, for 

each dietary supplement that you 

manufacture, to establish product 

specifications for the identity, purity, 

strength, and composition of the 

finished batch of the dietary 

supplement, and for limits on those 

types of contamination that may 

adulterate or may lead to adulteration of 

the finished batch of the dietary 

supplement, all to ensure the quality of 

the dietary supplement. Final 

§ 111.70(e) derives from proposed 

§ 111.35(e)(3) and (k). Final § 111.70(e) 

is consistent with comments, already 

discussed, recommending that the 

provisions of proposed § 111.35(k) 

regarding contaminants that could 

adulterate a product be incorporated 

into proposed § 111.35(e). 

6. Final § 111.70(f) 

Final § 111.70(f) requires you, if you 

receive a product from a supplier for 

packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier), to 

establish specifications to provide 

sufficient assurance that the product 

you receive is adequately identified and 

is consistent with your purchase order. 

Final § 111.70(f) derives from proposed 

§ 111.35(e)(1) which would, in part, 

require you to establish specifications 

for dietary supplements that you 

receive. Final § 111.70(f) includes 

changes we are making after considering 

comments. 

(Comment 170) One comment notes 

that labelers would not be subject to 

proposed § 111.35(e). Other comments 

request we clarify the roles of the 

various parties in the ‘‘pre-consumer 

supply chain’’ for dietary supplements. 

One comment suggests that 

manufacturers and packagers be 

responsible for establishing 

specifications only for the operations 

occurring in their own facility or for 

which they are otherwise responsible 

(e.g., subcontracted operations), not for 

upstream or downstream operations 

over which they may not have any 

control. This comment states that we 

intended to relieve packagers from 

establishing specifications for the 

dietary supplements that they package, 

and also states that such requirements 

should not be in the CGMP regulations. 

(Response) We have discussed, in 

section VI of this document, who is 

subject to the final rule under § 111.1 in 

what the comment describes as the 

‘‘pre-consumer supply chain’’ and do 

not repeat that discussion. We agree that 

packagers and labelers must establish 

specifications for the dietary 

supplements that they package and did 

not intend to relieve them of complying 

with relevant CGMP requirements. We 

recognize that a firm that only packages 

and labels a product may rely on 


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information about the content of the 

product that it receives from the 

manufacturer. The information may 

consist of an invoice, certificate, 

guarantee, or other form of verification 

as to what the product consists of so 

that the packager or labeler has adequate 

information about the dietary 

supplement it receives to label the 

product and to ensure that the product 

is consistent with its purchase order. 

Therefore, we are setting forth certain 

requirements that distinguish a product 

you receive for packaging or labeling as 

a dietary supplement (and for 

distribution rather than for return to the 

supplier) from a product you 

manufacture. One such requirement is 

final § 111.70(f) which requires you to 

establish specifications for a product 

you receive for packaging or labeling as 

a dietary supplement (and for 

distribution rather than for return to the 

supplier). 

The inclusion of final § 111.70(f), or 

any other provision that relates 

explicitly to a product you receive for 

packaging or labeling as a dietary 

supplement, does not alter the fact that 

such a product is no different from any 

other dietary supplement as far as the 

applicability of these CGMP 

requirements. 

Under final § 111.70(f), the 

specifications you establish for a 

product you receive for packaging or 

labeling as a dietary supplement must 

provide sufficient assurance that the 

received product is adequately 

identified and is consistent with your 

purchase order. For example, you may 

be purchasing tablets that provide 500 

mg (strength) (quantitative amount per 

serving) of vitamin C (identity). 

Therefore, your purchase order would 

need to include the identity and amount 

of vitamin C per tablet to distinguish it 

from other tablets of vitamin C that may 

contain only 60 mg, or from other 

vitamin tablets of 500 mg that you may 

also purchase. 

Final § 111.70(f) sets forth a 

requirement for a product you receive 

for packaging or labeling as a dietary 

supplement that will be distributed by 

you, rather than returned to the firm 

from which you receive the product. 

Thus, § 111.70(f) applies to product that 

has left the control of the person who 

manufactured the batch. 

If you are a packager or labeler who 

packages and labels for the 

manufacturer and you will return the 

packaged and labeled dietary 

supplement to the manufacturer, we 

would not consider that you are 

‘‘receiving’’ product within the meaning 

of final § 111.70(f). Thus, you would not 

be subject to final § 111.70(f). 

(Comment 171) Some comments 

assert that ‘‘packaging’’ should be 

included with ‘‘manufacturing process,’’

but that a firm involved only in 

‘‘holding’’ a product should not have to 

set specifications. 

(Response) Under final § 111.70(a), a 

person who holds packaged and labeled 

dietary supplements for distribution and 

who does no manufacturing, packaging, 

or labeling, would be required to 

establish a specification for any point, 

step, or stage in the manufacturing 

process where control is necessary to 

ensure the quality of the dietary 

supplement. For example, a person may 

need to establish a specification for the 

temperature at which the product will 

be held. However, a person who only 

holds packaged and labeled dietary 

supplements for distribution is not 

required to establish component 

specifications (final § 111.70(b)), inprocess specifications (final § 111.70(c)), 

specifications for labels and for 

packaging (final § 111.70(d)), product 

specifications (final § 111.70(e)), 

specifications for product received from 

a supplier for packaging as a dietary 

supplement (and for distribution rather 

than for return to the supplier) (final 

§ 111.70(f)), or specifications for the 

packaging and labeling of the finished 

packaged and labeled dietary 

supplements (final § 111.70(g)) because 

the person does not engage in any of 

those activities. This is consistent with 

the views expressed by the comments 

regarding the applicability of proposed 

§ 111.35(e) to persons who only hold 

packaged and labeled dietary 

supplements for distribution. 

7. Final § 111.70(g) 

Final § 111.70(g) requires you to 

establish specifications for the 

packaging and labeling of the finished 

packaged and labeled dietary 

supplements, including specifications 

that ensure you used the specified 

packaging and you applied the specified 

label. 

Final § 111.70(g) is a new provision 

we are adding for clarity and 

consistency. We had proposed to 

require that you conduct a material 

review and make a disposition decision 

of any packaged and labeled dietary 

supplements that do not meet 

specifications (proposed § 111.70(c)). 

We proposed minimum standards for 

packaged and labeled dietary 

supplements—i.e., we would require 

that the quality control unit collect 

representative samples of each batch of 

packaged and labeled dietary 

supplements to determine whether you 

used the packaging specified in the 

master manufacturing record and 

applied the label specified in the master 

manufacturing record (proposed 

§ 111.37(b)(11)(iv)). Final § 111.70(g) 

includes the minimum standards that 

we proposed to establish for packaged 

and labeled dietary supplements in 

proposed § 111.37(b)(11)(iv). 

To make clear that the use of 

packaging and labels for a final 

packaged and labeled product must be 

that which is specified in the master 

manufacturing record, we have created 

a separate provision (under final 

§ 111.70(g)) requiring you to create the 

relevant specifications to be met. 

Final § 111.70(g) requires you to 

establish specifications that ensure you 

use the ‘‘specified packaging’’ and to 

apply the ‘‘specified label’’ as we 

proposed under proposed 

§ 111.37(b)(11)(iv). We removed the 

words ‘‘specified in the master 

manufacturing record’’ as an editorial 

change that we are making to simplify 

the language of the requirement. 

As already explained (see discussion 

of final § 111.70(a)), the specifications 

you establish under final § 111.70 are 

regulatory specifications required by 

these final CGMP requirements. The 

final rule would not prevent you from 

establishing additional, nonregulatory 

specifications, such as specifications 

that largely address the appearance of 

the dietary supplement in an aesthetic 

sense. 

H. What is Your Responsibility for 

Determining Whether Established 

Specifications Are Met? (Final § 111.73) 

Final § 111.73 requires you to 

determine whether all specifications 

you establish under final § 111.70 are 

met. The criteria for determining 

whether the specifications that you 

establish under final § 111.70 are met 

are set forth in final § 111.75. The 

oversight by quality control personnel 

for determining whether specifications 

established under final § 111.70 are met 

in accordance with the criteria 

established under final § 111.75 and 

under what conditions quality control 

personnel can approve deviations from 

specifications are set forth in final 

§ 111.77 and final subpart F. Although 

final § 111.73 requires you to determine 

whether specifications are met, it is the 

responsibility of quality control 

personnel to conduct a material review 

and make a disposition decision if a 

specification established in accordance 

with final § 111.70 is not met. 

Final § 111.73 derives, in part, from 

proposed § 111.35(f), (g), and (h). Final 

§ 111.73 includes changes associated 

with reorganization, and other revisions 

associated with final § 111.70. Final 

§ 111.73 neither includes any finished 


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batch testing requirements that derive 

from proposed § 111.35(g)(3) nor 

specifies what you must do to determine 

whether all specifications are met 

because the requirements for what 

means and methods you must use to 

determine whether specifications are 

met, including certain requirements for 

testing, are set forth in final § 111.75. 

The comments relevant to final 

§ 111.73 are the general comments that 

recommend an overall approach that 

focuses on building quality into a 

dietary supplement throughout the 

production and process control system. 

Because the primary focus of the 

relevant comments is on the proposed 

requirements for testing, we discuss 

those comments when we describe the 

derivation of the testing requirements in 

final § 111.75. 

I. What Must You Do to Determine 

Whether Specifications Are Met? (Final 

§ 111.75) 

Final § 111.75 derives from proposed 

§§ 111.35(f), (g), (h), (k), and (l); 

111.37(b)(11); and 111.40(a) and (b). 

Final § 111.75 describes the steps you 

must take to determine whether 

specifications are met. 

(Comment 172) Many comments 

assert that the CGMPs for dietary 

supplements should place greater 

emphasis on in-process controls and 

HACCP principles. The comments state 

FDA’s narrow focus on finished product 

testing is not in line with the 

philosophy of HACCP, in which 

manufacturing steps are controlled and 

verified so as to result in end products 

that are safe, with minimal finished 

product testing. One comment cites a 

1997 document entitled ‘‘Hazard 

Analysis and Critical Control Point 

Principles and Application Guidelines’’

in which we state that ‘‘[A]n effective 

HACCP system requires little endproduct testing, since sufficient 

validated safeguards are built-in early in 

the process.’’ (Ref. 31). 

(Response) In the 1997 ANPRM, we 

asked for comments on whether certain, 

or all, of the requirements for 

manufacturing and handling dietary 

ingredients and dietary supplements 

may be more effectively addressed by a 

regulation based on the principles of 

HACCP, rather than the system outlined 

in the industry submission (62 FR 5700 

at 5708). HACCP is a science-based, 

systematic approach to preventing food 

safety problems by anticipating how 

such problems are most likely to occur 

and by installing effective measures to 

prevent them from occurring. The 

HACCP concept is a systematic 

approach to the identification and the 

assessment of risk (likelihood of 

occurrence and severity), and control of 

the biological, chemical, and physical 

hazards associated with a particular 

food production process or practice. 

HACCP is a preventive strategy. It is 

based on development by the food 

producer of a plan that anticipates food 

safety hazards and identifies the points 

in the production process where a 

failure would likely result in a hazard 

being created or allowed to persist; 

these points are referred to as critical 

control points (CCPs). 

Under HACCP, identified CCPs are 

systematically monitored, and records 

kept of that monitoring. Corrective 

actions are taken when control of a CCP 

is lost, including proper disposition of 

the food produced during that period, 

and these actions are documented. 

Thus, the focus of a HACCP-based 

approach is to anticipate food safety 

hazards, take actions to prevent them, 

and keep records of both the actions 

taken to prevent problems and the 

actions taken if a problem nonetheless 

occurs. 

As discussed in the preamble to the 

2003 CGMP Proposal (68 FR 12157 at 

12174), most of the comments that we 

received to the ANPRM opposed basing 

a CGMP regulation for dietary 

supplements on HACCP principles. 

Consistent with those comments, we 

proposed certain requirements that, 

although consistent with a HACCPbased approach, did not require a 

HACCP-based approach. For example, 

proposed § 111.65 would establish 

requirements for manufacturing 

operations, including several proposed 

requirements to prevent contamination 

of components or dietary supplements, 

but would not require that you develop 

a specific plan for the precautions that 

you would take, or that you keep 

records of any monitoring that was 

directed solely at preventing specific 

types of contamination. 

In contrast to the specific focus of 

HACCP to anticipate food safety 

hazards, take actions to prevent them, 

and keep records of both the actions 

taken to prevent problems and the 

actions taken if a problem nonetheless 

occurs, CGMP requires that you take all 

necessary steps to both prevent hazards 

and ensure that the product that you 

manufacture is what you established in 

your specifications. The proposed 

testing requirements were directed at 

ensuring that a dietary supplement 

meets all of its established 

specifications, including specifications 

for the identity, purity, strength, and 

composition, rather than on ensuring 

only that specific food safety hazards 

that you take steps to prevent are not, 

in fact, present in the dietary 

supplement. The comments that assert 

that the CGMP requirements should 

place greater emphasis on HACCP 

principles and, in so doing, reduce the 

requirements to test product at the 

finished batch stage, did not explain 

how the preventive measures that are 

associated with a HACCP plan would be 

effective at ensuring that a dietary 

supplement is what you established it to 

be in your specifications. Therefore, we 

are not, as the comments request, 

including additional HACCP 

requirements as part of the overall 

approach set forth in this final rule. 

In the 2003 CGMP Proposal, we noted 

that you may voluntarily choose to 

implement a HACCP plan that meets the 

requirements of the National Advisory 

Committee on Microbiological Criteria 

for Foods, but that proposed part 111 

would still apply to you (68 FR 12157 

at 12174). We also noted that any 

HACCP plans that are intended to meet 

the records requirements under 

proposed part 111 would be treated as 

records under the CGMP regulations. 

(Comment 173) One comment states 

that it supports a requirement that a 

firm ensure that specifications have 

been met and asserts that the 2003 

CGMP Proposal failed to do so. This 

comment asserts the specific testing 

requirements in proposed § 111.35(g)(1) 

and (g)(2) must be significantly 

modified and suggests that a more 

effective approach would be to establish 

separate requirements for ensuring that 

specifications are met in each of the four 

categories addressed by proposed 

§ 111.35(e): Goods received 

(§ 111.35(e)(1)), in-process controls 

(§ 111.35(e)(2)), manufactured goods 

(§ 111.35(e)(3)), and labels and 

packaging (§ 111.35(e)(4)). 

(Response) The final rule is consistent 

with this comment. Final § 111.70 

requires you to establish certain 

specifications (including specifications 

for components, in-process controls, the 

finished batch and packaging and 

labels), and final § 111.75 sets forth the 

requirements for what you must do to 

determine whether those specifications 

are met. 

1. Final § 111.75(a) 

Final § 111.75(a)(1) requires you, 

before you use a component that is a 

dietary ingredient, to conduct at least 

one appropriate test or examination to 

verify the identity of the dietary 

ingredient. We recognize, however, that 

it may be possible for a manufacturer to 

demonstrate, through various methods 

and processes in use over time for its 

particular operation, that a system of 

less than 100 percent identity testing 

would provide no material diminution 


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of assurance of the identity of the 

dietary ingredient as compared to the 

assurance provided by 100 percent 

identity testing. To provide an 

opportunity for a manufacturer to make 

such a showing and reduce the 

frequency of identity testing of 

components that are dietary ingredients 

from 100 percent to some lower 

frequency, we decided to provide, in an 

interim final rule published elsewhere 

in this issue of the Federal Register, a 

procedure that allows for submission to, 

and review by, FDA of an alternative to 

the required 100 percent identity testing 

of components that are dietary 

ingredients, provided certain conditions 

are met. 

Final § 111.75(a)(2) requires you, 

before you use a component, to confirm 

the identity of other components and 

determine whether other applicable 

component specifications established in 

accordance with § 111.70(b) are met. To 

do so, final § 111.75(a)(2) requires you 

to either conduct appropriate tests or 

examinations (final § 111.75(a)(2)(i)); or 

rely on a certificate of analysis from the 

suppler of the component that you 

receive (final § 111.75(a)(2)(ii)). Final 

§ 111.75(a)(2)(ii) sets forth the criteria 

that you must satisfy in order to rely on 

a certificate of analysis from a supplier: 

• You must first qualify the supplier 

by establishing the reliability of the 

supplier’s certificate of analysis through 

confirmation of the results of the 

supplier’s tests or examinations; 

• 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; 

• You must maintain documentation 

of how you qualified the supplier; 

• You must periodically re-confirm 

the supplier’s certificate of analysis; and 

• Quality control personnel must 

review and approve the documentation 

setting forth the basis for qualification 

(and re-qualification) of any supplier. 

Final § 111.75(a)(1) and (a)(2) derive, 

in part, from proposed § 111.35(g) and 

(h) and proposed § 111.40(a)(2) and 

(a)(3). Final § 111.75(a)(1) and (a)(2) 

include changes that we are making 

after considering comments to proposed 

§§ 111.35 and 111.40(a). 

(Comment 174) Many comments 

assert that a certificate of analysis from 

a properly certified supplier can be a 

key element of the manufacturing 

process, and reduce the need for testing 

at the finished batch stage. Some 

comments specifically recommend the 

dietary supplement manufacturer 

conduct identity tests to ensure that the 

correct component has been received 

(also, see comment 145 of this 

document). 

Some comments recommend an 

appropriate vendor qualification 

program, including a combination of 

vendor audits and product testing, to 

alleviate the need for complete testing of 

every lot of incoming components. 

Several comments stress that a 

meaningful certificate of analysis must 

be based on the results of actual 

analytical testing. One comment adds 

that reliance on a supplier’s certificate 

of analysis should be conditioned on a 

qualification program whereby the 

recipient independently verifies the 

supplier’s ability to conduct tests and 

verifies test results through 

confirmatory testing. 

Many comments provide suggestions 

for ways in which manufacturers could 

demonstrate the reliability of a 

certificate of analysis, which include the 

following: (1) Identity testing of 

ingredients and components, (2) 

maintenance of documentation of 

appropriate test results, (3) appropriate 

verification of the information provided 

initially and at appropriate intervals, 

and (4) documentation that any 

suppliers have adequate CGMP 

programs in place. 

Some comments recommend that 

vendor certification programs include 

plant visits and inspections, while other 

comments do not believe manufacturers 

should be required to conduct plant 

inspections. Other comments 

recommend that vendor certification 

programs include CGMP audits or 

process reviews at supplier facilities; 

verification of laboratory test results 

against a certificate of analysis; and 100 

percent inspection and testing of 

incoming materials for a specified 

period of time while reliability is being 

assessed. 

Some comments provide suggestions 

for the types of information that should 

be included on an acceptable certificate 

of analysis, such as moisture, sieve 

analysis, identity, and results of tests 

against established raw material 

specifications and specifications of any 

compendia referenced on the label. One 

comment suggests that a certificate of 

analysis could be converted into sworn 

affidavits to guarantee their reliability. 

Some comments suggest that a system of 

testing one batch for agreement with the 

certificate of analysis, and then relying 

on this information for future purchases, 

would work well if the suppliers are 

required to provide reliable and valid 

certificate of analysis documents. One 

comment suggests we issue guidelines 

as to what should be included in a 

properly verified certificate of analysis. 

Some comments address the 

requirement in proposed § 111.40(a)(2) 

to ‘‘Visually examine the suppliers 

invoice, guarantee, or certification 

* * * and perform testing, as needed, to 

determine whether specifications are 

met.’’ One comment agrees with this 

proposed requirement and asserts that 

the supplier’s certification is not 

sufficient to ensure that appropriate 

standards are met. Other comments, 

however, disagree with this aspect of 

the proposed requirement or ask for 

further clarification. A few comments 

assert that manufacturers should not 

have to retest material already tested by 

a supplier. Some comments note that a 

certificate of analysis can be used for 

ensuring received materials are 

consistent with the purchase order, and 

assert the certificate of analysis can be 

an appropriate way to ensure 

specifications are met without requiring 

testing. One comment suggests the 

phrase ‘‘perform testing, as needed’’ be 

replaced with ‘‘perform testing, if 

necessary’’ and that the CGMP 

regulations allow for the use of a 

certificate of analysis that has been 

verified through a vendor certification 

process. Another comment states that 

the provisions requiring testing in 

proposed § 111.40(a)(2) are more 

burdensome than those required of food 

and pharmaceutical products and cites 

the drug CGMP provision that permits 

the use of certificates of analysis in lieu 

of testing for conformity with written 

specifications. One comment supports 

the idea of testing upon receipt in the 

specific circumstance when testing 

cannot be performed on the finished 

product. 

Several comments contend that there 

is a conflict between the 2003 CGMP 

Proposal and our position during our 

stakeholder meetings. The comments 

assert that, at the meetings, FDA 

representatives recognized that a 

verified certificate of analysis is 

acceptable, provided it is based on 

appropriate testing from suppliers who 

are audited by their customers as to 

their testing and manufacturing 

practices. 

A few comments say the 2003 CGMP 

Proposal should allow more reliance on 

strict chain of custody and 

documentation requirements. Other 

comments recommend that 

manufacturers not be required to retest 

previously tested incoming ingredients 

if they arrive with the vendor’s seal 

intact. Rather, the purchaser should be 

able to rely on the vendor’s test results, 

as presented in a verified certificate of 

analysis, unless there has been a breach 

in quality control during distribution 

and subsequent manufacture. One 


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comment notes the Canadian 

regulations for Natural Health Products 

allow periodic testing of ingredients if a 

manufacturer has satisfactory evidence 

that the raw materials sold to him/her 

are consistently manufactured in 

compliance with established 

specifications. 

(Response) We agree that CGMP 

requires that a person who 

manufactures a dietary supplement 

conduct at least one appropriate test or 

examination to verify the identity of 

each dietary ingredient that will be used 

in the manufacture of the dietary 

supplement. For example, because some 

botanicals require microscopic 

examination and comparison to a 

reference to be distinguished, and 

because suppliers of such botanicals 

may manufacture several of these 

botanicals, it is important to verify that 

a botanical that you receive from a 

supplier is the correct botanical. In 

some cases, a single test or examination 

may be all that is needed to verify the 

identity of a dietary ingredient; in other 

cases, it may be necessary to conduct 

more than one test or examination. It is 

the responsibility of the manufacturer to 

determine the appropriate test(s) or 

examination(s) necessary to verify the 

identity of a dietary ingredient. 

The comments discussed the 

importance of testing all components for 

identity and did not appear to limit 

their recommendation for conducting 

identity tests to those components that 

are dietary ingredients. Based on the 

comments, we conclude that many firms 

would conduct an identity test for most 

ingredients and other components 

rather than limit identity testing to 

dietary ingredients. However, because 

dietary ingredients are the central 

defining ingredient of a dietary 

supplement, final § 111.75(a) only 

requires you to conduct tests or 

examinations to verify the identity of 

any component that is a dietary 

ingredient. As discussed previously in 

this section, we recognize, however, that 

it may be possible for a manufacturer to 

demonstrate, through various methods 

and processes in use over time for its 

particular operation, that a system of 

less than 100 percent identity testing 

would provide no material diminution 

of assurance of the identity of the 

dietary ingredient as compared to the 

assurance provided by 100 percent 

identity testing. To provide an 

opportunity for a manufacturer to make 

such a showing and reduce the 

frequency of identity testing of 

components that are dietary ingredients 

from 100 percent to some lower 

frequency, we decided to provide, in an 

interim final rule published elsewhere 

in this issue of the Federal Register, a 

procedure that allows for submission to, 

and review by, FDA of an alternative to 

the required 100 percent identity testing 

of components that are dietary 

ingredients, provided certain conditions 

are met. For components other than 

dietary ingredients you must confirm 

the identity of the component and you 

have the flexibility of relying on a 

certificate of analysis, in lieu of 

conducting a test or examination, to 

confirm identity. The preamble to the 

2003 CGMP Proposal discussed why we 

were not proposing that you could rely 

on a certificate of analysis, but did not 

express a view as to whether the 

establishment of minimum criteria for 

how you would qualify the supplier, 

and for what must be included on the 

certificate of analysis, could alleviate 

our concerns about whether the 

certificate of analysis could ensure 

certain attributes of dietary 

supplements. 

After considering the comments, we 

also are persuaded that it is possible to 

rely on a certificate of analysis from the 

supplier, for attributes other than 

identity of the dietary ingredient, 

provided you satisfy certain minimum 

criteria set forth in final 

§ 111.75(a)(2)(ii). These criteria include 

qualifying the supplier, maintaining 

documentation of how you qualified the 

supplier, periodically reconfirming the 

supplier’s certificate of analysis, and 

having quality control personnel review 

and approve the documentation setting 

forth the basis for qualifying the 

supplier. These criteria also require that 

the certificate of analysis, at a 

minimum, includes a description of the 

test or examination method(s) used, 

limits of the tests or examinations, and 

the actual results of the tests or 

examinations. Under final 

§ 111.75(a)(2)(ii)(A), to qualify the 

supplier you must establish the 

reliability of the supplier’s certificate of 

analysis through confirmation of the 

supplier’s tests or examinations. 

Certain comments request that we 

provide guidance on what should be 

included in a certificate of analysis. As 

stated earlier in this section, a certificate 

of analysis is a document, provided by 

the supplier of a component prior to or 

upon receipt of the component, that 

documents certain characteristics and 

attributes of the component. Instead of 

guidance, we are establishing, in final 

§ 111.75(a)(2)(ii)(B), minimum criteria 

that a certificate of analysis must meet 

to satisfy these CGMP requirements. As 

we gain experience in applying the 

CGMP regulations, we will consider 

whether it is appropriate to provide 

guidance on certificates of analysis. 

(Comment 175) One comment asks if 

a raw material contains an unknown 

amount of excipients, is it necessary to 

quantify the excipients or can a 

company simply assess the active 

material and rely on a vendor’s 

specification for the excipient content? 

(Response) To the extent that this 

comment is asking whether it is 

necessary to set a component 

specification for the strength of 

excipients that are present in a dietary 

supplement, the final rule does not 

require you to do so provided that such 

a component specification is not 

necessary to ensure that the 

specifications for the purity, strength, 

composition, or contamination limit for 

the dietary supplement manufactured 

using the excipients are met (final 

§ 111.70(b)(2)). If such a strength 

specification for an excipient is 

necessary to ensure that the purity, 

strength, or composition specifications 

are met, or that a contamination limit is 

met for the dietary supplement, you 

could, as the comment suggested, rely 

on a certificate of analysis for that 

quantitative information provided that 

you satisfy the criteria set forth in final 

§ 111.75(a). 

2. Final § 111.75(b) 

Final § 111.75(b) requires that you 

monitor the in-process points, steps, or 

stages where control is necessary to 

ensure the quality of the finished batch 

of dietary supplement, to determine 

whether the in-process specifications 

are met, and to detect any deviation or 

unanticipated occurrence that may 

result in a failure to meet specifications. 

Final § 111.75(b) derives from proposed 

§ 111.35(f) with revisions associated 

with final § 111.70(c)(1). 

(Comment 176) A few comments 

argue that it is not possible to monitor 

in-process for those specifications 

required under proposed § 111.35(e). 

One comment states that a specification 

such as identity is no longer identifiable 

at an in-process stage. This comment 

also notes any such requirement in 

proposed § 111.35(e) would be 

redundant, because proposed 

§ 111.35(h) requires a firm to ensure, 

through testing or examination, that all 

established specifications are met. 

Another comment contends that some 

specifications are not met until 

processing is complete, such as with 

liquid extracts. A few comments 

recommend that the requirement for 

monitoring be limited to ensuring that 

specifications established for in-process 

controls under proposed § 111.35(e)(2) 

and finished product under proposed 

§ 111.35(e)(3) are met. 


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One comment states it is not always 

possible for a manufacturer to monitor 

for strength and purity of raw materials 

during in-process steps. The comment 

suggests this proposed requirement be 

removed or revised. 

(Response) The comments may have 

misunderstood what we refer to as ‘‘inprocess’’ specifications. Under final 

§ 111.75(b), you must monitor the inprocess points, steps, or stages where 

control is necessary to ensure the 

quality of the finished batch of dietary 

supplement, to determine whether the 

in-process specifications are met, and to 

detect any deviation or occurrence that 

may result in a failure to meet 

specifications. The in-process 

specifications that you establish ensure 

that, for example, the specification for 

strength is achieved. If you must deliver 

a certain amount of powdered vitamin 

C to a mixture at a certain point in the 

process in order to achieve a final 

product that contains 60 mg of vitamin 

C, a critical point in the process is 

where ‘‘x’’ mg of vitamin C is added to 

ensure that the final product contains 60 

mg of vitamin C. You would monitor the 

operation to ensure that ‘‘x’’ mg of 

vitamin C is added. Your strength 

specification may be tested at the end of 

the process as a product specification, 

but your in-process specification to 

ensure the addition of ‘‘x’’ mg of 

vitamin C is a specification that is 

separate and distinct from the 

specification that you establish for 

strength, i.e., 60 mg vitamin C. You may 

determine that in-process specifications 

are met through a test or examination. 

You could monitor for the vitamin C 

product by checking the equipment you 

use to mix the vitamin C-containing 

product to ensure that the mixing 

process was carried out during the time 

period specified in the master 

manufacturing record to ensure 

uniformity in the finished batch. Other 

examples could include a measurement, 

such as checking pH during the course 

of a process, or removing samples 

during the course of a process to 

conduct a test for viscosity. There may 

be no need for certain in-process 

specifications to ensure that 

specifications for identity, purity, 

strength, and composition of the 

finished batch of dietary supplement are 

met. If there are no in-process points, 

steps, or stages at which any test or 

examination is needed to ensure that the 

identity specification for the finished 

batch of dietary supplement is met, then 

you would not need to establish an inprocess specification to ensure identity 

in the finished batch, and, therefore, 

would not need to conduct in-process 

monitoring for identity. 

(Comment 177) One comment 

requests clarification on what would be 

considered ‘‘in-process’’ for materials 

that are simply blended together to form 

a final product. The comment asks how 

a firm would test the samples if a final 

material cannot be tested due to 

interferences or lack of an available 

method. 

(Response) Examples of in-process 

specifications when materials are 

simply blended together are the mixing 

time and speed. 

(Comment 178) One comment points 

out that in-process testing for 

‘‘unanticipated occurrences’’ required 

under proposed § 111.35(f) would be 

difficult, because the manufacturer 

would not know what to test for. 

(Response) This comment may have 

misunderstood the provision, which did 

not propose to require that you test for 

an unanticipated occurrence. Rather, 

proposed § 111.35(i)(2) would require 

you to review the results of any 

monitoring, and conduct a material 

review and make a disposition decision, 

if there is any unanticipated occurrence 

that adulterates or could result in 

adulteration of a component or dietary 

supplement. An example of such an 

occurrence is leakage of extraneous 

material from a pipe onto a component. 

Quality control personnel, under final 

§ 111.113(a)(3), must conduct a material 

review and make a disposition decision 

if there is such an unanticipated 

occurrence during the manufacturing 

operations. 

(Comment 179) One comment 

suggests that the provision is a HACCP 

requirement and is unnecessary for 

dietary supplements whose production 

generally does not involve bacterial 

contamination. 

(Response) We disagree. It is not a 

HACCP requirement because the 

provisions deal with unanticipated 

occurrences. Dietary supplement 

production can involve bacterial 

contamination as discussed in section V 

of this document. The purpose of final 

§ 111.75(b) is to ensure that the product 

meets all specifications, which include 

specifications associated with 

contamination, and, therefore, is a 

necessary provision. 

3. Final § 111.75(c) and (d) 

Final § 111.75(c) requires you, for a 

subset of finished dietary supplement 

batches, which you identify through a 

sound statistical sampling plan (or for 

every finished batch), to verify that your 

finished batch of the dietary supplement 

meets product specifications for 

identity, purity, strength, composition, 

and limits on those types of 

contamination that may adulterate or 

that may lead to adulteration of the 

finished batch of the dietary 

supplement. Final § 111.75(c) also sets 

forth the following verification 

requirements: 

• You must select one or more 

established specifications for identity, 

purity, strength, composition, and limits 

on those types of contamination that 

may adulterate or that may lead to 

adulteration of the dietary supplement 

that, if tested or examined on the 

finished batch of the dietary 

supplement, would verify that the 

production and process control system 

is producing a dietary supplement that 

meets all product specifications (or only 

those product specifications not 

otherwise exempted from this provision 

by quality control personnel under final 

§ 111.75(d)); 

• You must conduct appropriate tests 

or examinations on the specifications 

selected in final § 111.75(c)(1); 

• You must provide adequate 

documentation of your basis for why 

meeting the specification(s) selected 

under final § 111.75(c)(1), through the 

use of appropriate tests or examinations 

conducted under final § 111.75(c)(2), 

will ensure that your finished batch of 

the dietary supplement meets all 

product specifications for identity, 

purity, strength, composition, and the 

limits on those types of contamination 

that may adulterate, or that may lead to 

the adulteration of, the dietary 

supplement; and 

• Quality control personnel must 

review and approve the documentation 

that you provide under final 

§ 111.75(c)(3). 

Final § 111.75(c) requires you to 

verify that your finished batch of dietary 

supplement meets specifications for 

identity, purity, strength, composition, 

and limits that you established for those 

types of contamination that may 

adulterate or that may lead to 

adulteration of the finished batch. You 

may verify this by either testing or 

examining: (1) Every finished batch for 

each of these specifications or (2) a 

subset of finished batches for the dietary 

supplement. The subset of batches 

tested must be identified using a sound 

statistical sampling plan. 

If you choose to test or examine a 

subset of finished batches of dietary 

supplement, you may test or examine 

each subset of batches for identity, 

purity, strength, composition, and limits 

on contamination that you established. 

Alternatively, you may determine that 

you can select one, two, or three, or 

other number of these specifications 

that, if determined to be in compliance 


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with specifications, would be able to 

verify that the other untested 

specifications are met. For example, you 

may be able to substantiate that, if you 

determine compliance with the 

specification for the identity and 

composition of a product for which no 

contamination limits are needed, the 

system is adequately controlling for the 

purity and strength of the product, 

without the need to test for compliance 

with the specifications for purity and 

strength. If so, you must document, 

under final § 111.75(c)(3) your basis for 

why this is so. Quality control 

personnel must review and approve 

such documentation under final 

§ 111.75(c)(4). 

Under final § 111.75(d), you may 

determine, in the previous example, that 

you could not verify, by testing for 

compliance with the specifications for 

identity and composition, that the 

purity specification is met, and there 

may be no scientifically valid method 

for testing or examining the finished 

batch to evaluate the purity in the 

finished batch of dietary supplement. In 

that case, you could exempt the 

specification for purity from the 

requirement in final § 111.75(c)(1) if you 

can document why the purity 

specification is met without such testing 

or examination. You could do so 

through, for example, documentation 

that meeting component and 

specifications for strength is sufficient, 

or through documentation that inprocess monitoring is sufficient. Quality 

control personnel must review and 

approve such documentation (final 

§ 111.75(d)). 

Final § 111.75(c) and (d) derive from 

proposed § 111.35(g) and (h) and 

include changes that we are making 

after considering comments. 

(Comment 180) Several comments 

assert that a more appropriate balance is 

needed between an effective process 

control system and a reasonable testing 

scheme calculated to confirm the 

quality of dietary supplements. The 

comments stress it is important to build 

quality into a product throughout the 

entire production process by relying on 

strong process controls rather than by 

testing at the finished batch stage. One 

comment asserts that in an appropriate 

process control system, testing is a 

means to monitor and ensure that the 

control system is functioning as 

intended. Several comments make a 

specific recommendation that the final 

rule include rigorous controls. 

Some comments support the 

requirement under proposed § 111.35(g) 

to test each batch of finished product 

when possible, and to perform testing of 

components and in-process testing 

when testing the finished product is not 

possible. Other comments object to the 

proposed requirements for finished 

product testing on the grounds that they 

are overly burdensome, duplicative, and 

unnecessary. 

Some comments suggest that a more 

practical approach to finished product 

testing would be to conduct identity 

testing of each component, combined 

with certification of the vendor by a 

program of complete testing for 

conformance with a certificate of 

analysis, as is allowed under the drug 

CGMP regulations. Some comments 

suggest manufacturers that have written 

procedures for each stage of their 

process, including raw material 

certification, production, and finished 

product analysis, and a written plan for 

qualifying the process, should be 

exempt from the proposed requirements 

to test each finished batch. Some 

comments urge us to give companies the 

flexibility to devise testing procedures. 

(Response) The approach in final 

§ 111.75(c) and (d) is consistent with 

these comments and is part of the 

overall approach of this final rule, 

which focuses on ensuring the quality of 

the dietary supplement throughout the 

production and process control system. 

The concept behind final § 111.75(c) 

and (d) is analogous to the overall 

concept of proposed § 111.35(g). Under 

proposed § 111.35(g) you could rely on 

a combination of meeting component 

specifications and in-process 

specifications when you are unable to 

test for a specification, provided you 

satisfied certain criteria. Under the final 

rule, you may rely on a combination of 

meeting component specifications and 

in-process specifications to verify that 

your product meets specifications, 

rather than test every batch to determine 

whether specifications are met, 

regardless of whether a test is available, 

provided you satisfy certain criteria. 

Thus, the final rule provides flexibility 

that is needed to build adequate 

controls early in the process to reduce 

the need for end product testing on 

every batch of finished dietary 

supplement. 

(Comment 181) One comment 

expresses concern that the requirement 

to use appropriate tests to determine 

compliance with specifications could be 

interpreted as requiring companies to 

test dietary supplements not only for 

compliance with company 

specifications, but also for compliance 

with any labeled specifications of the 

ingredient suppliers, such as for 

contaminants. The comment believes 

this would be redundant and overly 

burdensome. 

(Response) As we explain in section 

XXIV of this document, we have made 

changes to reduce the testing burden on 

companies while still requiring steps 

necessary to ensure the quality of 

dietary supplements. For example, 

under final § 111.75(a), instead of 

testing or examination (other than for 

identity of the dietary ingredients), 

firms may rely upon supplier 

certificates of analysis in certain 

circumstances. Also, we recognize, 

however, that it may be possible for a 

manufacturer to demonstrate, through 

various methods and processes in use 

over time for its particular operation, 

that a system of less than 100 percent 

identity testing would provide no 

material diminution of assurance of the 

identity of the dietary ingredient as 

compared to the assurance provided by 

100 percent identity testing. To provide 

an opportunity for a manufacturer to 

make such a showing and reduce the 

frequency of identity testing of 

components that are dietary ingredients 

from 100 percent to some lower 

frequency, we decided to provide, in an 

interim final rule published elsewhere 

in this issue of the Federal Register, a 

procedure that allows for submission to, 

and review by, FDA of an alternative to 

the required 100 percent identity testing 

of components that are dietary 

ingredients, provided certain conditions 

are met. In addition, under final 

§ 111.75(c), testing or examination for a 

portion of the finished batches is an 

option, and exemptions are provided for 

in final § 111.75(d). 

(Comment 182) One comment points 

out that, if a product cannot be tested 

for technical reasons at the final product 

stage, then it also cannot be tested at the 

final blending stage in the process, 

because the nature and composition of 

the product at both stages are virtually 

the same. Another comment asks 

whether a verification of content in the 

final product will suffice if there is no 

valid testing procedure. 

(Response) Under final § 111.75(c), 

you have flexibility to select one or 

more established specifications for 

identity, purity, strength, composition, 

and limits on those types of 

contamination that may adulterate or 

that may lead to adulteration of the 

dietary supplement that, if tested or 

examined on the finished batch of the 

dietary supplement, would verify that 

the production and process control 

system is producing a dietary 

supplement that meets all product 

specifications. Under final § 111.75(d), 

you have flexibility to exempt one or 

more product specifications from 

verification requirements, provided that 


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you satisfy the criteria established under 

final § 111.75(d). 

(Comment 183) Some comments 

request that the rule include 

requirements for dissolution, 

disintegration, and bioavailability 

testing for dietary supplements. These 

comments note that, although a product 

may contain the labeled amount, it may 

not dissolve readily in the body or be 

available for absorption. 

(Response) We decline to revise the 

rule as suggested by the comments. As 

discussed in the preamble to the 2003 

CGMP Proposal (68 FR 12157 at 12163), 

tests for dissolution, disintegration, and 

bioavailability of dietary supplements 

are examples of areas where scientific 

study is still evolving; thus it is 

premature to impose requirements for 

such tests. The comments provide no 

specific information that would alter 

this view or support the technical 

feasibility of conducting such tests for 

all types of dietary supplement 

products. However, nothing in this final 

rule would preclude a manufacturer 

from establishing such requirements. A 

manufacturer should have data to 

support any specifications it establishes 

for parameters such as dissolution, 

disintegration, and bioavailability. 

(Comment 184) One comment 

questions the requirements in the 2003 

CGMP Proposal that all manufacturers 

quantify certain marker compounds in 

their products. The comment offers two 

reasons why such testing should not be 

required for botanical products: Their 

food-like composition and legal status, 

and the assertion that scientifically 

valid analytical methods may prove to 

be irrelevant or even hinder the 

development of superior products. 

(Response) The final rule does not 

require any specific testing 

requirements, such as testing for marker 

compounds. You would determine the 

specific testing requirements, and 

whether to use a marker compound in 

those tests, depending on your product 

and process. In the 2003 CGMP Proposal 

(68 FR 12157 at 12172), we merely 

discussed how a marker compound 

could help you identify whether you 

have a particular species of an herb to 

differentiate, for example, between a 

poisonous and nonpoisonous species. 

4. Final § 111.75(e) 

Final § 111.75(e) requires you, before 

you package or label a product you 

receive for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier), to 

visually examine the product and have 

documentation to determine whether 

the specifications that you established 

under final § 111.70(f) are met. Final 

§ 111.75(e) derives from proposed 

§ 111.35(e)(1) and (g) and from proposed 

§ 111.40(a)(2). 

(Comment 185) Some comments 

request we clarify the roles and testing 

obligations of the various parties in the 

‘‘pre-consumer supply chain’’ for 

dietary supplements. Some comments 

argue that redundant tests should not be 

required at every transaction point in 

the pre-consumer supply chain. The 

comments contend that any testing 

already performed by a supplier, 

manufacturer, or packager should 

suffice, so long as other CGMP 

certification, and chain of custody 

standards, are met. Other comments 

urge us to give companies the flexibility 

to devise testing procedures and point 

out that different testing is needed for 

different roles in the supply chain. 

One comment requests clarification of 

the testing requirements applicable to 

packagers/labelers. The comment states 

it is unclear how a packager or labeler/ 

distributor could conduct testing of 

component ingredients if all the firm 

receives is a finished product for which 

there is no scientifically valid testing 

method. 

(Response) As discussed in section VI 

of this document, you are responsible 

for the CGMP requirements that are 

applicable to your operations. We agree 

that redundant tests should not be 

required. Further, we agree that it is the 

responsibility of the manufacturer to do 

component testing. The packager or 

labeler does not need to do any required 

component testing because the packager 

or labeler does not receive components, 

rather it receives a finished dietary 

supplement. Under final § 111.70(f) if 

you receive a product from a supplier 

for packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier), you 

must establish specifications to provide 

sufficient assurance that the product 

you receive is adequately identified and 

is consistent with your purchase order. 

Under final § 111.75(e), before you 

package or label such a product, you 

must visually examine the product and 

have documentation to determine 

whether the specifications that you 

established under final § 111.70(f) are 

met. Your documentation may consist of 

an invoice, certificate, guarantee, or 

other documentation from the supplier 

to ensure that the product is adequately 

identified and is the product that you 

ordered. Final § 111.75(e) does not 

require that the documentation consist 

of the result of testing or examination by 

the packager or labeler of such a 

product. 

As with final § 111.70(f), final 

§ 111.75(e) applies to ‘‘product that you 

receive for * * * for distribution rather 

than for return to the supplier’’ and, 

thus, applies to product that has left the 

control of the person who manufactured 

the batch. If you are a packager or 

labeler who packages and labels a 

dietary supplement for the 

manufacturer, and you will return the 

packaged and labeled dietary 

supplement to the manufacturer, we 

would not consider that you are 

‘‘receiving’’ product within the meaning 

of final § 111.75(e). Thus, you would not 

be subject to final § 111.70(f). 

5. Final § 111.75(f) 

Before you use packaging, final 

§ 111.75(f)(1) requires you, at a 

minimum, to conduct a visual 

identification of the containers and 

closures and review the supplier’s 

invoice, guarantee, or certification to 

determine whether packaging 

specifications are met. Before you use 

labels, final § 111.75(f)(2) requires you, 

at a minimum, to conduct a visual 

examination of the label and review the 

supplier’s invoice, guarantee, or 

certification to determine whether 

labeling specifications are met. Final 

§ 111.75(f)(1) and (f)(2) derive from 

proposed § 111.40(b)(2) which, in part, 

would require you, for packaging and 

labels you receive, to conduct at least a 

visual identification on the containers 

and closures. Proposed § 111.40(b)(2) 

also would require you, in part, for 

packaging and labels you receive, to 

quarantine the packaging and labels 

until your quality control unit tests or 

examines a representative sample to 

determine whether specifications are 

met. Consistent with changes that we 

are making to the requirements for 

packaging and labels that you receive 

(see discussion of final § 111.160 in 

section XII of this document), final 

§ 111.75(f)(1) and (f)(2) include a 

requirement analogous to proposed 

§ 111.40(a)(2) which would require you 

to visually examine the supplier’s 

invoice, guarantee, or certification to 

determine whether the components, 

dietary ingredients, or dietary 

supplements you receive are consistent 

with your purchase order and to 

perform testing, as needed, to determine 

whether specifications are met. 

6. Final § 111.75(g) 

Final § 111.75(g) requires you, at a 

minimum, to conduct a visual 

examination of the packaging and 

labeling of the finished packaged and 

labeled dietary supplements to 

determine whether you used the 

specified packaging and applied the 

specified label. Final § 111.75(g) derives 

from proposed § 111.37(b)(11)(iv) which 


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would require the quality control unit to 

collect representative samples of each 

batch of packaged and labeled dietary 

ingredients or dietary supplements to 

determine whether you used the 

packaging specified in the master 

manufacturing record and applied the 

label specified in the master 

manufacturing record. Final § 111.75(g) 

is associated with final § 111.70(g) 

which requires you to establish 

specifications for the packaging and 

labeling for the finished packaged and 

labeled dietary supplements, including 

specifications that ensure you used the 

specified packaging and applied the 

specified label. 

7. Final § 111.75(h) 

Final § 111.75(h)(1) requires you to 

ensure that the tests and examinations 

you use to determine whether the 

specifications are met are appropriate 

and scientifically valid methods. Final 

§ 111.75(h)(1) derives from proposed 

§ 111.35(h). Final § 111.75(h)(1) 

includes editorial changes associated 

with the reorganization and changes 

that we are making after considering 

comments. 

Final § 111.75(h)(2) requires that the 

tests and examinations you use include 

at least one of the following: Gross 

organoleptic analysis, macroscopic 

analysis, microscopic analysis, chemical 

analysis, or other scientifically valid 

methods. Final § 111.75(h)(2) derives 

from proposed § 111.35(l). 

(Comment 186) Some comments 

suggest that the tests listed in proposed 

§ 111.35(l) be incorporated into 

proposed § 111.35(h), relating to 

appropriate test methods. 

(Response) We agree with the 

comment, and final § 111.75(h)(2) 

combines these requirements as 

requested. 

(Comment 187) One comment states 

that the list of tests should be deleted 

because it is not sufficient to cover the 

types of testing that will be required for 

compliance with proposed § 111.35(g). 

(Response) The comment does not 

identify the types of tests that would not 

be covered. We believe that final 

§ 111.75(h)(2)(v)’s ‘‘catch-all’’ provision, 

which requires that one of the tests that 

you use be an ‘‘other scientifically valid 

method’’ is sufficient to cover all other 

types of testing required under this final 

rule. 

(Comment 188) One comment states 

that the final rule should make clear 

that organolepsis is an acceptable 

method for identity testing. The 

comment contends it is imperative for 

the survival of small businesses that 

organolepsis be allowed, coupled as 

necessary with macroscopic and 

morphological examination and 

comparison with voucher specimens or 

photographs. Another comment requests 

clarification of whether gross 

organoleptic analysis alone can be a test 

for releasing finished products. Some 

comments assert that several 

organizations have published relevant 

methods that include macroscopic 

methods that can be used in identifying 

herbal ingredients. 

(Response) Organolpetic analysis 

would be an acceptable method under 

the 2003 CGMP Proposal and remains 

an acceptable method under the final 

rule, which clarifies that the method 

you use, including organoleptic 

analysis, must be appropriate. 

Organoleptic analysis may not be an 

appropriate method of testing for certain 

substances. This is particularly true 

when the nature of the substance 

decreases the reliability of organoleptic 

analysis. For example, while 

organoleptic analysis may be an 

appropriate identity test for whole or 

coarsely-cut botanical parts, it may not 

be an appropriate identity test for 

powdered or extracted botanicals 

because of decreased reliability, or in 

those instances where misidentification 

of botanicals is known to occur. 

Additionally, we recognize 

‘‘macroscopic analysis’’ is one of the 

tests or examinations you may select to 

determine whether specifications are 

met. 

(Comment 189) One comment 

remarks that the appropriateness of the 

test depends on the material being 

tested, and the method selected by the 

manufacturer may be inappropriate. 

One comment believes the methods 

stated in proposed § 111.35(l) 

(organoleptic, microscopy, chemical) for 

establishment of identity and purity 

would not be applicable to animal 

products. This comment suggests that a 

separate list of test methods should be 

identified for those materials. 

(Response) We agree that the 

appropriateness of the test depends on 

the material being tested. However, we 

are not revising the rule to identify 

methods that are, or are not, appropriate 

for specific circumstances (such as the 

case of animal-derived ingredients). 

There are so many distinct 

circumstances that such a list would be 

neither practical nor useful. Beyond 

that, the manufacturer is responsible for 

choosing the appropriate test. 

(Comment 190) One comment asks us 

to clarify in the final rule the 

requirement that methods be 

scientifically valid applies only to 

quantitative methods. 

(Response) In proposed § 111.35(h), 

we did not intend that the proposed 

requirement that you use scientifically 

valid methods apply only to 

quantitative methods, because we also 

proposed that tests in accordance with 

proposed § 111.35 must include at least 

one of the following: (1) Gross 

organoleptic analysis, (2) microscopic 

analysis, (3) chemical analysis, or (4) 

other appropriate test. To clarify that the 

requirement that methods be 

scientifically valid applies to all the 

tests and examinations you use, rather 

than to quantitative tests alone, final 

§ 111.75(h)(1) does not use the term 

‘‘analytical.’’

(Comment 191) One comment states 

that the proposed definition of 

‘‘appropriate test’’ (i.e., ‘‘a scientifically 

valid analytical method’’) is extremely 

onerous and violates congressional 

intent. The comment believes that 

mandating specific methods is 

inappropriate, and dietary supplement 

CGMPs should comply with Executive 

Order 12866 and not impose additional 

requirements on small businesses that 

are better left to normal business 

practices. 

Several comments take issue with our 

statement that we were not aware of a 

situation where an appropriate 

scientifically valid method is not 

available when, in fact, valid test 

methods are not always available for 

testing dietary ingredients or dietary 

supplements. One comment contends 

the 2003 CGMP Proposal contains 

conflicting information about available 

test methods. For example, the preamble 

to the 2003 CGMP Proposal states that 

we are ‘‘not aware of a situation where 

an appropriate scientifically valid 

analytical method is not available,’’ and 

our cost analysis does not address costs 

of method development. At the same 

time, however, we set out alternatives to 

finished product testing in cases where 

adequate methods are unavailable, and 

we decline to require expiration dating 

because there may not be adequate 

methods available for assessing the 

strength of a dietary ingredient. The 

comment cites numerous ongoing efforts 

in methods development by both 

industry and government that illustrate 

the lack of existing methods necessary 

to confirm compliance with all quality 

specifications. 

(Response) These comments appear to 

take our statements out of context. In 

the 2003 CGMP Proposal, we stated: ‘‘If 

an AOAC or FDA method is not 

available, a scientifically valid 

analytical method is one that is based 

on scientific data or results published 

in, for example, scientific journals, 

references, text books, or proprietary 

research. Although there may not be an 

Association of Official Analytical 


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Chemist (AOAC) or FDA method 

available, we are not aware of a 

situation where an appropriate 

scientifically valid analytical method is 

not available’’ (68 FR 12157 at 12198). 

We also stated: ‘‘We recognize that 

certain tests for identity, purity, quality, 

strength, or composition for certain 

finished product may not be available 

due to complex finished matrices that 

would make such testing impracticable’’

(68 FR 12157 at 12197). We disagree 

that our statement acknowledging that 

the available tests may not be 

practicable in certain matrices is 

inherently inconsistent with our 

statement that we are not aware of a 

situation where an appropriate 

scientifically valid analytical method is 

not available. One statement relates to 

the availability of methods, the other 

relates to the practicality of using an 

available method in particular 

circumstances. 

In any case, under final § 111.75(d)(1) 

you may exempt a product specification 

from the verification requirements of 

final § 111.75(c)(1) if you show that: (1) 

The specifications selected to verify that 

the product meets all product 

specifications are not able to verify that 

the control system is producing a 

dietary supplement that meets the 

exempted product specification and (2) 

there is no scientifically valid method 

for testing or examining the exempted 

product specification at the finished 

batch stage. Final § 111.75(c)(1) also 

requires you to document why other 

information, such as component and inprocess testing, will determine whether 

the exempted product specification is 

met without finished batch testing. 

Although we agree that there may be 

some circumstances where there is not 

a scientifically valid method available 

for finished product testing, we believe 

that there would be some scientifically 

valid method available for component 

or in-process testing. 

(Comment 192) One comment 

encourages flexibility toward the 

development of a quality system that is 

based on a balance of prevention, 

appraisal, and process verification 

activities. Another comment asks 

whether the industry should use 

industry standards and tests now used. 

A few comments request that we 

clarify proposed § 111.35(h) to make it 

clear whether the section recommends 

or requires the use of available USP, 

AOAC International (formerly 

Association of Official Analytical 

Chemists) or FDA methods. One 

comment recommends that the final 

rule give companies flexibility to use 

the method(s) most suitable to the 

ingredient they are testing and the 

specification they have set. The 

comment adds that companies should 

then be required to ensure, through 

appropriate rationale and data, that the 

method is indeed suitable and produces 

accurate and reproducible results. 

(Response) We agree that companies 

should have the flexibility to adopt the 

method most suitable to the ingredient 

they are testing. As discussed in the 

preamble to the proposal (68 FR 12157 

at 12163 and 12208), official methods, 

such as AOAC International methods, 

are validated in collaborative studies 

using several laboratories under 

identical conditions and the AOAC 

International methods are often cited as 

‘‘official validated methods.’’ Other 

method validations are conducted in a 

single laboratory by repeating the same 

test multiple times. In the case of 

methods used to support specific 

regulatory applications to FDA, data and 

information about methods that are 

developed and conducted in a single 

laboratory by repeating the test multiple 

times are sent to us, together with 

appropriate samples and reference 

materials so the test can be repeated in 

an agency laboratory. Typical validation 

characteristics include accuracy, 

precision, specificity, detection limit, 

quantitation limit, linearity, range, and 

robustness. 

The process of method validation 

discussed in the previous paragraph is 

a formal process for demonstrating that 

procedures are suitable for their 

intended use. Although many methods 

that are scientifically valid have been 

formally validated, other methods may 

not have been subject to the formal 

validation process, e.g., by collaborative 

studies using multiple laboratories, but 

nonetheless remain scientifically valid 

because they are, in fact, suitable for 

their intended use. For this reason, we 

stated that the 2003 CGMP Proposal 

would permit tests using methods other 

than those that are officially validated 

(68 FR 12157 at 12163). Consistent with 

the view that we expressed in the 2003 

CGMP Proposal, we believe a 

scientifically valid method is one that is 

accurate, precise, and specific for its 

intended purpose. In other words, a 

scientifically valid test is one that 

consistently does what it is intended to 

do. 

Under final § 111.75(h)(1), you must 

ensure the tests and examinations you 

use to determine whether the 

specifications are met are appropriate, 

scientifically valid methods. Under final 

§ 111.75(h)(2) the tests and 

examinations you use must include at 

least one of the following: (1) Gross 

organoleptic analysis, (2) macroscopic 

analysis, (3) microscopic analysis, (4) 

chemical analysis, or (5) other 

scientifically valid methods. 

(Comment 193) One comment 

questions how a company would know 

of all the available scientifically valid 

methods when it deals with hundreds of 

items. The comment states it cannot be 

expected to have expertise in the assay 

methodology for so many different 

ingredients. 

Several comments suggest we make 

fuller use of available monographs and 

other resources on test methods and 

method development. These sources 

include USP and AHP monographs, 

AOAC International, the European 

Pharmacopoeia, and the WHO. The 

comments urge us to disseminate 

information on these additional 

resources. 

Many comments assert that several 

organizations have published relevant 

analytical methods, such as 

macroscopic, microscopic, and chemical 

methods, that can be used in identifying 

herbal ingredients. These comments 

suggest that we should acknowledge 

those methods and organizations as 

authoritative sources of quality 

standards. 

(Response) In the preamble to the 

2003 CGMP Proposal (68 FR 12157 at 

12209), we acknowledged that validated 

methods exist in official compendia for 

vitamins, minerals, and several 

botanicals, and we recommended you 

use validated methods whenever such 

methods are available. We explicitly 

stated that you may use validated 

methods that can be found in official 

references, such as AOAC International, 

USP, and others. 

As discussed in this section (see 

response to comment 196), we believe 

that it is sufficient to provide in this 

preamble general guidance on what we 

consider to be scientifically valid tests, 

such as those based on scientific data or 

results published in, for example, 

scientific journals, references, text 

books, or proprietary research, and leave 

it to the manufacturer to decide what 

scientifically valid tests or examinations 

to use in a given operation. In the 

future, we may consider issuing 

guidance as to sources of appropriate 

tests or examinations, along with other 

guidances that we may find useful that 

relate to certain dietary supplement 

CGMP. 

(Comment 194) One comment states 

the act prohibits us from imposing 

testing requirements for which 

scientifically valid methods are not 

generally available, and other comments 

believe that not all components have 

scientifically valid identification tests. 

Given the substantial ongoing efforts 

towards method development, the 


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comments believe that the proposed 

requirements for testing would impose 

standards on many products and 

ingredients that cannot be met through 

current and generally available 

methods. 

(Response) We disagree that the 

statute prohibits us from imposing 

testing requirements. Section 402(g)(2) 

of the act states that dietary supplement 

CGMP regulations ‘‘may not impose 

standards for which there is no current 

and generally available analytical 

methodology.’’ We are not imposing 

such standards. The manufacturer must 

establish specifications for its product 

and components, and we have provided 

flexibility for how the manufacturer can 

determine whether those specifications 

are met. The manufacturer can test, 

examine, rely on a certificate of analysis 

(other than to verify the identity of 

dietary ingredients), or, in the case of a 

specification that is exempted from 

periodic testing of a finished batch, rely 

on other information that ensures that 

such an exempted product specification 

is met. 

(Comment 195) One comment 

requests clarification on the definition 

of ‘‘examination’’ and asks whether it 

includes monitoring of process 

parameters as established in the master 

manufacturing record. If so, the 

comment questions whether this 

practice would satisfy the requirement 

now in final § 111.75(h)(1). 

(Response) Under final § 111.75(h), 

scientifically valid tests and 

examinations include techniques such 

as gross organoleptic analysis, 

macroscopic analysis, chemical 

analysis, and other scientifically valid 

methods. As discussed in the response 

to comment 169, monitoring in-process 

parameters could encompass tests such 

as measuring pH or viscosity. Such tests 

would fall under ‘‘other scientifically 

valid methods.’’

(Comment 196) One comment 

contends that botanical identification is 

largely ignored in the 2003 CGMP 

Proposal. The comment states that 

botanical identification forms the basic 

foundation for botanical authenticity 

and that manufacturers have a legal 

responsibility to ensure the authenticity 

of claimed ingredients. The comment 

recommends that specific requirements 

for authentication of botanical 

ingredients be included in the final rule. 

One comment points out the difficulty 

in identifying and analyzing all 

naturally occurring ingredients in herbs 

and plants and suggests several 

alternatives to testing for all such 

ingredients. Another comment requests 

that an herbal product containing 20 

percent or more ethanol have relaxed 

testing requirements due to the 

bacteriostata properties of ethanol. One 

comment lists some alternatives for 

testing naturally occurring ingredients. 

One comment requests clarification 

on the testing requirements for bovine 

cartilage products. The comment states 

there is no published method for 

extracting chondroitin sulfate from 

bovine cartilage. As a result, the 

comment assumes that testing for 

chondroitin sulfate would not be 

required for these products. 

(Response) We believe that it is 

sufficient to provide in this preamble 

general guidance about testing, such as 

our discussion that scientifically valid 

tests include official, validated methods 

as well as tests based on scientific data 

or results published in, for example, 

scientific journals, references, text 

books, or proprietary research. It is the 

manufacturer’s responsibility to choose 

which scientifically valid tests or 

examinations to use in a given 

operation. Therefore, the final rule does 

not address the specific testing 

circumstances described in these 

comments, such as testing requirements 

for an herbal product that contains 20 

percent or more ethanol, or for bovine 

cartilage products. The manufacturer is 

responsible for establishing 

specifications and meeting such 

specifications, consistent with the 

requirements in this final rule. In the 

future, we may consider issuing detailed 

guidance as to specific tests or 

examinations, along with other 

guidances that may be useful that relate 

to certain dietary supplement CGMP. 

With respect to the comments that 

discuss botanical identification, we note 

that the 2003 CGMP Proposal referred to 

the draft report of the Dietary 

Supplement Working Group of FDA’s 

Food Advisory Committee (68 FR 12157 

at 12161) (Ref. 32). The draft report 

discusses the selection of the most 

appropriate and reliable identity test 

and the general principles for 

consideration in setting performance 

standards for such tests (Ref. 32). This 

report may provide useful guidance. 

8. Final § 111.75(i) 

Final § 111.75(i) requires you to 

establish corrective action plans for use 

when an established specification is not 

met. Final § 111.75(i) derives from 

proposed § 111.35(i)(1). 

(Comment 197) One comment asks 

whether the proposed requirement to 

establish corrective action plans for use 

when an established specification is not 

met (proposed § 111.35(i)(1)) would 

apply to specifications for raw materials 

and finished goods as well as to inprocess specifications. 

(Response) The requirement to 

establish corrective action plans (final 

§ 111.75(i)) applies to components, inprocess specifications, and to the 

finished batch. 

(Comment 198) One comment states 

that corrective action plans would be 

difficult to prepare for a variety of 

situations, such as for complex 

multivitamin and mineral formulas. One 

comment recommends this requirement 

be deleted. Another comment asserts 

that establishment of corrective action 

plans should be at the manufacturer’s 

discretion. 

(Response) We disagree that the final 

rule should not require you to establish 

corrective plans or that having such 

plans should be at the manufacturer’s 

discretion. The purpose of having 

corrective action plans in place before a 

problem occurs is to help you to deal 

quickly and efficiently with problems as 

they arise. 

You may have a corrective action plan 

to determine the steps to take if 

something goes wrong such as not 

meeting a specification. Moreover, a 

corrective action plan may include steps 

not only for dealing with an acute 

problem, but also for dealing with steps 

you would take to followup after the 

acute problem is resolved. For example, 

after you resolve an acute problem, such 

as a failure to meet an in-process 

specification, your corrective action 

plan may include testing of every 

finished batch, rather than a subset of 

finished batches, for some period of 

time to verify that the problem is 

resolved. 

We acknowledge that it may not be 

practical to establish a corrective action 

plan for all circumstances, because not 

all circumstances are foreseeable. 

However, the comment asserting that it 

would be difficult to establish corrective 

action plans for the variety of situations 

that could come up for complex 

multivitamin and mineral formulas 

provided no basis for why 

manufacturers of such formulas could 

not anticipate specific situations that 

present potential problems. 

(Comment 199) Some comments 

recommend that proposed § 111.35(i)(1) 

state ‘‘Establish procedures,’’ rather than 

‘‘Establish corrective action plans.’’

(Response) The comments did not 

explain what, if any, practical difference 

would exist between ‘‘procedures’’ and 

‘‘corrective action plans.’’ A corrective 

action plan is a procedure for which you 

must have a record in the master 

manufacturing record (final 

§ 111.210(h)(5)). Because ‘‘corrective 

action plans’’ is a term that is commonly 

used in the industry, we have retained 

it in the final rule. 


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J. What Must You Do if Established 

Specifications Are Not Met? (Final 

§ 111.77) 

1. Final § 111.77 

As we explain in section II of this 

document, we reorganized the final rule 

to make it more ‘‘user-friendly’’ and to 

clarify the rule’s applicability to certain 

persons, items, or activities. Final 

§ 111.77 is a new provision that clarifies 

your responsibilities and identifies 

those responsibilities in a more ‘‘userfriendly’’ fashion. We have identified in 

final § 111.77 the consequences of not 

meeting the specifications you establish 

under subpart E and when you can 

consider a treatment, in-process 

adjustment, or reprocessing to correct a 

failure to meet and established 

specification for a component, dietary 

supplement, packaging, or label. 

Subpart F does identify these 

consequences in several provisions 

which deal with the responsibility of 

quality control personnel to review and 

approve or reject components, dietary 

supplements, packaging, and labels. We 

determined it would add clarity to state 

the consequences for not meeting a 

specification in the same subpart in 

which the requirements to establish 

specifications are located. 

2. Final § 111.77(a) 

Final § 111.77(a) requires that for 

specifications established under 

§ 111.70(a), (b)(2), (b)(3), (c), (d), (e), and 

(g) that you do not meet, quality control 

personnel, in accordance with the 

requirements in subpart F of this part, 

must reject the component, dietary 

supplement, package, or label unless it 

approves a treatment, an in-process 

adjustment, or reprocessing that will 

ensure the quality of the finished 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. No finished batch of dietary 

supplements may be released for 

distribution unless it complies with 

final § 111.123(b). 

This provision identifies those 

specifications, if not fully met, that may 

be able to be corrected by treatment, inprocess adjustment, or reprocessing and 

approved by quality control personnel. 

We emphasize, however, that even if, 

for example, corrections are approved, 

the finished batch of dietary supplement 

can not be released for distribution 

unless it is compliance with the 

requirements of final § 111.123(b) 

(discussed in section XI of this 

document). 

Final § 111.77(a) derives from the 

following proposed provisions: 

• Proposed § 111.50(d)(2), which 

would require the quality control unit 

not to approve and release for 

distribution any batch of dietary 

supplement that does not meet all 

specifications; 

• Proposed § 111.50(f), which would 

require you to not reprocess a batch that 

deviates from the master manufacturing 

record unless approved by the quality 

control unit. 

• Proposed § 111.50(g), which would 

require that a reprocessed batch of 

dietary supplement meet all 

specifications and that the quality 

control unit approve its release for 

distribution. 

• Proposed § 111.35(i)(4)(i), which 

would require you, for any deviation or 

unanticipated occurrence which 

resulted in or could lead to adulteration 

of the component, dietary supplement, 

packaging, or label, to reject the 

component, dietary supplement, 

packaging, or label, unless the quality 

control unit determines that in-process 

adjustments are possible to correct the 

deviation or occurrence. 

• Proposed § 111.35(i)(4)(ii), which 

would require you, for any deviation or 

unanticipated occurrence which 

resulted in or could lead to adulteration 

of the component, dietary supplement, 

packaging, or label, to not reprocess a 

rejected component or dietary 

supplement unless approved by the 

quality control unit. 

3. Final § 111.77(b) 

Final § 111.77(b) requires that for 

specifications established under final 

§ 111.70(b)(1) that you do not meet, 

quality control personnel must reject the 

component and the component must not 

be used in manufacturing the dietary 

supplement. Final § 111.77(b) 

complements final § 111.70(b)(1) which 

requires you to establish an identity 

specification for components; final 

§ 111.75(a)(1) which requires you to 

conduct at least one appropriate test or 

examination to verify the identity of any 

component that is a dietary ingredient; 

and final § 111.75(a)(2) which requires 

you to confirm the identity of all other 

components. As discussed earlier in this 

section, many comments recommended 

the final rule include a requirement for 

an identity test of incoming components 

to ensure quality and safety. We agree 

with these comments and earlier 

comments that point out it may not be 

possible to confirm the identity of some 

components after they have been 

processed into the finished batch of the 

dietary supplement. For these reasons, 

we have concluded that, if the 

component specification for identity is 

not met, you may not use the 

component in the manufacture of the 

dietary supplement. This component 

specification must be met and quality 

control personnel are restricted in what 

action must be taken if this specification 

is not met. 

4. Final § 111.77(c) 

Final § 111.77(c) requires that if you 

do not meet the specifications 

established under § 111.70(f), quality 

control personnel must reject the 

product and the product must not be 

packaged or labeled for distribution as 

a dietary supplement. As with final 

§ 111.77(b), final § 111.77(c) limits the 

actions you can take to package and 

label product you receive for packaging 

and labeling from a supplier for 

packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier). Final 

§ 111.77(c) complements final 

§ 111.70(f), which requires you to 

establish a specification for such 

received product and final § 111.75(e), 

which requires you to visually examine 

the product, before you package or label 

it, and have documentation to 

determine whether the specifications 

that you established under § 111.70(f) 

are met. If you do not meet the 

specifications under final § 111.70(f), 

you must reject the product and not 

package or label the product for 

distribution as a dietary supplement. 

K. Comments on Shelf Life 

In the preamble to the 2003 CGMP 

Proposal (68 FR 12157 at 12203), we 

stated that we had considered whether 

to propose requirements for expiration 

dating, shelf life dating, or ‘‘best if used 

by’’ dating (referred to in this preamble 

as shelf life or expiration dating). We 

recognized that there are current and 

generally available methods to 

determine the expiration date of some 

dietary ingredients, such as vitamin C. 

However, we were uncertain whether 

there are current and generally available 

methods to determine the expiration 

dating of other dietary ingredients, 

especially botanical dietary ingredients. 

We did not propose to require 

expiration dating because we had 

insufficient scientific information to 

determine the biological activity of 

certain dietary ingredients used in 

dietary supplements, and such 

information would be necessary to 

determine an expiration date. Further, 

because official validated testing 

methods (e.g., AOAC International or 

FDA) for dietary supplements are 

evolving, especially for botanical dietary 

ingredients, such methods are not 

always available to assess the strength of 


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a dietary ingredient in a dietary 

supplement. 

The preamble to the 2003 CGMP 

Proposal emphasized that, if you use an 

expiration date on a product, you 

should have data to support that date 

(68 FR 12157 at 12204). We 

recommended that you have a written 

testing program designed to assess the 

stability characteristics of the dietary 

supplement, and that you use the results 

of the stability testing to determine 

appropriate storage conditions and 

expiration dates. 

In the 2003 CGMP Proposal (68 FR 

12157 at 12204), we invited comment 

on whether any final rule should 

contain provisions regarding expiration 

dating and the feasibility of conducting 

tests needed to support such dates. We 

also invited comment on whether to 

require expiration dating on certain 

dietary ingredients and not others, for 

example, require expiration dating of 

vitamin, mineral, and amino acid, but 

not of botanical dietary ingredients. 

(Comment 200) Several comments 

agree with our decision not to require 

expiration dating on labels for dietary 

supplements at this time, because of the 

wide range of products and the need for 

additional data. Most of these comments 

state, however, that manufacturers 

should be allowed to include a ‘‘best if 

used by’’ date. One comment suggests 

addressing the issue in a separate 

rulemaking. Other comments support an 

expiration date because consumers and 

retailers expect one, and some markets 

require one. Some comments state that 

the expiration date or statement of 

product shelf life will help ensure that 

the product meets its label claims and 

potency. 

Many comments state an expiration 

date on a label must be supported by a 

rationale or data on stability testing. 

Some of those comments suggest that 

manufacturers should have flexibility in 

the type of supporting data used. 

Although label claims should be 

confirmed by shelf life testing when 

analytical methods exist, data could 

come from a manufacturer’s experience 

with the product or accelerated stability 

testing on similar products with the 

same storage container. One comment 

points out that some manufacturers 

already use stability testing. Another 

comment recommends that we provide 

a guidance document on supporting 

data. 

One comment suggests stringent 

supporting data are not needed for a 

‘‘best if used by’’ date, because that date 

provides a recommended time frame to 

ensure the best quality. Another 

comment asserts that the discussion 

about expiration dates in the 2003 

CGMP Proposal gives the impression 

that the required level of supporting 

data is similar to the requirements for 

drug labeling, rather than the 

requirements for food shelf life labeling. 

Another comment recommends that a 

general maximum shelf life of 4 or 5 

years should be included in the rule, 

with shortened or lengthened shelf lives 

for individual products as data become 

available. 

(Response) These comments do not 

provide data or information that would 

reduce the uncertainty about the 

feasibility of conducting tests to support 

an expiration date and, thus, do not 

persuade us to alter our position not to 

require that you establish an expiration 

date for your product. Indeed, the 

comments generally concur with that 

position. Because the final rule does not 

require that you establish an expiration 

date, we decline to offer guidance on the 

type of data that are acceptable to 

support an expiration date, other than to 

repeat that any expiration date that you 

place on a product label (including a 

‘‘best if used by’’ date) should be 

supported by data. 

L. What Representative Samples Must 

You Collect? (Final § 111.80) 

Final § 111.80 sets forth requirements 

to collect representative samples of 

components, packaging, and labels 

(final § 111.80(a)); in-process materials 

(final § 111.80(b)); the finished batch of 

dietary supplement (final § 111.80(c)); 

product you receive for packaging or 

labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier) (final § 111.80(d)); and 

packaged and labeled dietary 

supplements (final § 111.80(e)). Final 

§ 111.80(a) through (e) derive from 

proposed § 111.37(b)(11)(i) through 

(b)(11)(iv). 

1. Final § 111.80(a) 

Final § 111.80(a) requires you to 

collect representative samples of each 

unique lot of components, packaging, 

and labels that you use to determine 

whether the components, packaging, 

and labels meet specifications 

established in accordance with 

§ 111.70(b) and (d), and as applicable, 

final § 111.70(a) (and, when you receive 

components, packaging, or labels from a 

supplier, representative samples of each 

unique shipment, and of each unique lot 

within each unique shipment). Final 

§ 111.80(a) derives from proposed 

§ 111.37(b)(11)(i). Final § 111.80(a) 

includes changes related to our review 

of the proposed requirements for clarity. 

We had used the term ‘‘shipment lot’’ in 

several proposed requirements, 

including § 111.35(g)(1)(i) (requirement 

to test components that you receive), 

§ 111.37(b)(11)(i) (requirement to collect 

representative samples of components 

that you receive), § 111.40(a)(4) 

(requirements for components that you 

receive), § 111.40(b)(5) (requirements for 

packaging and labels that you receive), 

and § 111.50(c)(5) (requirement to 

identify materials that you use in the 

batch production record). Some of these 

proposed requirements (e.g., those in 

§§ 111.40(a)(4) and (b)(3) and 

111.50(b)(5)) make clear that you must 

be able to trace each lot of materials you 

receive to each separate shipment that 

contains that lot. To clarify and 

emphasize this meaning of shipment lot, 

we are revising proposed 

§ 111.37(b)(11)(i) so that the 

representative samples you collect must 

come from ‘‘each unique shipment, and 

of each unique lot within each unique 

shipment.’’ We make analogous 

revisions throughout the final rule as 

necessary. 

As discussed in this section, final 

§ 111.70(b) sets forth the requirements 

to establish specifications for 

components, final § 111.73 requires you 

to determine if the specifications 

established are met, and final 

§ 111.75(a) sets forth the criteria you use 

to determine whether these 

specifications are met. Likewise, final 

§ 111.70(f) sets forth the requirements to 

establish specifications for product that 

you receive from a supplier for 

packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier), final 

§ 111.73 requires you to determine if 

specifications established are met, and 

final § 111.75(e) sets forth the criteria to 

use to determine whether these 

specifications are met. 

For consistency with the regulations 

in final §§ 111.70 and 111.75, we are 

separating the requirement to collect 

representative samples of components 

(final § 111.80(a)) from the requirement 

to collect representative samples of 

product that you receive from a supplier 

for packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier) (final 

§ 111.(80)(d)). 

We did not receive comments specific 

to proposed § 111.37(b). 

2. Final 111.80(b) 

Final § 111.80(b) requires you to 

collect representative samples of inprocess materials for each manufactured 

batch at points, steps, or stages, in the 

manufacturing process as specified in 

the master manufacturing record, where 

control is necessary to ensure the 

identity, purity, strength, and 

composition of dietary supplements, to 


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determine whether the materials meet 

specifications established under final 

§ 111.70(c), and, as applicable, final 

§ 111.70(a). Final § 111.80(b) derives 

from proposed § 111.37(b)(11)(ii). 

We did not receive comments specific 

to proposed § 111.37(b)(11)(ii). 

3. Final 111.80(c) 

Final § 111.80(c) requires you to 

collect representative samples of a 

subset of finished batches of each 

dietary supplement you manufacture, 

which you identify through a sound 

statistical sampling plan (or otherwise 

every finished batch), before releasing 

for distribution, to verify that the 

finished batch of dietary supplement 

meets product specifications established 

in accordance with final § 111.70(e), 

and, as applicable, final § 111.70(a). 

Final § 111.80(c) derives from proposed 

§ 111.37(b)(11)(iii). Final § 111.80(c) 

includes changes associated with final 

§ 111.75(c) which provides flexibility 

for you to test or examine a subset of 

finished batches you select through a 

sound statistical sampling plan rather 

than to test or examine all finished 

batches. Under final § 111.75(c) the tests 

or examinations you conduct at the 

finished batch stage verify that your 

process is in control. 

We did not receive comments specific 

to proposed § 111.37(b)(11)(iii). 

4. Final § 111.80(d) 

Final § 111.80(d) requires you to 

collect representative samples of each 

unique shipment, and of each unique lot 

within each unique shipment, of 

product you receive for packaging or 

labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier) to determine whether the 

received product meets the 

specifications established under final 

§ 111.70(f), and, as applicable, final 

§ 111.70(a). Final § 111.80(d) derives 

from proposed § 111.37(b)(11)(i). We did 

not receive comments specific to this 

proposed requirement. However, we are 

making changes to final § 111.80(d) 

consistent with those described for final 

§ 111.80(a). 

5. Final § 111.80(e) 

Final § 111.80(e) requires you to 

collect representative samples of each 

lot of packaged and labeled dietary 

supplements to determine whether the 

packaging and labeling of the packaged 

and labeled dietary supplements meet 

specifications established in accordance 

with final §111.70(g), and, as applicable, 

final § 111.70(a). Final § 111.80(e) 

derives from proposed 

§ 111.37(b)(11)(iv). Final § 111.80(e) 

includes revisions associated with final 

§ 111.70(g), which requires you to 

establish specifications for the 

packaging and labeling of the finished 

packaged and labeled dietary 

supplements. Final § 111.70(g) includes 

specifications that determine whether 

you used the packaging specified in the 

master manufacturing record and you 

applied the label specified in the master 

manufacturing record. Under final 

§ 111.70(a) and (g) the parameters that 

we proposed to specify under proposed 

§ 111.37(b)(11)(iv) are the required 

specifications for packaged and labeled 

dietary supplements. 

Final § 111.80(e) includes a change to 

clarify the exact specifications by citing 

the relevant sections. Final § 111.80(e) 

also includes an editorial change in that 

you are required to ‘‘determine 

whether’’ specifications are met rather 

than to ‘‘determine that’’ specifications 

are met. We are making this change 

because ‘‘determine that specifications 

are met’’ may be interpreted as a 

predetermined outcome, i.e., that 

specifications will, in fact, be met. 

We did not receive comments specific 

to proposed § 111.37(b)(11)(iv). 

M. What Are the Requirements for 

Reserve Samples? (Final § 111.83) 

Final § 111.83 sets forth requirements 

to collect and hold reserve samples of 

dietary supplements. Final § 111.83 

derives from proposed §§ 111.37(b)(12), 

111.50, and 111.83(b)(2). 

Under proposed § 111.37(b)(12) we 

would require holding reserve samples 

as an operation performed by the quality 

control unit. Under proposed 

§ 111.50(h), we proposed that you 

collect representative reserve samples of 

each batch of dietary supplement. 

Consistent with the changes that we are 

making to final § 111.80, final § 111.83 

does not specify who must collect and 

hold the required reserve samples. 

However, under final § 111.105(g), 

quality control personnel retain 

oversight of the collection and holding 

of the required reserve samples. Because 

the requirement to collect and hold 

reserve samples is not an operation that 

must be performed by quality control 

personnel, we are including the 

requirement to collect reserve samples 

in subpart E as part of the elements of 

a production and process control system 

rather than in subpart F as part of the 

requirements for quality control 

personnel. 

For consistency with terms used 

elsewhere in the final rule, final 

§ 111.83 requires that you ‘‘hold’’

reserve samples rather than ‘‘keep’’

them. 

1. Final § 111.83(a) 

Final § 111.83(a) requires you to 

collect and hold reserve samples of each 

lot of packaged and labeled dietary 

supplements that you distribute. Final 

§ 111.83(a) derives, in part, from 

proposed § 111.37(b)(12), which would 

require the quality control unit to keep 

the reserve samples and, in part, from 

proposed § 111.50(h), which would 

require you to collect representative 

reserve samples from each batch of 

dietary supplement. 

(Comment 201) Several comments ask 

for clarification of the requirements for 

representative and reserve samples as 

proposed in § 111.37(b)(11) and (b)(12). 

One comment notes that proposed 

§ 111.37(b)(11) does not indicate 

whether representative samples are also 

collected to serve as the reserve samples 

described in proposed § 111.37(b)(12) 

and asks whether the items in proposed 

§ 111.37(b)(11)(i) through (b)(11)(iv) are 

to be kept as reserve samples. 

(Response) As discussed in section VI 

of this document, we are adding a 

definition of ‘‘reserve sample’’ to reduce 

the potential for confusion between 

requirements for reserve samples and 

requirements for representative samples. 

A reserve sample is a representative 

sample that is held for a designated 

period of time. 

2. Final § 111.83(b)(1) 

Final § 111.83(b)(1) requires the 

reserve samples to be held using the 

same container-closure system in which 

the packaged and labeled dietary 

supplement is distributed, or if 

distributing dietary supplements to be 

packaged and labeled, using a containerclosure system that provides essentially 

the same characteristics to protect 

against contamination or deterioration 

as the one in which it is distributed for 

packaging and labeling elsewhere. Final 

§ 111.83(b)(1) derives from proposed 

§ 111.83(b)(2) which we proposed to 

include with the requirements for 

holding and distributing. The final 

sections that derive from proposed 

§ 111.83(b)(2) are in subpart M (final 

§ 111.465). However, we are duplicating 

these requirements in final 

§ 111.83(b)(1) for clarity and ease of use, 

so that you have information about the 

requirements for the container-closure 

system for holding reserve samples of 

packaged and labeled dietary 

supplements in the same section as the 

requirements to collect the samples. 

3. Final § 111.83(b)(2) 

Final § 111.83(b)(2) requires that 

reserve samples be identified with the 

batch, lot, or control number. Final 


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§ 111.83(b)(2) derives from proposed 

§ 111.37(b)(12)(i) with editorial changes 

associated with the reorganization. We 

have added ‘‘control number’’ to the 

provision for consistency with other 

provisions of the final rule which refer 

to a ‘‘control number’’ in addition to a 

‘‘batch or lot number.’’

We did not receive comments specific 

to proposed § 111.37(b)(12)(i). 

4. Final § 111.83(b)(3) 

Final § 111.83(b)(3) requires that 

reserve samples be retained for 1 year 

past the shelf life date (if shelf life 

dating is used), or for 2 years from the 

date of distribution of the last batch of 

dietary supplements associated with 

those reserve samples, for use in 

appropriate investigations. Final 

§ 111.83(b)(3) derives from proposed 

§ 111.37(b)(12) which would require the 

quality control unit to keep the reserve 

samples for 3 years from the date of 

manufacture for use in appropriate 

investigations including, but not limited 

to, consumer complaint investigations 

to determine, for example, whether the 

dietary supplement associated with a 

consumer complaint failed to meet any 

of its specifications for identity, purity, 

quality, strength, and composition, as 

well as from proposed § 111.50(h) 

which would require reserve samples to 

be kept for 3 years from the date of 

manufacture. We discuss the change 

from 3 years to 2 years and the change 

from ‘‘date of manufacture’’ to ‘‘the date 

of distribution’’ in connection with the 

recordkeeping requirements in subpart 

P, in section XXI of this document. 

Final § 111.83(b)(3) thus provides 

flexibility in determining how long you 

must hold reserve samples of packaged 

and labeled dietary supplements. 

Final § 111.83(b)(3) does not include 

the proposed examples of investigations 

that may require the use of reserve 

samples because these examples are not 

requirements. 

(Comment 202) Many comments 

address the requirement to keep the 

reserve samples after manufacture and 

recommend that expiration dates be a 

factor when determining the amount of 

time reserve samples should be kept and 

maintained. Most of the comments 

recommend holding reserve samples of 

packaged and labeled dietary 

supplements for 3 years from the date of 

manufacture or, when an expiration 

date has been established by the 

manufacturer, for 1 year after the 

expiration date. Other comments 

recommend holding reserve samples for 

time periods ranging from 6 months to 

2 years after the expiration date. 

(Response) The final rule contains 

requirements similar to the suggestions 

made by the comments. The final rule 

provides flexibility to hold reserve 

samples for 1 year past the shelf life 

date, when such dating is used. Any 

shelf life date that you include on the 

label of the product should be 

supported by data. 

5. Final § 111.83(b)(4) 

Final § 111.83(b)(4) requires that 

reserve samples consist of at least twice 

the quantity necessary for all tests or 

examinations to determine whether or 

not the dietary supplement meets 

product specifications. Final 

§ 111.83(b)(4) derives from proposed 

§ 111.37(b)(12)(ii) which would require 

that the reserve samples consist of at 

least twice the quantity necessary for 

tests. 

Final § 111.83(b)(4) provides that the 

reserve samples may be used for 

examinations or tests and to determine 

whether or not the dietary supplement 

meets product specifications, as a 

revision associated with final § 111.75. 

(Comment 203) One comment agrees 

that twice the quantity necessary for 

testing should be collected and held. 

(Response) The final rule is consistent 

with this comment. 

N. Who Conducts a Material Review and 

Makes a Disposition Decision? (Final 

§ 111.87) 

Final § 111.87 requires quality control 

personnel to conduct all required 

material reviews and make all required 

disposition decisions. Final § 111.87 

derives from a number of proposed 

requirements for conducting a material 

review and making a disposition 

(§§ 111.35(i) and (n), 111.37(b)(5) and 

(b)(14), 111.40(a)(3), 111.50(d)(1), and 

111.85(a) and (c)). Under each of these 

provisions, the quality control unit 

would have an oversight role and would 

review and approve all material reviews 

and all disposition decisions. Under 

some of these provisions (i.e., 

§§ 111.50(d)(1) and 111.85(a) and 85(c)) 

the quality control unit would conduct 

the material review itself and make the 

disposition decision. 

(Comment 204) One comment 

disagrees that the quality control unit 

must conduct the material review and 

make the disposition decision. The 

comment argues that manufacturing 

personnel are better qualified to conduct 

the review and make disposition 

decisions because they are often 

engineers and have the relevant 

expertise regarding the use of machinery 

and people to produce a product. In 

contrast, the comment asserts that 

quality control unit personnel generally 

are chemists with expertise only in 

testing and little expertise in 

manufacturing. The comment asserts 

that the quality control unit should not 

be expected to make decisions 

concerning manufacturing operations; 

however, it should be informed of 

changes so it can evaluate the results of 

reprocessing on the finished product. 

(Response) We agree, in part, with the 

comments and the final rule simplifies 

the provisions regarding a material 

review and disposition decision. 

Quality control personnel can conduct 

the material review and disposition 

decision by reviewing the underlying 

information gathered or obtained by 

other qualified personnel and then 

making the final decision. Under the 

final rule, we retain the principle that 

qualified individuals other than quality 

control personnel can contribute to the 

quality control personnel’s material 

review and disposition decision. The 

final rule sets forth the following 

requirements: 

• Under final § 111.87, quality control 

personnel must conduct all required 

material reviews and make all required 

disposition decisions; 

• Under final § 111.103, you must 

establish and follow written procedures 

for conducting a material review and 

making a disposition decision; and 

• Under final § 111.140(b)(3)(vii), 

documentation of a material review and 

disposition decision and followup must 

include the signature of the 

individual(s) designated to perform the 

quality control operations, who 

conducted the material review and 

made the disposition decision, and of 

any qualified individual who provided 

information relevant to that material 

review and disposition decision. 

Taken in total, the final rule 

establishes a system in which you have 

flexibility to develop procedures that 

suit your organization, including having 

qualified individuals, other than the 

designated quality control personnel, 

provide information relevant to the 

material review and disposition 

decision. For example, under final 

§ 111.140(b)(3), you could have a 

qualified individual in the production 

department prepare a report that 

includes all the required documentation 

and information and provide a signed 

copy of that report to designated quality 

control personnel. An individual 

designated to perform quality control 

operations would then read that report, 

add to it if necessary, conduct any 

additional investigations if necessary, 

and if he or she agrees with the report, 

co-sign the report or an amended report 

that includes additional documentation 

or information, thus completing a 

material review and disposition 

decision. 


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The final rule provides for the 

participation of qualified individuals, 

other than those designated to perform 

quality control operations, in 

conducting the material review. In 

addition, as already discussed, under 

final § 111.12(b) you may assign a 

qualified individual who has 

responsibilities for operations other 

than quality control to perform quality 

control operations, provided that the 

individual has distinct and separate 

responsibilities related to performing 

quality control operations. 

O. What Requirements Apply to 

Treatments, In-Process Adjustments, 

and Reprocessing When There is a 

Deviation or Unanticipated Occurrence 

or When a Specification Established in 

Accordance with § 111.70 Is Not Met? 

(Final § 111.90) 

1. Final § 111.90 

Final § 111.90 is a unified provision 

that clarifies your responsibilities 

regarding treatment or in-process 

adjustments to a component, and inprocess adjustments or reprocessing of a 

dietary supplement, in a more ‘‘userfriendly’’ fashion. We have identified in 

one provision the restrictions that apply 

to these operations. Final § 111.90 

derives from proposed §§ 111.35(i)(4)(i), 

(i)(4)(ii), and (i)(4)(iii); 111.50(d)(1), (f), 

and (g); and 111.65(d). 

Final § 111.90 includes the following 

changes we are making to the proposed 

provisions for consistency and clarity: 

• We are making revisions to make 

the section consistent with the 

definition of ‘‘reprocessing’’ in final 

§ 111.3, which refers only to 

‘‘components or dietary supplements 

that have been previously removed from 

manufacturing.’’

• We are adding ‘‘treatments’’ as a 

step that quality control personnel 

could approve, because that term better 

describes actions that could be taken to 

correct a deviation or unanticipated 

occurrence with a component, 

packaging, or label. 

• We are clarifying that it is quality 

control personnel who reject 

components, packaging, or labels. 

• We are clarifying that quality 

control personnel approve the 

treatment, in-process adjustment, or 

reprocessing rather than determine 

whether the treatment, in-process 

adjustment, or reprocessing is possible. 

• We are clarifying that, with respect 

to labels, the provision applies to the 

potential that a label not specified in the 

master manufacturing record could be 

used. 

• We are making changes to be 

consistent with the new provision, final 

§ 111.77. 

(Comment 205) One comment 

recommends deletion of proposed 

§ 111.35(i)(4) and (i)(4)(i), arguing that 

the principles of those sections are 

covered under proposed § 111.35(i)(2) 

and (i)(3). 

(Response) We disagree with the 

comment’s assertion. The requirements 

of proposed § 111.35(i)(4) and (i)(4)(i) 

are not covered by proposed 

§ 111.35(i)(2) and (i)(3). All the sections 

are related, but deal with different 

aspects of corrective action. Proposed 

§ 111.35(i)(2) and (i)(3) would require 

the firm to conduct a material review 

and make a disposition decision, while 

proposed § 111.35(i)(4) would prohibit 

the use of rejected ingredients unless 

the quality control unit determines that 

in-process adjustments are possible to 

correct the deviations or occurrence. We 

are making no changes as suggested by 

this comment and the primary elements 

of proposed § 111.35(i)(4) are retained in 

final § 111.90. 

(Comment 206) A few comments state 

their support for the requirement that 

the quality control unit have the 

authority to determine whether 

adjustments are possible to correct a 

deviation. 

(Response) We are retaining the 

proposed requirement for quality 

control personnel in final § 111.90. 

2. Final § 111.90(a) 

Final § 111.90(a) requires that you 

must not reprocess a rejected dietary 

supplement or treat or provide an inprocess adjustment to a component, 

packaging, or label to make it suitable 

for use in the manufacture of a dietary 

supplement, unless: (1) Quality control 

personnel conduct a material review 

and make a disposition decision to 

approve the reprocessing, treatment, or 

in-process adjustment and (2) the 

reprocessing, treatment, or in-process 

adjustment is permitted by § 111.77. 

Final § 111.90(a) derives from 

proposed §§ 111.35(i)(4)(ii) and 

111.50(d)(1). We revised this provision 

to be consistent with the changes in 

final § 111.77. 

(Comment 207) Several comments 

state their support for proposed 

§ 111.35(i)(4)(ii), which would require 

the quality control unit to approve the 

reprocessing of any rejected component, 

dietary ingredient, or dietary 

supplement. However, not all comments 

agree that the quality control unit 

should have to conduct (under proposed 

§ 111.50(d)(1)), rather than review and 

approve, a material review and 

disposition decision. 

(Response) As discussed in this 

section, by ‘‘conduct a material review 

and make a disposition decision,’’ we 

do not intend to limit those who may 

participate in a material review and 

disposition decision to only those 

persons acting in their capacity as 

designated quality control personnel. 

Others may assist quality control 

personnel in gathering and considering 

information relevant to the review and 

decision, however the quality control 

personnel have the responsibility to 

conduct a material review and make 

disposition decisions. Thus, we are 

retaining in final § 111.90(a) the 

requirements in proposed 

§§ 111.25(i)(4)(ii) and 111.50(d)(1). 

3. Final § 111.90(b) 

Final § 111.90(b) requires that you 

must not reprocess any dietary 

supplement or treat or provide an inprocess adjustment to a component to 

make it suitable for use in the 

manufacture of a dietary supplement, 

unless: (1) Quality control personnel 

conduct a material review and make a 

disposition decision based on a 

scientifically valid reason and approve 

the reprocessing, treatment, or inprocess adjustment and (2) the 

reprocessing, treatment or in-process 

adjustment is permitted by § 111.77. 

Final § 111.90(b) derives from proposed 

§§ 111.35(i)(4)(iii), 111.50(f), and 

111.65(d). We revised this provision to 

be consistent with the changes in final 

§ 111.77. 

(Comment 208) As discussed in 

section VI of this document (discussion 

of the definition of ‘‘reprocessing’’), 

some comments object to the 

restrictions in the definition of 

reprocessing in proposed § 111.3 

because the definition would not permit 

the reprocessing of ingredients that may 

have been removed because of 

insanitary conditions even if there are 

processes available that are safe and 

effective in removing foreign matter, 

microorganisms, or chemicals that may 

have rendered the ingredient 

‘‘insanitary.’’ These comments also 

object to proposed § 111.35(i)(4)(iii) for 

the same reasons. A few comments 

argue that a manufacturer should be 

able to reprocess a component or dietary 

supplement if it has been rejected 

because of contamination with 

microorganisms or types of 

contamination, such as heavy metals, if 

the quality control unit approves the 

reprocessing. These comments indicate 

this is the industry practice, one based 

on a scientific rationale for doing the 

reprocessing and that ensures other 

quality attributes of the product are not 

affected. 

Some comments state that the 

requirement is more strict than the food 

or drug CGMP requirements, noting that 


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reprocessing is widely accepted and 

allowed in the food CGMPs. Other 

comments believe that the prohibition 

in proposed § 111.35(i)(4)(iii) against 

reprocessing materials contaminated 

with microorganisms should be limited 

to materials contaminated with healthhazardous microorganisms. 

(Response) As we discussed in the 

response to comment 53 for the 

definition of ‘‘reprocessing,’’ we agree 

with the comments that state that inprocess materials can be reprocessed 

when there are suitable processes 

available. However, as noted by the 

comments, it is critical that there be 

appropriate oversight of the 

reprocessing so the quality of the dietary 

supplement is not compromised. Final 

§ 111.90(b) provides for the flexibility 

requested by the comments, provided 

that there is oversight by quality control 

personnel. 

(Comment 209) Proposed 

§ 111.35(i)(4)(iii) mentions 

‘‘microorganism or other contaminants, 

such as heavy metals.’’ One comment 

proposes that other contaminants, such 

as pesticides and aflatoxin, should be 

mentioned. Another comment suggests 

that the final rule should specify limits 

for heavy metals in dietary 

supplements. 

(Response) We decline to revise the 

final rule as suggested by the comments. 

It is impractical to provide an 

exhaustive list of relevant types of 

contamination, and a list that is longer, 

but not exhaustive, is more likely to be 

misunderstood as suggesting that the 

only types of contamination that are 

significant are the types of 

contamination in the list. For that 

reason, we have eliminated the 

reference to contamination to clarify 

that in any instance where it is 

appropriate quality control personnel 

must ensure that the disposition 

decision is based on a scientifically 

valid reason and also approve the 

reprocessing. 

(Comment 210) One comment notes 

that in the May 9, 2003, satellite 

broadcast concerning the 2003 CGMP 

Proposal, we indicated that treating a 

component or dietary supplement with 

irradiation as a means to reduce or 

eliminate the microbial load was 

acceptable as long as the treatment was 

part of the process for producing that 

material. The comment asks for 

confirmation that irradiation of 

components or dietary supplements is 

allowed under part 179 (21 CFR part 

179), even though such treatments are 

not listed in the table provided in 

§ 179.26(b). 

(Response) We are unable to provide 

the requested confirmation. Under 

section 201(s) of the act, irradiation 

intended for use in producing, 

manufacturing, packing, processing, 

preparing, treating, packaging, 

transporting, or holding food is a food 

additive that requires premarket review 

and approval before it can be used in 

food. Our Office of Food Additive Safety 

is currently reviewing a food additive 

petition for the use of irradiation on 

dietary ingredients and dietary 

supplements. Until that review process 

is completed and we have authorized 

this use of irradiation through a final 

rule codified in part 179, irradiation of 

dietary ingredients and dietary 

supplements as a means to reduce or 

eliminate microbial loads is not 

permitted. However, you may use an 

irradiated component (such as a spice 

that is used to flavor a dietary 

supplement) when the irradiation of 

that component is allowed under 

§ 179.26. 

4. Final § 111.90(c) 

Final § 111.90(c) requires that any 

batch of dietary supplement that is 

reprocessed, that contains components 

that you have treated, or to which you 

have made in-process adjustments to 

make them suitable for use in the 

manufacture of the dietary supplement 

must be approved by quality control 

personnel and comply with final 

§ 111.123(b) before releasing for 

distribution. Final § 111.90(c) derives 

from proposed § 111.50(g). 

Final § 111.90(c) also includes 

conforming revisions to clarify that a 

dietary supplement that contains a 

component treated before use or 

adjusted in-process, or that has had inprocess adjustments to make it suitable 

for use in the manufacture of a dietary 

supplement, must be approved by 

quality control personnel and comply 

with final § 111.123(b) before releasing 

for distribution. We revised this 

provision to be consistent with the 

changes in final §§ 111.77 and 

111.123(b). 

Final § 111.90(c) also includes 

revisions to reflect the final provisions 

that relate to reprocessing and inprocess adjustments (see final 

§§ 111.113, 111.120, and 111.155). 

(Comment 211) One comment asserts 

that a reprocessed product should be 

retested to confirm that it meets product 

specifications. 

(Response) Under final § 111.75(c) 

and (d) quality control personnel have 

flexibility to determine whether tests or 

examinations are necessary to ensure 

that a reprocessed product meets 

product specifications. 

P. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.95) 

1. Final § 111.95(a) 

Final § 111.95(a) requires you to make 

and keep records required under this 

subpart in accordance with subpart P. 

Final § 111.95(a) derives from proposed 

§ 111.35(o). Some of the records 

required under subpart E are set forth as 

recordkeeping requirements in other 

subparts of this final rule, such as those 

related to receiving records for 

components, packaging, and labels in 

subpart G, and the results of testing or 

examination in subpart J. The record 

requirements not specifically required 

in other related subparts are listed in 

subpart E. 

(Comment 212) One comment 

supports the recordkeeping 

requirements, states that the records 

provide a valuable paper trail that will 

allow manufacturers to identify and fix 

problems in the process, and suggests 

the requirements protect consumers 

from adulterated and misbranded 

products. 

(Response) We agree. Under final 

§ 111.95(a), a firm must make and keep 

records required by subpart E in 

accordance with subpart P. As 

discussed in this section, firms are 

required to keep the records necessary 

for determining whether their products 

are made in accordance with 

specifications. This will help them 

identify and correct any problems. In 

addition, under subpart P, the records 

must be kept for 1 year past the shelf life 

date (if shelf life dating is used) or 2 

years beyond the date of distribution of 

the last batch of dietary supplements 

associated with those records. 

Moreover, firms must make their 

records available to us for inspection 

and copying, which will permit us to 

determine whether firms are 

manufacturing, packaging, labeling, and 

holding dietary supplements in 

accordance with the requirements of 

this rule. 

2. Final § 111.95(b) 

Final § 111.95(b) specifies the records 

you must make and keep under subpart 

E. Under the reorganization several 

recordkeeping requirements of proposed 

§ 111.35 are set forth in other subparts. 

Final § 111.95(b)(1) requires you to 

make and keep records of the 

specifications established. Final 

§ 111.95(b)(1) derives from proposed 

§ 111.35(o)(1). 

Final § 111.95(b)(2) requires you to 

make and keep records of your 

qualification of a supplier for the 

purpose of relying on the supplier’s 


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certificate of analysis. Final 

§ 111.95(b)(2) is a record that is required 

under final § 111.75(a)(2)(B). 

Final § 111.95(b)(3) requires you to 

make and keep documentation for why 

meeting in-process specifications, in 

combination with meeting component 

specifications, helps ensure that the 

dietary supplement meets the 

specifications for identity, purity, 

strength, and composition and for limits 

on those types of contamination that 

may adulterate or may lead to 

adulteration of the finished batch of the 

dietary supplement. Final § 111.95(b)(3) 

refers to records required under final 

§ 111.70(c)(2). 

Final § 111.95(b)(4) requires you to 

make and keep documentation for why 

the results of appropriate tests or 

examinations for the product 

specifications selected under final 

§ 111.75(c)(1) ensures that the dietary 

supplement meets all product 

specifications. Final § 111.95(b)(4) is a 

record that is required under final 

§ 111.75(c)(3). 

Final § 111.95(b)(5) requires you to 

make and keep documentation for why 

any component and in-process testing, 

examination, or monitoring, and any 

other information, will ensure that a 

product specification that is exempted 

under final § 111.75(d) is met without 

verification through periodic testing of 

the finished batch, including 

documentation that the selected 

specifications tested or examined under 

final § 111.75(c)(1) are not able to verify 

that the production and process control 

system is producing a dietary 

supplement that meets the exempted 

product specification and there is no 

scientifically valid method for testing or 

examining such exempted product 

specification at the finished batch stage. 

Final § 111.95(b)(5) refers to a record 

required under final § 111.75(d)(1). As 

previously discussed in this section, we 

are issuing an interim final rule, 

published elsewhere in this issue of the 

Federal Register, that sets forth a 

procedure for requesting an exemption 

from the requirement that the 

manufacturer conduct at least one 

appropriate test or examination to verify 

the identity of any component that is a 

dietary ingredient. Included in the 

interim final rule is an amendment to 

final § 111.95(b) adding a new 

paragraph (b)(6) requiring the retention 

of FDA’s response to a petition 

submitted under § 111.75(a)(1)(ii) that 

provides for an exemption from the 

provision of § 111.75(a)(1)(i). 

(Comment 213) One comment 

recommends the recordkeeping 

requirements of proposed § 111.35(m) 

be moved to follow the requirements for 

appropriate test methods because these 

requirements are related and probably 

best understood without intervening 

information. 

(Response) Consistent with this 

comment, the recordkeeping 

requirements of proposed § 111.35(m) 

are set forth in final subpart J instead of 

subpart E. 

XI. Comments on Requirements for 

Quality Control (Final Subpart F) 

A. Organization of Final Subpart F 

Proposed § 111.37 set forth 

requirements for quality control 

operations. Other proposed 

requirements related to quality control 

operations were set forth in other 

sections. For example, proposed 

§ 111.40(a) would require the quality 

control unit to perform operations 

associated with components that you 

use in the manufacturing process. 

Proposed § 111.45 would establish 

requirements for the master 

manufacturing record and would have 

the quality control unit review and 

approve each master manufacturing 

record. Proposed § 111.50 would have 

the quality control unit review batch 

production records. 

As shown in table 7 of this document, 

the final rule reorganizes the 

requirements related to quality control 

operations into a distinct subpart (final 

Subpart F—Production and Process 

Control System: Requirements for 

Quality Control Operations). Table 7 

lists the sections in final subpart F and 

identifies the proposed sections that 

form the basis for the sections in the 

final rule. 

TABLE 7.—DERIVATION OF SECTIONS

IN FINAL SUBPART F 

Final Rule 2003 CGMP 

Proposal 

§ 111.103 What are the 

requirements under 

this subpart F for written procedures? 

N/A 

§ 111.105 What must 

quality control personnel do? 

§ 111.37(a), 

(b)(1), (b)(11), 

and (b)(12) 

§ 111.110 What quality 

control operations are 

required for laboratory 

operations associated 

with the production 

and process control 

system? 

§ 111.37(b)(9) 

and (b)(13) 

TABLE 7.—DERIVATION OF SECTIONS

IN FINAL SUBPART F—Continued 

Final Rule 2003 CGMP 

Proposal 

§ 111.113 What quality 

control operations are 

required for a material 

review and disposition 

decision? 

§ 111.35(i)(2), 

(i)(3), (i)(4)(i), 

(i)(4)(ii), (j), 

and (n) 

§ 111.37(b)(3) 

§ 111.37(c) 

§ 111.40(a)(3) 

and (b)(2) 

§ 111.50(d)(1) 

§ 111.65(d) 

§ 111.70(c) 

§ 111.117 What quality 

control operations are 

required for equipment, instruments, and 

controls? 

§ 111.30(b)(4), 

(b)(6), (b)(7), 

and (b)(8) 

§ 111.120 What quality 

control operations are 

required for components, packaging, and 

labels before use in 

the manufacture of a 

dietary supplement? 

§ 111.35(i)(4)(i) 

and (i)(4)(ii) 

§ 111.37(b)(2) 

and (b)(10) 

§ 111.40(a)(3) 

and (b)(2) 

§ 111.50(e)(1) 

§ 111.123 What quality 

control operations are 

required for the master 

manufacturing record, 

the batch production 

record, and manufacturing operations? 

§ 111.35(e)(2), 

(f), (i)(2), and 

(o)(2) 

§ 111.37(b)(2), 

(b)(4), (b)(5), 

and (b)(11)(iii) 

§ 111.45(c) 

§ 111.50(d)(1) 

and (d)(2) 

§ 111.50(g) 

§ 111.127 What quality 

control operations are 

required for packaging 

and labeling operations? 

§ 111.37(b)(2) 

and (b)(10) 

§ 111.40(a)(2) 

and (a)(3) 

§ 111.70(c), (d), 

and (e) 

§ 111.130 What quality 

control operations are 

required for returned 

dietary supplements? 

§ 111.37(b)(2) 

and (b)(15) 

§ 111.85(a) 

§ 111.135 What quality 

control operations are 

required for product 

complaints? 

§ 111.95 

§ 111.140 Under this 

subpart F, what 

records must you 

make and keep? 

§ 111.35(j) 

§ 111.37(c) and 

(d) 

B. Highlights of Changes to the 

Proposed Requirements for Quality 

Control Operations 

1. Revisions 

The final rule: 

• Reflects that the rule applies to 

persons who manufacture, package, 

label, or hold dietary supplements 


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unless subject to an exclusion under 

§ 111.1; 

• Changes the requirement for a 

quality control unit to a requirement for 

quality control operations performed by 

quality control personnel; 

• Requires quality control personnel 

to review and approve documentation 

for why meeting in-process 

specifications will ensure the 

specifications for identity, purity, 

strength, and composition of a dietary 

supplement are met; 

• Requires quality control personnel 

to review and approve documentation 

setting forth the basis for qualifying a 

supplier of a component; 

• Requires quality control personnel 

to review and approve documentation of 

your basis for why meeting certain 

selected specifications in a subset of 

finished batches will ensure your 

finished batch of the dietary supplement 

meets all product specifications for 

identity, purity, strength, and 

composition and limits on those types 

of contamination that may adulterate, or 

that may lead to the adulteration of, the 

dietary supplement; and 

• Requires quality control personnel 

to review and approve documentation 

for why a product specification 

exempted from the verification 

requirements in final subpart E is met 

without verification through periodic 

testing of the finished batch. 

2. Changes Associated With the 

Reorganization 

The final rule: 

• Reduces redundant provisions and 

• Combines parts of various proposed 

requirements that were scattered 

throughout the 2003 CGMP Proposal. 

3. Changes After Considering Comments 

The final rule: 

• Incorporates a new requirement to 

establish, and keep as a record, written 

procedures for quality control 

operations; 

• Simplifies the requirements 

associated with conducting a material 

review and making a disposition 

decision; 

• Requires quality control personnel 

to ensure that representative samples 

are collected rather than collecting these 

samples; 

• Requires quality control personnel 

to ensure that reserve samples are held 

rather than quality control personnel 

holding these samples; 

• Requires quality control personnel 

to ensure tests or examinations are 

appropriate rather than conduct these 

tests or examinations; and 

• Requires review by quality control 

personnel of all records for calibration 

of instruments, and for calibrations, 

inspections, and checks of automatic, 

mechanical, or electronic equipment to 

be performed on a periodic basis rather 

than at the time the record is made. 

C. General Comments on Proposed 

§ 111.37 (Final Subpart F) 

(Comment 214) Some comments 

support the use of a quality control unit 

and recognize it as an important need in 

manufacturing operations. Some 

comments assert the quality control unit 

may not have all the responsibilities 

listed in proposed § 111.37 because 

there may be some duties contracted out 

to someone else, such as testing that 

could be sent to a contract laboratory, or 

some duties that may be better suited for 

employees in other organizational units. 

As an example, a few comments note 

that the instrument and equipment 

calibration functions in proposed 

§ 111.37 may be better performed by 

individuals responsible for the 

equipment in their particular 

operational area, by those in a unit 

dedicated to equipment maintenance 

and calibration, or possibly by a third 

party, who is qualified by training and/ 

or experience, to do these functions. 

Similarly, other comments note that 

other groups with the appropriate 

expertise may be assigned or required to 

review and approve proposed changes 

or procedures in manufacturing 

operations or to conduct material 

reviews and make disposition decisions. 

These comments assert the quality 

control unit should have overall 

responsibility and oversight for quality 

control functions but also should be 

able to rely on the expertise of other 

persons in the organization to 

accomplish the tasks. 

(Response) As already discussed with 

respect to the definition of quality 

control personnel in section VI of this 

document, these comments may have 

misunderstood the quality control unit’s 

role under the proposed rule. 

Consequently, we have added final 

§ 111.12(b) in subpart B, discussed in 

section VII of this document, to state 

you must identify who is responsible for 

your quality control operations. Each 

person who is designated to perform 

quality control operations must be 

qualified to do so and have distinct and 

separate responsibilities related to 

performing such operations from those 

responsibilities that the person 

otherwise has when not performing 

such operations. 

The final rule requires quality control 

personnel to ensure all appropriate tests 

and examinations are conducted, and 

review and approve the results of all 

tests and examinations, but does not 

require that quality control personnel 

conduct the tests or examinations. Thus, 

you would not need to consider that an 

individual who conducts tests or 

examinations at a laboratory under 

contract to your organization is 

performing a quality control operation 

that must be performed by quality 

control personnel. However, you may 

choose to designate that individual as 

part of your quality control personnel 

and require that the tests or 

examinations conducted by that 

individual be quality control operations. 

Importantly, however, for the purposes 

of this final rule, we consider that a 

quality control operation performed by 

an individual under contract to you or 

by another third party is no different 

than a quality control operation 

performed by your employees who are 

designated to perform such operation. If, 

during the course of an inspection, we 

find the requirements of this final rule 

were not followed, we will hold you, 

rather than the contractor or other third 

party, responsible. The applicability of 

this final rule to contractors is discussed 

in detail in section VI of this document. 

(Comment 215) Several comments 

request that the quality control unit 

focus on reviewing tasks performed by 

others rather than on performing the 

tasks itself. 

(Response) We agree with these 

comments and have revised several 

provisions accordingly. For example, in 

the 2003 CGMP Proposal we would 

require the quality control unit to 

perform appropriate tests and 

examinations of incoming materials, inprocess materials, each finished batch of 

dietary supplements, and each batch of 

packaged and labeled dietary 

supplements (proposed § 111.37(b)(13)). 

Under the final rule, quality control 

operations include ensuring appropriate 

tests and examinations are conducted 

(final § 111.110(b)) but do not include 

conducting these tests and 

examinations. 

(Comment 216) One comment asks 

whether we expect the quality control 

unit to approve operational activities as 

soon as they occur or collectively at the 

end of the process. This and other 

comments argue the quality control 

function is usually accomplished by a 

team of qualified persons with the 

quality control unit having the overall 

responsibility and authority to perform 

a collective, post-processing, final 

approval. 

(Response) The time at which quality 

control personnel conduct assigned 

duties will vary by the specific 

operation, the size and complexity of 

the operation, and how quality control 

functions are assigned to qualified 


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persons. For example, the final rule 

requires quality control personnel to 

determine whether components 

conform to specifications, and to release 

components from quarantine before you 

use them in the manufacture of a dietary 

supplement (final § 111.120). However, 

this final rule does not require, for 

example, that quality control personnel 

determine whether components 

conform to specifications as soon as you 

receive them, although it may be 

common business practice to do so. 

Regardless of when quality control 

personnel perform their operations, 

quality control personnel have the 

ultimate responsibility for ensuring 

manufacturing, packaging, labeling, and 

holding operations are performed in a 

manner that will ensure the quality of 

the dietary supplement and that the 

dietary supplement is packaged and 

labeled as specified in the master 

manufacturing record. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.103) 

We received many comments that 

recommend written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to comments on specific 

provisions in the same section. 

Final § 111.103 requires that you 

establish and follow written procedures 

for the responsibilities of the quality 

control operations. Final § 111.103 

specifically identifies two of the written 

procedures you must establish and 

follow, i.e., written procedures for 

conducting a material review and 

making a disposition decision and for 

approving or rejecting any reprocessing. 

E. What Must Quality Control Personnel 

Do? (Final § 111.105) 

Final § 111.105 broadly captures the 

responsibility of quality control 

personnel to provide oversight for 

manufacturing, packaging, labeling, and 

holding operations. It requires quality 

control personnel to ensure that your 

manufacturing, packaging, labeling, and 

holding operations ensure the quality of 

the dietary supplement and that the 

dietary supplement is packaged and 

labeled as specified in the master 

manufacturing record. Final § 111.105 

derives from proposed § 111.37(a) 

which would require you to use a 

quality control unit to ensure your 

manufacturing, packaging, labeling, and 

holding operations in the production of 

dietary supplements are performed in a 

manner that prevents adulteration and 

misbranding, including ensuring dietary 

supplements meet specifications for 

identity, purity, quality, strength, and 

composition. 

This final rule focuses on ensuring 

that the manufacturer establishes 

specifications for its dietary 

supplements; includes those 

specifications in the master 

manufacturing record; meets those 

specifications and manufactures, 

packages, labels, and holds the product 

in a manner that will ensure the quality 

of the dietary supplement; and that the 

dietary supplement is packaged and 

labeled as specified in the master 

manufacturing record. Because of that 

focus, the labeling requirements of the 

final rule address the operation of 

putting the label that is specified in the 

master manufacturing record on the 

product rather than the content of a 

product label that meets all of the 

labeling requirements of the act and our 

implementing regulations. The failure to 

put the label identified in the master 

manufacturing record on the finished 

product would be a violation of this 

final rule. In addition, if the label on the 

product does not correctly reflect the 

ingredients, the label would misbrand 

the product under section 403 of the act. 

For purposes of this final rule, the 

labeling operations are CGMP 

requirements and relate to the label 

identified in the master manufacturing 

record. Therefore, we are deleting 

‘‘misbranding’’ from proposed 

§ 111.37(a) (final § 111.105) since the act 

of misbranding other than applying a 

label different from the one identified in 

the master manufacturing record is not 

considered a CGMP violation in the 

context of this final rule. Any 

misbranding is still a violation of the 

act, however, and manufacturers must 

comply with all applicable statutory and 

regulatory requirements in addition to 

the requirements of this final rule. 

This series of changes emphasizes the 

need to ensure the quality of a dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. As discussed in detail in the rest 

of this section, final § 111.105 also 

requires that quality control personnel 

perform certain operations and groups 

of operations. 

1. Final § 111.105(a) 

Final § 111.105(a) requires that 

quality control personnel approve or 

reject all processes, specifications, 

written procedures, controls, tests, and 

examinations, and deviations from or 

modifications to them, that may affect 

the identity, purity, strength, or 

composition of a dietary supplement. 

Final § 111.105(a) derives from 

proposed § 111.37(b)(1). 

(Comment 217) One comment 

recommends revising proposed 

§ 111.37(b)(1) by replacing ‘‘* * * 

identity, purity, quality, strength, and 

composition’’ with ‘‘* * * identity, 

purity, quality, strength, or 

composition.’’ The comment asserts the 

quality control unit must be responsible 

for approving or rejecting anything that 

may affect one of these attributes. 

(Response) We agree with this 

comment. Under proposed 

§ 111.37(b)(1) we had intended that the 

quality control unit be responsible, for 

example, for approving a test that would 

establish the identity of a component 

even if that test did not also establish 

the strength of that component. Final 

§ 111.105(a) changes ‘‘and’’ to ‘‘or’’ as 

requested by this comment. 

(Comment 218) One comment 

recommends the quality control unit be 

responsible for maintaining the master 

copies of all current and approved 

written procedures, for distributing 

copies of approved written procedures 

to relevant personnel, and for collecting 

and destroying outdated Standard 

Operating Procedures (SOPs) (except 

designated historical SOP files). 

(Response) This comment is 

consistent with the underlying principle 

that quality control personnel oversee 

the design and conduct of the 

operations associated with the 

production of a dietary supplement. 

After considering these comments, final 

§ 111.105(a) requires quality control 

personnel to approve all written 

procedures that may affect the identity, 

purity, strength, or composition of a 

dietary supplement. With respect to the 

other suggested duties of quality control 

personnel, we are leaving the decision 

as to who performs them, up to the 

individual firm to best suit its overall 

operations. 

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

Final § 111.105(b) requires quality 

control personnel to review and approve 

the documentation setting forth the 

basis for qualification of any supplier. 

Final § 111.105(c) requires quality 

control personnel to review and approve 

the documentation setting forth the 

basis for why meeting in-process 

specifications, in combination with 

meeting component specifications, will 

help ensure that specifications for the 

identity, purity, strength, and 

composition of the dietary supplement 

are met. Final § 111.105(d) requires 

quality control personnel to review and 

approve the documentation setting forth 

the basis for why the results of 

appropriate tests or examinations for 

each product specification selected 

under final § 111.75(c)(1) will ensure 


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that the finished batch of the dietary 

supplement meets product 

specifications. Final § 111.105(e) 

requires quality control personnel to 

review and approve the basis and 

documentation for why any product 

specification is exempted from the 

verification requirements in final 

§ 111.75(c)(1), and for why any 

component and in-process testing, 

examination, or monitoring, or other 

methods will ensure that such exempted 

product specification is met without 

verification through periodic testing of 

the finished batch. 

Final § 111.105(b), (c), (d), and (e) are 

requirements associated with the 

requirements established in final 

§§ 111.70(c)(3) and 111.75(a)(ii)(2)(E), 

(c)(4), (d)(1) and (d)(2). 

3. Final § 111.105(f) 

Final § 111.105(f) requires quality 

control personnel to ensure that 

required representative samples are 

collected. Final § 111.105(f) differs 

slightly from proposed § 111.37(b)(11)(i) 

through (b)(11)(iv) which would require 

the quality control unit to collect 

representative samples of incoming 

materials, in-process materials, each 

finished batch of dietary supplements, 

and each batch of packaged and labeled 

dietary supplements. 

After considering comments 

requesting the quality control unit focus 

on reviewing tasks performed by others 

rather than on performing the tasks 

themselves, the final rule does not 

specify that quality control personnel 

must collect representative samples. 

Under final § 111.105(f), however, 

quality control personnel retain 

oversight of sample collection. 

4. Final § 111.105(g) 

Final § 111.105(g) requires quality 

control personnel to ensure that 

required reserve samples are collected 

and held. Final § 111.105(g) derives 

from proposed § 111.37(b)(12) which 

would require the quality control unit to 

keep reserve samples. 

After considering comments 

requesting the quality control unit focus 

on reviewing tasks performed by others 

rather than on performing the tasks 

themselves, the final rule does not 

specify that quality control personnel 

must keep reserve samples. Under final 

§ 111.105(g), however, quality control 

personnel retain oversight of sample 

collection and holding. 

5. Final § 111.105(h) 

Final § 111.105(h) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include determining whether 

all specifications established in 

accordance with final § 111.70(a) are 

met. Final § 111.105(h) derives from 

proposed § 111.37(b)(2) which would 

require that the quality control unit 

determine whether all components, 

dietary supplements, packaging, and 

labels conform to specifications. Under 

the final rule, we are identifying each of 

the specifications subject to review by 

quality control personnel under final 

§ 111.77. The requirement for quality 

control personnel to determine whether 

specifications established under final 

§ 111.70(a) are met is included for 

consistency. This requirement is also 

consistent with final § 111.73 which 

requires that the production and process 

control system must include a 

determination of whether all of the 

established specifications under final 

§ 111.70(a) are met. 

6. Final § 111.105(i) 

Final § 111.105(i) requires quality 

control personnel to perform other 

operations required under subpart F. 

Final § 111.105(i) is associated with the 

reorganization. Under the 2003 CGMP 

Proposal, proposed § 111.37(a) broadly 

captured the responsibility of the 

quality control unit to provide oversight 

for your manufacturing, packaging, 

labeling, and holding operations. 

Proposed § 111.37(b) listed specific 

operations that we would require the 

quality control unit to perform. Final 

§ 111.105 now captures the 

responsibility of quality control 

personnel to provide oversight for your 

manufacturing, packaging, labeling, and 

holding operations. The specific 

operations that quality control 

personnel must perform to provide that 

oversight are set forth in final 

§ 111.105(a) through (h) and in final 

§§ 111.110, 111.113, 111.117, 111.120, 

111.123, 111.127, 111.130, 111.135, and 

111.140. 

F. What Quality Control Operations Are 

Required for Laboratory Operations 

Associated With the Production and 

Process Control System? (Final 

§ 111.110) 

Final § 111.110 sets forth the 

minimum required operations that 

quality control personnel must perform 

with respect to laboratory operations 

associated with the production and 

process control system. 

1. Final § 111.110(a) 

Final § 111.110(a) requires that 

quality control operations for laboratory 

operations include reviewing and 

approving all laboratory control 

processes associated with the 

production and process control system. 

Final § 111.110(a) derives, in part, from 

proposed § 111.37(b)(9) which would 

require that the quality control unit 

review and approve all laboratory 

control processes. For clarity, we are 

adding that the laboratory operations 

covered by final § 111.110 are those 

associated with the production and 

process control system. We want to 

make clear that laboratory operations 

such as those in your research and 

development department are not subject 

to final § 111.110. 

We did not receive comments specific 

to quality control operations under 

proposed § 111.37(b)(9). 

2. Final § 111.110(b) 

Final § 111.110(b) requires that 

quality control operations for laboratory 

operations associated with the 

production and process control system 

include ensuring all tests and 

examinations required under final 

§ 111.75 are conducted. Final 

§ 111.110(b) derives, in part, from 

proposed § 111.37(b)(13) which would 

require the quality control unit to 

perform appropriate tests and 

examinations of incoming materials, inprocess materials, each finished batch of 

dietary supplements, and each batch of 

packaged and labeled dietary 

supplements. 

Proposed § 111.37(b)(13) would list 

the types of materials that must be 

tested, including components, 

packaging, labels, dietary ingredients, 

and dietary supplements that you 

receive; the batch production at the inprocess and finished batch stages; and 

packaged and labeled dietary 

supplements. This list would include 

materials that, at a minimum, would be 

tested under the 2003 CGMP Proposal. 

Under the final rule, the minimum 

requirements for testing or examination 

of the materials listed in proposed 

§ 111.37(b)(13) are set forth in final 

§ 111.75. To simplify and clarify 

proposed § 111.37(b)(13), final 

§ 111.110(b) replaces this list with ‘‘all 

tests and examinations required under 

§ 111.75.’’

3. Final § 111.110(c) 

Final § 111.110(c) requires that 

quality control operations for laboratory 

operations associated with the 

production and process control system 

include reviewing and approving the 

results of all tests and examinations 

required under final § 111.75. Final 

§ 111.110(c) derives from proposed 

§ 111.37(b)(9), which would require, in 

part, that the quality control unit review 

and approve all testing results. Final 

§ 111.110(c) requires that quality control 


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personnel review and approve the 

results of examinations as well as tests. 

This revision reflects the flexibility 

provided in the final rule to use either 

tests or examinations to determine 

whether specifications are met, 

provided that the test or examination is 

an appropriate, scientifically valid 

method. 

As with final § 111.110(b), we provide 

in final § 111.110(c) that the tests and 

examinations are those required under 

final § 111.75. 

We did not receive comments specific 

to quality control operations under 

proposed § 111.37(b)(9). 

G. What Quality Control Operations Are 

Required for a Material Review and 

Disposition Decision? (Final § 111.113) 

Final § 111.113 derives from several 

proposed provisions, including 

§§ 111.35(i), (j), and (n); 111.37(b)(3); 

111.40(a)(3) and (b)(2); 111.50(d)(1); 

111.65(d); and 111.70(c). All these 

proposed requirements are related to 

one or more aspects associated with a 

material review and disposition, 

including the circumstances that require 

a material review and disposition 

decision, the documentation that must 

be included in a material review and 

disposition decision, any restrictions on 

who must conduct the material review 

and make the disposition decision, and 

the need for oversight by the quality 

control unit. As discussed in section X 

of this document, we simplified the 

provisions regarding a material review 

and disposition decision (final 

§ 111.87), emphasizing the importance 

of oversight by quality control personnel 

and retaining the principle that 

qualified individuals other than those 

who are designated quality control 

personnel can contribute to the material 

review and disposition decision. The 

final rule sets forth the following 

requirements for quality control 

personnel that relate to final § 111.113: 

• Under final § 111.87, quality 

control personnel must conduct all 

required material reviews and make all 

required disposition decisions; 

• Under final § 111.103, you must 

establish and follow written procedures 

for conducting a material review and 

making a disposition decision; and 

• Under final § 111.140(b)(3)(vii), 

documentation of a material review and 

disposition decision and followup must 

include the signature of the individual, 

designated to perform the quality 

control operation, who conducted the 

material review and made the 

disposition decision and of any 

qualified individual who provided 

information relevant to that material 

review and disposition decision. 

The final rule establishes a system in 

which you have the flexibility to 

develop procedures that suit your 

organization, including having qualified 

individuals, who are not designated to 

perform the quality control operation, 

provide information relevant to the 

material review and disposition 

decision. For example, under final 

§ 111.140(b)(3), you could have a 

qualified individual in the production 

department assist quality control 

personnel in conducting a material 

review by preparing a report that 

includes all the required documentation 

and information and providing a signed 

copy of that report to quality control 

personnel. An individual who is 

designated to perform the quality 

control operation could then use that 

report as part of the material review, 

conduct any further investigations, as 

necessary, and decide to accept, amend, 

or reject the report. 

1. Final § 111.113(a) 

Under final § 111.113(a) quality 

control personnel must conduct a 

material review and make a disposition 

decision if: 

• A specification established in 

accordance with § 111.70 is not met; 

• A batch deviates from the master 

manufacturing record, including when 

any step established in the master 

manufacturing record is not completed 

and including any deviation from 

specifications; 

• There is any unanticipated 

occurrence during the manufacturing 

operations that adulterates or may lead 

to adulteration of the component, 

dietary supplement, or packaging, or 

could lead to the use of a label not 

specified in the master manufacturing 

record; 

• Calibration of an instrument or 

control suggests a problem that may 

have resulted in a failure to ensure the 

quality of a batch or batches of a dietary 

supplement; or 

• A dietary supplement is returned. 

Final § 111.113(a) is substantially 

similar to proposed § 111.35(i)(3), which 

would require, in part, that you make a 

material disposition decision for any 

component, dietary supplement, 

packaging, or label: 

• If a component, dietary supplement, 

packaging, or label fails to meet 

established specifications; 

• If any step established in the master 

manufacturing record is not completed; 

• If there is any unanticipated 

occurrence during the manufacturing 

operations that adulterates or may lead 

to adulteration of the component, 

dietary supplement, packaging, or label; 

• If calibration of an instrument or 

control suggests a problem that may 

have caused batches of a dietary 

supplement to become adulterated; or 

• If a dietary supplement is returned. 

Final § 111.113(a) also incorporates 

elements from other proposed sections 

regarding the circumstances that require 

a material review and disposition 

decision as follows: 

• Proposed § 111.35(n), which would 

require you, for any specification that is 

not met, to conduct a material review 

and disposition decision under 

proposed § 111.35(i); 

• Proposed § 111.40(a)(3), which 

would require you, for components, 

dietary ingredients, or dietary 

supplements you receive, to conduct a 

material review and make a disposition 

decision if specifications are not met; 

• Proposed § 111.40(b)(2), which 

would require that for packaging and 

labels you receive, you must conduct a 

material review and make a disposition 

decision if specifications are not met; 

• Proposed § 111.50(d)(1), which 

would require that if a batch deviates 

from the master manufacturing record, 

including any deviation from 

specifications, the quality control unit 

must conduct a material review and 

make a disposition decision and record 

any decision in the batch production 

record; 

• Proposed § 111.65(d), which would 

require you to conduct a material review 

and make a disposition decision in 

accordance with proposed § 111.35(i) 

for any component, dietary ingredient, 

or dietary supplement that fails to meet 

specifications or that is or may be 

adulterated; and 

• Proposed § 111.70(c), which would 

require you to conduct a material review 

and make a disposition decision of any 

packaged and labeled dietary 

supplements that do not meet 

specifications. 

In final § 111.113(a) we are 

incorporating, into a single unified 

provision, the various proposed 

circumstances that would require a 

material review and disposition 

decision under the 2003 CGMP 

Proposal. We included revisions 

associated with final § 111.87 which 

requires quality control personnel to 

conduct any required material review 

and make any required disposition 

decision. We also included revisions 

associated with final § 111.90 that relate 

to the impact on labeling operations due 

to deviations and unanticipated 

occurrences. 

In establishing final § 111.113(a)(1), 

we are deleting the specific reference to 

the articles (components, dietary 

supplements, packaging, and labels) 


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required to undergo a material review. 

We are deleting these references, in part, 

to simplify the provision. Under final 

§ 111.113(a) quality control personnel 

must conduct a material review and 

make a disposition decision if any 

specification established in accordance 

with final § 111.70 is not met. It is not 

necessary to repeat, in final § 111.113, 

the list of specifications that is clearly 

set forth in final § 111.70. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.35(i)(3) and (n), 

111.40(a)(3) and (b)(2), 111.50(d)(1), 

111.65(d), or 111.70(c). 

2. Final § 111.113(b) 

Final § 111.113(b)(1) requires that, 

when there is a deviation or 

unanticipated occurrence during the 

production and in-process control 

system that results in or could lead to 

adulteration of a component, dietary 

supplement, or packaging, or could lead 

to the use of a label not specified in the 

master manufacturing record, quality 

control personnel must reject the 

component, dietary supplement, or 

packaging, or label unless it approves a 

treatment, an in-process adjustment, or 

reprocessing to correct the applicable 

deviation or occurrence. 

Final § 111.113(b)(1) derives from the 

following proposed provisions: 

• Proposed § 111.35(i)(4)(i) which, in 

part, would require that, for any 

deviation or unanticipated occurrence 

which resulted in or could lead to 

adulteration of the component, dietary 

ingredient, dietary supplement, 

packaging, or label, you reject the 

component, dietary ingredient, dietary 

supplement, packaging, or label, unless 

the quality control unit determines that 

in-process adjustments are possible to 

correct the deviation or occurrence; 

• Proposed § 111.35(i)(4)(ii) which, in 

part, would require that, for any 

deviation or unanticipated occurrence 

which resulted in or could lead to 

adulteration of the component, dietary 

ingredient, dietary supplement, 

packaging, or label, you not reprocess a 

rejected component or dietary 

supplement unless approved by the 

quality control unit; and 

• Proposed § 111.37(b)(3) which, in 

part, would require the quality control 

unit to approve or reject all dietary 

ingredients, dietary supplements, 

components, packaging, and labels. 

For consistency with other provisions 

in final subpart F, final § 111.113(b)(1) 

requires that quality control personnel 

‘‘reject’’ a component, dietary 

supplement, packaging, or label. We 

also included revisions that are 

associated with final § 111.90. 

Final § 111.113(b)(2) requires that 

when a specification established in 

accordance with § 111.70 is not met, 

quality control personnel must reject the 

component, dietary supplement, 

package, or label, unless quality control 

personnel approve a treatment, an inprocess adjustment, or reprocessing, as 

permitted in final § 111.77. This 

provision has been added as a result of 

the new provision, final § 111.77 which 

provides for what happens when certain 

specifications are not met, the 

responsibilities of quality control 

personnel, and the changes made to 

final § 111.90. 

(Comment 219) Several comments 

request that the quality control unit 

focus on reviewing tasks performed by 

others rather than on performing the 

tasks itself. 

(Response) We agree, and final 

§ 111.113(b) provides that quality 

control personnel ‘‘approve’’ an inprocess adjustment rather than 

‘‘determine whether’’ the in-process 

adjustment is possible. 

3. Final § 111.113(c) 

Final § 111.113(c) requires the person 

who conducts a material review and 

makes the disposition decision, at the 

time of performance, to document that 

material review and disposition 

decision. Final § 111.113(c) derives from 

proposed § 111.35(j) which, in part, 

would require that the person who 

conducts the material review and makes 

the disposition decision must, at the 

time of performance, document every 

material review and disposition 

decision in proposed § 111.35(i). 

As an editorial revision, final 

§ 111.113(c) requires documentation of 

‘‘that’’ decision rather than ‘‘every’’

decision. As a practical matter, under 

final § 111.113(c) every material review 

and disposition decision is documented. 

We did not receive comments specific 

to quality control operations under 

proposed § 111.35(j). 

H. What Quality Control Operations Are 

Required for Equipment, Instruments, 

and Controls? (Final § 111.117) 

Final § 111.117 (proposed 

§ 111.37(b)(6) through (b)(8)) sets forth 

the minimum required operations that 

quality control personnel must perform 

with respect to equipment, instruments, 

and controls. 

1. Final § 111.117(a) through (c) 

Final § 111.117(a) through (c) requires 

the quality control operations for 

equipment, instruments, and controls to 

include: 

• Reviewing and approving all 

processes for calibrating instruments 

and controls; 

• Periodically reviewing all records 

for calibration of instruments and 

controls; and 

• Periodically reviewing all records 

for calibrations, inspections, and checks 

of automated, mechanical, or electronic 

equipment. 

Final § 111.117(a), (b), and (c) derive 

from proposed § 111.37(b)(6), (b)(7), and 

(b)(8) which would require the quality 

control unit to: 

• Review and approve all processes 

for calibrating instruments or controls; 

• Review all records for calibration of 

instruments, apparatus, gauges, and 

recording devices; and 

• Review all records for equipment 

calibrations, inspections, and checks. 

Final § 111.117 includes the following 

changes we are making for consistency 

with the requirements, set forth in 

subpart D, for equipment and utensils: 

• We have deleted the terms 

‘‘apparatus,’’ ‘‘gauges,’’ and ‘‘recording 

devices’’ from proposed § 111.37(b)(7) 

as they would fall under the terms 

‘‘instruments and controls’’ in final 

§ 111.117, and because subpart D does 

not use the terms ‘‘apparatus,’’

‘‘gauges,’’ or ‘‘recording devices.’’

• We are characterizing the records 

for equipment calibrations, inspections, 

and checks as records for calibrations, 

inspections, and checks of ‘‘automated, 

mechanical, or electronic equipment,’’

because final § 111.30(c) requires you to 

calibrate, inspect, or check ‘‘automated, 

mechanical, or electronic equipment.’’

(Comment 220) One comment argues 

the requirements for oversight by the 

quality control unit in proposed 

§ 111.37(b)(7) and (b)(8) are excessive 

and go beyond requirements for both the 

drug CGMPs and food CGMPs. The 

comment recommends revising 

proposed § 111.37(b)(7) and (b)(8) to 

require a review of all records when 

there is a negative impact on the 

product due to a calibration failure. 

Other comments refer to the related 

requirements in proposed § 111.30(b)(1) 

that the quality control unit approve 

calibrations, inspections, or checks of 

automatic, mechanical, or electronic 

equipment. These comments assert the 

requirement for the quality control unit 

to approve such calibrations, 

inspections, and checks of equipment is 

too prescriptive and that qualified 

persons outside of the quality control 

unit should be able to approve these 

calibrations, inspections, or checks. 

These comments also assert the quality 

control unit should perform audits of 

the records generated to ensure the 

appropriate calibrations, inspections, 


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and checks are being adequately 

performed at the required intervals. 

(Response) As already discussed with 

respect to proposed § 111.30(b)(1) (final 

§ 111.30(c)), we disagree that the review 

by quality control personnel should be 

limited to circumstances when there has 

been a calibration failure. One of the 

oversight functions of quality control 

personnel is to prevent problems with 

the product you distribute by finding 

any problems with the equipment you 

use to produce the product rather than 

to investigate the cause of a problem 

with a product that you already 

distributed. However, we agree it is 

sufficient to review the records of 

calibrations, inspections, and checks of 

automated, mechanical, or electronic 

equipment periodically, for example, on 

an annual basis, rather than to approve 

each record when it is made. A periodic 

review can uncover trends in the 

performance of the equipment that have 

the potential to adversely affect the 

quality of the dietary supplement and 

that may not be obvious by merely 

approving each record when it is made. 

Seeing such trends would enable quality 

control personnel to recommend actions 

to correct the trend. Therefore, we have 

revised the proposed requirement so 

that under final § 111.117(c) quality 

control personnel must review all 

records of calibrations, inspections, and 

checks of automatic, mechanical, or 

electronic equipment on a periodic 

basis. Likewise, we have revised the 

rule so that the quality control 

personnel’s review of all records of 

equipment calibrations also is on a 

periodic basis. 

(Comment 221) A few comments 

argue the review of calibration records 

may be conducted by a qualified person 

other than the quality control unit, such 

as by a supervisor or by a separate 

department dedicated to equipment 

maintenance and calibration. These 

comments assert the quality control unit 

should approve calibration processes, 

but review of completed calibration 

records by the dedicated department is 

sufficient to assure compliance with the 

approved process. 

(Response) As already discussed, 

many comments about the quality 

control unit may have misunderstood 

the proposed definition of ‘‘quality 

control unit’’ (now replaced by ‘‘quality 

control personnel’’). Under final 

§ 111.12(b), you must identify who is 

responsible for your quality control 

operations. Each person who is 

identified to perform quality control 

operations must be qualified to do so 

and have distinct and separate 

responsibilities related to performing 

such operations from those 

responsibilities that the person 

otherwise has when not performing 

such operations. Thus, in the situation 

described by these comments, you could 

identify a qualified person in a 

department dedicated to equipment 

maintenance and calibration to perform 

quality control operations for equipment 

calibration. Neither the definition of 

‘‘quality control personnel,’’ nor the 

requirements of final § 111.12(b), would 

preclude a person who performs 

‘‘Operation X’’ from being identified as 

the person who performs quality control 

operations for ‘‘Operation X.’’ However, 

we strongly recommend that the person 

you identify to perform a given quality 

control operation be a different person 

than the person who performed the 

operation that is subject to quality 

control oversight. 

2. Final § 111.117(d) 

Final § 111.117(d) requires that 

quality control operations for 

equipment, instruments, and controls 

include reviewing and approving 

controls to ensure automated, 

mechanical, or electronic equipment 

functions in accordance with its 

intended use. Final § 111.117(d) derives, 

in part, from proposed § 111.30(b)(4) 

(final § 111.30(e)) which would require 

that, for any automated, mechanical, or 

electronic equipment you use, you must 

establish and use appropriate controls 

and the controls are approved by your 

quality control unit to ensure that the 

equipment functions in accordance with 

its intended use. We are clarifying the 

proposed requirement related to quality 

control personnel in final § 111.117(d). 

We did not receive comments specific 

to this responsibility of the quality 

control unit in proposed § 111.30(b)(4). 

I. What Quality Control Operations Are 

Required for Components, Packaging, 

and Labels Before Use in the 

Manufacture of a Dietary Supplement? 

(Final § 111.120) 

Final § 111.120 sets forth the 

minimum required operations that 

quality control personnel must perform 

with respect to components, packaging, 

and labels before use in the manufacture 

of a dietary supplement. Some of the 

proposed provisions that form the basis 

for final § 111.120 included 

requirements for ‘‘dietary supplements 

that you receive.’’ For example, 

proposed § 111.40(a) would require you, 

for components or dietary supplements 

you receive, to visually examine 

containers and documentation provided 

by the supplier, quarantine the materials 

until they are released by the quality 

control unit, and identify the materials 

in a manner that allows you to trace the 

shipment you receive to the product 

that you manufacture and distribute. 

The final rule separates these and other 

requirements for quality control 

operations for ‘‘product that you receive 

from a supplier’’ for packaging or 

labeling as a dietary supplement from 

the analogous requirements for 

components. Thus, the requirements for 

quality control operations for product 

you receive for packaging and labeling 

as a dietary supplement (and for 

distribution rather than for return to the 

supplier) are found in final § 111.127 

rather than final § 111.120. 

1. Final § 111.120(a) 

Final § 111.120(a) requires that 

quality control operations for 

components, packaging, and labels 

include reviewing all receiving records 

for components, packaging, and labels 

before use. Final § 111.120(a) derives 

from the following proposed provisions: 

• Proposed § 111.37(b)(10) which, in 

part, would require the quality control 

unit to review and approve all 

packaging and label records which 

include, but are not limited to, crossreferencing receiving and batch 

production records; 

• Proposed § 111.40(a)(3) which, in 

part, would require that you quarantine 

dietary supplements until your quality 

control unit reviews the supplier’s 

invoice, guarantee, or certification; and 

• Proposed § 111.50(e)(1) which, in 

part, would require the quality control 

unit to document its review of 

component receiving records. 

(Comment 222) One comment asserts 

that the proposed requirement that the 

review of the batch record by the quality 

control unit include cross-referencing of 

receiving records with the batch 

production record is redundant and 

should be mandatory only in cases 

where a specification has not been met. 

This comment asserts the quality 

control unit has already reviewed and 

approved components, packaging, and 

labels prior to their release and has used 

unique identifiers for these raw 

materials as they are recorded on related 

documentation and records, which 

allow traceability back to this 

documentation for review when 

necessary. This comment also asserts all 

material review and disposition 

decisions must be documented and 

these will include the unique identifiers 

that tie them to particular raw or inprocess materials. 

Another comment asserts that the 

quality control unit should only need to 

repeat a review of the receiving records 

as a result of conducting an 

investigation or a material review, as is 

required for drugs, and to require 


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otherwise would be redundant. This 

comment also states requiring the 

quality control unit to repeat its review 

of the receiving records places a fairly 

large burden on the quality control unit 

because this re-review must be 

performed for each and every batch 

production record. The comments assert 

the requirement should be completed 

properly and only once. 

(Response) In the preamble to the 

2003 CGMP Proposal (68 FR 12157 at 

12200), we stated that cross-referencing 

receiving and batch production records 

means the quality control unit must 

verify that the batch record includes 

certain documentation of the receiving 

records for the components such as the 

unique identifier assigned to the 

shipment lot of components, testing 

results, a material review and 

disposition decision, if conducted, and 

approval for use by the quality control 

unit. We agree with the comments that 

the review of records such as receiving 

records (including proper 

documentation of a unique identifier for 

components, packaging, and labels), if 

done properly the first time it is 

performed, need not be repeated. 

Therefore, the final rule does not 

include any requirement for crossreferencing receiving records with the 

batch production record as we would 

require under proposed § 111.37(b)(10). 

As noted, we have changed ‘‘quality 

control unit’’ to ‘‘quality control 

personnel.’’ We agree that crossreferencing receiving and batch 

production records is an appropriate 

step to take when conducting a material 

review and making a disposition when, 

for example, a specification is not met. 

We encourage firms to include this 

activity in the written procedures for 

conducting a material review and 

making a disposition decision. 

2. Final § 111.120(b) 

Final § 111.120(b) requires that 

quality control operations for 

components, packaging, and labels 

include determining whether all 

components, packaging, and labels 

conform to specifications established 

under § 111.70(b) and (d) before use. 

Final § 111.120(b) derives from 

proposed § 111.37(b)(2). 

We did not receive comments specific 

to quality control operations under 

proposed § 111.37(b)(2). For clarity, we 

have identified the specifications as 

those required under final § 111.70(b) 

and (d). 

3. Final § 111.120(c) 

Final § 111.120(c) requires that 

quality control operations for 

components, packaging, and labels 

include conducting any required 

material review and making any 

required disposition decision before 

use. Final § 111.120(c) derives from the 

following proposed provisions: 

• Proposed § 111.40(a)(3) which, in 

part, would require you to conduct a 

material review and make a disposition 

decision if specifications are not met for 

components; and 

• Proposed § 111.40(b)(2) which, in 

part, would require you to conduct a 

material review and make a disposition 

decision if specifications are not met for 

packaging and labels. 

Final § 111.120(c) includes revisions 

associated with final § 111.87 which 

requires quality control personnel to 

conduct any required material review 

and make any required disposition 

decision. 

(Comment 223) One comment 

recommends the quality control unit 

have authority to allow usage of 

material that has failed to meet 

specifications if the defect will not 

significantly affect the overall quality of 

the finished product even if 

reprocessing is not an option. The 

comment gives an example of a material 

that fails to meet particle size 

specifications designed to maximize the 

efficiency of processing of the material, 

but ultimately does not impair strength, 

and asserts the quality unit should have 

the authority to release the material for 

use. 

(Response) The final rule provides for 

a process in which quality control 

personnel determine whether a 

component meets specifications and 

conduct a material review and make a 

disposition decision if a component 

does not meet one or more 

specifications. The final rule does not 

prohibit the use of a component that 

does not meet all component 

specifications other than the identity 

specification. For example, under final 

§ 111.120(d) quality control personnel 

may approve an in-process adjustment 

of a component to make it suitable for 

use in the manufacture of a dietary 

supplement (see discussion of final 

§ 111.120(d) in the following 

paragraphs). Under final § 111.123(b) 

quality control personnel must not 

approve and release for distribution any 

batch of dietary supplement, including 

any reprocessed batch, that does not 

meet all product specifications or is not 

a quality product. Thus, although a 

disposition decision could be made 

under final § 111.120(c) to use a 

component even if it does not meet 

certain specifications, that decision 

should take into account whether the 

failure for the component to meet 

specifications will ultimately cause the 

dietary supplement to fail to meet 

product specifications. 

4. Final § 111.120(d) 

Final § 111.120(d) requires that 

quality control operations for 

components, packaging, and labels 

include approving, or rejecting, any 

treatment and in-process adjustments of 

components, packaging, or labels to 

make them suitable for use in the 

manufacture of a dietary supplement. 

Final § 111.120(d) derives from the 

following proposed provisions: 

• Proposed § 111.35(i)(4)(i) which, in 

part, would require that you reject the 

component, packaging, or label, unless 

the quality control unit determines that 

in-process adjustments are possible to 

correct the deviation or occurrence and 

• Proposed § 111.35(i)(4)(ii) which 

would have prohibited you from 

reprocessing a rejected component 

unless approved by the quality control 

unit. 

Final § 111.120(d) includes a revision 

associated with final § 111.90(c), and 

refers to ‘‘treatment and in-process 

adjustments to make them suitable for 

use in the manufacture of a dietary 

supplement’’ (see discussion of final 

§ 111.90(c) in section X of this 

document). 

(Comment 224) Several comments 

request the quality control unit focus on 

reviewing tasks performed by others 

rather than on performing the tasks 

itself. 

(Response) Final § 111.120(d) 

includes a revision that quality control 

personnel ‘‘approve’’ a treatment rather 

than ‘‘determine that’’ the treatment is 

possible. 

(Comment 225) A few comments 

support the proposed requirement that 

the quality control unit have the 

authority to approve reprocessing 

measures. 

(Response) These comments are 

consistent with proposed § 111.35(i) and 

(i)(4)(ii) and final § 111.120(d), as 

applicable to quality control personnel. 

(Comment 226) One comment states 

that the decision to reprocess a material 

belongs within the particular 

operational unit, and that the role of the 

quality control unit should be to 

approve the results of the reprocessing. 

(Response) We disagree that the role 

of quality control personnel should be 

limited to approving the results of 

reprocessing or, in this case, of the 

treatment or in-process adjustments of 

components, packaging, or labels. An 

underlying principle of these CGMP 

requirements is that quality control 

personnel oversee the design and 

conduct of manufacturing, packaging, 

labeling, and holding operations. A 


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decision about when reprocessing is, or 

is not, appropriate requires oversight. 

As already discussed, under final 

§ 111.12(b) you must identify who is 

responsible for your quality control 

operations. Each person who is 

identified to perform quality control 

operations must be qualified to do so 

and have distinct and separate 

responsibilities related to performing 

such operations from those 

responsibilities that the person 

otherwise has when not performing 

such operations. 

5. Final § 111.120(e) 

Final § 111.120(e) requires that 

quality control operations for 

components, packaging, and labels 

include approving and releasing from 

quarantine all components, packaging, 

and labels before they are used. Final 

§ 111.120(e) derives from the following 

proposed provisions: 

• Proposed § 111.40(a)(3) which, in 

part, would require that you quarantine 

components until your quality control 

unit approves the components and 

releases them from quarantine and 

• Proposed § 111.40(b)(2) which, in 

part, would require that you quarantine 

packaging and labels until your quality 

control unit approves the packaging and 

labels and releases them from 

quarantine. 

We did not receive comments specific 

to quality control operations under 

proposed § 111.40(a)(3) or (b)(2). 

J. What Quality Control Operations Are 

Required for the Master Manufacturing 

Record, the Batch Production Record, 

and Manufacturing Operations? (Final 

§ 111.123) 

Final § 111.123 sets forth the 

minimum required operations that 

quality control personnel must perform 

with respect to the master 

manufacturing record, the batch 

production record, and manufacturing 

operations. 

1. Final § 111.123(a)(1) 

Final § 111.123(a)(1) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include reviewing and 

approving all master manufacturing 

records and all modifications to the 

master manufacturing records. Final 

§ 111.123(a)(1) derives from duplicate 

proposed requirements, in proposed 

§§ 111.37(b)(4) and 111.45(c), with no 

changes other than the editorial changes 

associated with the reorganization. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.37(b)(4) or 111.45(c), 

but have combined them as final 

§ 111.123(a)(1). 

2. Final § 111.123(a)(2) 

Final § 111.123(a)(2) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include reviewing and 

approving all batch production-related 

records. Final § 111.123(a)(2) derives 

from proposed § 111.37(b)(5), which 

would require, in part, the quality 

control unit to review and approve all 

batch production-related records. 

Proposed § 111.37(b)(5) explicitly 

stated, in part, that the batch record 

would include, but not be limited to, 

cross-referencing receiving and batch 

production records. 

(Comment 227) One comment 

expresses concern that proposed 

§ 111.37(b) does not state specifically 

that the complete batch history, 

including batch record, analytical 

records, quality control records, yields, 

and packaging records should be 

reviewed and approved by the quality 

control unit before the batch is shipped. 

The comment believes these are 

important requirements that should be 

clearly stated. 

(Response) Proposed § 111.37(b)(5) 

would require that the quality control 

unit ‘‘review and approve all batch 

production-related records, including 

but not limited to * * *’’ We disagree 

with the comment that this proposed 

provision would not include what the 

comment describes. To the extent that 

the comments interpreted the list of 

records to mean that only the partial 

listing of records was required, we have 

modified final § 111.123(a)(2) to require 

quality control personnel to review all 

batch production-related records. We do 

not emphasize any particular aspect of 

the batch production record. This 

reduces the potential to misinterpret the 

requirement as being limited to the 

specific items cited. 

(Comment 228) As already discussed 

in detail with respect to final 

§ 111.120(a), some comments assert the 

proposed requirement that the review of 

the batch record by the quality control 

unit include cross-referencing of 

receiving records with the batch 

production record is redundant to other 

requirements that the quality control 

unit review receiving records for 

components, packaging, and labels. In 

general, these comments assert the 

requirement should be completed 

properly and only once. 

(Response) We agree with the 

comments that the review of records, 

such as receiving records, if done 

properly the first time that it is 

performed, need not be repeated. 

Therefore, the final rule does not 

include any requirements for crossreferencing receiving records with the 

batch production record as we would 

require under proposed § 111.37(b)(5). 

3. Final § 111.123(a)(3) 

Final § 111.123(a)(3) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include reviewing all 

monitoring required under subpart E. 

Final § 111.123(a)(3) derives from the 

following proposed provisions: 

• Proposed § 111.35(f) which would 

require you to monitor the in-process 

control points, steps, or stages to ensure 

that specifications established under 

proposed § 111.35(e) are met and to 

detect any unanticipated occurrence 

that may result in adulteration; 

• Proposed § 111.35(e)(2) which 

would require you to establish a 

specification for any point, step, or stage 

in the manufacturing process where 

control is necessary to prevent 

adulteration, including the in-process 

controls in the master manufacturing 

record where control is necessary to 

ensure the identity, purity, quality, 

strength, and composition of dietary 

supplements; 

• Proposed § 111.35(i)(2) which 

would require you to review the results 

of the monitoring required under 

proposed § 111.35(f) and conduct a 

material review if an established 

specification is not met or if there is any 

unanticipated occurrence that 

adulterates or could result in 

adulteration; 

• Proposed § 111.35(o)(2) which 

would require you to make and retain 

records to ensure you follow the 

requirements of proposed § 111.35, 

including the actual results obtained 

during the monitoring operation; and 

• Proposed § 111.37(b)(5) which 

would require the quality control unit to 

review and approve all batch 

production-related records. 

Under the final rule, the results of the 

monitoring required under proposed 

§ 111.35(f) must be kept in the batch 

record (see the discussion of the batch 

record in section XIV of this document). 

Quality control personnel must review 

the results of the required monitoring. 

(Comment 229) One comment 

suggests the phrase ‘‘review the results 

of the monitoring required by this 

section’’ be deleted from proposed 

§ 111.35(i)(2) because it is unnecessary 

and can be read as narrowing any final 

rule. This comments points out the only 

required monitoring in the proposal 

appears in § 111.35(f) related to 


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monitoring of in-process control points, 

steps, or stages, and that such 

monitoring would not necessarily find 

all failures in specifications, for 

example, specifications related to raw 

materials or labels. 

(Response) We disagree with the 

comment that the quoted language 

narrows the final rule. Monitoring that 

relates to in-process control points, 

steps, or stages would be required under 

proposed § 111.35(f) and is now 

required in final § 111.123(a)(3). 

However, in practice, a manufacturer 

must monitor its entire operation to 

ensure that the requirements of the final 

rule are met. For example, under final 

§ 111.73, a manufacturer must 

determine whether specifications 

established under final § 111.70 are met 

and under final § 111.75(a) and (f) a 

manufacturer must use certain criteria 

to determine whether specifications for 

components and labels, respectively, are 

met. Thus, there are sufficient controls 

in other requirements to ensure the 

entire production and process controls 

are functioning as intended. 

4. Final § 111.123(a)(4) 

Final § 111.123(a)(4) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include conducting any 

required material review and making 

any required disposition decision. Final 

§ 111.123(a)(4) derives from the 

following proposed provisions: 

• Proposed § 111.37(b)(5) which, in 

part, would require the quality control 

unit to approve a material review and 

disposition decision related to batch 

production records; and 

• Proposed § 111.50(d)(1) which, in 

part, would require, if a batch deviates 

from the master manufacturing record, 

including any deviation from 

specifications, the quality control unit 

to conduct a material review and make 

a disposition decision. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.37(b)(5) or 111.50(d)(1). 

5. Final § 111.123(a)(5) 

Final § 111.123(a)(5) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include approving or 

rejecting any reprocessing. Final 

§ 111.123(a)(5) derives from proposed 

§ 111.37(b)(5) which would require the 

quality control unit to approve any 

reprocessing. For consistency with other 

provisions in this final rule (such as 

final § 111.90), final § 111.123(a)(5) 

includes a revision that quality control 

personnel must approve—or reject—any 

reprocessing. 

We did not receive comments specific 

to quality control operations under 

proposed § 111.37(b)(5). 

6. Final § 111.123(a)(6) 

Final § 111.123(a)(6) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include determining whether 

all in-process specifications established 

in accordance with § 111.70(c) are met. 

Final § 111.123(a)(6) derives from the 

following proposed provisions: 

• Proposed § 111.35(f) which would 

require you to monitor the in-process 

control points, steps, or stages to ensure 

specifications are met (including the inprocess specifications required under 

proposed § 111.35(e)(2)) and 

• Proposed § 111.37(a) which, in part, 

would require the quality control unit to 

ensure your manufacturing, packaging, 

labeling, and holding operations are 

performed in a manner that prevents 

adulteration, including that such 

operations ensure the dietary 

supplement meets its specifications for 

identity, purity, quality, strength, and 

composition. 

Final § 111.123(a)(6) is consistent 

with the overall approach, set forth in 

final §§ 111.70, 111.73, and 111.75, that 

focuses on ensuring the quality of the 

dietary supplement throughout the 

production and process control system. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.35(e)(2) or (f), or 

111.37(a). 

7. Final § 111.123(a)(7) 

Final § 111.123(a)(7) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include determining whether 

each finished batch conforms to product 

specifications established in accordance 

with final § 111.70(e). Final 

§ 111.123(a)(7) derives from proposed 

§ 111.37(b)(2) which, in part, would 

require the quality control unit to 

determine whether all dietary 

supplements conform to specifications. 

We did not receive comments specific 

to quality control operations under 

proposed § 111.37(b)(2). 

8. Final § 111.123(a)(8) 

Final § 111.123(a)(8) requires that 

quality control operations for the master 

manufacturing record, the batch 

production record, and manufacturing 

operations include approving and 

releasing, or rejecting, each finished 

batch for distribution, including any 

reprocessed finished batch. Final 

§ 111.123(a)(8) derives from the 

following proposed provisions: 

• Proposed § 111.37(b)(5) which, in 

part, would require the quality control 

unit to approve batch production 

records for releasing finished batches for 

distribution; 

• Proposed § 111.50(d)(2) which 

would require the quality control unit to 

not approve and release for distribution 

any batch that does not meet all 

specifications; and 

• Proposed § 111.50(g) which would 

require the quality control unit to not 

approve and release for distribution any 

reprocessed batch of dietary supplement 

that does not meet all specifications. 

We did not receive comments specific 

to the proposed provisions cited above. 

9. Final § 111.123(b) 

Final § 111.123(b) requires that 

quality control personnel must not 

approve and release for distribution: 

• any batch of dietary supplement for 

which any component in the batch does 

not meet its identity specification; 

• any batch of dietary supplement, 

including any reprocessed batch, that 

does not meet all product specifications 

established in accordance with 

§ 111.70(e); 

• any batch of dietary supplement, 

including any reprocessed batch, that 

has not been manufactured, packaged, 

labeled, and held under conditions to 

prevent adulteration under section 

402(a)(1), (a)(2), (a)(3), and (a)(4) of the 

act; and 

• any product received from a 

supplier for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier) for 

which sufficient assurance is not 

provided to adequately identify the 

product and to determine that the 

product is consistent with your 

purchase order. 

Final § 111.123(b) derives from the 

following proposed provisions: 

• Proposed § 111.50(d)(2) which 

would require the quality control unit to 

not approve and release for distribution 

any batch of dietary supplement that 

does not meet all specifications; 

• Proposed § 111.50(g) which would 

require that a reprocessed batch of 

dietary supplement meet all 

specifications and that the quality 

control unit approve its release for 

distribution; and 

• Proposed § 111.37(b)(11)(iii) which 

would require the quality control unit to 

collect representative samples of each 

batch of dietary supplement 

manufactured to determine, before 

releasing for distribution, whether the 

dietary supplement meets its 


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specifications for identity, purity, 

quality, strength, and composition. 

The final provision clarifies all of the 

responsibilities of quality control 

personnel and includes provisions 

consistent with changes made to final 

§§ 111.73, 111.77, and 111.90. 

We did not receive comments specific 

to those aspects of proposed 

§§ 111.50(g) and 111.37(b)(11)(iii) that 

are relevant to final § 111.123(b). We 

discuss in the following paragraphs 

comments we received to proposed 

§ 111.50(d)(2). 

(Comment 230) Several comments 

object to proposed § 111.50(d)(2) 

because it would prohibit the release of 

any batch that does not meet all 

specifications. Other comments suggest 

the prohibition should apply to meeting 

‘‘release specifications’’ or ‘‘essential 

manufacturer specifications’’ rather than 

‘‘all specifications’’ because in-process 

deviations and minor deviations may 

not affect product quality. 

(Response) A finished dietary 

supplement that is ready for release for 

distribution must meet component 

specifications for identity established 

under final § 111.70(b) and all product 

specifications established for the batch 

under final § 111.70(e) and must be 

manufactured in a manner to prevent 

adulteration under section 402(a)(1), 

(a)(2), (a)(3), and (a)(4) of the act. The 

final rule does not prevent you from 

establishing additional specifications 

that do not affect the identity, purity, 

strength, composition, or contaminant 

levels of your finished dietary 

supplement. Such a specification is not 

a component specification for identity 

or a product specification that is 

required under the final rule. Final 

§ 111.123(b) would not preclude you 

from releasing a product that fails to 

meet a specification that is not a 

component specification for identity or 

a product specification established 

under final § 111.70 provided quality 

control personnel approve such release. 

Final § 111.123(b) would not preclude 

you from releasing a product that you 

are permitted to release under final 

§ 111.77. 

(Comment 231) Some comments note 

that proposed § 111.50(d)(2) would not 

allow the quality control unit to conduct 

an investigation, and make a disposition 

decision, of the failure of a batch to 

meet specifications. These comments 

assert proposed § 111.50(d)(2) therefore 

restricts the provision in proposed 

§ 111.50(d)(1) which would require that, 

if a batch deviates from the master 

manufacturing record, including any 

deviation from specifications, the 

quality control unit must conduct a 

material review and make a disposition 

decision. The comments argue the 

quality control unit should have the 

authority to release products with minor 

deviations. 

(Response) As discussed previously 

(see discussion of final § 111.90 in 

subpart E in section X of this 

document), we acknowledge that some 

specifications, such as component, other 

than for identity, and in-process 

specifications, that are not met may be 

able to be corrected by a treatment or an 

in-process adjustment. Quality control 

personnel would need to conduct a 

material review and disposition 

decision for any such specification not 

met. If there are specifications for any 

point, step, or stage in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record (final § 111.70(a)), you must 

determine whether these specifications 

are met (final § 111.73). 

Final § 111.123(b) does not preclude 

you, for example, from releasing a 

product that was the subject of a 

material review because sampling 

procedures had not been followed if, as 

a corrective action, the appropriate 

samples were collected and subjected to 

appropriate tests and examinations. 

K. What Quality Control Operations Are 

Required for Packaging and Labeling 

Operations? (Final § 111.127) 

Final § 111.127 sets forth the required 

operations that quality control 

personnel must perform with respect to 

packaging and labeling operations. 

1. Final § 111.127(a) and (b) 

Final § 111.127(a) and (b) set forth 

requirements for product you receive for 

packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier). 

Final § 111.127(a) and (b) apply to 

product that has left the control of the 

person who manufactured the batch; for 

example, the purchase of dietary 

supplements in bulk for packaging or 

labeling by a person who will distribute 

the packaged and labeled dietary 

supplements under a private label. If 

you are a packager or labeler who 

operates under contract to the 

manufacturer, and you will return the 

dietary supplement to the manufacturer, 

we would not consider that you are 

‘‘receiving’’ product within the meaning 

of final § 111.127(a) and (b). We would 

consider you to be no different than an 

operating unit of the manufacturer. In 

section VI of this document (subpart A), 

we discuss in detail the scope of this 

final rule and its applicability to 

contractors. 

a. Final § 111.127(a). Final 

§ 111.127(a) requires that quality control 

operations for packaging and labeling 

operations include reviewing the results 

of any visual examination and 

documentation to ensure that 

specifications established under final 

§ 111.70(f) are met for product you 

receive for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier). 

Final § 111.127(a) derives from the 

following proposed provisions: 

• Proposed § 111.40(a)(2) which 

would require you to visually examine 

the supplier’s invoice, guarantee, or 

certification to ensure that dietary 

supplements you receive are consistent 

with your purchase order and perform 

testing, as needed, to determine whether 

specifications are met and 

• Proposed § 111.40(a)(3) which 

would, in part, require you to 

quarantine dietary supplements you 

receive until your quality control unit 

reviews the supplier’s invoice, 

guarantee, or certification and performs 

testing, as needed, of a representative 

sample to determine that specifications 

are met. 

Final § 111.127(a) includes revisions 

associated with final §§ 111.70(f) and 

111.75(e) which set forth requirements 

for all products you receive from a 

supplier for packaging or labeling as 

dietary supplements (and for 

distribution rather than for return to the 

supplier). As discussed in section X of 

this document, under final § 111.70(f) if 

you receive such product, you must 

establish specifications to provide 

sufficient assurance that the product 

you receive is adequately identified and 

is consistent with your purchase order. 

In addition, under final § 111.75(e) 

before you package or label such 

products, you must visually examine 

the products and have documentation to 

determine whether the specifications 

that you established under final 

§ 111.70(f) are met. The documentation 

you have to satisfy the requirements of 

final § 111.75(e) is not limited to a 

supplier’s invoice, guarantee, or 

certification and, thus, final § 111.127(a) 

incorporates the standard set by final 

§ 111.75(e) (i.e., documentation) rather 

than the proposed standard of the 

supplier’s invoice, guarantee, or 

certification. In addition, consistent 

with final § 111.75(e), final § 111.127(a) 

requires quality control personnel to 

review the results of the visual 

examination but not otherwise review 

the results of tests or examinations. 


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We did not receive comments specific 

to quality control operations under 

proposed § 111.40(a)(2) or (a)(3). 

b. Final § 111.127(b). Final 

§ 111.127(b) requires that quality control 

operations for packaging and labeling 

operations include approving, and 

releasing from quarantine, all products 

you receive for packaging and labeling 

as a dietary supplement (and for 

distribution rather than for return to the 

supplier) before the products are used 

for packaging and labeling. Final 

§ 111.127(b) derives from proposed 

§ 111.40(a)(3) which, in part, would 

require you to quarantine dietary 

supplements that you receive until your 

quality control unit reviews the 

supplier’s invoice, guarantee, or 

certification and performs testing, as 

needed, of a representative sample to 

determine that specifications are met, 

and approves and releases the dietary 

supplements from quarantine before you 

use them. 

As with final § 111.127(a), final 

§ 111.127(b) includes revisions 

associated with changes made in final 

§§ 111.70(f) and 111.75(e). 

We did not receive comments specific 

to quality control operations under 

proposed § 111.40(a)(3). 

2. Final § 111.127(c) 

Final § 111.127(c) requires that 

quality control operations for packaging 

and labeling operations include 

reviewing and approving all records for 

packaging and label operations. Final 

§ 111.127(c) derives from proposed 

§ 111.37(b)(10) which, in part, would 

require the quality control unit to 

review and approve all packaging and 

label records. 

We did not receive comments specific 

to quality control operations under 

proposed § 111.37(b)(10). 

3. Final § 111.127(d) 

Final § 111.127(d) requires that 

quality control operations for packaging 

and labeling operations include 

determining whether the finished 

packaged and labeled dietary 

supplement conforms to specifications 

established in accordance with final 

§ 111.70(g). Final § 111.127(d) derives 

from the following proposed provisions: 

• Proposed § 111.37(b)(2) which, in 

part, would require the quality control 

unit to determine whether all dietary 

supplements conform to specifications 

and 

• Proposed § 111.37(b)(11)(iv) which, 

in part, would require the quality 

control unit to collect representative 

samples of each batch of packaged and 

labeled dietary supplements to 

determine that you used the packaging 

specified in the master manufacturing 

record and applied the label specified in 

the master manufacturing record. 

For clarity, final § 111.127(d) 

identifies the specifications as those 

established in final § 111.70(g). 

We did not receive comments specific 

to quality control operations under 

proposed § 111.37(b)(2) or (b)(11)(iv). 

4. Final § 111.127(e) 

Final § 111.127(e) requires that 

quality control operations for packaging 

and labeling operations include 

conducting any required material 

review and making any required 

disposition decision. Final § 111.127(e) 

derives from the following proposed 

provisions: 

• Proposed § 111.70(c) which would 

require you to conduct a material review 

and make a disposition decision of any 

packaged and labeled dietary 

supplement that does not meet 

specifications and 

• Proposed § 111.40(a)(3) which, in 

part, would require you, if 

specifications are not met for a received 

dietary supplement, to conduct a 

material review and make a disposition 

decision. 

Final § 111.127(e) includes revisions 

associated with final § 111.87 which 

requires quality control personnel to 

conduct any required material review 

and make any required disposition 

decision. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.70(c) or 111.40(a)(3). 

5. Final § 111.127(f) and (g) 

Final § 111.127(f) requires that quality 

control operations for packaging and 

labeling operations include approving 

or rejecting any repackaging of a 

packaged dietary supplement. Final 

§ 111.127(g) requires that quality control 

operations for returned dietary 

supplements include approving or 

rejecting any relabeling of a packaged 

and labeled dietary supplement. Final 

§ 111.127(f) and (g) derive from the 

following proposed provisions: 

• Proposed § 111.37(b)(10) which, in 

part, would require the quality control 

unit to approve any repackaging and 

relabeling and 

• Proposed § 111.70(d) which would 

require the quality control unit to 

approve and document any repackaging 

or relabeling of a dietary supplement. 

For consistency with other provisions 

in this final rule (such as final § 111.90), 

final § 111.127(f) and (g) provide that 

quality control personnel must clearly 

choose between approving—or 

rejecting—any repackaged or relabeled 

dietary supplements. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.37(b)(10) or 111.70(d). 

6. Final § 111.127(h) 

Final § 111.127(h) requires that 

quality control operations for packaging 

and labeling operations include 

approving for release, or rejecting, any 

packaged and labeled dietary 

supplement (including a repackaged or 

relabeled dietary supplement) for 

distribution. Final § 111.127(h) derives 

from the following proposed provisions: 

• Proposed § 111.37(b)(10) which, in 

part, would require the quality control 

unit to approve the release of packaged 

and labeled dietary supplements for 

distribution; and 

• Proposed § 111.70(e) which, in part, 

would require the quality control unit to 

approve or reject the release of any 

repackaged or relabeled dietary 

supplement. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.37(b)(10) or 111.70(e). 

L. What Quality Control Operations Are 

Required for Returned Dietary 

Supplements? (Final § 111.130) 

Final § 111.130 sets forth the 

minimum required operations quality 

control personnel must perform with 

respect to returned dietary supplements. 

Final § 111.130 modifies proposed 

§ 111.85 which set forth requirements 

for returned dietary ingredients and 

dietary supplements, including 

requirements for quality control 

operations for returned dietary 

supplements. We did not explicitly 

include quality control operations with 

respect to returned dietary supplements 

under proposed § 111.37 but did 

include quality control operations in 

proposed § 111.85 for returned dietary 

supplements. The provisions of the final 

rule that pertain to returned dietary 

supplements are set forth in final 

subpart N. However, we are duplicating 

these requirements in subpart F to make 

clear that once returned products are 

back within your control, quality 

control personnel must perform 

appropriate operations before the 

products are redistributed, if they are 

approved for redistribution. Any 

returned dietary supplements that are 

reprocessed must be returned to your 

production and process control system, 

and, therefore, must be properly 

reviewed by quality control personnel. 

1. Final § 111.130(a) 

Final § 111.130(a) requires that 

quality control operations for returned 

dietary supplements include conducting 

any required material review and 


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making any required disposition 

decision. Final § 111.130(a) differs 

slightly from proposed § 111.85(a) 

which, in part, would require the 

quality control unit to conduct a 

material review and make a disposition 

decision for any returned dietary 

supplement. 

(Comment 232–233) Some comments 

support the proposed requirement to 

specify that it is the quality control unit 

that conducts the material review and 

makes the disposition decision 

regarding returned dietary supplement 

products. 

(Response) These comments are 

consistent with proposed § 111.85(a) 

which is being incorporated into final 

§ 111.130(a). 

2. Final § 111.130(a)(1) and (a)(2) 

Final § 111.130(a)(1) requires that 

quality control operations for returned 

dietary supplements include 

determining whether tests or 

examination are necessary to determine 

compliance with product specifications 

established in accordance with final 

§ 111.70(e). 

Final § 111.130(a)(2) requires that the 

review and disposition decision for 

returned dietary supplements include 

review of the results of any tests or 

examinations that are conducted to 

determine compliance with product 

specifications established in accordance 

with final § 111.70(e). 

3. Final § 111.130(b) 

Final § 111.130(b) requires that 

quality control operations for returned 

dietary supplements include approving 

or rejecting any salvage and 

redistribution of any returned dietary 

supplement. Final § 111.130(b) derives 

from proposed § 111.37(b)(15) which, in 

part, would require the quality control 

unit to approve the distribution of 

returned dietary supplements. As 

discussed in the preamble to the 2003 

CGMP Proposal, ‘‘salvage’’ means to 

return to distribution without 

reprocessing (68 FR 12157 at 12215). 

For consistency with other regulations 

in this final rule (such as final § 111.90), 

final § 111.130(e) provides that quality 

control personnel must clearly choose 

between approving—or rejecting—any 

salvage and redistribution. 

(Comment 234) Some comments 

support the proposed requirement to 

specify that it is the quality control unit 

who approves, or rejects, a returned 

dietary supplement for redistribution. 

(Response) These comments are 

consistent with proposed § 111.37(b)(15) 

which is being incorporated into final 

§ 111.130(b). 

4. Final § 111.130(c) 

Final § 111.130(c) requires that 

quality control operations for returned 

dietary supplements include approving 

or rejecting any reprocessing of any 

returned dietary supplement. Final 

§ 111.130(c) derives from proposed 

§ 111.37(b)(15) which, in part, would 

require the quality control unit to 

approve the reprocessing of returned 

dietary supplements. For consistency 

with other provisions of this final rule 

(such as final § 111.90), final 

§ 111.130(c) provides that quality 

control personnel must clearly choose 

between approving—or rejecting—any 

reprocessing. 

(Comment 235) One comment argues 

that the responsibility to decide whether 

a returned dietary supplement is 

reprocessed belongs with qualified 

persons in manufacturing operations, 

and the only responsibility of the 

quality control unit is to approve the 

reprocessed product for distribution. 

(Response) We disagree with the 

comment. An underlying principle of 

these CGMP requirements is that quality 

control personnel oversee the design 

and conduct of manufacturing, 

packaging, labeling, and holding 

operations. A decision about when 

reprocessing is, or is not, appropriate 

requires oversight. 

5. Final § 111.130(d) 

Final § 111.130(d) requires that 

quality control operations for returned 

dietary supplements include 

determining whether the reprocessed 

dietary supplement meets product 

specifications and either approving for 

release, or rejecting, any returned 

dietary supplement that is reprocessed. 

Final § 111.130(d) derives from the 

following proposed provisions: 

• Proposed § 111.37(b)(2) which, in 

part, would require the quality control 

unit to determine whether all dietary 

supplements conform to specifications; 

and 

• Proposed § 111.65(d) which, in part, 

would require you, if a material review 

and disposition decision allows you to 

reprocess a dietary supplement, to 

ensure it meets specifications and is 

approved by the quality control unit. 

For consistency with other regulations 

in this final rule (such as final § 111.90), 

final § 111.130(d) provides that quality 

control personnel must clearly choose 

between approving—or rejecting—a 

reprocessed dietary supplement. 

We did not receive comments specific 

to quality control operations under 

proposed §§ 111.37(b)(2) or 111.65(d). 

M. What Quality Control Operations Are 

Required for Product Complaints? (Final 

§ 111.135) 

Final § 111.135 requires that quality 

control operations for product 

complaints include reviewing and 

approving decisions about whether to 

investigate a product complaint and 

reviewing and approving the findings 

and followup action of any investigation 

performed. 

Final § 111.135 derives from proposed 

§ 111.95 which would set forth 

requirements for consumer complaints 

(now ‘‘product complaints’’), including 

requirements for quality control 

operations for consumer complaints. We 

did not explicitly include quality 

control operations with respect to 

consumer complaints under proposed 

§ 111.37 but did include quality control 

operations in proposed § 111.95 for 

review and investigation of consumer 

complaints. The final rule’s product 

complaint requirements are now set 

forth in final subpart O. However, we 

have duplicated the requirements for 

quality control operations for product 

complaints in subpart F to make clear 

that your investigation of the product 

complaint has the potential to uncover 

a problem with your production and 

process control system and, therefore, 

quality control personnel must exercise 

appropriate oversight of your 

investigation of any product complaint. 

N. What Records Must You Make and 

Keep? (Final § 111.140) 

Final § 111.140 sets forth the 

requirements for records that quality 

control personnel must make and keep. 

1. Final § 111.140(a) 

Final § 111.140(a) requires quality 

control personnel to make and keep 

records required under subpart F in 

accordance with subpart P. Final 

§ 111.140(a) derives from proposed 

§ 111.37(d) with editorial revisions 

associated with the reorganization. 

Other than comments that generally 

opposed the requirements to make and 

keep records, and to have records 

available for inspection and copying by 

FDA when requested (see the discussion 

in section V of this document), we did 

not receive comments specific to 

proposed § 111.37(d). 

2. Final § 111.140(b)(1) 

The final rule (final § 111.103) 

requires you to establish and follow 

written procedures for the 

responsibilities of the quality control 

operations, including written 

procedures for conducting a material 

review and making a disposition 

decision and for approving or rejecting 


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reprocessing. The written procedures 

are records. Therefore, final 

§ 111.140(b)(1) requires you to make and 

keep a record of the written procedures 

for the responsibilities of the quality 

control operations. 

3. Final § 111.140(b)(2) 

Final § 111.140(b)(2) requires written 

documentation, at the time of 

performance, that quality control 

personnel performed the review, 

approval, or rejection requirements 

under subpart F. Final § 111.140(b)(2)(i) 

requires quality control personnel to 

record the date that the review, 

approval, or rejection was performed. 

Final § 111.140(b)(2)(ii) requires quality 

control personnel to record the 

signature of the person performing the 

review, approval, or rejection. Final 

§ 111.140(b)(2) derives from proposed 

§ 111.37(c) with revisions associated 

with the reorganization. 

We did not receive comments specific 

to proposed § 111.37(c). 

4. Final § 111.140(b)(3) 

Final § 111.140(b)(3) requires quality 

control personnel to document any 

material review and disposition 

decision and followup and include the 

documentation in the batch record. 

Final § 111.140(b)(3) derives from 

proposed § 111.35(j) with revisions 

associated with the reorganization and a 

revision, associated with final § 111.87 

which requires quality control 

personnel to conduct the material 

review and make the disposition 

decision. 

Final § 111.140(b)(3) details the type 

of information that must be included as 

part of this documentation. Five 

paragraphs derive from proposed 

§ 111.35(j)(1) through (j)(5), with 

editorial changes associated with the 

reorganization. One paragraph is 

associated with final § 111.90(b) which 

requires that you not reprocess any 

component or dietary supplement that 

is rejected or treat a component or make 

an in-process adjustment to make it 

suitable for use in the manufacture of a 

dietary supplement, unless quality 

control personnel conduct a material 

review and make a disposition decision 

that is based on a scientifically valid 

reason and approve the reprocessing, 

treatment, or in-process adjustment. 

Another paragraph derives, in part, from 

proposed § 111.37(c)(2) which would 

require the signature of the quality 

control unit person performing the 

requirement. 

The documentation that must be 

included under final § 111.140(b)(3) is 

as follows: 

• Section 111.140(b)(3)(i)—

Identification of the specific deviation 

or the unanticipated occurrence; 

• Section 111.140(b)(3)(ii)—A 

description of your investigation into 

the cause of the deviation from the 

specification or the unanticipated 

occurrence; 

• Section 111.140(b)(3)(iii)—An 

evaluation of whether the deviation or 

unanticipated occurrence has resulted 

in or could lead to a failure to ensure 

the quality of the dietary supplement or 

a failure to package and label the dietary 

supplement as specified in the master 

manufacturing record; 

• Section 111.140(b)(3)(iv)—

Identification of the action(s) taken to 

correct, and prevent a recurrence of, the 

deviation or the unanticipated 

occurrence; 

• Section 111.140(b)(3)(v)—An 

explanation of what you did with the 

component, dietary supplement, 

packaging, or label; 

• Section 111.140(b)(3)(vi)—A 

scientifically valid reason for any 

reprocessing of a dietary supplement 

that is rejected, or the treatment or inprocess adjustment of a component that 

is rejected; and 

• Section 111.140(b)(3)(vii)—The 

signature of the individual(s) designated 

to perform the quality control operation, 

who conducted the material review and 

made the disposition decision, and of 

each qualified individual who provided 

information relevant to that material 

review and disposition decision. 

We did not receive comments specific 

to proposed § 111.35(j). 

XII. Comments on the Production and 

Process Control System: Requirements 

for Components, Packaging, and Labels, 

and for Product that You Receive for 

Packaging or Labeling as a Dietary 

Supplement (Final Subpart G) 

A. Organization of Final Subpart G 

In the 2003 CGMP Proposal, the 

requirements for production and 

process controls related to components, 

packaging, dietary ingredients, labels, 

and dietary supplements that you 

receive were set forth in proposed 

§ 111.40. As shown in table 8 of this 

document, we are reorganizing the 

requirements related to components, 

packaging, labels, and product that you 

receive for packaging and labeling as a 

dietary supplement, into a distinct 

subpart (final Subpart G—Production 

and Process Control System: 

Requirements for Components, 

Packaging, and Labels, and for Product 

that You Receive for Packaging or 

Labeling as a Dietary Supplement). 

Table 8 lists the sections in final subpart 

G and identifies the sections in the 2003 

CGMP Proposal that form the basis of 

the final rule. 

TABLE 8.—DERIVATION OF SECTIONS

IN FINAL SUBPART G 

Final Rule 2003 CGMP 

Proposal 

§ 111.153 What Are the 

requirements under 

this subpart G for written procedures? 

N/A 

§ 111.155 What requirements apply to components of dietary supplements? § 111.40(a)(1) 

through (a)(5) 

§ 111.35(d)(1) 

throug (d)(5) 

§ 111.160 What requirements apply to packaging and labels received? § 111.35(e)(4) 

§ 111.40(a)(2) 

and (b) 

§ 111.165 What requirements apply to a product received for packaging or labeling as a 

dietary supplement 

(and for distribution 

rather than for return 

to the supplier)? 

§ 111.40(a) 

§ 111.170 What requirements apply to rejected components, 

packaging, and labels, 

and to rejected products that are received 

for packaging or labeling as a dietary supplement? 

§ 111.74 

§ 111.180 Under this 

subpart G, what 

records must you 

make and keep? 

§ 111.40(c)(1)(i) 

through 

(c)(1)(iv) and 

(c)(2) 

§ 111.35(d)(4) 

B. Highlights of Changes to the 

Proposed Requirements for 

Components, Packaging, and Labels, 

and Product That You Receive for 

Packaging or Labeling as a Dietary 

Supplement 

1. Revisions 

The final rule: 

• Applies to persons who 

manufacture, package, label, or hold a 

dietary supplement unless subject to an 

exclusion in § 111.1. 

• Includes requirements that apply to 

components, including components that 

are dietary ingredients, regardless of 

whether you receive the components or 

manufacture them yourself (final 

§§ 111.70(b) and 111.75(a)). 

• Separates the requirements for 

product you receive from a supplier for 

packaging or labeling as a dietary 

supplement (and for distribution rather 


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than for return to the supplier) (final 

§ 111.165) from the requirements for 

components (final § 111.155). 

2. Changes After Considering Comments 

The final rule incorporates a new 

requirement to establish and follow 

written procedures for fulfilling the 

requirements for components, 

packaging, labels, and product you 

receive from a supplier for packaging or 

labeling as a dietary supplement for 

distribution rather than for return to the 

supplier. 

C. General Comments on Proposed 

§ 111.40 (Final Subpart G) 

(Comment 236) One comment states 

that many companies use an electronic 

material resource planning system to 

control the status of inventory, and 

assert this type of system provides 

suitable controls to ensure only 

materials that are approved by the 

quality control unit are used. The 

comment notes only the quality control 

unit has the authority to release any 

material in quarantine and asks whether 

such a system would comply with the 

requirements of the proposed 

regulation. 

(Response) Based on the limited 

information provided by the comment, 

it appears the electronic inventory 

system that the comment describes 

would comply with the requirements of 

final § 111.155(c)(3) to quarantine 

components until quality control 

personnel release them for use in 

manufacture, provided that appropriate 

controls are established and used to 

ensure the system functions in 

accordance with its intended use as 

required by final § 111.30(e). We are 

making no changes based on this 

comment. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.153) 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

Final § 111.153 requires you to 

establish and follow written procedures 

for fulfilling the requirements of subpart 

G. Under final § 111.180(b)(1), as a 

conforming requirement, we require you 

to make and keep records of such 

written procedures. Such records would 

be available to us under the 

requirements in Subpart P—Records 

and Recordkeeping. 

E. What Requirements Apply to 

Components of Dietary Supplements? 

(Final § 111.155) 

The final rule applies only to persons 

who manufacture, package, label, or 

hold dietary supplements unless subject 

to an exclusion under final § 111.1. The 

effect of this revision is that the 

requirements that derive from proposed 

§ 111.40(a) for components you receive 

now apply to all components, whether 

you receive them or manufacture them 

yourself. 

The final rule separates the 

requirements for product you receive 

from a supplier for packaging or labeling 

as a dietary supplement (and for 

distribution rather than for return to the 

supplier) (final § 111.165) from the 

analogous requirements for components, 

packaging, and labels (final § 111.155). 

1. Proposed § 111.35(d) 

In proposed § 111.35(d), we would 

require that any substance, other than a 

‘‘dietary ingredient’’ within the meaning 

of section 201(ff) of the act, that is 

subject to section 409 of the act, be: (1) 

Authorized for use as a food additive 

under section 409 of the act; or (2) 

authorized by a prior sanction 

consistent with § 170.3(l) (21 CFR 

170.3(l)); or (3) if used as a color 

additive, subject to a listing that, by the 

terms of that listing (including a listing 

for use in coloring foods generally), 

includes the use in a dietary 

supplement; or (4) GRAS for use in a 

dietary supplement. We also proposed 

that any claim that a substance is GRAS 

must be supported by a citation to the 

agency’s regulations or by an 

explanation for why there is general 

recognition of safety of the use of the 

substance in a dietary supplement. 

Further, under § 111.35(d)(5), we 

proposed to require that you comply 

with all other applicable statutory and 

regulatory requirements under the act. 

We received several comments 

objecting to one or more of the 

provisions of proposed § 111.35(d) and 

to our statement in the preamble to the 

2003 CGMP Proposal regarding how we 

would apply the provisions of proposed 

§ 111.35(d)(4). After considering these 

comments, we have deleted the 

requirements in § 111.35(d) in this final 

rule. 

(Comment 237) Several comments 

recommend proposed § 111.35(d) be 

deleted because the statute already 

requires that ingredients, other than 

‘‘dietary ingredients,’’ be approved as a 

food additive or a color additive, or be 

GRAS. Some comments assert that 

proposed § 111.35(d) and proposed 

§ 111.5 already require compliance with 

all other applicable statutory and 

regulatory requirements under the act, 

and therefore, there is no need to refer 

to food additive, color additive, and 

GRAS requirements. Some comments 

assert that proposed § 111.35(d) is 

unnecessary because there is no such 

requirement in the food CGMPs. Other 

comments assert this proposed 

requirement should be deleted because 

it is only tangentially related to the 

manufacturing process, and CGMP 

should be focused on setting minimum 

standards for manufacturing systems 

and steps in the production and 

distribution of dietary supplements that 

are required to produce safe and 

accurately labeled products. Other 

comments assert that because the drug 

CGMPs do not have such a requirement, 

dietary supplement CGMPs should not 

have such a requirement. 

Other comments did not object to the 

principle underlying proposed 

§ 111.35(d), i.e., that we need to ensure 

GRAS substances used in dietary 

supplements are GRAS under the 

manufacturer’s specified use. However 

many comments disagreed, for various 

reasons, with the proposed requirement 

in § 111.35(d)(4) that a claim that a 

substance is GRAS must be supported 

by a citation to our regulations or by an 

explanation for why there is general 

recognition of safety of the use of the 

substance in a dietary supplement. 

(Response) We agree that proposed 

§ 111.35(d) is unnecessary because there 

are already existing statutory and 

regulatory requirements related to the 

lawful use of ingredients used in dietary 

supplements. We do not have to repeat 

those requirements in this final rule. 

Ensuring the ingredients you use to 

manufacture a dietary supplement are 

lawful under the applicable statutory 

and regulatory requirements is the 

responsibility of the dietary supplement 

manufacturer. 

For the reasons set forth in the 

previous paragraphs, we are deleting 

proposed § 111.35(d)(4) from the final 

rule. Because we are deleting this 

provision, it is unnecessary to respond 

to the various comments related to the 

documentation that proposed 

§ 111.35(d)(4) would have required, or 

whether we could not have included 

such requirements in the dietary 

supplement CGMP final rule because 

the requirements are not in food or drug 

CGMP regulations. 

We also agree that proposed 

§ 111.35(d)(5) is redundant to proposed 

§ 111.5 and final § 111.5 and are 

therefore not repeating proposed 

§ 111.35(d)(5) in final § 111.35. 

Although we are deleting § 111.35(d) 

from the final rule, there were several 


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10Although we refer to the term ‘‘food additive’’

in the preamble, the reader should also consider 

color additives and substances prior-sanctioned for 

such use as being relevant to the discussion. 

11It is important to note that it is the use of the 

substance, not the substance itself, that must be 

GRAS. The amount of a substance in the food is a 

critical factor in determining whether the use 

would be GRAS. 

comments that we received, and 

respond to in the following paragraphs, 

that seemed to question whether 

existing statutory and regulatory 

requirements apply to the use of 

ingredients in a dietary supplement. 

(Comment 238) One comment 

suggests components not found in 

finished goods in a material amount 

should not be subject to the same GRAS 

requirements as those found in a 

material amount. Another comment 

states dietary supplements are excluded 

from the food additive definition in 

section 201(s) of the act, and that 

components that constitute the dietary 

supplement are also excluded from the 

food additive definition. The comment 

suggests that, under proposed 

§ 111.35(d), we are erroneously trying to 

maintain food additive authority for 

dietary supplements. 

(Response) The assertion that dietary 

supplements and all of their 

components are not subject to the food 

additive provisions of the act’s 

definition is incorrect. We do maintain 

authority over the use of certain 

substances, as color additives, food 

additives,10 or GRAS substances that 

may be used in manufacturing dietary 

supplements. 

The food additive definition in 

section 201(s) of the act excludes ‘‘an 

ingredient described in paragraph (ff) in, 

or intended for use in, a dietary 

supplement.’’ Thus, a ‘‘dietary 

ingredient’’ described in section 

201(ff)(1) of the act is not a ‘‘food 

additive.’’ Nor can the use of a dietary 

ingredient be considered to be GRAS, 

since the GRAS status itself is an 

exception to the definition of a food 

additive. However, ingredients that may 

be used in a dietary supplement, other 

than those excepted in section 201(s), 

are subject to our regulatory authority as 

a food additive, unless their use is 

GRAS or authorized by a prior sanction. 

Thus, it is incorrect to say, as the 

comment asserts, that dietary 

supplements and all of their 

components are not subject to the food 

additive definition. 

We also disagree that components not 

found in finished goods in a material 

amount should not be subject to the 

same GRAS requirements as those found 

in a material amount. It is not clear what 

the comment meant by ‘‘material 

amount.’’ A food additive means ‘‘any 

substance the intended use of which 

results or may reasonably be expected to 

result, directly or indirectly, in its 

becoming a component or otherwise 

affecting the characteristics of any food’’

if the use of such substance is not GRAS 

(section 201(s) of the act).11 We have 

discretion to determine whether an 

ingredient is one where the agency 

would find the presence to be ‘‘de 

minimis’’ (Monsanto v. Kennedy, 613 

F.2d 947, 956 (D.C. Cir. 1979)). 

However, whether the agency would 

find it appropriate to exercise such 

discretion with respect to the use of a 

particular ingredient is beyond the 

scope of this final rule. 

(Comment 239) Several comments 

questioned whether certain ingredients 

would be considered GRAS. One 

comment stated excipients regularly 

used in pharmaceuticals for many years 

and safely used in dietary supplements 

may not be considered GRAS for use in 

foods, approved for use as a food 

additive, or considered a dietary 

ingredient. An example provided was 

‘‘croscarmellose sodium’’ used for 

disintegration. The comment asks 

permission to use any recognized 

excipient, an excipient that is 

monographed in a recognized 

compendium, used in drug products, or 

shown to be in use prior to the 

implementation of the final rule. Other 

comments stated proposed § 111.35(d) 

would be overly burdensome since 

many ingredients are GRAS for broad 

food use, have been used in dietary 

supplements without specific 

recognition as a GRAS use, and should 

be permitted. Other comments state 

substances listed in the USP National 

Formulary, Food Chemical Codex, the 

American Pharmaceutical Associations 

Handbook of Pharmaceutical Excipients, 

and FDA’s inactive ingredient guide are 

considered GRAS based on a history of 

common use even though there is no 

listing of these substances as GRAS. 

(Response) The GRAS status of 

specific uses of excipients cannot be 

treated as a general class and is beyond 

the scope of this final rule. It is possible 

that the data needed to support safe uses 

as an excipient in a drug may be widely 

known among experts and form a basis 

for a consensus that use in a dietary 

supplement is safe. However, use of 

drugs containing the excipient may be 

short term or may be intermittent, 

leading to far less exposure than routine 

use in some dietary supplements. As 

human exposure increases, not only 

does the safety profile of the intended 

excipient become more important, but 

the purity specifications also become 

more critical. We advise persons who 

need more information about the basis 

for concluding that a use of a substance 

is GRAS to consult § 170.30 and our 

GRAS Proposal to establish a 

notification program for the use of 

GRAS substances (62 FR 18938, April 

17, 1997). 

(Comment 240) Some comments 

assert it is not feasible to require that 

starting materials used by bulk 

ingredient manufacturers be GRAS or 

approved food additives. The comments 

state many ingredients are not food 

grade substances or approved for use in 

food until after processing. One 

comment states raw materials may 

become dietary ingredients after 

processing, but the materials from 

which the dietary ingredient is derived 

are not considered to be a GRAS 

ingredient, a dietary ingredient, or a 

dietary supplement. The comment gives 

examples of Ginkgo biloba leaves or 

Saw palmetto or cartilage. The comment 

asks us to consider natural products 

(from animal, mineral, or vegetable 

origin) to be included in the rule as 

potential raw materials for nutritional 

supplements. Another comment 

expresses concern that a soy isolate, 

from which natural vitamin E is 

derived, would not be considered a 

GRAS substance. 

(Response) These comments seem to 

be concerned about the regulatory status 

of substances used as raw materials in 

the manufacture of a dietary ingredient 

or dietary supplement. An important 

consideration, however, is whether such 

materials become a component of the 

dietary ingredient or dietary 

supplement. 

Dietary ingredient manufacturers who 

manufacture dietary ingredients for 

further processing by another person 

into a dietary supplement are outside 

the scope of this final rule. However, 

such manufacturers are still subject to 

other applicable statutory and 

regulatory provisions. For example, if 

you are a dietary ingredient 

manufacturer that uses a material in the 

manufacture of a dietary ingredient, and 

the material becomes part of the dietary 

ingredient, we would consider it to be 

part of the dietary ingredient and 

subject to the exception to the food 

additive definition in section 201(s)(6) 

of the act. However, because the 

material becomes a component of the 

dietary ingredient, you are subject to the 

applicable statutory and regulatory 

requirements that would apply to the 

dietary ingredient, including the safety 

of the dietary ingredient. 

If you use a material, other than a 

dietary ingredient, in the manufacture of 

a dietary supplement, that becomes a 


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part of the dietary supplement, you are 

subject to the applicable statutory and 

regulatory requirements that apply to 

the use of such material, including its 

safety for such use. In this case, the use 

of the material would be subject to 

regulation as a food additive (unless it 

is GRAS or prior-sanctioned). 

Alternatively, if you use material in 

the manufacture of a dietary ingredient 

or a dietary supplement that does not 

become part of the dietary ingredient or 

dietary supplement, then we would not 

consider the material to be a food. 

(Comment 241) Several comments 

state the color additive provision would 

be too restrictive if it only allowed 

colors listed for use in a dietary 

supplement, rather than colors listed for 

use in foods generally. Some comments 

note none of the color additives 

currently approved generally for ‘‘food’’

use is approved specifically for dietary 

supplements within the food category. 

Another comment argues we gave no 

rationale for requiring a categorical 

listing under specific color additives for 

dietary supplements. The comment 

states color additives are not used in 

any greater amount in supplements than 

in foods and, if anything, are probably 

used less because supplements are 

consumed in smaller amounts than 

foods and less color additive must be 

used to achieve the desired effect. One 

comment notes it was not familiar with 

any evidence to indicate that a color 

additive (whether it is certified or 

exempt) found by us to be safe for use 

in foods is not safe in dietary 

supplements. 

(Response) We acknowledge that the 

combination of proposed § 111.35(d)(3) 

and several color additive listings is 

confusing and could lead to incorrect 

conclusions about whether specific 

color additives may lawfully be used in 

a dietary supplement. As the comments 

point out, some listings for color 

additives (such as for the certified colors 

FD&C Blue No. 1 (21 CFR 74.101) and 

FD&C Red No. 40 (21 CFR 74.340)) list 

the color additive ‘‘for coloring foods 

(including dietary supplements) 

generally’’ (i.e., the listings specifically 

identify dietary supplements as a food 

category in which the color additive 

may be used). In contrast, some listings 

for color additives (such as for annatto 

extract (21 CFR 73.30) and for betacarotene (21 CFR 73.95)) list the color 

additive ‘‘for coloring foods generally’’

(i.e., without specifically identifying 

dietary supplements as a food category 

in which the color additive may be 

used). In general, the terms of either of 

these two kinds of listings (i.e., ‘‘for 

coloring foods (including dietary 

supplements) generally’’ and ‘‘for 

coloring foods generally’’) mean we saw 

no need for restriction of the use of the 

color additive when FDA approved the 

listing of that color additive. Thus, a 

color additive listed for use in food 

generally may be used in a dietary 

supplement. 

Although most listings of color 

additives provide for the use of the color 

additive in food generally, some listings 

for color additives restrict the use of the 

color additive in terms of the food 

category in which it may be used. For 

example, under 21 CFR 73.125 sodium 

copper chlorophyllin may be safely 

used to color citrus-based dry beverage 

mixes in an amount not exceeding 0.2 

percent in the dry mix, and the terms of 

this listing would not include the use in 

a dietary supplement. We list a color 

additive with restrictions such as these 

when for example, the person who 

submits a petition for us to approve the 

listing of a color additive only requests 

a specific use, or when the available 

data and information only support the 

safety of a limited consumption of the 

color additive. 

2. Final § 111.155(a) 

Final § 111.155(a) (proposed 

§ 111.40(a)(1)) requires you to visually 

examine each immediate container or 

grouping of immediate containers in a 

shipment you receive for appropriate 

content label, container damage, or 

broken seals to determine whether the 

container condition may have resulted 

in contamination or deterioration of the 

components. Final § 111.155(a) is 

substantially similar to proposed 

§ 111.40(a)(1) which would require you, 

for components you receive, to visually 

examine each container or grouping of 

containers in a shipment for appropriate 

content label, container damage, or 

broken seals to determine whether the 

container condition has resulted in 

contamination or deterioration of the 

components. Because you do not receive 

shipments for components you make, 

we are revising proposed § 111.40(a) so 

that it applies only to shipments of 

components you receive. We have 

added the word ‘‘immediate’’ to identify 

the container as the one in contact with 

the dietary supplement or component. 

We also have changed ‘‘has resulted’’ to 

‘‘may have resulted’’ since in some 

cases you may not be able to make a 

final determination from a visual 

inspection alone whether the container 

condition has resulted in contamination 

or deterioration of the components. 

(Comment 242) One comment 

supports the proposed requirements of 

proposed § 111.40(a) as an effective 

guideline for the inspection of 

purchased ingredients. 

(Response) The provisions of final 

§ 111.155(a) are requirements, not 

guidelines, as stated by the comment. 

3. Final § 111.155(b) 

Final § 111.155(b) (proposed 

§ 111.40(a)(2)) requires you to visually 

examine the supplier’s invoice, 

guarantee, or certification in a shipment 

you receive to ensure that the 

components are consistent with your 

purchase order. Final § 111.155(b) is 

substantially similar to proposed 

§ 111.40(a)(2) which would require you 

to visually examine the supplier’s 

invoice, guarantee, or certification to 

ensure the components are consistent 

with your purchase order and perform 

testing, as needed, to determine whether 

specifications are met. As with final 

§ 111.155(a), final § 111.155(b) clarifies 

that the invoice, guarantee, or 

certification comes in the shipment you 

receive. 

Final § 111.155(b) does not include 

any requirements related to testing 

components. Final § 111.75(a) sets forth 

the requirements to test or examine 

components; final §§ 111.110 and 

111.120 set forth requirements for 

quality control personnel to ensure that 

appropriate tests or examinations are 

conducted, review the results of any 

tests or examination, determine whether 

components conform to specifications, 

and approve the components before 

they are used in the manufacture of a 

dietary supplement. Given this set of 

requirements, it would be redundant to 

set forth requirements regarding testing 

for components in final subpart G. 

We did not receive comments specific 

to the requirements of proposed 

§ 111.40(a)(2). 

4. Final § 111.155(c) 

Final § 111.155(c) (proposed 

§ 111.40(a)(3)) requires you to 

quarantine components before you use 

them in the manufacture of a dietary 

supplement until: 

• You collect representative samples 

of each unique lot of components (and, 

for components that you receive, of each 

unique shipment, and of each unique lot 

within each unique shipment); 

• Quality control personnel review 

and approve the results of any test or 

examinations conducted on 

components; and 

• Quality control personnel approve 

the components for use in the 

manufacture of a dietary supplement, 

including approval of any treatment 

(including in-process adjustments) of 

components to make them suitable for 

use in the manufacture of a dietary 

supplement, and release them from 

quarantine. 


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Final § 111.155 modifies proposed 

§ 111.40(a)(3) which would require: 

• You to quarantine components until 

your quality control unit reviews the 

supplier’s invoice, guarantee, or 

certification; 

• The quality control unit to perform 

testing, as needed, of a representative 

sample to determine that specifications 

are met; 

• You to conduct a material review 

and make a disposition decision if 

specifications are not met; and 

• The quality control unit to approve 

and release the components from 

quarantine before you use them. 

Final § 111.155(c) includes revisions 

related to the following changes to other 

provisions already discussed. 

• Under final § 111.110, quality 

control personnel ensure that all 

appropriate tests and examinations are 

conducted, and review and approve the 

results of tests and examinations 

conducted on components, but quality 

control personnel are not required to 

conduct the tests or examinations; 

• Under final § 111.80(a), we 

establish the convention in this final 

rule of referring to ‘‘each unique lot 

within each unique shipment’’ rather 

than ‘‘each shipment lot;’’

• The requirements to conduct a 

material review and make a disposition 

decision are already set forth in final 

§§ 111.87, 111.113, and 111.120 and, 

therefore, are not repeated in final 

§ 111.155; and 

• Under final § 111.90(c), any batch of 

dietary supplement that is reprocessed, 

that contains components that you have 

treated, or to which you have made inprocess adjustments to make them 

suitable for use in the manufacture of 

the dietary supplement, must meet all 

product specifications for the dietary 

supplement and be approved by quality 

control personnel before being released 

for distribution. 

(Comment 243) Some comments 

address the requirement to quarantine 

components before you use them and 

assert that it is not feasible to quarantine 

incoming materials in a continuous 

extraction and purification operation, 

such as one built adjacent to a soy 

crushing or vegetable oil refinery to 

receive a continuous side stream flow 

from that operation. One comment 

explains that in such operations, 

quarantine and quality control approval 

occurs later in the process after the 

material has been isolated and 

concentrated in a stable matrix suitable 

for holding. One comment suggests 

proposed § 111.40(a)(3) state 

‘‘quarantine components or dietary 

supplements as applicable * * *’’. 

(Response) We decline to revise 

proposed § 111.40(a)(3) as suggested by 

the comments. The comment describes 

a situation where a manufacturer of a 

dietary supplement is also 

manufacturing a dietary ingredient or 

other component but only provides 

limited information. It appears that, 

however, the procedures described for 

quarantine of the isolated, stable matrix, 

with subsequent evaluation by quality 

control personnel before release for use 

in the manufacture of the dietary 

supplement, would satisfy the 

requirements of final § 111.155(c), 

provided quality control personnel are 

able to determine that all specifications 

for the component are met. 

(Comment 244) One comment states 

that plant personnel who are not 

formally part of the manufacturer’s 

quality control unit can conduct the 

quality control functions required for 

the release of materials from quarantine 

before use. 

(Response) As already discussed with 

respect to the definition of quality 

control personnel (see section VI of this 

document), these comments may have 

misunderstood the role of the quality 

control unit (now quality control 

personnel). To clarify that role, final 

§ 111.12(b) states you must identify a 

qualified person who is responsible for 

your quality control operations. 

(Comment 245) One comment 

suggests components that cannot be 

used in a short time should be retested 

at least yearly. 

(Response) We are making no changes 

to the provision after considering this 

comment. Whether any tests or 

examinations must be repeated over 

time, or whether the information in a 

certificate of analysis remains valid over 

time, is a matter to be decided by the 

manufacturer based on the established 

characteristics and shelf life of the 

component. 

5. Final § 111.155(d) 

Final § 111.155(d)(1) (proposed 

§ 111.40(a)(4)) requires you to identify 

each unique lot within each unique 

shipment of components you receive 

and any lot of components that you 

produce in a manner that allows you to 

trace the lot to the supplier, the date 

received, the name of the component, 

the status of the component (e.g., 

quarantined, approved, or rejected), and 

to the dietary supplement you 

manufactured and distributed. Final 

§ 111.155(d)(2) requires you to use this 

unique identifier whenever you record 

the disposition of each unique lot 

within each unique shipment of 

components that you receive and any lot 

of components that you produce. 

Final § 111.155(d)(1) and (d)(2) are 

substantially similar to proposed 

§ 111.40(a)(4) which would require you 

to identify each lot of components in a 

shipment in a manner that allows you 

to trace the shipment to the supplier, 

the date received, the name of the 

component, and the status (e.g., 

quarantined, approved, or rejected), and 

to trace the shipment lot to the dietary 

supplement you manufactured and 

distributed. Proposed § 111.40(a)(4) also 

would require you to use this unique 

identifier whenever you record the 

disposition of each shipment lot 

received. 

Final § 111.155(d)(1) and (d)(2) 

include revisions associated with final 

§ 111.80(a). 

We did not receive comments specific 

to proposed § 111.40(a)(4). 

6. Final § 111.155(e) 

Final § 111.155(e) (proposed 

§ 111.40(a)(5)) requires you to hold 

components under conditions that will 

protect against contamination and 

deterioration and avoid mixups. 

We did not receive comments specific 

to proposed § 111.40(a)(5). 

F. What Requirements Apply to 

Packaging and Labels Received? (Final 

§ 111.160) 

1. Final § 111.160(a) 

Final § 111.160(a) (proposed 

§ 111.40(b)(1)) requires you to visually 

examine each immediate container or 

grouping of immediate containers in a 

shipment for appropriate content label, 

container damage, or broken seals to 

determine whether the container 

condition may have resulted in 

contamination or deterioration of the 

packaging and labels. Final § 111.160(a) 

is similar to proposed § 111.40(b)(1) 

with the addition of the word 

‘‘immediate’’ to identify the container as 

the container that is in contact with the 

packaging or labels and substituting 

‘‘may have’’ for ‘‘has’’ before the word 

‘‘resulted’’ as discussed in this section. 

We did not receive comments specific 

to proposed § 111.40(b)(1). 

2. Final § 111.160(b) 

Final § 111.160(b) requires you to 

visually examine the supplier’s invoice, 

guarantee, or certification in a shipment 

to ensure the packaging or labels are 

consistent with your purchase order. 

Final § 111.160(b) is a new requirement 

that is analogous to proposed 

§ 111.40(a)(2). We are requiring in final 

§ 111.160(b), that, as part of your visual 

identification, you compare what was 

received, based on the supplier’s 

invoice, guarantee, or certification, with 


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your purchase order so you can ensure 

your specifications for packaging and 

labels are met. This is consistent with 

what you would do with respect to 

components and dietary supplements 

you receive. Without final § 111.160(b), 

the review by quality control personnel 

under final § 111.120(a) would be a 

matter of performing receiving 

operations rather than performing 

quality control operations; as already 

discussed in this section, some 

comments asserted the quality control 

unit should focus on reviewing the work 

of others rather than conducting the 

operations themselves. Thus, final 

§ 111.160 is consistent with these 

comments. 

3. Final § 111.160(c) 

Final § 111.160(c) requires you to 

quarantine packaging and labels before 

you use them in the manufacture of a 

dietary supplement until: 

• You collect representative samples 

of each unique shipment, and of each 

unique lot within each unique 

shipment, of packaging and labels and, 

at a minimum, conduct a visual 

identification of the immediate 

containers and closures; 

• Quality control personnel review 

and approve the results of any tests or 

examinations conducted on the 

packaging and labels; and 

• Quality control personnel approve 

the packaging and labels for use in the 

manufacture of a dietary supplement 

and release them from quarantine. 

Final § 111.160(c) is similar to 

proposed § 111.40(b)(2) which would 

require that: 

• You quarantine packaging and 

labels until your quality control unit 

tests or examines a representative 

sample to determine that specifications 

are met; 

• You conduct at least a visual 

identification of the containers and 

closures; 

• If specifications are not met, you 

conduct a material review and make a 

disposition decision; and 

• Your quality control unit approve 

and release packaging and labels from 

quarantine before you use them. 

Final § 111.160(c) includes revisions 

that reflect the following change already 

discussed in this final rule: 

• Refers to ‘‘each unique lot within 

each unique shipment’’ rather than 

‘‘each shipment lot’’. 

We did not receive comments specific 

to proposed § 111.40(b)(2). 

4. Final § 111.160(d) 

Final § 111.160(d)(1) requires you to 

identify each unique lot within each 

unique shipment of packaging and 

labels in a manner that allows you to 

trace the lot to the supplier, the date 

received, the name of the packaging and 

label, the status of the packaging and 

label (e.g., quarantined, approved, or 

rejected), and to the dietary supplement 

you distributed. Final § 111.160(d)(2) 

requires you to use this unique 

identifier whenever you record the 

disposition of each unique lot within 

each unique shipment of packaging and 

labels. Final § 111.160(d) derives from 

proposed § 111.40(b)(3) which would 

require you to identify each shipment 

lot of packaging and labels in a manner 

that allows you to trace the shipment lot 

to the supplier, the date received, the 

name of the packaging and label and the 

status (e.g., quarantined, approved, or 

rejected) and to trace the shipment lot 

to the dietary supplement manufactured 

and distributed. Proposed § 111.40(b)(3) 

also would require that you use this 

unique identifier whenever you record 

the disposition of each shipment lot 

received. 

Final § 111.160(d) includes revisions 

that reflect the following changes 

already discussed in this final rule: 

• Reference to ‘‘each unique lot 

within each unique shipment’’ rather 

than ‘‘each shipment lot.’’

• As a clarification, final 

§ 111.160(d)(2) refers to the ‘‘dietary 

supplement that you distributed’’ rather 

than to the ‘‘dietary supplement 

manufactured and distributed’’ to avoid 

a narrow—and incorrect—interpretation 

of ‘‘manufactured.’’ Under proposed 

§ 111.40(b)(3), we used the term 

‘‘manufactured’’ in a broad sense that 

includes any aspect of the 

manufacturing process rather than a 

narrow sense that applied to 

manufacturing operations for producing 

a batch of dietary supplement. Both 

proposed § 111.40(b)(3) and final 

§ 111.160(e) address the need to trace 

the packaging and labels that you use to 

the product that you distribute, 

regardless of whether your role in the 

manufacturing process includes the 

production of the batch or includes only 

packaging a dietary supplement you 

receive from a supplier. 

(Comment 246) One comment 

believes packaging and labels are rarely 

the source of quality problems. This 

comment suggests proposed 

§ 111.40(b)(3) allow the use of packaging 

approved by the quality control unit 

without the need to use a specific lot 

identification number. The comment 

explains that this type of flexibility is 

needed when they have dozens of short 

run lots each day and use less than a 

carton of packaging supplies for each 

run. 

(Response) This comment may have 

misinterpreted proposed § 111.40(b)(3). 

Under proposed § 111.40(b)(3) (final 

§ 111.160(d)) you must assign the 

identifier to each unique lot within each 

unique shipment of packaging and 

labels when you receive them rather 

than each time that you use them. This 

number would stay the same for each of 

the short runs described by the 

comment. We are making no changes to 

the requirement. 

5. Final § 111.160(e) 

Final § 111.160(e) requires you to 

hold packaging and labels under 

conditions that will protect against 

contamination and deterioration, and 

avoid mixups. Final § 111.160(e) is 

identical to proposed § 111.40(b)(4). 

We did not receive comments specific 

to proposed § 111.40(b)(4). 

G. What Requirements Apply to a 

Product Received for Packaging or 

Labeling as a Dietary Supplement (and 

for distribution rather than for return to 

the supplier)? (Final § 111.165) 

Final § 111.165 (proposed § 111.40(a)) 

sets out actions you must take when you 

receive a product for packaging and 

labeling and for distribution. Final 

§ 111.165 includes editorial changes 

associated with the reorganization and 

revisions that reflect changes we are 

making to other sections of the final 

rule. 

Final § 111.165 sets forth 

requirements for ‘‘product that you 

receive from a supplier for packaging or 

labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier)’’ rather than for ‘‘dietary 

supplements that you receive.’’

The final rule separates the 

requirements in proposed § 111.40(a) for 

product that you receive from a supplier 

for packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier) (final 

§ 111.165) from the analogous 

requirements for components, 

packaging, and labels (final § 111.155). 

1. Final § 111.165(a) 

Final § 111.165(a) requires you to 

visually examine each immediate 

container or grouping of immediate 

containers in a shipment of product you 

receive for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier) for 

appropriate content label, container 

damage, or broken seals to determine 

whether the container condition may 

have resulted in contamination or 

deterioration of the received product. 

Final § 111.165(a) is substantially 

similar to proposed § 111.40(a)(1) 


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which, in part, would impose this 

requirement for dietary supplements 

you receive. We have added the word 

‘‘immediate’’ to identify the container as 

the container that is in contact with the 

product you receive for packaging or 

labeling as a dietary supplement and 

substituted ‘‘may have’’ for ‘‘has’’ before 

the word ‘‘resulted’’ as explained in this 

section. 

2. Final § 111.165(b) 

Final § 111.165(b) requires you to 

visually examine the supplier’s invoice, 

guarantee, or certification in a shipment 

of the received product to ensure the 

received product is consistent with your 

purchase order. Final § 111.165(b) is 

substantially similar to proposed 

§ 111.40(a)(2) which, in part, would 

establish a similar requirement for 

dietary supplements that you receive. 

3. Final § 111.165(c) 

Final § 111.165(c) requires you to 

quarantine the received product until: 

• You collect representative samples 

of each unique shipment, and of each 

unique lot within each unique 

shipment, of received product; 

• Quality control personnel review 

and approve the documentation to 

determine whether the received product 

meets the specifications that you 

established under § 111.70(f); and 

• Quality control personnel approve 

the received product for packaging or 

labeling as a dietary supplement and 

release the received product from 

quarantine. 

Final § 111.165(c) is similar to 

proposed § 111.40(a)(3) which, in part, 

would require that: 

• You quarantine dietary 

supplements that you receive until your 

quality control unit reviews the 

suppliers invoice, guarantee, or 

certification; 

• The quality control unit performs 

testing, as needed, of a representative 

sample to determine that specifications 

are met; 

• You conduct a material review and 

make a disposition decision if 

specifications are not met; and 

• The quality control unit approves 

and releases the dietary supplements 

that you receive from quarantine before 

you use them. 

Final § 111.165(c) includes revisions 

that reflect that under final § 111.75(e) 

before you package or label a product 

you received for packaging or labeling 

as a dietary supplement, you must 

visually examine the product and have 

documentation to determine whether 

the specifications you established under 

§ 111.70(f) are met, but not otherwise 

examine or conduct tests. 

4. Final § 111.165(d) 

Final § 111.165(d)(1) requires that you 

identify each unique lot within each 

unique shipment of received product in 

a manner that allows you to trace the lot 

to the supplier, the date received, the 

name of the received product, the status 

of the received product (e.g., 

quarantined, approved, or rejected), and 

to the product you packaged or labeled 

and distributed as a dietary supplement. 

Final § 111.165(d)(2) requires you to use 

this unique identifier whenever you 

record the disposition of each unique lot 

within each unique shipment of the 

received product. Final § 111.165(d) 

derives from proposed § 111.40(a)(4) 

which would require you, in part, to 

identify each lot of dietary supplements 

in a shipment in a manner that allows 

you to trace the shipment to the 

supplier, the date received, the name of 

the dietary supplement, and the status 

(e.g., quarantined, approved, or 

rejected), and to trace the shipment lot 

to the dietary supplement manufactured 

and distributed. Proposed § 111.40(a)(4) 

also would require you to use this 

identifier whenever you record the 

disposition of each shipment lot 

received. 

Final § 111.165(d) includes a revision 

associated with final § 111.80 referring 

to ‘‘each unique lot within each unique 

shipment’’ rather than ‘‘each shipment 

lot.’’

5. Final § 111.165(e) 

Final § 111.165(e) requires you to 

hold the received product under 

conditions that will protect against 

contamination and deterioration, and 

avoid mixups. Final § 111.165(e) derives 

from proposed § 111.40(a)(5) with 

editorial changes associated with the 

reorganization. 

H. What Requirements Apply to 

Rejected Components, Packaging, and 

Labels, and to Rejected Products That 

Are Received for Packaging or Labeling 

as a Dietary Supplement? (Final 

§ 111.170) 

Final § 111.170 requires you to clearly 

identify, hold, and control under a 

quarantine system for appropriate 

disposition any component, packaging, 

and label, and any product you receive 

for packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier), that is 

rejected and unsuitable for use in 

manufacturing, packaging, or labeling 

operations. Final § 111.170 is 

substantially similar to proposed 

§ 111.74 which would require you to 

clearly identify, hold, and control under 

a quarantine system any component, 

dietary supplement, packaging, and 

label that is rejected and unsuitable for 

use in manufacturing, packaging, or 

labeling operations. 

We did not receive comments specific 

to proposed § 111.74. Final § 111.170 

includes revisions associated with the 

series of provisions that distinguish a 

product you receive for packaging or 

labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier) from a dietary supplement 

you manufacture. 

I. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.180) 

Final § 111.180 sets forth the 

requirements to make and keep records 

associated with components, packaging, 

labels, and product you receive for 

packaging and labeling as a dietary 

supplement. Final § 111.180 derives 

from proposed § 111.40(c). 

1. Final § 111.180(a) 

Final § 111.180(a) requires you to 

make and keep records required under 

subpart G in accordance with subpart P. 

Final § 111.180(a) derives from 

proposed § 111.40(c)(2), with editorial 

changes associated with the 

reorganization. 

We did not receive comments specific 

to the requirements set forth in final 

§ 111.180(a). 

2. Final § 111.180(b)(1) 

Final § 111.153 requires you to 

establish and follow written procedures 

to fulfill the requirements of subpart G. 

These written procedures are records. 

Therefore, final § 111.180(b)(1) requires 

you to make and keep a record of the 

written procedures for fulfilling the 

requirements of subpart G. 

3. Final § 111.180(b)(2) 

Final § 111.180(b)(2) requires you to 

make and keep receiving records 

(including records such as certificates of 

analysis, suppliers’ invoices, and 

suppliers’ guarantees) for components, 

packaging, and labels, and for products 

you receive for packaging or labeling as 

dietary supplements (and for 

distribution rather than for return to the 

supplier). Final § 111.180(b)(2) derives 

from proposed § 111.40(c)(2) with 

editorial changes associated with the 

reorganization. Final § 111.180(b)(2) 

also includes revisions associated with 

the series of provisions that distinguish 

a product you receive for packaging or 

labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier) from a dietary supplement 

you manufacture. Because the final rule 

provides that you may rely, under 


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certain circumstances, on a certificate of 

analysis to ensure that some component 

specifications are met (final 

§ 111.75(a)(2)(ii)) and that you may rely, 

in part, on documentation to determine 

whether specifications for received 

products are met, we specifically 

identify a certificate of analysis and 

common forms of documentation as 

being ‘‘receiving records’’ for purposes 

of this rule. 

(Comment 247) One comment on 

proposed § 111.40(c)(2) points out the 

recordkeeping requirements of any final 

rule will be a costly burden for a 

company that produces multiple 

ingredient products in several packaging 

configurations and will be much greater 

than the burden for a company that 

produces batches of single ingredient 

products in one packaging 

configuration. 

(Response) We acknowledge that 

companies that produce multiple 

ingredient products in several packaging 

configurations will have more records to 

keep than companies that produce 

single ingredient products in one 

packaging configuration. However, these 

records are necessary to be able to 

determine the source of the component, 

packaging, and labels, so that if 

adulteration of the dietary supplement 

occurs, the records will show the source 

of the material so that its use can be 

stopped. 

4. Final § 111.180(b)(3) 

Final § 111.180(b)(3) requires you to 

make and keep documentation that the 

requirements of subpart G were met. 

Under final § 111.180(b)(3)(i), the 

person who performs the required 

activity must document, at the time of 

performance, that the required operation 

was performed. Under final 

§ 111.180(b)(3)(ii), the documentation 

must include: 

• The date that the components, 

packaging, labels, or products you 

receive for packaging or labeling as a 

dietary supplement were received; 

• The initials of the person 

performing the required operation; 

• The results of any tests or 

examinations conducted on 

components, packaging, or labels, and of 

any visual examination of product you 

receive for packaging or labeling as a 

dietary supplement; and 

• Any material review and 

disposition decision conducted on 

components, packaging, labels, or 

products that you receive for packaging 

or labeling as a dietary supplement. 

Final § 111.180(b)(3) differs from 

proposed § 111.40(c)(1)(i) through 

(c)(1)(iv), by referring to ‘‘required 

operation’’ rather than ‘‘requirement.’’

Additionally as a conforming revision 

associated with final § 111.75(a) which 

requires appropriate tests and 

examinations, final § 111.180(b)(3) 

requires you to include in the 

documentation the results of any 

examinations as well as tests. Final 

§ 111.180(b)(3) also includes revisions 

associated with the series of changes 

that distinguish a product that you 

receive for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier) 

from a dietary supplement that you 

manufacture. 

(Comment 248) A few comments note 

proposed § 111.40(c) requires the 

signature of the person performing the 

requirement, whereas other sections of 

the 2003 CGMP Proposal, such as 

proposed § 111.50(c)(2), only require the 

initials of the person performing the 

requirement. One comment requests the 

format for the requirement to document 

the person performing the step be made 

consistent throughout the regulations. 

(Response) We agree that the identity 

of the person performing a requirement 

should be required throughout the final 

rule and that this can be accomplished 

through initials except for operations 

that are performed by quality control 

personnel. Therefore, we are revising 

the requirements so that a signature 

(and not initials) is required for any 

operation performed by quality control 

personnel (see final § 111.140). Because 

§ 111.40(c)(1)(ii) is not a quality control 

operation, we also revised proposed 

§ 111.40(c)(1)(ii) (final § 111.180(b)(3)) 

to require the initials, rather than the 

signature, of the person performing the 

required operation. Initials are required 

for other circumstances that do not 

involve quality control operations, 

including final § 111.180(b)(3). 

However, whenever this final rule 

requires initials, a signature is also 

acceptable, because a signature would 

achieve the goal of identifying the 

person who performed the requirement. 

XIII. Comments on the Production and 

Process Control System: Requirements 

for the Master Manufacturing Record 

(Final Subpart H) 

A. Organization of Final Subpart H 

In the 2003 CGMP Proposal, the 

requirements for the master 

manufacturing record were set forth in 

proposed § 111.45. As shown in table 9 

of this document, we are setting forth 

the requirements for the master 

manufacturing record in a distinct 

subpart (final Subpart H—Production 

and Process Control System: 

Requirements for the Master 

Manufacturing Record). Table 9 lists the 

sections in final subpart H and 

identifies the proposed provisions that 

form the basis for the final rule. 

TABLE 9.—DERIVATION OF SECTIONS

IN FINAL SUBPART H 

Final Rule 2003 CGMP 

Proposal 

§ 111.205 What is the 

requirement to establish a master manufacturing record? 

§ 111.45(a)(1), 

(a)(2), and (d) 

§ 111.210 What must the 

master manufacturing 

record include? 

§ 111.45(b) 

The requirements in final subpart H 

are set forth from the perspective of the 

manufacture of a batch of a dietary 

supplement. You must comply with all 

requirements that pertain to your 

activity. However, you must comply 

with the requirement to prepare and 

follow a ‘‘master manufacturing record’’

regardless of whether you manufacture 

a batch, or whether you package or label 

product you receive from a supplier for 

packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier). If you 

are a packager or labeler, you only need 

to include those parts relevant to your 

process. For example, if you are a 

labeler, under final § 111.210(c) you 

would not need to include an accurate 

statement of the weight or measure of 

each component to be used because you 

would be starting from packages already 

filled. 

B. Highlights of Changes to the 

Proposed Requirements for the Master 

Manufacturing Record 

1. Revisions 

The final rule: 

• Includes revisions that reflect that 

the final rule applies to persons who 

manufacture, package, label, or hold 

dietary supplements unless subject to an 

exclusion in § 111.1; 

• Includes revisions so the 

requirements for the master 

manufacturing record are consistent 

with final § 111.70(a) which requires 

you to establish a specification for any 

point, step, or stage in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record; and 

• Includes a revision associated with 

final § 111.75(h), which provides for the 

use of either tests or examinations for 

complying with the requirements of part 

111. 


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2. Changes Associated With the 

Reorganization 

The proposed requirement 

(§ 111.45(c)) that the quality control unit 

approve each master manufacturing 

record and any modifications to a 

master manufacturing record is set forth 

as final § 111.123(a) in subpart F, rather 

than in final subpart H, with the 

changes we made to the definition of 

‘‘quality control unit’’ to ‘‘quality 

control personnel’’ as explained in 

section VI of this document (subpart A). 

3. Changes After Considering Comments 

The final rule: 

• Retains a requirement to state any 

intentional overage of a dietary 

ingredient but does not require an 

explanation for such an overage; 

• Provides flexibility to include either 

a representative label, or a crossreference to the physical location of the 

actual or representative label if an actual 

label is not provided; and 

• Provides flexibility for what must 

be included in written instructions 

when operations are not conducted 

manually. 

C. General Comments on Proposed 

§ 111.45 (Final Subpart H) 

1. Comments on Written Procedures 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

As discussed in section IV of this 

document, we do not require you to 

establish and follow written procedures 

for preparing a master manufacturing 

record. 

2. Comments That Support Proposed 

§ 111.45 

(Comment 249) A few comments 

support the proposed requirements for 

the master manufacturing record. One 

comment states that properly recorded 

quality control measures, such as the 

batch production and master 

manufacturing records, will aid 

manufacturers in producing dietary 

supplements in a consistent and 

uniform manner, as well as serve as 

tools to assess possible sources of 

contamination and flaws in the 

production process. Another comment 

asserts the master manufacturing and 

batch production records probably have 

the second greatest impact on overall 

product quality, surpassed only by the 

quality of the ‘‘people’’ manufacturing 

the product. 

(Response) We agree the master 

manufacturing record requirements in 

the 2003 CGMP Proposal are important 

for reasons that include those expressed 

in the comments. Establishing a master 

manufacturing record will help to 

ensure the quality of the dietary 

supplement. The proposed requirements 

for the master manufacturing record 

have been codified as subpart H in this 

final rule. 

D. What Is the Requirement to Establish 

a Master Manufacturing Record? (Final 

§ 111.205) 

Final § 111.205 (proposed § 111.45(a) 

and (d)) sets forth the requirement to 

prepare and follow a written master 

manufacturing record. 

1. Final § 111.205(a) 

Final § 111.205(a) requires you to 

prepare and follow a written master 

manufacturing record for each unique 

formulation of dietary supplement that 

you manufacture, and for each batch 

size, to ensure uniformity in the 

finished batch from batch to batch. Final 

§ 111.205(a) is similar to proposed 

§ 111.45(a) which would require you to 

prepare and follow a written master 

manufacturing record for each type of 

dietary supplement you manufacture 

and for each batch size to ensure 

uniformity from batch to batch. 

(Comment 250) Some comments 

suggest the phrase ‘‘to ensure uniformity 

from batch to batch’’ be changed to ‘‘to 

ensure that specifications are met from 

batch to batch.’’ One comment states the 

term ‘‘uniformity’’ could be interpreted 

to mean that two batches would be 

exactly the same, down to the minutest 

detail. The comment expresses concern 

about how batches of herbal products 

will meet this standard of ‘‘uniformity’’

from batch to batch. 

(Response) These comments may have 

misinterpreted the term ‘‘uniformity’’ as 

we used it in proposed § 111.45(a). 

Uniformity means that the 

specifications you establish for identity, 

purity, strength, and composition of the 

finished batch must be the same 

throughout a given batch, e.g., at the 

beginning, middle, and end of a 

production run. To emphasize this, we 

have revised the requirement so it is 

clear that the uniformity relates to ‘‘the 

finished batch.’’ Whether two batches 

must be exactly the same, down to the 

minutest level, would depend on the 

specifications the manufacturer 

establishes for the finished batch under 

final § 111.70(e). Although a finished 

batch must meet those specifications 

‘‘from batch to batch,’’ it is up to the 

manufacturer to determine what those 

specifications will be. We are making no 

changes to the requirement. 

(Comment 251) Some comments 

assert that the proposed requirement to 

prepare a separate record ‘‘for each 

batch size’’ is burdensome, particularly 

for smaller firms who specialize in 

custom blended products. These 

comments would revise the rule so the 

master manufacturing record includes a 

master formula with instructions for 

how to adjust the amount of ingredients 

to add depending on the batch size, 

with the actual amounts included in the 

applicable batch record. 

(Response) We disagree with these 

comments. Requiring a separate master 

manufacturing record for each batch 

size will lessen the likelihood of 

mistakes that can happen when a 

formula is ‘‘multiplied up’’ or ‘‘divided 

down,’’ particularly in light of the 

requirement that quality control 

personnel review and approve each 

master manufacturing record (final 

§ 111.123(a)). Moreover, it is not clear 

that the scenario described in the 

comments would lessen any burden, 

because a new ‘‘formula,’’ based on the 

master formula, would still need to be 

prepared for each batch. 

In essence, these comments suggest 

shifting the burden from a requirement 

to prepare a master manufacturing 

record to a requirement to prepare a 

batch record. Under final § 111.123, 

quality control personnel review the 

master manufacturing record before that 

record is used, but review the batch 

record only after the batch is prepared. 

Shifting the requirement in the manner 

suggested by these comments would 

defeat the purpose of having quality 

control personnel review and approve 

each ‘‘formula.’’ We are not making the 

suggested changes to proposed 

§ 111.45(a). 

We are changing the word ‘‘type’’ to 

‘‘unique formulation’’ to clarify that the 

requirement for a master manufacturing 

record applies to each different dietary 

supplement whether it is a different 

strength, includes any different 

ingredients, is a capsule or tablet, or 

includes minor variations. 

2. Final § 111.205(b)(1) 

Final § 111.205(b)(1) requires that the 

master manufacturing record identify 

specifications for each point, step, or 

stage in the manufacturing process 

where control is necessary to ensure the 

quality of the dietary supplement and 

that the dietary supplement is packaged 

and labeled as specified in the master 

manufacturing record. Final 

§ 111.205(b)(1) derives from proposed 

§ 111.45(a)(1). We received no 

comments specific to proposed 


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§ 111.45(a)(1). We revised this section to 

include changes that we made to 

§ 111.70(a). 

3. Final § 111.205(b)(2) 

Final § 111.205(b)(2) requires that the 

master manufacturing record establish 

controls and procedures to ensure that 

each batch of dietary supplement you 

manufacture meets the specifications 

identified in accordance with 

§ 111.205(b)(1). Final § 111.205(b)(2) 

derives from proposed § 111.45(a)(2) 

with grammatical changes and changes 

associated with the reorganization. We 

did not receive comments specific to 

proposed § 111.45(a)(2). 

4. Final § 111.205(c) 

Final § 111.205(c) requires you to 

make and keep master manufacturing 

records in accordance with subpart P. 

Final § 111.205(c) derives from 

proposed § 111.45(a) and (d), and 

clarifies that you must prepare and keep 

the master manufacturing records. We 

did not receive comments specific to 

proposed § 111.45(d), and comments 

relevant to § 111.45(a) are discussed in 

the response to comment 250. 

E. What Must the Master Manufacturing 

Record Include? (Final § 111.210) 

Final § 111.210 sets forth the 

requirements for what the master 

manufacturing record must include. 

Final § 111.210 derives from proposed 

§ 111.45(b). 

1. Final § 111.210(a) 

Final § 111.210(a) requires that the 

master manufacturing record include 

the name of the dietary supplement to 

be manufactured and the strength, 

concentration, weight, or measure of 

each dietary ingredient for each batch 

size. Final § 111.210(a) derives from 

proposed § 111.45(b)(1). 

(Comment 252) One comment 

supports listing the weight or measure 

for each ingredient but believes that 

including the strength and 

concentration is unnecessary. This 

comment also suggests that the identity 

of each ingredient can be controlled 

using a unique item number identifier, 

along with a brief description of the 

ingredient. 

(Response) Proposed § 111.45(b)(1) 

would require the master manufacturing 

record to include strength, 

concentration, weight, or measure of 

each dietary ingredient for each batch 

size. We did not intend that all would 

be required. The purpose of this 

requirement is to ensure the correct 

dietary ingredient and amount are used 

in a given batch. To the extent that 

weight or measure best describes what 

that dietary ingredient is and how much 

is to be used in a given batch, the 

manufacturer could use weight or 

measure. To the extent that a 

manufacturer determines, for a 

particular dietary ingredient, strength, 

or concentration would best describe 

what is to be used in a given batch, the 

manufacturer could use those instead. 

We are giving firms the flexibility to use 

the measure that they determine best 

describes the amount of dietary 

ingredient to use in their batch. For 

example, assume you are manufacturing 

a million tablets of a vitamin C product 

in 250 mg tablets and the only other 

ingredients in your product are starch, 

microcrystalline cellulose, and 

dicalcium phosphate. Under proposed 

§ 111.45(b)(1) (final § 111.210(a)) your 

master manufacturing record would 

state: ‘‘Vitamin C 250 mg, 1,000,000 

tablets.’’ As another example, if you are 

manufacturing 100 liters of a liquid 

dietary supplement that provides tuna 

oil as a dietary ingredient, and the only 

other ingredients are alpha-tocopherols 

for use as an antioxidant, then your 

master manufacturing record would 

state: ‘‘Tuna oil, 100 liters.’’

The unique identifier comment states 

‘‘the identity of each dietary ingredient 

can be controlled instead with the use 

of a unique item identifier, along with 

a brief description of the ingredient.’’ It 

is not clear what the comment meant by 

‘‘a brief description of the ingredient.’’

If the ‘‘brief description of the 

ingredient’’ includes the identity, then it 

would comply with the final rule. Firms 

are free to use unique identifiers in 

addition to the identity. If, however, the 

comment means something other than 

identity, the comment fails to explain 

how the identity will be controlled to 

prevent manufacturing errors. In the 

absence of such an explanation, we have 

no basis to make the requested change. 

Moreover, under final § 111.205(c) the 

master manufacturing record is a record 

you must make and keep in accordance 

with final § 111.610 in final subpart P. 

Under final § 111.610, the master 

manufacturing record must be available 

during the record retention period for 

inspection and copying by us when we 

request that you do so. A master 

manufacturing record that does not 

identify the dietary ingredient and the 

weight or measure of the dietary 

ingredient would not allow an FDA 

investigator to determine, for example, 

how your master manufacturing record 

relates to the finished dietary 

supplement and to the product label of 

that dietary supplement. 

(Comment 253) One comment 

recommends the weight or measure be 

expressed per unit or portion, or per 

unit of weight or measure of the 

product, for each batch size. 

(Response) The final rule does not 

prescribe the units you must use. Thus, 

firms have the flexibility to include this 

information in the way that best suits 

their product. 

2. Final § 111.210(b) 

Final § 111.210(b) requires that the 

master manufacturing record include a 

complete list of components to be used. 

Final § 111.210(b) is identical to 

proposed § 111.45(b)(2). We did not 

receive comments specific to proposed 

§ 111.45(b)(2). 

3. Final § 111.210(c) 

Final § 111.210(c) requires that the 

master manufacturing record include an 

accurate statement of the weight or 

measure of each component to be used. 

Final § 111.210(c) is identical to 

proposed § 111.45(b)(3). We did not 

receive comments specific to proposed 

§ 111.45(b)(3). 

4. Final § 111.210(d) 

Final § 111.210(d) requires that the 

master manufacturing record include 

the identity and weight or measure of 

each dietary ingredient that will be 

declared on the Supplement Facts label 

and the identity of each ingredient that 

will be declared on the ingredients list 

of the dietary supplement. Final 

§ 111.210(d) is similar to proposed 

§ 111.45(b)(4). We have removed the 

phrase ‘‘in compliance with section 

403(s) of the act’’ as it is unnecessary in 

the context of compliance with the 

dietary supplement CGMP 

requirements. The manufacturer must 

still comply with section 403(s) and 

failure to do so will result in a 

misbranding violation, not a CGMP 

violation under this final rule. 

(Comment 254) One comment 

supports having the identity and weight 

or measure of each dietary ingredient as 

required by proposed § 111.45(b)(4), but 

asserts it is unnecessary for the verbiage 

to identically match the corresponding 

label statements. This comment also 

asserts that the ingredients can be 

controlled in the master manufacturing 

record by use of a unique identifier, 

instead of the ingredient name, along 

with a brief description of the 

ingredient. 

(Response) We disagree for the 

reasons stated in response to comment 

252 and decline to revise the provision 

in this manner. 

5. Final § 111.210(e) 

Final § 111.210(e) requires that the 

master manufacturing record include a 

statement of any intentional overage 


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amount of a dietary ingredient. Final 

§ 111.210(e) derives from proposed 

§ 111.45(b)(5) which would require you 

to explain any intentional excess 

amount of a dietary ingredient. 

(Comment 255) Some comments 

request us to modify this requirement. 

Several comments note that a 

manufacturer may design products with 

overage levels adjusted so the product 

always tests at least 100 percent of the 

amount claimed on the label throughout 

the declared shelf life. One comment 

states it should be sufficient to identify 

any overage amount, rather than having 

to explain it. 

(Response) We understand that some 

firms design products using an 

additional amount of certain ingredients 

to ensure the product meets its 

specifications for the amount of the 

ingredient during the expected shelf life 

of the product. We agree it is not 

necessary to include the reason for 

adding the intentional excess amount. 

We also understand it would be more 

appropriate to refer to the additional 

amount as an ‘‘overage’’ amount rather 

than an ‘‘excess’’ amount, because 

‘‘overage’’ is commonly used in the 

industry to convey the practice that is 

now the subject of final § 111.260(e). 

Therefore, we have revised proposed 

§ 111.45(b)(1) to use the term ‘‘overage’’

rather than ‘‘excess’’ and to delete the 

proposed requirement to include the 

reason for the intended overage. As 

discussed in the preamble to the 2003 

CGMP Proposal (68 FR 12157 at 12203), 

the amount of overage should be limited 

to the amount needed to meet the 

amounts listed in accordance with final 

§ 111.210(d). 

6. Final § 111.210(f) 

Final § 111.210(f) requires that the 

master manufacturing record include a 

statement of theoretical yield of a 

manufactured dietary supplement 

expected at each point, step, or stage of 

the manufacturing process where 

control is needed to ensure the quality 

of the dietary supplement, and the 

expected yield when you finish 

manufacturing the dietary supplement, 

including the maximum and minimum 

percentages of theoretical yield beyond 

which a deviation investigation of a 

batch is necessary and material review 

is conducted and disposition decision is 

made. Final § 111.210(f) derives from 

proposed § 111.45(b)(6). We revised the 

section to state ‘‘beyond which a 

deviation investigation of a batch is 

necessary’’ rather than ‘‘beyond which a 

deviation is performed’’ for clarity. 

(Comment 256) One comment 

suggests the term ‘‘maximum and 

minimum percentages’’ in proposed 

§ 111.45(b)(6) be replaced with the term 

‘‘normal range.’’

Another comment recommends 

proposed § 111.45(b)(6) be replaced 

with: ‘‘A statement of theoretical yield 

of a manufactured dietary ingredient or 

dietary supplement expected at 

appropriate phases of manufacturing.’’

This comment states the detail in this 

proposed requirement should be 

eliminated because the manufacturer 

should decide where and when to 

include a statement about theoretical 

yield. 

(Response) Final § 111.210(f) clearly 

communicates when it is necessary to 

conduct a material review and make a 

disposition decision. The comment’s 

suggestions do not improve the 

communication or clarify this point. 

Final § 111.210(f) gives firms the 

flexibility to decide what steps, in the 

manufacturing process, are points, 

steps, or stages where control is needed 

to ensure the quality of the dietary 

supplement. A statement about 

theoretical yield is necessary at each 

such point, step, or stage including at 

the finished batch stage so that you will 

know, when you manufacture a batch, 

whether the process is proceeding as 

expected or whether something is 

wrong. For example, your master 

manufacturing record could state the 

theoretical yield after mixing a series of 

components is 100 percent, because 

nothing about the additional step would 

remove any material from the 

production system. When 

manufacturing the batch, a yield of less 

than 100 percent would tell you 

something was wrong, for example, if 

there was an obstruction that prevented 

a component that was being delivered 

by automated equipment from actually 

entering the production vessel. For a 

process such as recrystallization, 

knowing the theoretical yield is critical, 

because if the expected yield is not 

achieved at a given step it may mean 

that the process did not proceed as 

intended. 

(Comment 257) One comment argues 

it is not possible for the majority of 

supplement products, especially 

botanicals, to provide 100 percent of the 

claimed amount of the botanical, 

because botanicals are inherently of 

uneven consistency, density, and 

particle size. This comment 

recommends that we allow for 

variability in yield, especially for 

botanicals. 

(Response) Final § 111.210(f) does not 

specify what the yield must be, so no 

revision is necessary. It is the 

manufacturer’s responsibility to 

manufacture the product in a way that 

will ensure that a product contains what 

the manufacturer has established in its 

specifications and its master 

manufacturing record. The 

manufacturer must establish 

specifications for the identity, purity, 

strength, and composition and limits on 

contamination and other specifications 

the manufacturer decides are necessary 

to ensure the quality of the dietary 

supplements that it makes, and design 

and implement a production and 

process control system that will ensure 

those specifications are met. In the 

situation described by the comment, it 

is the manufacturer’s responsibility to 

design and implement a production and 

process control system that will ensure 

the quality of the dietary supplement 

regardless of the problems presented by 

the nature of the ingredients. 

7. Final § 111.210(g) 

Final § 111.210(g) requires that the 

master manufacturing record include a 

description of packaging and a 

representative label, or a cross-reference 

to the physical location of the actual or 

representative label. Final § 111.210(g) 

derives from proposed § 111.45(b)(7), 

which would require a description of 

packaging and a copy of the label to be 

used. 

(Comment 258) One comment 

supports the proposed requirement that 

the master manufacturing record 

contain a copy of the dietary 

supplement label. Other comments 

contend that the proposed requirement 

to include a copy of the label is neither 

appropriate nor necessary. Some 

comments state that companies often do 

not have a label available to include in 

the master manufacturing record and 

believe that a description of the 

packaging or label in the master 

manufacturing record should be 

sufficient. Another comment, by a 

company that produces many different 

brands for each bulk product, asserts 

that updating labels in the record would 

be burdensome and suggests wording 

similar to that used by USP, for which 

a positive identification of all labeling 

used is permitted. One comment asks 

whether the packaging and label copy 

requirements can be in separate 

documents cross-referenced in the 

master manufacturing record, because 

some companies treat tablet 

manufacturing and packaging as two 

separate and distinct operational 

elements. This comment explains that 

the master manufacturing record 

includes the specifics required to 

manufacture the tablets, but the actual 

description of packaging and label copy 

requirements are contained in separate 

documents cross-referenced to the 


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master manufacturing record by a 

product part number. 

(Response) We understand there may 

be some circumstances where it would 

be impractical to have actual copies of 

labels in the master manufacturing 

record. If an actual label is not available, 

you may include a representative label 

in the master manufacturing record. A 

representative label could be a graphic 

representation of the label, including 

the exact statements that would be on 

the product label, or a detailed 

description of the statements and other 

information (such as pictures or 

graphics) that will be on the actual 

label. The representative label must be 

an accurate representation of the label 

that will be affixed to the dietary 

supplement distributed. We also agree 

that it would be acceptable to crossreference the physical location of the 

actual or representative label. 

Finally, because the actual or 

representative label is a record that you 

must make and keep in accordance with 

final § 111.610 in final subpart P, it 

must be readily available during the 

retention period for inspection or 

copying by FDA. Thus, we are revising 

proposed § 111.45(b)(6) (final 

§ 111.210(g)) as discussed above. 

(Comment 259) One comment states 

that a company that manufactures a 

dietary supplement under contract to 

another company would not have access 

to the product label. 

(Response) Under final § 111.210(g) a 

company that manufactures a dietary 

supplement under contract could 

comply with the requirement by, for 

example, providing the name and 

address of the company who contracted 

for the manufacture of the batch as the 

cross-reference to the physical location 

of the label. 

8. Final § 111.210(h)(1) 

Final § 111.210(h)(1) requires that the 

master manufacturing record include 

written instructions for specifications 

for each point, step, or stage in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. Final § 111.210(h)(1) is similar 

to proposed § 111.45(b)(8)(i) which 

would require that the master 

manufacturing record include written 

instructions for specifications for each 

point, step, or stage in manufacturing 

the dietary supplement necessary to 

prevent adulteration. Final 

§ 111.210(h)(1) includes changes that we 

are making for consistency with final 

§ 111.70(a). 

We did not receive comments specific 

to proposed § 111.45(b)(8)(i). 

9. Final § 111.210(h)(2) 

Final § 111.210(h)(2) requires that the 

master manufacturing record include 

written instructions for procedures for 

sampling, and a cross-reference to 

procedures for tests or examinations. 

Final § 111.210(h)(2) derives from 

proposed § 111.45(b)(8)(ii), which 

would require that the master 

manufacturing record include written 

instructions for sampling and testing. 

(Comment 260) A few comments 

object to including certain written 

instructions for sampling and testing 

procedures in the master manufacturing 

record. One comment states that this 

documentation, such as laboratory 

testing procedures, would be a 

burdensome task and should be 

maintained separate from the master 

manufacturing record and be retrievable 

by appropriate cross-referencing 

information. 

(Response) As we discussed in the 

preamble to the 2003 CGMP Proposal 

(68 FR 12157 at 12204), the written 

instructions are similar to a recipe. As 

such, the written instructions must 

include instructions related to 

procedures for sampling plans so you 

can collect appropriate samples for tests 

or examinations. We agree, however, 

that it is not necessary for the master 

manufacturing record to include written 

instructions for tests or examinations. 

Accordingly, we have revised the 

provision to permit the master 

manufacturing record to include a crossreference to the procedures for tests or 

examinations. The final rule includes a 

requirement that you establish and 

follow written procedures for laboratory 

operations, including for tests and 

examinations that you conduct to 

determine whether specifications are 

met (final § 111.303). In essence, these 

written procedures for tests and 

examinations would constitute the 

written instructions that we proposed 

under § 111.45(b)(8)(ii) for testing 

procedures. This requirement for 

written procedures is generally 

described in section IV of this 

document. 

10. Final § 111.210(h)(3) 

Final § 111.210(h)(3) requires that the 

master manufacturing record include 

written instructions for specific actions 

necessary to perform and verify each 

point, step, or stage in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. Final § 111.210(h)(3) derives 

from proposed § 111.45(b)(8)(iii) which 

would require that the master 

manufacturing record include written 

instructions for specific actions 

necessary to perform and verify each 

point, step, or stage necessary to meet 

specifications and otherwise prevent 

adulteration. Final § 111.210(h)(3) 

includes changes for consistency with 

final § 111.70(a). 

Final § 111.210(h)(3)(i) requires that 

the specific actions include verifying 

the weight or measure of any 

component and verifying the addition of 

any component. Final § 111.210(h)(3)(ii) 

requires that, for manual operations, the 

specific actions include: (1) One person 

weighing or measuring a component 

and another person verifying the weight 

or measure and (2) one person adding a 

component and another person 

verifying the addition. Final 

§ 111.210(h)(3)(i) and (h)(3)(ii) derive 

from proposed § 111.45(b)(8))(iii). 

(Comment 261) Some comments 

suggest the requirement to have more 

than one person involved in performing 

and verifying each point, step, or stage 

in the manufacturing process is overly 

prescriptive and that alternative, 

reliable methods for verifying the 

weighing and addition of components 

should be permitted. One comment 

explains many manufacturers use bar 

code systems to identify the weight and 

identity of components both before and 

after weighing. In such cases, a 

computer generated weight record and 

corresponding bar code can be created 

and affixed to the container by one 

individual as reliable verification of the 

material’s contents and weight. 

Likewise, the addition of components to 

a blender can be adequately controlled 

and verified by one person through 

scanning technology that allows reliable 

verification of the identity and weight of 

components added to a blender without 

the need for a second person. 

(Response) These comments describe 

a system partially under the control of 

automated equipment. Final § 111.30 

establishes a series of requirements for 

automated equipment. We agree that, 

with such requirements in place for an 

automated system such as that 

described by the comments, the 

requirement to verify the weight or 

measure of a component, or to verify the 

addition of a component, can be 

achieved without requiring that one 

person do the weighing or measuring 

and another person verify the weighing 

or measuring and without requiring that 

one person add the component and 

another person verify the addition. 

Therefore, final § 111.210(h)(3) provides 

both that the written instructions must 


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include verifying the weight or measure 

of any component and verifying the 

addition of any component and that, for 

manual operations, the written 

instructions must include: (1) One 

person weighing or measuring a 

component and another person 

verifying the weight or measure and (2) 

one person adding a component and 

another person verifying the addition. 

The final rule makes clear that there 

must be a verification step and gives 

firms flexibility, when the weighing or 

addition is not done manually, to 

determine how they would accomplish 

the verification. 

11. Final § 111.210(h)(4) 

Final § 111.210(h)(4) requires that the 

master manufacturing record include 

written instructions for special 

notations and precautions to be 

followed. Final § 111.210(h)(4) derives 

from proposed § 111.45(b)(8)(iv). We did 

not receive comments specific to 

proposed § 111.45(b)(8)(iv). 

12. Final § 111.210(h)(5) 

Final § 111.210(h)(5) requires that the 

master manufacturing record include 

written instructions for corrective action 

plans for use when a specification is not 

met. Final § 111.210(h)(5) derives from 

proposed § 111.45(b)(8)(v). 

(Comment 262) Several comments 

argue pre-established corrective action 

plans are not useful for complex failure 

scenarios, and that the quality control 

unit should instead approve corrective 

action procedures on a case-by-case 

basis. One comment suggests the rule 

should refer to ‘‘procedures’’ rather than 

specifying ‘‘corrective action plans.’’

(Response) We acknowledge that 

corrective action plans would be 

focused on each point, step, or stage 

where control is necessary to ensure the 

quality of the dietary supplement. We 

also acknowledge that it may not be 

practical to establish a corrective action 

plan for all foreseeable circumstances. 

In circumstances such as the complex 

failure scenario described by the 

comments, the documentation of the 

material review and disposition 

decision (rather than the corrective 

action plan) would identify the action 

taken to correct, and prevent a 

recurrence of, the deviation and discuss 

what you did with the batch (final 

§ 111.140(b)(3)(iv) and (b)(3)(v)). 

However, we disagree that the fact that 

it may not be practical to establish a 

corrective action plan for all foreseeable 

circumstances means you could not 

establish a corrective action plan at each 

point, step, or stage where you can, in 

fact, predict a scenario and provide a 

plan for action when that scenario 

presents itself. Therefore, for any 

circumstance you can predict, final 

§ 111.210(h)(5) requires that you 

establish corrective action plan. 

F. Quality Control Responsibility 

(Proposed § 111.45(c)) 

In proposed § 111.45(c) we would 

require the quality control unit to 

review and approve each master 

manufacturing record and any 

modifications to a master manufacturing 

record. As part of the reorganization, 

this requirement is set forth under final 

§ 111.123(a) in subpart F for quality 

control personnel. There is no reason to 

repeat the requirement in final subpart 

H and, thus, it does not appear in final 

subpart H. 

XIV. Comments on the Production and 

Process Control System: Requirements 

for the Batch Production Record (Final 

Subpart I) 

A. Organization of Final Subpart I 

In the 2003 CGMP Proposal, the 

proposed requirements for the batch 

production record were set forth in 

§ 111.50. As shown in table 10 of this 

document, we are setting forth the 

requirements for the batch production 

record in a distinct subpart (final 

Subpart I—Production and Process 

Control System: Requirements for the 

Batch Production Record) that contains 

the requirements that derive from 

proposed § 111.50. In addition, we are 

moving some proposed requirements 

from §§ 111.35 and 111.37 into final 

subpart I. Table 10 lists the sections in 

final subpart I and identifies the 

provisions that form the basis for the 

final rule. 

TABLE 10.—DERIVATION OF SECTIONS

IN FINAL SUBPART I 

Final Rule 2003 CGMP 

Proposal 

§ 111.255 What is the 

requirement to establish a batch production 

record? 

§ 111.50(a), (b), 

and (i) 

§ 111.260 What must the 

batch record include? 

§ 111.35(i)(2), 

(j), (m), and 

(o)(2) 

§ 111.37(b)(3), 

(b)(5), and 

(b)(9) 

§ 111.50(c)(1) 

through 

(c)(11), 

(c)(13), 

(c)(14), (d)(2), 

(e), and (g) 

§ 111.70(b)(6), 

(e), and (g) 

The requirements in final subpart I 

are set forth from the perspective of the 

manufacture of a batch of a dietary 

supplement. However, you must comply 

with the requirement to prepare and 

follow a ‘‘batch production record’’ or a 

‘‘batch record’’ regardless of whether 

you manufacture a batch or whether you 

package or label product you receive 

from a supplier for packaging or labeling 

as a dietary supplement (and for 

distribution rather than for return to the 

supplier). As discussed in section VI of 

this document, if you are a packager or 

labeler, you only need to include those 

parts relevant to your process. For 

example, if you are a labeler under final 

§ 111.260(e) you would not need to 

include the identity and weight or 

measure of each component used, 

because you would be starting from 

packages that already had been filled. 

B. Highlights of Changes to the 

Proposed Requirements for the Batch 

Production Record 

1. Revisions 

The final rule: 

• Includes revisions that reflect that 

the final rule applies to persons who 

manufacture, package, label, or hold 

dietary supplements unless subject to an 

exclusion in § 111.1. 

• Does not use the term ‘‘shipment 

lot’’ when referring to components. 

2. Changes Associated With the 

Reorganization 

• Several provisions derive in whole 

or in part from proposed §§ 111.35, 

111.37, or 111.70. 

• Several requirements in proposed 

§ 111.50 are redundant to requirements 

set forth in other subparts and are not 

repeated in subpart I. 

• Several proposed requirements for 

reprocessing are moved to final § 111.90 

in final subpart E. 

• The proposed requirement to 

collect reserve samples of each batch of 

dietary supplement is moved to final 

§ 111.83 in subpart E, where we clarify 

that the requirement relates to each lot 

of packaged and labeled dietary 

supplement rather than to a finished 

batch awaiting packaging and labeling. 

3. Changes After Considering Comments 

The final rule: 

• Provides flexibility for firms to 

document information about the 

maintenance, cleaning, and sanitizing of 

equipment used in producing the batch 

in either the batch production record or 

in individual equipment logs that it 

cross-references in the batch production 

record. 

• Provides flexibility for firms to 

include in the batch production record 


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either the results of any testing or 

examination performed, or a crossreference to the results of any testing or 

examination. 

C. What Is the Requirement to Establish 

a Batch Production Record? (Final 

§ 111.255) 

Final § 111.255(a) requires you to 

prepare a batch production record every 

time you manufacture a batch of a 

dietary supplement. Final § 111.255(b) 

requires that the batch production 

record include complete information 

relating to the production and control of 

each batch. Final § 111.255(a) and (b) 

derive from proposed § 111.50(a), with a 

nonsubstantive revision that divides the 

proposed requirements into two 

separate paragraphs. 

Final § 111.255(c) requires your batch 

production record to accurately follow 

the appropriate master manufacturing 

record and you to perform each step in 

the production of the batch. Final 

§ 111.255(c) derives from proposed 

§111.50(b). 

Final § 111.255(d) requires you to 

make and keep batch production 

records in accordance with subpart P. 

Final § 111.255(d) derives from 

proposed § 111.50(i) with editorial 

changes associated with the 

reorganization. 

We did not receive comments specific 

to proposed § 111.50(a), (b), or (i). 

D. What Must the Batch Record Include? 

(Final § 111.260) 

1. Final § 111.260(a) 

Final § 111.260(a) requires the batch 

production record to include the batch, 

lot, or control number: (1) Of the 

finished batch of dietary supplement 

and (2) that you assign in accordance 

with § 111.415(f) for each lot of 

packaged and labeled dietary 

supplement from the finished batch of 

dietary supplement, and for each lot of 

dietary supplement, from the finished 

batch of dietary supplement, that you 

distribute to another person for 

packaging or labeling. 

Final § 111.260(a) derives, in part, 

from proposed § 111.50(c)(1), which 

would require the batch, lot, or control 

number in the batch production record. 

Consistent with comments that 

requested that we clarify responsibilities 

when more than one party is involved 

with the manufacturing, packaging, 

labeling, or holding of a dietary 

supplement (see section VI of this 

document), we have added the 

requirements of final § 111.260(a)(1), 

(a)(2)(i), and (a)(2)(ii) to ensure that you 

are able to determine the manufacturing 

history and control of the packaged and 

labeled dietary supplement from all 

stages of manufacturing through 

distribution, and to be consistent with 

other provisions of this final rule. In the 

discussion of subpart L (section XVII of 

this document), we explain in detail 

final § 111.410(d), which requires you to 

be able to determine the complete 

manufacturing history and control of the 

packaged and labeled dietary 

supplement through distribution. In that 

same section, we explain final 

§ 111.415(f) which requires you to 

assign a batch, lot, or control number to 

each lot of packaged and labeled dietary 

supplement from a finished batch and 

each lot of dietary supplement from a 

finished batch that you distribute to 

another person for packaging and 

labeling. In that way, these batch, lot, or 

control numbers can be used to 

determine the manufacturing history 

and control of the batch. However, you 

can determine how you track the batch, 

lot, or control number of the packaged 

and labeled dietary supplement, or 

dietary supplement you send to another 

person for packaging and labeling, to a 

distributed dietary supplement. 

We did not receive comments specific 

to proposed § 111.50(c)(1). We respond 

to comments relevant to final subpart L 

in section XVII of this document. 

2. Final § 111.260(b) 

Final § 111.260(b) requires that the 

batch production record include the 

identity of equipment and processing 

lines used in producing the batch and 

derives from proposed § 111.50(c)(3). 

We did not receive comments specific 

to proposed § 111.50(c)(3). 

3. Final § 111.260(c) 

Final § 111.260(c) requires that the 

batch production record include the 

date and time of the maintenance, 

cleaning, and sanitizing of the 

equipment and processing lines used in 

producing the batch, or a cross-reference 

to records, such as individual 

equipment logs, where this information 

is retained. Final § 111.260(c) derives 

from proposed § 111.50(c)(4). 

(Comment 263) Many comments 

argue that it is not necessary or 

appropriate to retain the records of 

maintenance, cleaning, and sanitizing 

equipment and processing lines in the 

batch production record. These 

comments request that the final rule 

provide flexibility to retain such records 

in individual equipment files or log 

books for easy access. One comment 

recommends the requirement to retain 

such records be set forth within subpart 

D. 

(Response) As discussed in section IX 

of this document (final § 111.35(b)(2)), 

we agree with these comments. 

Consistent with final § 111.35(b)(2), 

final § 111.260(c) provides flexibility to 

retain the records of maintenance, 

cleaning, and sanitizing equipment and 

processing lines in either the batch 

production record or another record you 

cross-reference in the batch production 

record. 

4. Final § 111.260(d) 

Final § 111.260(d) requires that the 

batch production record include the 

unique identifier you assigned to each 

component (or, when applicable, to a 

product you receive from a supplier for 

packaging or labeling as a dietary 

supplement), packaging, and label used. 

Final § 111.260(d) derives from 

proposed § 111.50(c)(5), which would 

require that the batch record include the 

shipment lot unique identifier of each 

component, dietary supplement, 

packaging, and label used. Consistent 

with the convention we are establishing 

under final §§ 111.80(a), 111.155, and 

111.160, final § 111.260(d) does not use 

the term ‘‘shipment lot.’’

We did not receive comments specific 

to proposed § 111.50(c)(5). 

5. Final § 111.260(e) and (f) 

Final § 111.260(e) requires that the 

batch production record include the 

identity and weight or measure of each 

component used and derives from 

proposed § 111.50(c)(6). 

Final § 111.260(f) requires that the 

batch record include a statement of the 

actual yield and a statement of the 

percentage of theoretical yield at 

appropriate phases of processing. Final 

§ 111.260(f) derives from proposed 

§ 111.50(c)(9). 

(Comment 264) A few comments 

argue that the requirements in proposed 

§ 111.50(c)(6) are not applicable to 

continuous operations and that yield 

information required in proposed 

§ 111.50(c)(9) is irrelevant for quality 

control in continuous operations used 

for producing dietary ingredients. One 

of these comments also discusses 

‘‘continuous operations,’’ such as a 

continuous operation built adjacent to a 

soy crushing or vegetable oil refinery to 

receive a continuous side stream flow 

from that operation (see the discussion 

of final § 111.155(c) in section XII of this 

document). This comment explains that 

in such operations, quarantine and 

quality control approval occurs after the 

material has been isolated and 

concentrated in a stable matrix suitable 

for holding. 

(Response) Based on the limited 

information provided by these 

comments, it appears that they are 

describing the manufacture of a ‘‘dietary 


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ingredient’’ or other component that 

will subsequently be used in the 

manufacture of a dietary supplement. 

Therefore, in this scenario, the identity 

and weight or measure of the stable 

matrix must be taken. The statement of 

the actual yield and the theoretical yield 

refers to the batch in which the stable 

matrix is added as a component. 

6. Final § 111.260(g) 

Final § 111.260(g) requires that the 

batch production record include the 

actual results obtained during any 

monitoring operation. Final § 111.260(g) 

derives from proposed § 111.35(o)(2) 

which would require you to make and 

retain records of the actual results 

obtained during monitoring of the inprocess production. Consistent with the 

reorganization we are specifying that the 

records of monitoring be located in the 

batch production record, because the 

monitoring is associated with the batch 

production. 

We did not receive comments specific 

to proposed § 111.35(o)(2). 

7. Final § 111.260(h) 

Final § 111.260(h) requires that the 

batch production record include the 

results of any testing or examination 

performed during the batch production, 

or a cross-reference to such results. 

Final § 111.260(h) derives from 

proposed § 111.50(c)(10) which would 

require you to record the actual results 

of any testing performed during 

production of the batch. 

(Comment 265) A few comments 

object to the requirement in proposed 

§ 111.50(c)(10) that actual test results be 

included in the batch production 

record. These comments state test 

results are typically retained in other 

records, such as laboratory records, and 

that it would be duplicative to include 

such results in the batch production 

record. One comment states the ‘‘actual’’

(original record of) test results may not 

be available to the manufacturer when 

the testing is performed electronically or 

an outside laboratory does the testing. 

This comment adds for test results 

obtained in-house, original records are 

typically kept as part of the master 

laboratory records and cross-referenced 

in batch records. 

(Response) After considering these 

comments, we are providing flexibility 

to either include the results of tests or 

examinations in the batch production 

record, or provide a cross-reference to 

such results. We note that final 

§ 111.260(h) does not require that you 

have the original documentation of the 

test results. If an outside laboratory has 

performed testing for you, you must 

obtain a copy of the test results and 

include these in your batch production 

record or in another appropriate record 

that you can cross-reference and make 

readily available for inspection. 

8. Final § 111.260(i) 

Final § 111.260(i) requires that the 

batch production record include 

documentation that the finished dietary 

supplement meets specifications 

established in accordance with 

§ 111.70(e) and (g). Final § 111.260(i) 

derives from proposed § 111.50(c)(11). 

We have made a change to identify 

which required specifications the 

dietary supplement must meet. 

We did not receive comments specific 

to proposed § 111.50(c)(11). 

9. Final § 111.260(j) 

Final § 111.260(j) sets forth the 

requirements for documentation you 

must make and include in the batch 

production record, at the time of 

performance, of the manufacture of the 

batch. Final § 111.260(j) derives from 

proposed § 111.50(c)(2) and (c)(7). 

a. Final §111.260(j)(1). Final 

§ 111.260(j)(1) requires documentation, 

at the time of performance, of the date 

on which each step of the master 

manufacturing record was performed. 

Final §111.260(j)(1) derives from 

proposed § 111.50(c)(2). We did not 

receive comments specific to proposed 

§ 111.50(c)(2). 

b. Final §111.260(j)(2). Final 

§ 111.260(j)(2) requires documentation, 

at the time of performance, of the 

initials of the persons performing each 

step in the master manufacturing record. 

Final § 111.260(j)(2) derives from the 

second part of proposed 

§ 111.50(c)(2),(c)(7) and (c)(8). 

(Comment 266) One comment asks 

whether the persons responsible for 

batch production must be identified by 

name or by position. 

(Response) The requirement is for the 

initials of the name of the person rather 

than for identification of the position. 

Requiring that the record include the 

initials of the person(s) performing each 

step in the master manufacturing record 

means that the person performing the 

step is the person who physically 

initials the batch record at the time the 

person performs the step. The intent is 

for the person to acknowledge that he or 

she performed the requirement rather 

than to merely provide information that 

would identify that person. 

(Comment 267) One comment asks 

whether we will allow electronic 

signatures for batch production records, 

laboratory test results, and quality 

control unit documentation. The 

comment notes that many companies 

have fully computerized, automated 

production and quality control 

management systems that utilize 

password-protected (or otherwise 

secure) means of entering data at key 

quality control steps. 

(Response) The use of electronic 

signatures is governed by our 

regulations in part 11, which control 

whether electronic signatures are 

permitted. Our guidance entitled 

‘‘Guidance for Industry Part 11, 

Electronic Records; Electronic 

Signatures—Scope and Application,’’

available at http://www.fda.gov/cder/ 

guidance/5667fnl.htm, discusses the use 

of electronic signatures (Ref. 33). 

c. Final § 111.260(j)(2)(i) through 

§ 111.260(j)(2)(iv). Final 

§ 111.260(j)(2)(i) requires you to 

document at the time of performance 

the initials of the person responsible for 

weighing or measuring each component 

used in the batch, and final 

§ 111.260(j)(2)(ii) requires you to 

document at the time of performance 

the initials of the person responsible for 

verifying the weight or measure of each 

component used in the batch. Final 

§ 111.260(j)(2)(i) and (j)(2)(ii) derive 

from proposed § 111.50(c)(2)(i) and 

(c)(7), respectively. 

Final § 111.260(j)(2)(iii) requires you 

to document, at the time of 

performance, the initials of the person 

responsible for adding the component to 

the batch; and final § 111.260(j)(2)(iv) 

requires you to document, at the time of 

performance, the initials of the person 

responsible for verifying the addition of 

components to the batch. Final 

§ 111.260(j)(2)(iii) derives from 

proposed § 111.50(c)(2)(ii) and final 

§ 111.260(j)(2)(iv) derives from proposed 

§ 111.50(c)(8). 

We did not receive comments specific 

to proposed § 111.50(c)(2)(i) and 

(c)(2)(ii) or § 111.50(c)(7) and (c)(8). 

10. Final § 111.260(k) 

Final § 111.260(k) sets forth the 

requirements for documentation you 

must make and include in the batch 

production record, at the time of 

performance, of the packaging and 

labeling operations. Final § 111.260(k) 

derives from proposed § 111.70(g) 

which we discuss in the following 

paragraphs. 

In final § 111.260(k)(3), we are 

eliminating proposed § 111.70(g)(4) 

which would require that the 

documentation include any material 

reviews and disposition decisions for 

packaging and labels, because it would 

be redundant to final 

§ 111.180(b)(4)(ii)(D). 

a. General comments on proposed 

§ 111.70(g). 


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(Comment 268) Some comments 

assert that the requirement of proposed 

§ 111.70(g) that all packaging releases be 

placed in the batch production record is 

unnecessary. According to the 

comments, most packaging material lots 

are used in multiple batches. The 

comments assert that a requirement for 

this disposition information to be 

copied into each batch production 

record is unnecessary as long as lot 

traceability exists and this information 

is kept in a central file. 

(Response) These comments may have 

misinterpreted proposed § 111.70(g). It 

would require that the documentation 

in the batch production record for 

packaging and label operations include: 

(1) The identity and quantity of the 

packaging and labels used and 

reconciliation of any discrepancies 

between issuance and use, (2) the 

examination conducted in accordance 

with proposed § 111.70(b)(7), (3) the 

conclusions reached from retests 

conducted in accordance with proposed 

§ 111.70(e), and (4) any material reviews 

and disposition decisions for packaging 

and labels. None of these proposed 

requirements would require that 

‘‘packaging releases’’ be included in the 

batch record. 

The requirements for documentation 

for packaging you receive are set forth 

in final § 111.180(b) in subpart G. 

b. Final § 111.260(k)(1). Final 

§ 111.260(k)(1) requires the 

documentation of packaging and 

labeling operations to include the 

unique identifier you assigned to 

packaging and labels used, the quantity 

of the packaging and labels used, and, 

when label reconciliation is required, 

reconciliation of any discrepancies 

between issuance and use of labels. 

Final § 111.260(k)(1) derives from 

proposed § 111.70(g)(1) which would 

require that the documentation include 

the identity and quantity of the 

packaging and labels used and 

reconciliation of any discrepancies 

between issuance and use. For 

consistency with other provisions of 

this final rule, such as final 

§ 111.160(e)(1), final § 111.260(k)(1) 

requires ‘‘the unique identifier you 

assigned to packaging and labels used,’’

rather than ‘‘the identity of packaging 

and labels used.’’ Final § 111.260(k)(1) 

also includes changes we are making 

after considering comments. 

(Comment 269) Some comments 

assert comprehensive label 

reconciliation should not be required if 

appropriate electronic controls are 

instituted to ensure that correct labels 

are used during labeling operations. The 

comments state this alternative is 

permitted for labeling operations for 

drug products, which are generally 

identical or similar in nature to labeling 

operations for dietary supplements. As 

such, the comments assert the same 

flexibility should be afforded to dietary 

supplement manufacturers. Some 

comments specifically suggest changing 

the language of proposed § 111.70(g)(1) 

to read ‘‘The identity and quantity of the 

packaging and labels used and either 

reconciliation of any discrepancies 

between issuance and use or use of 

appropriate electronic or 

electromechanical equipment to 

conduct a 100-percent examination for 

labeling during or after completion of 

finishing operations.’’

(Response) We agree that label 

reconciliation need not be required for 

cut or rolled labels if a 100-percent 

examination for correct labels is 

performed by appropriate electronic or 

electromechanical equipment during or 

after completion of finishing operations. 

Thus we have made two changes in this 

final rule in addition to the changes in 

final § 111.260(k)(1) that provide there 

must be label reconciliation when such 

reconciliation is required either to 

account for discrepancies or to ensure 

the use of the label that is specified in 

the master manufacturing record. First, 

we have revised the final rule in subpart 

L (for packaging and labeling 

operations) to provide that you need not 

conduct label reconciliation if a 100- 

percent examination for correct labels is 

performed by appropriate electronic or 

electromechanical equipment during or 

after completion of finishing operations 

(see discussion of final § 111.410(b) in 

subpart L in section XVI of this 

document). Second, final 

§ 111.260(k)(1), requires you to include 

documentation in the batch production 

of reconciliation of any discrepancies 

between issuance and use of labels only 

when label reconciliation is required. 

c. Final § 111.260(k)(2). Final 

§ 111.260(k)(2) requires the 

documentation of packaging and 

labeling operations to include an actual 

or representative label, or a crossreference to the physical location of the 

actual or representative label specified 

in the master manufacturing record. 

Final § 111.260(k)(2) derives from 

proposed § 111.50(c)(12) which would 

require that the batch production record 

include copies of all container labels 

used and the results of examinations 

conducted during the label operation to 

ensure that the containers have the 

correct label. 

(Comment 270) A few comments ask 

that we clarify the container labels that 

proposed § 111.50(c)(12) is referring to. 

Specifically, these comments ask 

whether proposed § 111.50(c)(12) is 

referring to finished product labels, bulk 

material labels, or in-process container 

labels. One comment asserts proposed 

§ 111.50(c)(12) is unnecessary for 

ensuring the dosage form of dietary 

supplements meets specifications. 

One comment finds proposed 

§ 111.50(c)(12) confusing, because it 

does not specify what is meant by ‘‘label 

operation.’’ This comment notes that 

during the course of manufacturing 

operations, containers holding inprocess materials are often labeled but 

the comment assumes that proposed 

§ 111.50(c)(12) does not require the 

retention of copies of in-process 

container labels, which would not add 

significant value toward the assurance 

of a quality product. 

In general, these comments ask for 

clarification of proposed § 111.50(c)(12), 

and suggest it be deleted. 

(Response) Proposed § 111.50(c)(12) 

referred to the product label that would 

be affixed to the containers that hold the 

packaged and labeled dietary 

supplement. We did not receive any 

comments that a related requirement (in 

proposed § 111.45(b)(7) in the master 

manufacturing record) was confusing or 

needed clarification. We therefore 

believe that the requirement that the 

batch production record include a label 

will be clearer if we state the 

requirement in a way that is similar to 

the requirement in proposed 

§ 111.45(b)(7). However, because 

comments to proposed § 111.45(b)(7) 

persuaded us to provide flexibility for 

(1) having a representative label rather 

than an actual label and (2) crossreferencing the physical location of the 

actual or representative label that is 

specified in the master manufacturing 

record, we are providing the same 

flexibility for having a label in the batch 

production record. Therefore, we are 

revising the proposed requirement that 

the batch production record include 

‘‘copies of all container labels used’’ so 

that, under final § 111.260(k)(2), the 

batch production record must include 

an actual or representative label, or a 

cross-reference to the physical location 

for the actual or representative label that 

is specified in the master manufacturing 

record. 

However, we are not requiring in final 

§ 111.260(k)(2) that the batch 

production record include the results of 

examinations conducted during the 

label operation to ensure that the 

containers have the correct label that is 

specified in the master manufacturing 

record, because this would be 

redundant to final § 111.260(k)(3). 

d. Final § 111.260(k)(3). Final 

§ 111.260(k)(3) requires that the 

documentation of packaging and 


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labeling operations include the results 

of any tests or examinations conducted 

on packaged and labeled dietary 

supplements (including repackaged or 

relabeled dietary supplements), or a 

cross-reference to such results. Final 

§ 111.260(k)(3) combines the proposed 

requirements of proposed § 111.70(g)(2) 

which would require that the 

documentation include the results of 

examinations conducted in accordance 

with proposed § 111.70(b)(7), and 

proposed § 111.70(g)(3) which would 

require that the documentation include 

the conclusions from retests conducted 

in accordance with proposed § 111.70. 

For consistency with other requirements 

for documentation that must be in the 

batch record, final § 111.260(k)(3) 

requires you to include ‘‘the results of 

any tests or examinations,’’ rather than 

‘‘the examination’’ (proposed 

§ 111.70(g)(2)) and ‘‘conclusions’’

(proposed § 111.70(g)(3)). Final 

§ 111.260(k)(3) also includes editorial 

revisions associated with combining 

proposed § 111.70(g)(2) and (g)(3). 

We did not receive comments specific 

to proposed § 111.70(g)(2) or (g)(3). 

11. Final § 111.260(l) 

Final § 111.260(l) sets forth the 

requirements for documentation quality 

control personnel must make at the time 

of performance and that must be 

included in the batch production 

record. Final § 111.260(l) derives from 

proposed §§ 111.35(i)(2), (j), (m), (o)(2); 

111.37(b)(3), (b)(5), and (b)(9); 

111.50(c)(1) through (c)(11), (c)(13), 

(c)(14), (d)(2), (e), and (g); 111.70(b)(6); 

and 111.70(g). 

a. Final § 111.260(l)(1). Final 

§ 111.260(l)(1) requires quality control 

personnel to document at the time of 

performance the review of the batch 

production record. Final § 111.260(l)(1) 

derives from the following proposed 

regulations: 

• § 111.50(d), which would require 

that the quality control unit review in 

accordance with § 111.37(b)(5) the batch 

production record established in 

§ 111.50(c); and 

• § 111.50(e), which would require 

that the quality control unit document 

at the time of performance in 

accordance with § 111.37(c), the review 

performed in accordance with 

§ 111.50(d). 

Final § 111.260(l)(1) includes editorial 

changes associated with the 

reorganization. We did not receive 

comments specific to proposed 

§ 111.50(d) or (e). 

b. Final § 111.260(l)(1)(i). Final 

§ 111.260(l)(1)(i) requires the 

documentation by quality control 

personnel to include review of any 

monitoring operation required under 

subpart E. Final § 111.260(l)(1)(i) 

derives from proposed § 111.35(i)(2) 

which would require that you review, 

among other things, the results of the 

monitoring of the in-process control 

points, steps, or stages to ensure 

specifications are met. As discussed in 

section XI of this document (final 

§ 111.123(a)(3)), the final rule requires 

quality control personnel to review the 

required monitoring. 

We did not receive comments specific 

to proposed § 111.35(i)(2). 

c. Final § 111.260(l)(1)(ii). Final 

§ 111.260(l)(1)(ii) requires the 

documentation by quality control 

personnel to include the review by 

quality control personnel of the results 

of any tests or examinations, including 

tests or examinations conducted on 

components, in-process materials, 

finished batches of dietary supplements, 

and packaged and labeled dietary 

supplements. Final § 111.260(l)(1)(ii) 

derives from the following proposed 

provisions: 

• Proposed § 111.50(e)(1) which 

would require that the documentation 

by the quality control unit include 

review of component, dietary 

ingredient, and dietary supplement 

receiving records, including review of 

testing and examination results and 

• Proposed § 111.37(b)(9) which 

would require, in part, the quality 

control unit to review all testing results. 

(Comment 271) A few comments 

assert that the proposed requirement 

that the quality control unit review 

receiving records as part of its review of 

the batch record is redundant and 

should be eliminated. One comment 

argues that it is unnecessarily 

burdensome to require the quality 

control unit to re-review and crossreference all receiving records, noting 

that the quality control unit already has 

performed a review of these records 

when the components or dietary 

supplements were received, approved, 

and released for use. The comment 

asserts the quality control unit should 

only have to repeat this review if it is 

conducting an investigation or a 

material review. 

(Response) We agree with the 

comments. Therefore, final 

§ 111.260(l)(1)(ii) retains the 

requirements of proposed 

§§ 111.37(b)(9) and 111.50(e)(1) to 

review the results of testing and 

examination, but does not require 

quality control personnel to document, 

as part of the review of the batch record, 

receiving records for components and 

dietary supplements. 

d. Final § 111.260(l)(2). Final 

§ 111.260(l)(2) requires that the 

documentation by quality control 

personnel include that quality control 

personnel approved or rejected any 

reprocessing or repackaging. Final 

§ 111.260(l)(2) derives from proposed 

§ 111.50(c)(14) which would require 

that the batch production record include 

the signature of the quality control unit 

to document its review of the batch 

production record and any approval for 

reprocessing or repackaging. For 

consistency with other provisions in 

this final rule (such as final § 111.90), 

final § 111.260(l)(2) includes a revision 

that quality control personnel must 

clearly choose between approving—or 

rejecting—any reprocessing or 

repackaging. 

We did not receive comments specific 

to proposed § 111.50(c)(14). 

e. Final § 111.260(l)(3). Final 

§ 111.260(l)(3) requires the 

documentation by quality control 

personnel to include that it approved 

and released, or rejected, the batch for 

distribution, including any reprocessed 

batch. Final § 111.260(l)(3) derives from 

the following proposed regulations: 

• Proposed § 111.37(b)(5) which 

would require, in part, the quality 

control unit to review the batch 

production record to approve the batch 

for release for distribution; 

• Proposed § 111.50(d)(2) which 

would require the quality control unit 

not to approve and release for 

distribution any batch of dietary 

ingredients or dietary supplement that 

does not meet all specifications; and 

• Proposed § 111.50(g) which would 

require, in part, the results of the 

reevaluation by the quality control unit 

to be documented in the batch 

production record. 

For consistency with other provisions 

of this final rule (such as final § 111.90), 

final § 111.260(l)(3) requires that quality 

control personnel must clearly choose 

between approving—or rejecting—the 

batch for distribution. We did not 

receive comments specific to those parts 

of proposed §§ 111.37(b)(5) or 

111.50(d)(2) that we are setting forth in 

final § 111.260(l)(3). 

f. Final § 111.260(l)(4). Final 

§ 111.260(l)(4) requires the batch 

production record to include 

documentation, at the time of 

performance, that quality control 

personnel approved and released, or 

rejected, the packaged and labeled 

dietary supplement, including any 

repackaged or relabeled dietary 

supplement. Final § 111.260(l)(4) 

derives from the following proposed 

regulations: 

• Proposed § 111.37(b)(3) which 

would require, in part, that the quality 


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control unit approve or reject all dietary 

supplements and 

• Proposed § 111.70(e) which would 

require, in part, that any repackaged or 

relabeled dietary supplement meet all 

specifications and that the quality 

control unit must approve or reject their 

release for distribution. 

We did not receive comments specific 

to those parts of proposed 

§§ 111.37(b)(3) or 111.70(e) that we are 

setting forth in final § 111.260(l)(4). 

12. Final § 111.260(m) 

Final § 111.260(m) requires the batch 

production record to include 

documentation, at the time of 

performance, of any required material 

review and disposition decision. Final 

§ 111.260(m) derives from the following 

proposed provisions: 

• Proposed § 111.50(c)(13) which 

would require that the batch production 

record include any documented review 

and disposition decision and 

• Proposed § 111.35(j) which would 

require that the person who conducts 

the material review and makes the 

disposition decision document that 

activity, at the time of performance, in 

the batch production record. 

We did not receive comments specific 

to proposed §§ 111.35(j) or 

111.50(c)(13). 

13. Final § 111.260(n) 

Final § 111.260(n) requires that the 

batch production record include 

documentation, at the time of 

performance, of any reprocessing. We 

have added this requirement in 

conjunction with the requirement for 

written procedures for the quality 

control operations for approving or 

rejecting any reprocessing, discussed 

generally in section IV of this document. 

E. Review of Batch Production Record 

Deviations (Proposed § 111.50(d)(1), 

(e)(2), (e)(3), and (e)(4)) 

Proposed §111.50(d)(1) would 

require, if a batch deviates from the 

master manufacturing record, including 

any deviation from specifications, the 

quality control unit to conduct a 

material review and make a disposition 

decision and record any decision in the 

batch production record. Under final 

§ 111.87 quality control personnel must 

conduct any required material review 

and make any required disposition 

decision; under final § 111.113(a)(2) 

quality control personnel must conduct 

a material review and make a 

disposition decision if a batch deviates 

from the master manufacturing record, 

including any deviation from 

specifications. Given the requirements 

of final §§ 111.87 and 111.113, it would 

be redundant to include proposed 

§ 111.50(d)(1) in final subpart I. 

Proposed § 111.50(e)(2) would require 

that the review of the batch production 

record and documentation by the 

quality control unit include 

identification of any deviation from the 

master manufacturing record that may 

have caused a batch or any of its 

components to fail to meet 

specifications identified in the master 

production record. Proposed 

§ 111.50(e)(3) would require that the 

review of the batch production record 

and documentation by the quality 

control unit include records of 

investigations, conclusions, and 

corrective actions performed in 

accordance with proposed § 111.50(d). 

Proposed § 111.50(e)(4) would require 

that the review of the batch production 

record and documentation by the 

quality control unit include the identity 

of the person qualified by training and 

experience who performed the 

investigation in accordance with 

§ 111.50(d). 

Each of these requirements is already 

included in final § 111.140(b)(3) which 

sets forth the requirements for the 

documentation that quality control 

personnel must include for any required 

material review and disposition 

decision. In addition, under final 

§ 111.260(m), the batch production 

record must include documentation of 

any required material review and 

disposition decision. Given the 

requirements of final §§ 111.140(b)(3) 

and 111.260(m), it would be redundant 

to include proposed § 111.50(e)(2), 

(e)(3), and (e)(4) in final subpart I, and 

we are not including them. 

XV. Comments on Production and 

Process Control System: Requirements 

for Laboratory Operations (Final 

Subpart J) 

A. Organization of Final Subpart J 

In the 2003 CGMP Proposal, the 

proposed requirements for production 

and process controls for laboratory 

operations were set forth in proposed 

§ 111.60(a) through (d). As shown in 

table 11 of this document, we are 

reorganizing the requirements for 

laboratory operations into a distinct 

subpart (final Subpart J—Production 

and Process Control System: 

Requirements for Laboratory 

Operations). Table 11 lists the sections 

in final subpart J and identifies the 

proposed sections that form the basis of 

the final rule. 

TABLE 11.—DERIVATION OF SECTIONS

IN FINAL SUBPART J 

Final Rule 2003 CGMP 

Proposal 

§ 111.303 What are the 

requirements under 

this subpart J for written procedures? 

N/A 

§ 111.310 What are the 

requirements for the 

laboratory facilities 

that you use? 

§ 111.60(a) 

§ 111.315 What are the 

requirements for laboratory control processes? 

§ 111.60(b)(1) 

§ 111.320 What requirements apply to laboratory methods for testing and examination? § 111.60(c) and 

(d) 

§ 111.325 Under this 

subpart J, what 

records must you 

make and keep? 

§ 111.60(b)(2) 

and (b)(3) 

B. Highlights of the Changes to the 

Proposed Requirements for Laboratory 

Operations 

1. Revisions 

The final rule applies to persons who 

manufacture, package, label, or hold 

dietary supplements unless subject to an 

exclusion in § 111.1. 

2. Changes Associated With the 

Reorganization 

This subpart contains fewer details, 

compared to the 2003 CGMP Proposal, 

regarding the requirements for 

collecting representative samples and 

for testing, because these details are set 

forth elsewhere in this final rule (i.e., in 

final §§ 111.75 and 111.80) and would 

be redundant in final subpart J. 

3. Changes After Considering Comments 

The final rule: 

• Includes a new requirement to 

establish and follow written procedures 

for laboratory operations, including 

written procedures for the tests and 

examinations you conduct to determine 

whether or not specifications are met. 

• Requires you to identify and use the 

appropriate ‘‘scientifically valid 

method,’’ rather than an appropriate 

‘‘validated testing method,’’ for each 

established specification for which 

testing or examination is required to 

determine whether the specification is 

met. 


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C. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.303) 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

Final § 111.303 requires you to 

establish and follow written procedures 

for laboratory operations, including 

written procedures for the tests and 

examinations you conduct to determine 

whether specifications are met. 

D. What Are the Requirements for the 

Laboratory Facilities That You Use? 

(Final § 111.310) 

Final § 111.310 requires you to use 

adequate laboratory facilities to perform 

whatever testing and examinations are 

necessary to determine whether: (1) 

Components that you use meet 

specifications; (2) in-process 

specifications are met as specified in the 

master manufacturing record; and (3) 

dietary supplements that you 

manufacture meet specifications. Final 

§ 111.310(a) is substantially similar to 

proposed § 111.60(a). The requirement 

for ‘‘adequate laboratory facilities’’ is to 

ensure that the facilities used are 

designed and suitable for carrying out 

the necessary tests and examinations. 

Other CGMP requirements of this final 

rule would apply to the manufacturer’s 

laboratory facilities, such as Subpart C—

Physical Plant and Grounds, and 

Subpart D—Equipment and Utensils, 

and should be considered in assessing 

the adequacy of the laboratory facilities. 

If the tests and examinations are carried 

out by an outside laboratory, you will be 

responsible for ensuring that the test 

and examinations are adequately 

performed. 

(Comment 272) One comment states 

that proposed § 111.60(a) would be 

highly disruptive to the dietary 

supplement industry and would impose 

a great burden on companies that 

traditionally rely on certification of 

ingredient suppliers. Some comments 

assert it would be redundant to require 

testing by companies who are suppliers 

of dietary ingredients, as well as by 

companies who receive the dietary 

supplements, to determine whether the 

dietary ingredients meet specifications. 

(Response) The final rule already 

includes changes that address the 

concerns raised by these comments. As 

discussed in section X of this document 

regarding final § 111.75(a), the final rule 

permits the use of certificates of analysis 

for specifications other than the identity 

of a dietary ingredient. 

E. What Are the Requirements for 

Laboratory Control Processes? (Final 

§ 111.315) 

Final § 111.315 sets forth the 

minimum laboratory control processes 

that you must establish and follow. 

These laboratory control processes must 

be reviewed and approved by quality 

control personnel. 

1. Final § 111.315(a) 

Final § 111.315(a) requires the 

laboratory control processes you 

establish and follow to include the use 

of criteria for establishing appropriate 

specifications. Final § 111.315(a) is 

identical to proposed § 111.60(b)(1)(ii). 

We did not receive comments specific 

to proposed § 111.60(b)(1)(ii). 

2. Final § 111.315(b) 

Final § 111.315(b) requires you to 

establish and follow laboratory control 

processes that are reviewed and 

approved by quality control personnel, 

including the use of sampling plans for 

obtaining representative samples, in 

accordance with subpart E, of: (1) 

Components, packaging, and labels; (2) 

in-process materials; (3) finished 

batches of dietary supplements; (4) 

product you receive for packaging or 

labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier); and (5) packaged and 

labeled dietary supplements. Final 

§ 111.315(b) derives from proposed 

§ 111.60(b)(1)(iii)(A) through 

(b)(1)(iii)(E). 

Final § 111.315(b) combines the 

proposed requirements of 

§ 111.60(b)(1)(iii)(A) and (b)(1)(iii)(D) for 

consistency with final § 111.80(a) which 

combines the requirements to collect 

representative samples of components, 

packaging, and labels. However, for 

consistency with other requirements 

established by this final rule, we are 

separating the requirements to collect 

representative samples of ‘‘dietary 

supplements received’’ (which the final 

rule refers to as ‘‘product that you 

receive for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier,’’

or ‘‘received product’’)) from the 

requirements to collect representative 

samples of components. 

(Comment 273) Some comments note 

that proposed § 111.60(b)(1)(iii) restates 

the requirements, already contained in 

proposed § 111.37(b)(11)(i) through 

(b)(11)(iv), that the quality control unit 

collect representative samples. These 

comments request proposed 

§ 111.60(b)(1)(iii) be deleted, because it 

is more appropriately described as a 

quality control function rather than as a 

laboratory function. 

(Response) We disagree that the 

proposed requirement to use a sampling 

plan is more appropriately described as 

a quality control function than as a 

laboratory function. Under both the 

proposed and the final rule, the 

sampling plans that are part of the 

laboratory control operations are subject 

to approval by quality control personnel 

(‘‘unit’’ in the proposed rule) but are not 

developed by quality control personnel. 

We are making no changes based on this 

comment. 

(Comment 274) One comment asserts 

sampling can be better accomplished at 

the point of packaging rather than at a 

laboratory remote from the packaging 

operation. 

(Response) This comment 

misinterprets proposed 

§ 111.60(b)(1)(iii) which proposed to 

establish a process (i.e., the use of a 

sampling plan) rather than to direct that 

a particular operating unit (such as a 

laboratory) collect samples. We are 

making no changes based on this 

comment. 

3. Final § 111.315(c) 

Final § 111.315(c) requires the 

laboratory control processes you 

establish and follow include use of 

criteria for selecting appropriate 

examination and testing methods. Final 

§ 111.315(c) is identical to proposed 

§ 111.60(b)(1)(i). 

(Comment 275) One comment 

recommends that a contract laboratory 

hired by a person who is subject to the 

final rule be able to determine the 

specific type of test that is most 

appropriate. 

(Response) Nothing in the final rule 

would preclude you from relying on the 

recommendation of the contract 

laboratory in selecting an appropriate 

test or examination. However, the 

manufacturer of the dietary supplement 

has the responsibility to comply with 

these CGMP requirements, including the 

requirement to select appropriate tests, 

regardless of who conducts the tests. 

4. Final § 111.315(d) 

Final § 111.315(d) requires the 

laboratory control processes you 

establish and follow to include use of 

criteria for selecting standard reference 

materials used in performing tests and 

examinations. Final § 111.315(d) derives 

from proposed § 111.60(b)(1)(iv). 

(Comment 276) Several comments 

support the use of standard reference 

materials. Some comments distinguish 

between a reference standard (which 

they describe as a highly purified 


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compound that is well characterized 

and is used in quantitative assays for 

single chemical entities) and a reference 

material (which they describe as similar 

to a reference standard but with less 

specificity). These comments urge us to 

recognize the difference between 

reference standards and reference 

materials and to require the use of both 

in the final rule. 

(Response) The comments that 

request we recognize a difference 

between certain types of reference 

materials are consistent with proposed 

§ 111.60(b)(1)(iv) and with statements 

that we made in the preamble to the 

2003 CGMP Proposal. We distinguished 

two general types of reference materials: 

(1) Compendia reference standards that 

do not require characterization and (2) 

noncompendia standards that should be 

of the highest purity that can be 

obtained by reasonable effort and that 

should be thoroughly characterized to 

ensure their identity, purity, quality, 

and strength. We recommended you use 

compendia reference standards 

whenever possible, and that you 

establish appropriately characterized inhouse materials prepared from 

representative lots if no compendia 

reference standard exists. 

We also discussed reference materials 

from the perspective of the type of test 

or examination. For organoleptic 

examinations, we described an 

authenticated plant reference material 

as material that has been authenticated 

as the correct plant species and correct 

plant part(s) by a qualified plant 

taxonomist. For microscopic and 

chemical tests (including calibration 

tests), we described a reference material 

as a highly purified compound that is 

well characterized. 

To the extent that the comments are 

recommending that both compendia 

reference standards and noncompendia 

reference standards comply with any 

final rule, this final rule would allow for 

the use of both compendia reference 

standards and noncompendia reference 

standards. However, to the extent that 

the comments are requesting this final 

rule require that both types of reference 

materials be used, we disagree. We see 

no reason to require, for example, that 

a firm with access to compendia 

standards be required to develop 

noncompendia standards. Likewise, 

given that we have acknowledged that 

noncompendia standards may be used, 

we see no reason to require the use of 

compendia standards in all 

circumstances. 

(Comment 277) One comment 

expresses confusion about the preamble 

discussion of proposed § 111.60(b)(1)(iv) 

and suggests the preamble specify that 

reference standards be established 

appropriate to the assay procedure for 

which they are used. 

(Response) Reference materials 

should be appropriate to the assay 

procedure for which they are used. 

(Comment 278) Several comments 

recommend we acknowledge certain 

reference materials as authoritative 

sources for botanical ingredients, such 

as American Herbal Pharmacopoeia, 

European Pharmacopoeia, and the 

World Health Organization, in part 

because other sources include only a 

limited number of botanicals as 

supplements. In the comments’ view, 

explicit acknowledgment by FDA would 

encourage manufacturers to use 

independent standards, increase CGMP 

compliance, and show that validation is 

not limited to quantitative chemical 

methods. 

(Response) We decline to 

acknowledge certain reference materials 

as authoritative sources for botanical 

ingredients. Such a request is outside 

the scope of this final rule. 

(Comment 279) One comment 

believes we should designate USP to 

develop appropriate standards. 

(Response) This comment is outside 

the scope of this final rule. 

5. Final § 111.315(e) 

Final § 111.315(e) requires that the 

laboratory control processes you must 

establish and follow include use of test 

methods and examinations in 

accordance with established criteria. 

Final § 111.315(e) derives from 

proposed § 111.60(b)(1)(vi). 

We did not receive comments specific 

to proposed § 111.60(b)(1)(vi). 

F. What Requirements Apply to 

Laboratory Methods for Testing and 

Examination? (Final § 111.320) 

1. Final § 111.320(a) 

Final § 111.320(a) requires you to 

verify that laboratory examination and 

testing methodologies are appropriate 

for their intended use. Final § 111.320(a) 

is identical to proposed § 111.60(c). 

(Comment 280) One comment states 

that this decision should be made by a 

qualified person, whether in-house or at 

a contract laboratory. 

(Response) We agree. Nothing in the 

final rule would preclude you from 

relying on the judgment of a qualified 

person at a contract laboratory to satisfy 

the requirements of final § 111.320(a). 

We would not consider that a 

recommendation from a contract 

laboratory is any different from a 

recommendation from an operating unit 

of the manufacturer. However, the 

manufacturer of the dietary supplement 

has the responsibility to comply with 

these CGMP requirements, including the 

requirement to select appropriate tests, 

regardless of who conducts the tests. 

(Comment 281) One comment 

suggests modifying proposed § 111.60(c) 

to add ‘‘reference materials and/or 

reference standards’’ to the list of 

elements that must be verified to be 

appropriate for their intended use. 

(Response) If reference materials and 

reference standards are used as part of 

the test or examination method, then 

such materials and standards are 

already required to be verified under the 

language in proposed § 111.60(c). Thus, 

there is no need for the modification 

and we decline to modify the language 

of final § 111.320(a). 

2. Final § 111.320(b) 

Final § 111.320(b) requires you to 

identify and use the appropriate 

scientifically valid method for each 

established specification for which 

testing or examination is required to 

determine whether the specification is 

met. Final § 111.320(b) derives from 

proposed § 111.60(d) which would 

require you to identify and use an 

appropriate validated testing method for 

each established specification for which 

testing is required to determine whether 

the specification is met. Final 

§ 111.320(b) includes a provision 

associated with final § 111.75(h) which 

provides flexibility to use examinations 

as well as tests to determine whether 

specifications are met. 

(Comment 282) Many comments 

express concern about the amount of 

testing required for the validation of the 

appropriate test method. Several 

comments object to the use of the terms 

‘‘validations’’ and ‘‘validated’’ which 

they assert have a specific meaning in 

a pharmaceutical context and would be 

overly burdensome in this rule. Other 

comments assert that methods already 

recognized as official standards do not 

need to be ‘‘validated,’’ but simply 

‘‘verified’’ as to suitability. Some 

comments suggest substituting 

‘‘scientifically valid testing method’’ for 

‘‘appropriate validated testing method.’’

One comment suggests ‘‘qualifications’’

replace ‘‘validations.’’ Another 

comment suggests test methods need 

not be validated if they are ‘‘proven to 

be suitable under actual conditions of 

use.’’ Another comment suggests adding 

‘‘established by the manufacturer’’ after 

‘‘appropriate validated test method.’’

One comment recommends the final 

rule give companies the flexibility to 

adopt the method most suitable to the 

ingredient they are testing, regardless of 

whether the method is, or is not, an 

‘‘official method’’ such as those 


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established by AOAC International or 

FDA. 

(Response) In the preamble to the 

2003 CGMP Proposal (68 FR 12157 at 

12208), we stated that test method 

validation determines whether a newlydeveloped or existing test method is 

accurate, precise, and specific for its 

intended purpose and involves 

evaluating the test method on multiple 

occasions or in multiple test facilities. 

We explained that official methods, 

such as AOAC International methods, 

are validated in collaborative studies 

using several laboratories under 

identical conditions and that the AOAC 

International methods are often cited as 

‘‘official validated methods.’’ We also 

explained that other method validations 

are conducted in a single laboratory by 

repeating the same test multiple times. 

Typical validation characteristics 

include accuracy, precision, specificity, 

detection limit, quantitation limit, 

linearity, range, and robustness. 

The process of method validation 

discussed above is a formal process for 

demonstrating that procedures are 

suitable for their intended use. 

Although all methods that are formally 

validated are considered ‘‘scientifically 

valid,’’ other methods that are based on 

scientific data or results published in, 

for example, scientific journals, 

references, text books, or proprietary 

research can be scientifically valid even 

if they are not formally ‘‘validated’’ in 

collaborative studies (68 FR 12157 at 

12198). 

We agree that companies should have 

flexibility to adopt the method most 

suitable to the ingredient they are 

testing. Consistent with the view that 

we expressed in the preamble to 2003 

CGMP Proposal (68 FR 12157 at 12198), 

we believe that a scientifically valid 

method is one that is accurate, precise, 

and specific for its intended purpose. In 

other words, a scientifically valid 

method is one that consistently does 

what it is intended to do. 

Because we acknowledge that 

methods that are based on scientific 

data or results published in, for 

example, scientific journals, references, 

text books, or proprietary research can 

be scientifically valid even if they are 

not formally ‘‘validated,’’ we are 

revising proposed § 111.60(d). Under 

final § 111.320(b) you must identify and 

use an appropriate ‘‘scientifically valid 

method’’ (rather than a ‘‘validated 

method’’) for each established 

specification for which testing or 

examination is required to determine 

whether the specification is met. 

However, we continue to recommend 

that you use tests and examinations that 

already have been validated when such 

tests are available. 

(Comment 283) One comment 

specifically asks how much 

modification of a validated method is 

allowed before the method must be revalidated by the laboratory. The 

comment cites an example of moisture 

testing in which the testing method 

needs to be modified to provide a more 

valid moisture reading. 

(Response) In the preamble to the 

2003 CGMP proposal (68 FR 12157 at 

12209), we recommended that, if you 

modify an officially validated method, 

you document the reason for the 

modification and have data to show that 

the modified method produces results 

that are at least as accurate and reliable 

as the established method for the 

material being tested. We also 

recommended that you have complete 

records of any testing and 

standardization of laboratory reference 

standards, reagents, and standard 

solutions that you use in your laboratory 

operations. We are making no changes 

to these recommendations in this final 

rule. 

(Comment 284) Several comments 

request the final rule incorporate by 

reference authoritative sources of 

compendial methods. 

(Response) We decline this request for 

the reasons discussed in response to 

comments 193 and 196. 

G. Appropriate Test Method Validation 

(Proposed § 111.60(b)(1)(v)) 

Proposed § 111.60(b)(1)(v) would 

require the laboratory control processes 

you establish and follow to include the 

use of appropriate test method 

validations. Because the final rule does 

not require that you use a validated 

method for any tests or examinations 

that you conduct, we are removing 

proposed § 111.60(b)(1)(v). 

H. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.325) 

Final § 111.325 sets forth the 

requirements for records that quality 

control personnel must make and keep. 

1. Final § 111.325(a) 

Final § 111.325(a) requires you to 

make and keep records required under 

subpart J in accordance with subpart P. 

Final § 111.325(a) derives from 

proposed § 111.60(b)(3), which would 

require you to keep laboratory 

examination and testing records in 

accordance with proposed § 111.125. 

Because final § 111.303 requires you to 

establish and follow written procedures 

for laboratory operations, the records 

you must make and keep under final 

§ 111.325 are not limited to laboratory 

examination and testing records, but 

also include the written procedures. 

Final § 111.325(a) also includes editorial 

revisions associated with the 

reorganization and editorial revisions 

for consistency with the recordkeeping 

requirements in subparts P. 

We did not receive comments specific 

to proposed § 111.60(b)(3). 

2. Final § 111.325(b)(1) 

The final rule includes a new 

requirement (final § 111.303) that you 

establish and follow written procedures 

for laboratory operations, including 

written procedures for the tests and 

examinations you conduct to determine 

whether specifications are met. Those 

written procedures are records. 

Therefore, final § 111.325(b)(1) requires 

you to make and keep a record of the 

written procedures for laboratory 

operations, including written 

procedures for the tests and 

examinations that you conduct to 

determine whether specifications are 

met. 

3. Final § 111.325(b)(2) 

Final § 111.325(b)(2) sets forth 

requirements for documenting that you 

followed the laboratory methodology 

established in accordance with this 

subpart. Final § 111.325(b)(2)(i) requires 

that the person who conducts the testing 

and examination document, at the time 

of performance, that laboratory 

methodology established in accordance 

with this subpart is followed. Final 

§ 111.325(b)(2)(ii) requires that the 

documentation include the results of the 

testing and examination. Final 

§ 111.325(b)(2) derives from proposed 

§ 111.60(b)(2) with revisions associated 

with the reorganization. 

(Comment 285) One comment states 

that, without appropriate 

documentation, there would be no 

assurance that the appropriate testing 

was indeed performed and that the 

product’s identity, purity, quality, 

strength, and composition are what they 

are represented to be. 

(Response) We agree and have 

retained the requirement in this final 

provision. 

XVI. Comments on the Production and 

Process Control System: Requirements 

for Manufacturing Operations (Final 

Subpart K) 

A. Organization of Final Subpart K 

In the 2003 CGMP Proposal, the 

requirements for manufacturing 

operations were set forth in § 111.65. As 

shown in table 12 of this document, we 

are establishing the requirements for 


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manufacturing operations in a distinct 

subpart (final Subpart K—Production 

and Process Control System: 

Requirements for Manufacturing 

Operations). In addition, we are 

incorporating some requirements from 

proposed § 111.74 relating to rejected 

components, dietary supplements, and 

packaging and labels into final subpart 

K. Table 12 lists the sections in final 

subpart K and identifies the proposed 

sections that form the basis of the final 

rule. 

TABLE 12.—DERIVATION OF SECTIONS

IN FINAL SUBPART K 

Final Rule 2003 CGMP 

Proposal 

§ 111.353 What are the 

requirements under 

this subpart K for written procedures? 

N/A 

§ 111.355 What are the 

design requirements 

for manufacturing operations? 

§ 111.65(a) 

§ 111.360 What are the 

requirements for sanitation? 

§ 111.65(b) 

§ 111.365 What precautions must you 

take to prevent contamination? 

§ 111.65(c) 

§ 111.370 What requirements apply to rejected dietary supplements? § 111.74 

§ 111.375 Under this 

subpart K, what 

records must you 

make and keep? 

N/A 

B. Highlights of Changes to the 

Proposed Requirements for 

Manufacturing Operations 

1. Revisions 

The final rule: 

• Applies to persons who 

manufacture, package, label, or hold 

dietary supplements unless subject to an 

exclusion in § 111.1 and 

• Reflects changes relevant to this 

subpart that we are making to final 

subpart C concerning water standards. 

2. Changes Made After Considering 

Comments 

The final rule requires written 

procedures for manufacturing 

operations. 

3. Revisions Associated With the 

Reorganization 

The final rule sets forth in final 

§ 111.90, rather than in subpart K, the 

requirements for in-process adjustments 

or reprocessing. 

C. General Comments on Manufacturing 

Operations 

(Comment 286) Some comments 

support proposed § 111.65 as a ‘‘good 

model’’ for an appropriate level of 

flexibility, noting that proposed § 111.65 

clearly states the requirements and 

presents relevant factors that must be 

considered when determining how to 

best meet the requirements of the rule. 

(Response) We acknowledge these 

comments and utilize many elements of 

proposed § 111.65 in final § 111.355. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.353) 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

We are including a new provision, 

final § 111.353, to require that you 

establish and follow written procedures 

for manufacturing operations. 

E. What Are the Design Requirements 

for Manufacturing Operations? (Final 

§ 111.355) 

Final § 111.355 requires you to design 

or select manufacturing processes to 

ensure that product specifications are 

consistently met. Final § 111.355 

derives from proposed § 111.65(a) 

which would require you to design or 

select manufacturing processes to 

ensure that dietary supplement 

specifications are consistently achieved. 

Final § 111.355 refers to ‘‘product 

specifications’’ rather than ‘‘dietary 

supplement specifications’’ to conform 

with final § 111.70(e). We have 

substituted the word ‘‘met’’ for 

‘‘achieved’’ to comply with plain 

language initiatives and to be consistent 

with other provisions. 

We did not receive comments specific 

to proposed § 111.65(a). 

F. What Are the Requirements for 

Sanitation? (Final § 111.360) 

Final § 111.360 requires you to 

conduct all manufacturing operations in 

accordance with adequate sanitation 

principles. Final § 111.360 derives from 

proposed § 111.65(b). We did not 

receive comments specific to proposed 

§ 111.65(b). 

G. What Precautions Must You Take to 

Prevent Contamination? (Final 

§ 111.365) 

Final § 111.365 requires you to take 

all necessary precautions during the 

manufacture of a dietary supplement to 

prevent contamination of components 

or dietary supplements. Final § 111.365 

derives from proposed § 111.65(c)(1) 

through (c)(11). 

1. Final § 111.365(a) 

Final § 111.365(a) requires that the 

necessary precautions include 

performing manufacturing operations 

under conditions and controls that 

protect against the potential for growth 

of microorganisms and the potential for 

contamination. Final § 111.365(a) 

derives from proposed § 111.65(c)(1). 

(Comment 287) One comment 

contends that the requirement in 

proposed § 111.65(c)(1) to protect 

‘‘against the potential for growth of 

microorganisms,’’ does not take into 

account processes that have a kill step. 

The comment recommends that 

proposed § 111.65(c)(1) be revised to be 

more consistent with § 110.80(b)(2) and 

state, ‘‘performing manufacturing 

operations under such conditions and 

controls as are necessary to minimize 

the potential for the growth of 

undesirable microorganisms, or for the 

contamination of the product.’’

(Response) We decline to modify final 

§ 111.365(a) as requested by the 

comment because the provision 

accomplishes what is requested by the 

comment. We defined ‘‘microorganism’’

in the 2003 CGMP Proposal similar to 

how we describe ‘‘undesirable 

microorganisms’’ in § 110.3(i). Further, 

we decline to use the words ‘‘minimize 

the potential for growth’’ instead of 

‘‘protect against the potential for 

growth’’ because the word ‘‘minimize’’

suggests a lesser standard than ‘‘protect 

against’’ the potential for growth of 

microorganisms. 

We would consider that you are not 

complying with the final rule if you do 

not perform manufacturing operations 

under conditions and controls that 

protect against the potential for growth 

of microorganisms and the potential for 

contamination, regardless of whether 

you use a kill step. Although a kill step 

may be necessary in some 

circumstances, it is not a substitute for 

conditions and controls that protect 

against the potential for growth of 

microorganisms and the potential for 

contamination. Therefore, we decline to 

make the change requested by this 

comment. 


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2. Final § 111.365(b) 

Final § 111.365(b) requires that 

necessary precautions include washing 

or cleaning components that contain 

soil or other contaminants. Final 

§ 111.365(b) is identical to proposed 

§ 111.65(c)(2). We did not receive 

comments specific to proposed 

§ 111.65(c)(2). 

3. Final 111.365(c) 

Final § 111.365(c) requires that the 

necessary precautions include using 

water that, at a minimum, complies 

with the applicable Federal, State, and 

local requirements and does not 

contaminate the dietary supplement 

when the water may become a 

component of the finished batch of 

dietary supplement. 

The proposed requirements would set 

forth parallel requirements for water 

that is used in the manufacture of a 

dietary supplement for both your 

physical plant (proposed § 111.15(d)(2)) 

and for manufacturing operations 

(proposed § 111.65(c)(3)). Thus, 

proposed § 111.15(d)(2) would require 

that water that contacts components, 

dietary ingredients, dietary 

supplements, or any contact surface 

must, at a minimum, comply with the 

NPDW regulations prescribed by the 

Environmental Protection Agency under 

40 CFR part 141 and any State and local 

requirements. 

As discussed in section VIII of this 

document (final § 111.15(e)(2) in 

subpart C), we are revising proposed 

§ 111.15(d)(2) to require in the final rule 

that water, used in the manufacture of 

a dietary supplement in a manner such 

that the water may become a component 

of the dietary supplement, i.e., when 

such water contacts components, 

dietary supplements, or any contact 

surface, must, at a minimum, comply 

with applicable Federal, State, and local 

requirements and not contaminate the 

dietary supplement. Given the parallel 

nature of proposed § 111.65(c)(3) and 

proposed § 111.15(d)(2), we are revising 

proposed § 111.65(c) to be consistent 

with the revisions we are making to 

proposed § 111.15(d)(2) (final 

§ 111.15(e)(2)). 

Final § 111.365(c) also includes 

grammatical changes consistent with the 

structure of final § 111.365. 

(Comment 288) One comment asks 

that the words ‘‘or equivalent quality 

water’’ be added to ‘‘water that meets 

the National Primary Drinking Water 

regulations’’ in proposed § 111.65(c)(3) 

to allow for ingredients manufactured in 

facilities outside the United States. 

(Response) As stated in response to 

comment 91, dietary supplements 

manufactured in a foreign country 

would be subject to the requirements of 

this final rule. Although the 

Environmental Protection Agency 

NPDW regulations would not apply to a 

foreign manufacturer, the foreign 

manufacturer would need to use water 

that is of a standard required in this 

final rule and that achieves the same 

level of performance required of 

domestic manufacturers. The water used 

by the foreign facility must not 

contaminate the dietary supplement that 

is manufactured. We decline to add ‘‘or 

equivalent water quality’’ because that 

would suggest domestic firms would not 

need to follow whatever Federal, State, 

and local requirements are applicable. 

(Comment 289) One comment 

recommends that proposed 

§ 111.65(c)(3) be revised to be consistent 

with proposed § 111.15(d)(1), which 

would require you to provide water that 

is safe and of adequate sanitary quality, 

at suitable temperatures, and under 

pressure as needed, in all areas where 

water is necessary for: (1) 

Manufacturing dietary ingredients or 

dietary supplements; (2) making ice that 

comes in contact with components, 

dietary ingredients, dietary 

supplements, or contact surfaces; (3) 

cleaning any surface; and (4) employee 

bathrooms and hand-washing facilities. 

(Response) We do not agree with the 

comment that we should be consistent 

in the water requirement related to 

proposed § 111.15(d)(1) and the 

requirement in proposed § 111.65(c)(3). 

The requirement in proposed 

§ 111.15(d)(1) describes a variety of 

manufacturing operations where water 

is used. For example, water that is safe 

and of adequate sanitary quality, as 

described in the proposed rule, for 

purposes of manufacturing dietary 

supplements or that comes into contact 

with a dietary supplement would be 

water that would have been required to 

comply with the requirement in 

proposed § 111.15(d)(2). Under the 

proposed rule and under the final rule, 

if such water is subject to 

Environmental Protection Agency 

NPDW, then the water must meet 

Environmental Protection Agency 

NPDW requirements at point of use. 

Proposed § 111.15(d)(1) has been 

revised and simplified in final 

§ 111.15(e)(1) to require you to provide 

water that is safe and sanitary, at 

suitable temperatures, and under 

pressure as needed, for all uses where 

water does not become a component of 

the dietary supplement. Water that is 

safe and sanitary for cleaning the floor 

in a facility would not need to meet 

standards for drinking water, but such 

water could not be a source of 

contamination of the dietary 

supplement. The standard ‘‘safe and 

sanitary’’ in final § 111.15(e)(1) allows 

some flexibility for the manufacturer in 

deciding what water it can use in 

various operations for which no other 

requirements in this final rule apply. 

The requirements of final § 111.365(c) 

are consistent with the changes in final 

§ 111.15(e). 

4. Final § 111.365(d) 

Final § 111.365(d) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 

to prevent contamination of components 

or dietary supplements include 

performing chemical, microbiological, 

or other testing, as necessary to prevent 

the use of contaminated components. 

Final § 111.365(d) derives from 

proposed § 111.65(c)(4). 

(Comment 290) One comment asserts 

that requirements for testing belong in 

proposed § 111.25 (proposed 

requirements for equipment and 

utensils) rather than in proposed 

§ 111.65 (proposed requirements for 

manufacturing operations). 

(Response) In our discussion of 

proposed § 111.65(c)(4) in the 2003 

CGMP Proposal (68 FR 12157 at 12210), 

we stated that you consider identifying 

those areas in the processing and 

production areas where chemical, 

microbial, or other forms of 

contamination are most likely to occur. 

We also stated that chemical, microbial, 

or other testing is necessary to identify 

areas where sanitation measures have 

not been adequate or where products 

may become adulterated. These remarks 

reflect that the proposed requirement in 

proposed § 111.65(c)(4) is directed to 

facilities rather than to equipment and 

utensils. For example, under proposed 

§ 111.65(c)(4), we encouraged you to 

establish a testing program that 

monitors levels of microorganisms at 

key places in your physical plant where 

you process and produce your products. 

Thus, we disagree with the comment 

that the testing requirements belong in 

proposed § 111.25 and are not making 

any changes in final § 111.365(d). 

5. Final § 111.365(e) 

Final § 111.365(e) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 

to prevent contamination of components 

or dietary supplements include 

sterilizing, pasteurizing, freezing, 

refrigerating, controlling hydrogen-ion 

concentration (pH), controlling 

humidity, controlling water activity 

(aw), or using any other effective means 

to remove, destroy, or prevent the 

growth of microorganisms, and prevent 


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decomposition. Final § 111.365(e) 

derives from proposed § 111.65(c)(5). 

(Comment 291) One comment asserts 

that only sanitary practices are needed 

to prevent microbial contamination or 

decomposition, and, therefore, requests 

that we clarify the processes listed in 

proposed § 111.65(c)(5) are optional. 

(Response) We disagree with this 

comment. Good sanitary practices are 

important, but they are not the only 

precaution to take to prevent a 

component or dietary supplement from 

contamination with microorganisms. In 

the preamble to the 2003 CGMP 

Proposal, we gave the example of bovine 

colostrum, which is the lacteal secretion 

that precedes milk after a cow gives 

birth and is a substance that is used in 

dietary supplements. We also stated that 

we consider that bovine colostrum 

likely presents the same potential health 

risks as bovine milk, which can contain 

pathogenic organisms capable of 

causing diseases in man such as 

tuberculosis, undulant fever, or 

gastrointestinal disease and, thus, must 

be pasteurized (21 CFR 1240.61). Under 

final § 111.365(e) you must sterilize or 

pasteurize bovine colostrums, or take 

other steps, to remove or destroy 

microorganisms that could be present in 

bovine colostrum. Under final 

§ 111.365(e) we list various ways that, 

depending upon the particular situation, 

would be effective in removing, 

destroying, or preventing the growth of 

microorganisms and preventing 

decomposition. You must decide for 

your given operation what means to use 

to remove, destroy, or prevent the 

growth of microorganisms and prevent 

deterioration of your components and 

dietary supplements so that you ensure 

the quality of the dietary supplement. 

(Comment 292) Some comments 

recommend adding ‘‘irradiating’’ to the 

list of practices to prevent the growth of 

microorganisms in proposed 

§ 111.65(c)(5) similar to the industry 

CGMP provision, ‘‘Production and 

Process Controls,’’ section (d)(5), 

published in the 1997 ANPRM. 

(Response) We decline to revise the 

provision as suggested by these 

comments. We are not adding 

‘‘irradiating’’ to the list of practices 

because, at this time, irradiation of 

dietary ingredients and dietary 

supplements, as a means to reduce or 

eliminate microbial loads, is not 

permitted. CFSAN is currently 

reviewing the use of irradiation for the 

control of microbial contamination on 

dietary supplements and ingredients 

(including dietary ingredients) used in 

the manufacture of dietary supplements 

(68 FR 25048, May 9, 2003). If we 

authorize this use of irradiation you 

could then use irradiation in 

compliance with that rule to comply 

with final § 111.365(e) as an ‘‘other 

effective means.’’

6. Final § 111.365(f) 

Final § 111.365(f) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 

to prevent contamination of components 

or dietary supplements include holding 

components and dietary supplements 

that can support the rapid growth of 

microorganisms of public health 

significance in a manner that prevents 

the components and dietary 

supplements from becoming 

adulterated. Final § 111.365(f) derives 

from proposed § 111.65(c)(6). We did 

not receive comments specific to 

proposed § 111.65(c)(6). 

7. Final § 111.365(g) 

Final § 111.365(g) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 

to prevent contamination of components 

or dietary supplements include 

identifying and holding any 

components or dietary supplements, for 

which a material review and disposition 

decision is required, in a manner that 

protects components or dietary 

supplements that are not under a 

material review against contamination 

and mixups with those under a material 

review. Final § 111.365(g) is 

substantially similar to proposed 

§ 111.65(c)(7). We did not receive 

comments specific to proposed 

§ 111.65(c)(7). 

8. Final § 111.365(h) 

Final § 111.365(h) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 

to prevent contamination of components 

or dietary supplements include 

performing mechanical manufacturing 

steps (such as cutting, sorting, 

inspecting, shredding, drying, grinding, 

blending, and sifting) by any effective 

means to protect the dietary 

supplements against contamination. 

Final § 111.365(h) derives from 

proposed § 111.65(c)(8). Such steps 

must include consideration of: (1) 

Cleaning and sanitizing contact 

surfaces, (2) using temperature controls, 

and (3) using time controls. 

(Comment 293) One comment 

suggests that the time controls required 

in proposed § 111.65(c)(8)(iii) are not 

always necessary. 

(Response) As written, proposed 

§ 111.65(c)(8) acknowledges that time 

controls are not always necessary, 

because the provision requires that you 

consider using time controls, and 

implement them if they are necessary to 

prevent contamination of components 

or dietary supplements. Final 

§ 111.65(h) retains this same language. 

9. Final § 111.365(i) 

Final § 111.365(i) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 

to prevent contamination of components 

or dietary supplements include using 

effective measures to protect against the 

inclusion of metal or other foreign 

material in components or dietary 

supplements. Compliance with this 

requirement must include consideration 

of the use of: (1) Filters or strainers, (2) 

traps, (3) magnets, or (4) electronic 

metal detectors. Final § 111.365(i) 

derives from proposed § 111.65(c)(9). 

(Comment 294) One comment 

contends it is sufficient to require in 

proposed § 111.65(c)(9) that 

manufacturers inspect their equipment 

before and after use to determine if any 

piece is missing, and if so, the entire 

batch should be disposed of. The 

comment states metal detection devices 

are not 100 percent effective and that 

inspection of equipment before and after 

use would be preferable. 

(Response) We disagree with the 

comment. As discussed in the 2003 

CGMP Proposal, the purpose behind 

proposed § 111.65(c)(9) is to ensure that 

no metal or foreign material becomes a 

source of possible contamination and 

not to establish mechanisms to be used 

after contamination has or is suspected 

to have occurred (68 FR 12157 at 

12211). The source of metal 

contamination is not limited to 

manufacturing equipment. For example, 

metal contamination could occur 

through using utensils such as metal 

brushes during processing of natural 

products. It would be impractical to 

determine whether contamination has 

occurred by examining the brush. 

10. Final § 111.365(j) 

Final § 111.365(j) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 

to prevent contamination of components 

or dietary supplements include 

segregating and identifying all 

containers for a specific batch of dietary 

supplements to identify their contents 

and, when necessary, the phase of 

manufacturing. Final § 111.365(j) 

derives from proposed § 111.65(c)(10). 

We did not receive comments specific to 

proposed § 111.65(c)(10). 

11. Final § 111.365(k) 

Final § 111.365(k) requires that the 

necessary precautions you take during 

the manufacture of a dietary supplement 


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to prevent contamination of components 

or dietary supplements include 

identifying all processing lines and 

major equipment used during 

manufacturing to indicate their 

contents, including the name of the 

dietary supplement and the specific 

batch or lot number and, when 

necessary, the phase of manufacturing. 

Final § 111.365(k) derives from 

proposed § 111.65(c)(11). 

(Comment 295) One comment 

suggests continuous processes should be 

excluded from the requirement in 

proposed § 111.65(c)(11) to identify 

specific batch or lot numbers. The 

comment explains that in continuous 

bulk operations for manufacturing 

dietary ingredients, the batch or lot 

number often is not identified until after 

the materials have been blended and 

moved into a storage bin. 

(Response) We are making no changes 

to proposed § 111.65(c)(11) in final 

§ 111.365(k) because the comment 

describes a situation where the 

manufacturer is manufacturing a dietary 

ingredient, and the final rule does not 

apply to the manufacture of a ‘‘dietary 

ingredient’’ within the meaning of 

section 201(ff) of the act. 

H. What Requirements Apply to 

Rejected Dietary Supplements? (Final 

§ 111.370) 

Final § 111.370 requires you to clearly 

identify, hold, and control under a 

quarantine system for appropriate 

disposition any dietary supplement that 

is rejected and unsuitable for use in 

manufacturing, packaging, or label 

operations. Final § 111.370 derives from 

proposed § 111.74 which would require 

that you clearly identify, hold, and 

control under a quarantine system any 

component, dietary ingredient, dietary 

supplement, packaging, and label that is 

rejected and unsuitable for use in 

manufacturing, packaging, or label 

operations. Because the requirements 

regarding components, packaging, and 

labels that are rejected and unsuitable 

for use are already set forth in final 

§ 111.170, final § 111.370 addresses only 

the requirements for dietary 

supplements. 

We did not receive comments specific 

to proposed § 111.74. 

I. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.375) 

In order to ensure that records are 

maintained as required under subpart P, 

we are adding a new § 111.375. This 

section requires that you make and keep 

records of the written procedures you 

establish for manufacturing operations. 

These written procedures are required 

under final § 111.353. 

XVII. Comments on the Production and 

Process Control System: Requirements 

for Packaging and Labeling Operations 

(Final Subpart L) 

A. Organization of Final Subpart L 

In the 2003 CGMP Proposal, the 

requirements for packaging and labeling 

operations were set forth in § 111.70. As 

shown in table 13 of this document, the 

final rule reorganizes the requirements 

related to quality control operations into 

a distinct subpart (final Subpart L—

Production and Process Control System: 

Requirements for Packaging and 

Labeling Operations). Table 13 lists the 

sections in final subpart L and identifies 

the proposed sections that form the 

basis of the final rule. 

TABLE 13.—DERIVATION OF SECTIONS

IN FINAL SUBPART L 

Final Rule 2003 CGMP 

Proposal 

§ 111.403 What are the 

requirements under 

this subpart L for written procedures? 

N/A 

§111.410 What requirements apply to packaging and labels? § 111.70(a), 

(b)(6), and (f) 

§ 111.415 What requirements apply to filling, 

assembling, packaging, labeling, and 

related operations? 

§ 111.70(b) 

§111.420 What requirements apply to repackaging and relabeling? § 111.70(d) and 

(e) 

§111.425 What requirements apply to a packaged and labeled dietary supplement that is 

rejected for distribution? 

§ 111.74 

§ 111.430 Under this 

subpart L, what 

records must you 

make and keep? 

§ 111.70(g) and 

(h) 

B. Highlights of Changes to the 

Proposed Requirements for Packaging 

and Labeling Operations 

1. Revisions 

The final rule: 

• Reflects that the final rule applies to 

persons who manufacture, package, 

label, or hold dietary supplements 

unless subject to an exclusion in 

§ 111.1. 

• Reflects that the labeling 

requirements of the rule address the 

operation of putting the label specified 

in the master manufacturing record on 

the final product. 

• Clarifies the applicability of the rule 

to labeling operations. 

2. Changes Associated With the 

Reorganization 

We are moving to final § 111.260(k) in 

subpart I the requirements for the 

documentation, in the batch production 

record, of packaging and labeling 

operations (proposed § 111.70(g)). 

3. Changes After Considering Comments 

The final rule: 

• Requires you to establish and 

follow written procedures for packaging 

and labeling operations. 

• Provides for an exception to the 

requirements for label reconciliation for 

cut or rolled labels if a 100-percent 

examination for correct labels is 

performed by appropriate electronic or 

electromechanical equipment during or 

after completion of finishing operations. 

• Clarifies the requirement for 

‘‘retesting or re-examining’’ any 

repackaged or relabeled dietary 

supplements, i.e., consistent with final 

§ 111.75(g) you must examine a 

representative sample of each batch of 

repackaged or relabeled dietary 

supplements to determine whether 

repackaged or relabeled dietary 

supplements meet all specifications 

established in accordance with 

§ 111.70(g). 

C. General Comments on Proposed 

Requirements for Packaging and 

Labeling Operations 

(Comment 296) Some comments 

assert that the proposed packaging and 

labeling requirements are unnecessarily 

stringent for dietary ingredients, 

because the potential for abuse is 

primarily at the final product stage. 

(Response) To the extent that the 

comment is saying that a dietary 

ingredient manufacturer who 

manufactures, packages, labels, and 

holds a dietary ingredient that is further 

processed and incorporated into a 

dietary supplement by another person 

should not have to comply with the 

packaging and labeling requirements in 

subpart L, we agree. We are modifying 

the scope of the rule as to who is subject 

to the CGMP requirements, as discussed 

in section VI of this document (subpart 

A). The final rule applies to persons 

who manufacture, package, label, or 

hold dietary supplements unless subject 

to an exclusion in § 111.1. 

(Comment 297) Several comments 

assert that it is imperative that a dietary 

supplement contain what it purports on 

its label. Some comments state that the 


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amounts of ingredients listed on the 

label must accurately reflect what is in 

the package. 

(Response) To the extent that the 

comments are suggesting that there need 

to be requirements for labeling 

operations as part of CGMP to ensure 

that the label applied to the dietary 

supplement is the label specified in the 

master manufacturing record for the 

finished product, we agree. To the 

extent that the comments suggest that 

CGMP requirements should ensure the 

quality of the dietary supplement 

manufactured, we also agree. If 

consumers believe that dietary 

supplements contain the ingredients as 

labeled, as with any other product they 

purchase, then CGMP requirements 

should help to ensure that dietary 

supplements are manufactured 

consistently to ensure the quality of the 

dietary supplement and to help ensure 

the proper identity and amount of 

ingredients identified on the label. 

D. General Comments on Requirements 

for What Must Be on the Product Label 

Rather Than for Labeling Operations 

(Comment 298) Some comments 

express disappointment that the 2003 

CGMP Proposal does not address 

product claims included on product 

labels. These comments state that, if 

FDA is not going to review label claims, 

it should, at a minimum, require the 

following statement be placed on 

dietary supplement products: ‘‘This 

product has not been reviewed for safety 

and efficacy by the FDA.’’ These 

comments assert that such a statement 

should be included on all dietary 

supplement products, regardless of 

whether the product makes structure/ 

function claims. These comments also 

recommend that dietary supplement 

labeling encourage consumers to share 

information about their use of the 

dietary supplements with their 

pharmacists and physicians and 

encourage consumers to seek the input 

of a health care provider if symptoms 

that prompted use of the dietary 

supplement are not resolved. 

One comment requests we establish 

specific label content to include on 

dietary supplement labels. The 

comment asserts that the technology 

and mechanical tools exist to produce 

expanded labeling for dietary 

supplements efficiently and costeffectively. The comment asserts that 

the content should include a complete 

listing of ingredients, relative 

percentages, batch or lot number, 

intended use, safety information, 

directions, and product information. 

Specifically, the comment supports the 

labeling recommendations of the U.S. 

Department of Health and Human 

Services (HHS), Office of the Inspector 

General (OIG) ‘‘Dietary Supplement 

Labels: Key Elements,’’ March 2003, 

publication no. OEI–01–01–00120, 

available at http://oig.hhs.gov/oei/ 

reports/oei–01–01–00120.pdf) (Ref. 34). 

The comment endorses the HHS/OIG 

recommendations, with the addition of 

batch or lot number on the label. The 

comment also endorses the OIG’s 

proposed label presentation which calls 

for: (1) A standardized format with 

similar types of information in a similar 

order across supplements; (2) distinct 

product features to assist consumers in 

distinguishing supplements from other 

health care products; (3) readability, 

with language and visual cues that are 

easily understood by consumers; (4) 

balance to present information in a fair 

and balanced format that omits 

marketing and sales pitches; and (5) 

constructive use of space whereby 

innovative packaging is employed to 

expand label space. 

Several comments address whether 

we should permit manufacturers to state 

on their products that the manufacturer 

of the product is in compliance with 

FDA CGMP requirements. Several 

comments assert that a CGMP statement 

on labels should not be allowed. These 

comments assert that the proposed 

‘‘made in a CGMP facility’’ language is 

fraught with potential misuse, and that 

the potential for confusion is 

overwhelming. These comments state 

that the rule also should be modified to 

exclude other similar statements such as 

‘‘produced using good laboratory 

practices,’’ ‘‘produced using good 

practices,’’ or ‘‘produced in compliance 

with USP good manufacturing 

practices.’’ According to these 

comments, similar statements currently 

appear on dietary supplement labels 

and also may be misleading. These 

comments assert that CGMP 

requirements are not voluntary and 

should not be marketed as such. 

Some comments state that a voluntary 

label statement that a dietary 

supplement complies with CGMP 

should be allowed. According to these 

comments, there are several third party 

organizations such as USP and National 

Nutritional Foods Association (NNFA) 

that have proposed or established CGMP 

requirements as rigorous as, or more 

rigorous than, those proposed by FDA. 

These comments assert that a voluntary 

statement that characterizes the nature 

of the GMP compliance should be 

allowed. 

(Response) The comments related to 

requests about specific label content, 

such as ingredient listing, relative 

percentage of ingredients, intended use, 

safety information, label format, use of 

label space, and directions and product 

information are outside the scope of this 

final rule. Further, with respect to 

requiring specific statements about 

dietary supplement product, such as, 

‘‘This product has not been reviewed for 

safety and efficacy by the FDA,’’ or 

‘‘This product has been produced using 

good manufacturing practice,’’ we have 

stated previously that the manufacturer 

is responsible for ensuring that any 

voluntary labeling statements on its 

dietary supplement products are 

truthful and not misleading (68 FR 

12157 at 12164). We would review the 

lawfulness of such statements under 

sections 403(a)(1) and 201(n) of the act. 

We did not propose to require any 

specific statements. We stated that an 

unqualified statement such as 

‘‘produced in compliance with dietary 

supplement current good manufacturing 

practice requirements,’’ without more, 

could suggest a product may be safe and 

effective or somehow superior to other 

dietary supplement products that are 

subject to the same CGMP requirements 

(id.). Further, we stated that such a 

statement would likely be considered 

misleading by us under sections 

403(a)(1) and 201(n) of the act, but that 

including language clarifying to 

consumers that all dietary supplements 

must be manufactured in compliance 

with CGMP requirements and that such 

compliance does not mean that the 

dietary supplement is safe or effective 

may be a way to cure that unqualified 

statement (id.). Thus, we are not 

prohibiting voluntary statements on the 

dietary supplement label, provided that 

such statements are truthful and not 

misleading. 

(Comment 299) Some comments 

assert that the labeling standards found 

in the 2003 CGMP Proposal should be 

uniformly applied across manufacturers, 

regardless of size, because consumers 

are unlikely to differentiate between 

small companies and large ones when 

selecting dietary supplements. These 

comments assert that we should, 

therefore, only allow 1 year for labeling 

compliance for all manufacturers 

regardless of their size. 

Some comments assert that small 

manufacturers are more likely to suffer 

competitively if their labels lack 

important ingredient and other 

information relative to labeling 

employed by their larger competitors. 

These comments argue that enhanced 

labeling is a cost-effective packaging 

feature and should not represent a 

significant cost burden when 

outsourced to a qualified printpackaging vendor. Moreover, labels 

already represent a budgeted cost item 


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for dietary supplement producers. 

Labels with additional content would 

add little to manufacturer overhead. 

(Response) These comments may have 

misinterpreted the 2003 CGMP 

Proposal. The CGMP requirements do 

not impose any requirements for the 

specific content of the label. We discuss 

the requirements necessary to determine 

the complete manufacturing history and 

control of a packaged and labeled 

dietary supplement through distribution 

in this subpart in our discussion on 

final § 111.410(d). To the extent that 

businesses with fewer than 500 

employees want to comply with the 

CGMP requirements for labeling 

operations in a shorter timeframe than 

what we are allowing in this final rule, 

such businesses may do so. However, to 

assist businesses with fewer than 500 

employees in complying with dietary 

supplement CGMPs, we are giving 

businesses with fewer than 500 but 20 

or more employees a compliance date of 

24 months after the date of publication 

of this final rule, and we are giving 

businesses with fewer than 20 

employees a compliance date of 36 

months after the date of publication of 

this final rule. 

E. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.403) 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

Final § 111.403 requires you to 

establish and follow written procedures 

for packaging and labeling operations. 

Under final 111.430(b), relating to 

records you must make and keep, we 

require that you make and keep records 

of such written procedures. 

F. What Requirements Apply to 

Packaging and Labels? (Final § 111.410) 

1. Final § 111.410(a) 

Final § 111.410(a) requires that you 

take necessary actions to determine 

whether the packaging for dietary 

supplements meets specifications so 

that the condition of the packaging will 

ensure the quality of your dietary 

supplements. Final § 111.410(a) is 

similar to proposed § 111.70(a) which 

would require you to take necessary 

actions to ensure that each packaging 

container for holding dietary ingredients 

or dietary supplements meets 

specifications so that the condition of 

the packaging container will not 

contaminate your dietary supplements 

or cause them to deteriorate. We have 

made changes to be consistent with final 

§ 111.70 and the definition of ‘‘quality’’

by substituting the phrase ‘‘ensure the 

quality of your dietary supplement’’

instead of using the words 

‘‘contamination’’ and ‘‘deterioration’’

which would be encompassed in the 

definition of ‘‘quality.’’ We are deleting 

the words ‘‘container’’ and ‘‘holding’’

from final § 111.410(a) to emphasize 

that all packaging must meet 

specifications and ensure the quality of 

the dietary supplement. 

(Comment 300) One comment 

requests the removal of the word ‘‘each’’

from proposed § 111.70(a) because the 

inclusion of the word mandates that 

each and every container, rather than a 

representative sample, be inspected. 

(Response) Because the final rule only 

requires the use of representative 

samples to ensure compliance, as 

provided in final § 111.80, to reduce the 

potential for confusion, we are deleting 

the word ‘‘each’’ and making associated 

grammatical revisions. 

(Comment 301) Some comments 

request we clarify our expectations 

under proposed § 111.70(a) with respect 

to substantiating that packaging 

containers meet specifications and will 

not contaminate dietary supplements. 

The comments assert that it is not 

necessary for a manufacturer to test 

these types of products proactively, and 

that a continuing product guarantee 

combined with a statement of intended 

use from the manufacturer of the 

packaging material should suffice to 

meet the proposed requirements. The 

comments assert this is consistent with 

expected practice in other industries 

that FDA regulates. 

(Response) Final § 111.410(a) 

reiterates the requirement of final 

§ 111.70(d) to establish packaging 

specifications and the requirement of 

final § 111.75(f)(1) to determine whether 

packaging specifications are met. Under 

final § 111.75(f)(1), to determine 

whether packaging meets its 

specifications, you must conduct a 

visual identification of the containers 

and closures and review the supplier’s 

invoice, guarantee, or certification. 

Thus, the final rule does not require that 

you test packaging proactively, and does 

allow you to rely on documentation 

such as a continuing product guarantee 

combined with a statement of intended 

use from the manufacturer of the 

packaging. 

As we discussed in the preamble to 

2003 CGMP Proposal (68 FR 12157 at 

12212), proposed § 111.70(a) would 

require you to take into account factors 

such as whether your product is 

sensitive to light when setting 

specifications for packaging. Other 

factors to consider include whether your 

product is sensitive to moisture or could 

interact with certain kinds of packaging. 

(For other requirements related to 

packaging, see final §§ 111.70(d), (f), (g), 

and 111.160.) 

2. Final § 111.410(b) 

Final § 111.410(b) requires you to 

control the issuance and use of 

packaging and labels and reconciliation 

of any issuance and use discrepancies, 

except that label reconciliation is not 

required for cut or rolled labels if a 100- 

percent examination for correct labels is 

performed by appropriate electronic or 

electromechanical equipment during or 

after completion of finishing operations. 

Final § 111.410(b) derives from 

proposed § 111.70(f)(1) which would 

require you to control the issuance and 

use of packaging and labels and 

reconciliation of any issuance and use 

discrepancies. 

(Comment 302) Some comments 

assert that comprehensive label 

reconciliation should not be required if 

appropriate electronic controls are 

instituted to ensure that correct labels 

are used during labeling operations. The 

comments state this alternative is 

permitted for labeling operations for 

drug products, which are generally 

identical or similar in nature to labeling 

operations for dietary supplements. As 

such, the comments assert that the same 

flexibility should be afforded to dietary 

supplement manufacturers. 

(Response) We agree with these 

comments and the revisions are 

reflected in final § 111.410(b) (proposed 

§ 111.70(f)(1)). 

3. Final § 111.410(c) 

Final § 111.410(c) requires you to 

examine, before packaging and labeling 

operations, packaging and labels for 

each batch of dietary supplement to 

determine whether the packaging and 

labels conform to the master 

manufacturing record. Final § 111.410(c) 

derives from proposed § 111.70(f)(2). We 

did not receive comments specific to 

proposed § 111.70(f)(2). 

4. Final § 111.410(d) 

Final § 111.410(d) requires you to be 

able to determine the complete 

manufacturing history and control of the 

packaged and labeled dietary 

supplement through distribution. We 

are revising the language of proposed 

§ 111.70(b)(6) and including in final 

§ 111.410 the similar requirement stated 

in proposed § 111.70(b)(6). Section 

111.410 is where we chose to place this 

requirement because it is likely that you 

will affix the batch, lot, or control 


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number that you used for the finished 

batch of dietary supplement on the 

immediate container or on the product 

label as the means to trace the product 

through distribution, although this is 

not required. Other means are 

acceptable besides the use of a batch, 

lot, or control number. 

(Comment 303) Some comments 

assert that we do not propose in the 

2003 CGMP Proposal the affixing of a lot 

number to the container of product 

marketed to the consumer. These 

comments assert that all the 

recordkeeping in the 2003 CGMP 

Proposal is of little value unless issues 

can be traced back from the individual 

container, perhaps received from a 

customer complaint, to a specific batch. 

These comments state that such labeling 

should be a requirement. 

(Response) We agree that it is 

necessary to be able to trace a dietary 

supplement in distribution to a specific 

batch or lot of product. We disagree that 

we did not provide any requirements in 

the 2003 CGMP Proposal that would 

require you to be able to trace a 

distributed dietary supplement to a 

specific batch or lot. 

In proposed § 111.70(b)(6) we stated 

that a batch, lot, or control number is 

necessary for you to trace the 

manufacturing history for a particular 

batch, which will help you investigate 

and correct any safety problems for a 

batch or to recall a dietary supplement. 

We discussed the fact that, without such 

a batch, lot, or control number, 

consumers would be unable to 

determine which product was the 

subject of a recall and they would not 

know which product to stop using, or 

there would be a need to recall more 

product than otherwise may be 

necessary (68 FR 12157 at 12212). 

We also proposed several other 

requirements related to the need to be 

able to trace the components, packaging, 

and labeling used in the manufacture of 

a dietary supplement with the 

distributed dietary supplement. Under 

proposed § 111.40(a) (with respect to 

components and dietary supplements) 

and proposed § 111.40(b)(3) (with 

respect to packaging and labeling) we 

would require you to identify each lot 

of product received in a shipment in a 

manner to allow you to trace the 

shipment lot to the dietary supplement 

manufactured and distributed. In the 

preamble to the 2003 CGMP Proposal 

(68 FR 12157 at 12202), we stated that 

using a unique identifier throughout the 

manufacturing process will make it 

possible to track and account for 

components and dietary supplements 

received to any necessary investigation 

of consumer complaints. In proposed 

§ 111.50(c)(1) we provided that the 

batch production record must include a 

batch, lot, or control number, and in 

proposed § 111.50(c)(5) we provided 

that the batch production record must 

include the shipment lot unique 

identifier of each component, dietary 

ingredient, dietary supplement, 

packaging, and label used. Further, in 

proposed § 111.85(d), we required that 

you conduct an investigation if a 

returned dietary supplement implicates 

associated batches. Thus, we proposed 

to require that you be able to trace a 

dietary supplement through 

distribution. However, we did not 

require you to use a specific 

mechanism, such as affixing a batch, lot, 

or control number to the immediate 

container or product label. Under the 

2003 CGMP Proposal, the manufacturer 

would have flexibility to determine the 

method to trace its product in 

distribution to the batch, lot, or control 

number assigned to the finished batch 

or lot of dietary supplement. 

In final § 111.415(f), we require you to 

assign a batch, lot, or control number to: 

(1) Each lot of packaged and labeled 

dietary supplement from a finished 

batch of dietary supplement and (2) 

each lot of dietary supplement, from a 

finished batch of dietary supplement, 

that you distribute to another person for 

packaging or labeling. We do not require 

you to affix this batch, lot, or control 

number to the immediate container or 

the product label. Instead, we provide 

flexibility for you to determine how you 

track the batch, lot, or control number 

you assign to each lot of packaged and 

labeled dietary supplement from a 

finished batch of dietary supplement, 

and each lot of dietary supplement from 

a finished batch of dietary supplement 

you distribute to another person for 

packaging or labeling, to distributed 

dietary supplements. To clarify that we 

do not require you to affix a batch, lot, 

or control number on the immediate 

container or product label, final 

§ 111.410(d) provides that you must be 

able to determine the complete 

manufacturing history and control of the 

packaged and labeled dietary 

supplement through distribution by a 

method of your choice. For example, a 

dietary supplement manufacturer may 

make one type of product that it 

distributes to a select few customers and 

may be able to trace its dietary 

supplement using dates on distribution 

records to such customers, or may use 

different containers or labeling, other 

than a batch, lot, or control number that 

is affixed to the label. 

We are retaining the use of a unique 

identifier in final §§ 111.155(d), 

111.160(d), and 111.260(a), (d), and (k). 

These requirements relate to the 

tracking of a component, packaging, 

labeling, or dietary supplement 

throughout the manufacturing process. 

The use of a batch, lot, or control 

number or other unique identifier, as 

required, for product in the 

manufacturing process is needed for 

tracking components, packaging, and 

labels used to manufacture, package, or 

label a dietary supplement so that once 

a batch is identified, the components, 

packaging, and labels used in a batch 

will also be known. But by contrast, 

when the distribution of a final product 

may be distributed to a few select 

customers, or where every unique batch 

is placed in a different type of container, 

there may not be a need to use batch, 

lot, or control numbers affixed to the 

immediate container or product labels 

to be able to trace the product. 

This final rule will enhance the 

benefits of the new statutory 

requirement for mandatory reporting to 

FDA of serious adverse events as the 

result of the enactment of the ‘‘Dietary 

Supplement and Non-Prescription Drug 

Consumer Protection Act’’ (Public Law 

109–462), signed into law on December 

22, 2006. This final rule will facilitate 

the additional traceback activities taking 

place as a result of the additional 

serious adverse events discovered 

through mandatory reporting. We will 

evaluate such mandatory reports for 

patterns or ‘‘signals’’ of problems with 

particular products so that further harm 

to consumers may be prevented by 

removing the products and, in some 

cases, related products from the 

marketplace. This cannot be done 

without first quickly and accurately 

identifying the products of interest. To 

efficiently determine which specific 

products or group of products are 

associated with the serious (or nonserious) adverse event report, traceback 

ability is crucial. This final rule 

includes requirements that will provide 

the information needed to quickly and 

accurately conduct a sufficient 

traceback. The provisions that require 

maintenance of records for production 

processes include records such as batch 

records, unique identifiers, and master 

manufacturing records. The 

recordkeeping provisions of this final 

rule give us access to those records, so 

we will have an enhanced ability to 

investigate the serious adverse events 

reported to us, using records such as 

information on ingredients, processing, 

storage, composition, and distribution. 

This enhanced ability to track 

information related to serious adverse 

events will increase both the accuracy 

and the speed of the response to such 


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events, which may in many cases 

reduce the number of illnesses or deaths 

associated with unsafe dietary 

supplements. 

G. What Requirements Apply to Filling, 

Assembling, Packaging, Labeling, and 

Related Operations? (Final § 111.415) 

Final § 111.415 requires that you fill, 

assemble, package, label, and perform 

other related operations in a way that 

ensures the quality of the dietary 

supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. Final § 111.415 also requires that 

you do these functions using any 

effective means you choose, including: 

(1) Cleaning and sanitizing all filling 

and packaging equipment, utensils, and 

dietary supplement packaging, as 

appropriate; (2) protecting 

manufactured dietary supplements from 

contamination, particularly airborne 

contamination; (3) using sanitary 

handling procedures; (4) establishing 

physical or spatial separation of 

packaging and label operations from 

operations on other components and 

dietary supplements to prevent mixups; 

(5) identifying, by any effective means, 

filled dietary supplement containers 

that are set aside and held in unlabeled 

condition for future label operations, to 

prevent mixups; (6) assigning a batch, 

lot, or control number to each lot of 

packaged and labeled dietary 

supplement from a finished batch of 

dietary supplement and each lot of 

dietary supplement from a finished 

batch of dietary supplement that you 

distribute to another person for 

packaging or labeling; (7) examining a 

representative sample of each batch of 

the packaged and labeled dietary 

supplement to determine whether the 

dietary supplement meets specifications 

established in accordance with final 

§ 111.70(g); and (8) suitably disposing of 

labels and packaging for dietary 

supplements that are obsolete or 

incorrect to ensure that they are not 

used in any future packaging and 

labeling operations. 

Final § 111.415 derives from proposed 

§ 111.70(b). We revised the section to be 

consistent with other revisions. 

(Comment 304) Some comments 

request clarification as to what 

specifications we are referring to in 

proposed § 111.70(b)(7). The comments 

state that if we are referring to 

specifications required by proposed 

§ 111.35(e), then we should indicate so 

in any final rule. The comment asserts 

that, if we intend this provision to mean 

that persons who simply package, label, 

and store dietary supplements must 

conduct full product testing, then 

proposed § 111.70(b)(7) is unwarranted 

and unreasonable. 

The comments assert that full product 

testing should not be required for 

companies that merely package, label, 

and store finished products. The 

comments assert that in-route 

contamination from the facility of a 

supplier or manufacturer to the facility 

of a packager, labeler, or distributor 

facility is unlikely to occur if the proper 

environmental conditions are 

maintained as required by other 

provisions of the 2003 CGMP Proposal. 

The comments assert that the 

responsibility for raw material and 

finished product testing should lie 

solely with the companies that handle 

the raw materials and dietary 

ingredients and that perform 

manufacturing duties. According to the 

comments, assuming the supplier/ 

manufacturer complies with the final 

rule and adequately performs the 

required testing, reasonable cost/benefit 

analysis would dictate that redundant 

testing not be performed. Therefore, the 

comments assert that those who perform 

packaging and labeling operations 

should only be required to test those 

areas of contamination that are likely to 

occur during the shipment, or in the 

receipt, identification, packaging, and 

holding areas of production operations 

(e.g., surface contamination). 

The comments state it is our duty to 

ensure that the industry is complying 

with any final rule, not the duty of 

certain segments of the industry to 

ensure that other segments of the 

industry are complying. Since in-route 

contamination is unlikely and rare, 

consumers would enjoy little or no 

benefit from redundant testing at a 

tremendous cost to the industry, 

particularly small businesses. 

(Response) The term ‘‘specifications’’

in proposed § 111.70(b)(7) included any 

specifications that you established for 

packaged and labeled dietary 

supplements under proposed 

§ 111.35(e). In final § 111.415(g), we 

identify the specifications as those you 

establish in accordance with final 

§ 111.70(g). In final § 111.70(g), we 

require you to establish specifications 

for the packaging and labeling for the 

finished packaged and labeled dietary 

supplements. We distinguish these 

specifications (final § 111.70(g)) from 

product specifications you must 

establish for a finished batch that you 

manufacture (final § 111.70(e)). The 

specifications that you establish and 

follow ensure that your product is what 

you establish in your master 

manufacturing record. As discussed in 

sections VI and section XII of this 

document, a master manufacturing 

record for a firm that only packages and 

labels the dietary supplement would 

include specifications that are 

applicable to its operations and would 

not include specifications related to, for 

example, components. 

H. What Requirements Apply to 

Repackaging and Relabeling? (Final 

§ 111.420) 

1. Final § 111.420(a) 

Final § 111.420(a) provides that you 

may repackage or relabel dietary 

supplements only after your quality 

control personnel have approved such 

repackaging or relabeling. Final 

§ 111.420(a) is similar to proposed 

§ 111.70(d) with a restructuring of the 

provision for clarity. We did not receive 

comments specific to proposed 

§ 111.70(d). 

2. Final § 111.420(b) and (c) 

Final § 111.420(b) requires you to 

examine a representative sample of each 

batch of repackaged or relabeled dietary 

supplements to determine whether the 

repackaged or relabeled dietary 

supplements meet all specifications 

established in accordance with 

§ 111.70(g). Final § 111.420(c) requires 

that quality control personnel approve 

or reject each batch of repackaged or 

relabeled dietary supplement prior to its 

release for distribution. Final 

§ 111.420(b) and (c) derive from 

proposed § 111.70(e) which would 

require you to retest or re-examine any 

repackaged or relabeled dietary 

supplements. Proposed § 111.70(e) also 

would require that any repackaged or 

relabeled dietary supplements meet all 

specifications and that the quality 

control unit approve or reject their 

release for distribution. 

(Comment 305) Some comments 

assert that the proposed requirement 

that directs companies to retest or reexamine any repackaged or relabeled 

dietary supplement unnecessarily 

restricts the ability of the quality control 

unit to make an appropriate disposition 

decision. These comments assert that 

testing would not be necessary, for 

example, when a packager repackages a 

multiple vitamin softgel from a 500- 

count bottle to a 60-count bottle. The 

comments also assert that it would be 

costly to retest such product, and that 

such testing would not benefit 

consumer health and safety. The 

comments would revise proposed 

§ 111.70(e) to give the quality control 

unit the authority to make an 

appropriate disposition decision, e.g., to 

assess the repackaged dietary 

supplement for conformity to 

specifications. 


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(Response) We agree that there are 

circumstances, such as those described 

by these comments, when testing would 

not be necessary. However, we disagree 

that it would not be necessary to 

‘‘examine’’ a representative sample of 

the repackaged and relabeled dietary 

supplement to determine whether the 

required specifications are met, i.e., that 

you used the specified packaging and 

applied the specified label. If no 

examination of a representative sample 

took place, there would be no basis for 

the determination. We believe that final 

§ 111.420(b) makes this clear. 

I. What Requirements Apply to a 

Packaged and Labeled Dietary 

Supplement That Is Rejected for 

Distribution? (Final § 111.425) 

Final § 111.425 requires you to clearly 

identify, hold, and control under a 

quarantine system for appropriate 

disposition any packaged and labeled 

dietary supplement that is rejected for 

distribution. Final § 111.425 derives 

from proposed § 111.74 which would 

require you to clearly identify, hold, and 

control under a quarantine system any 

component, dietary ingredient, dietary 

supplement, packaging, and label that is 

rejected and unsuitable for use in 

manufacturing, packaging, or label 

operations. Under the final rule, the 

requirements of proposed § 111.74 for 

components, packaging, and labels are 

being set forth in final § 111.170, and 

the requirements for a finished batch of 

dietary supplement are set forth in final 

§ 111.370. Although the proposal did 

not include any packaged and labeled 

dietary supplement rejected for 

distribution, we are making this change 

to be consistent with the principle that 

rejected components, dietary 

supplements, packaging, or labels 

unsuitable for the distribution supply 

include finished product already 

packaged and labeled. 

J. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.430) 

1. Final § 111.430(a) 

Final § 111.430(a) requires you to 

make and keep records required under 

this subpart in accordance with subpart 

P. Final § 111.430(a) derives from 

proposed § 111.70(h) with revisions 

associated with the reorganization. We 

did not receive comments specific to 

proposed § 111.70(h). 

2. Final § 111.430(b) 

As discussed in this section, final 

§ 111.403 requires you to establish and 

follow written procedures for packaging 

and labeling operations. The written 

procedures are records. Therefore, final 

§ 111.430(b) requires you to make and 

keep records of the written procedures 

for packaging and labeling operations. 

XVIII. Comments on Holding and 

Distributing (Final Subpart M) 

A. Organization of Final Subpart M 

In the 2003 CGMP Proposal, the 

requirements for holding operations 

were set forth in §§ 111.80, 111.82, and 

111.83 in subpart F; the requirements 

for distribution operations were set forth 

in proposed § 111.90 in subpart F. As 

shown in table 14 of this document, the 

final rule moves the requirements 

related to holding and distributing 

operations to a new subpart (final 

Subpart M—Holding and Distributing). 

Table 14 lists the sections in the final 

rule and identifies the sections that form 

the basis of the final rule. 

TABLE 14.—DERIVATION OF SECTIONS

IN FINAL SUBPART M 

Final Rule 2003 CGMP 

Proposal 

§ 111.453 What are the 

requirements under 

this subpart M for written procedures? 

N/A 

§ 111.455 What requirements apply to holding 

components, dietary 

supplements, packaging, and labels? 

§ 111.80 

§ 111.460 What requirements apply to holding 

in-process material? 

§ 111.82 

§ 111.465 What requirements apply to holding 

reserve samples of dietary supplements? 

§ 111.83(b)(1) 

and (b)(2) 

§ 111.470 What requirements apply to distributing dietary supplements? § 111.90 

§ 111.475 Under this 

subpart M, what 

records must you 

make and keep? 

N/A 

B. Highlights of Changes to the 

Proposed Requirements for Holding and 

Distributing 

1. Revisions 

The final rule includes changes that 

reflect that the scope of the final rule 

applies to persons who manufacture, 

package, label, or hold dietary 

supplements, unless subject to an 

exclusion in § 111.1. 

2. Changes Associated With the 

Reorganization 

Final § 111.465 in subpart M 

duplicates the requirement of final 

§ 111.83(b)(3) to retain reserve samples 

of dietary supplements for 1 year past 

the shelf life date (if shelf life dating is 

used) or for 2 years from the date of 

distribution of the last batch of dietary 

supplements associated with the reserve 

samples. We are duplicating this 

requirement in this subpart because we 

believe that it will be useful to include 

the length of time that you must hold 

reserve samples in each place of the 

codified where it is logical to look for 

this information. 

3. Changes After Considering Comments 

The final rule: 

• Does not require that you collect 

reserve samples of components; 

• Provides flexibility as to the 

container-closure system used to hold 

reserve samples of dietary supplements; 

• Includes a new requirement for 

written procedures; and 

• Includes a new requirement to 

make and keep records of product 

distribution and written procedures. 

C. General Comments on Proposed 

§§ 111.80, 111.82, 111.83, and 111.85 

(Comment 306) One comment 

requests that factory sealed finished 

products, which have been specifically 

manufactured to be held and 

transported in a variety of conditions, be 

excluded from the requirements for 

holding. Another comment states that 

there are many types of companies or 

individuals in the supply chain who 

may ‘‘hold’’ a dietary supplement after 

final production, packaging, and 

labeling is complete. This comment 

seeks clarification that brokers, 

distributors, or wholesalers would be 

subject only to the proposed 

requirements for holding in proposed 

§ 111.90. 

(Response) If you hold a dietary 

supplement, you are subject to all 

applicable requirements of these CGMP 

regulations related to your operation. 

For example, if you are a wholesaler, 

you would be subject to the 

requirements in final § 111.470 for the 

dietary supplements you are holding for 

distribution as well as other applicable 

requirements, such as those related to 

personnel, physical plant and grounds, 

equipment and utensils, quality control, 

returned dietary supplements, and 

product complaints. We decline to list 

all of the requirements that would be 

applicable because individual 

operations may vary. However, we 

provide the following examples of 


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requirements that would, or would not, 

apply in some specific circumstances. 

For example, if the dietary supplements 

that you hold require refrigeration, your 

refrigeration equipment must comply 

with the requirements to be fitted with 

an indicating thermometer, temperaturemeasuring device, or temperaturerecording device that shows the 

temperature accurately within the 

compartment, and have an automated 

device for regulating temperature or an 

automatic alarm system to indicate a 

significant temperature change in a 

manual operation. However, you would 

not be required to establish 

specifications for the finished batch of 

the dietary supplement, for product that 

is received for packaging or labeling, or 

for packaged and labeled dietary 

supplements or to determine whether 

such specifications are met if you only 

hold the product and do not perform 

any other functions. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.453) 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

We are including a new provision, 

§ 111.453 ‘‘What are the requirements 

under this subpart M for written 

procedures?’’ which requires you to 

establish and follow written procedures 

for holding and distribution operations. 

E. What Requirements Apply to Holding 

Components, Dietary Supplements, 

Packaging, and Labels? (Final § 111.455) 

1. Final § 111.455(a) 

Final § 111.455(a) requires you to 

hold components and dietary 

supplements under appropriate 

conditions of temperature, humidity, 

and light so that the identity, purity, 

strength, and composition of the 

components and dietary supplements 

are not affected. Final § 111.455(a) 

derives from proposed § 111.80(a) 

which would require that you hold 

components, dietary ingredients, and 

dietary supplements under appropriate 

conditions of temperature, humidity, 

and light so that the identity, purity, 

quality, strength, and composition of the 

components, dietary ingredients, and 

dietary supplements are not affected. 

We did not receive comments specific 

to proposed § 111.80(a). 

2. Final § 111.455(b) 

Final § 111.455(b) requires you to 

hold packaging and labels under 

appropriate conditions so that the 

packaging and labels are not adversely 

affected. Final § 111.455(b) derives from 

proposed § 111.80(b) with modifications 

for consistency with other provisions 

addressing packaging and labels. 

We did not receive comments specific 

to proposed § 111.80(b). 

3. Final § 111.455(c) 

Final § 111.455(c) requires you to 

hold components, dietary supplements, 

packaging, and labels under conditions 

that do not lead to the mixup, 

contamination, or deterioration of 

components, dietary supplements, 

packaging, and labels. Final § 111.455(c) 

derives from proposed § 111.80(c). 

We did not receive comments specific 

to proposed § 111.80(c). 

F. What Requirements Apply to Holding 

In-Process Material? (Final § 111.460) 

1. Final § 111.460(a) 

Final § 111.460(a) requires you to 

identify and hold in-process material 

under conditions that protect against 

mixups, contamination, and 

deterioration. Final § 111.460(a) is 

similar to proposed § 111.82(a) with a 

grammatical change (i.e., a change from 

‘‘that will protect them’’ to ‘‘that 

protect’’). 

We did not receive comments specific 

to proposed § 111.82(a). 

2. Final § 111.460(b) 

Final § 111.460(b) requires you to 

hold in-process material under 

appropriate conditions of temperature, 

humidity, and light. Final § 111.460(b) 

is identical to proposed § 111.82(b). 

(Comment 307) One comment asserts 

it would be impractical, unnecessary, 

and extremely burdensome to maintain 

reserve samples of in-process materials. 

The comment asserts that collecting and 

holding samples of in-process materials 

would duplicate the requirement to 

collect and hold reserve samples of 

finished dietary supplements and 

require significant additional 

documentation, time, and storage space. 

(Response) This comment may have 

misinterpreted proposed § 111.37(b)(11) 

(final §111.80(g)) which included 

requirements for collecting 

representative, rather than reserve, 

samples of in-process materials. The 

representative sample is used for those 

tests or examinations conducted to 

determine whether the batch meets 

specifications. A representative sample 

is held for only a short period of time, 

i.e., the time between the collection and 

the test or examination. Neither the 

2003 CGMP Proposal nor this final rule 

includes a requirement to maintain a 

reserve sample of in-process materials. 

G. Proposed Requirement for Holding 

Reserve Samples of Components 

(Proposed § 111.83(a)) 

Proposed § 111.83(a) would require 

you to hold any collected reserve 

samples of components or dietary 

ingredients in a manner that protects 

against contamination and deterioration. 

(Comment 308) One comment 

requests the final rule not require that 

manufacturers of dietary supplements 

collect and hold reserve samples of 

components. The comment asserts that 

all components can be traced back to 

their source (i.e., the vendor or 

manufacturer of the material) for a more 

in-depth investigation if a dietary 

supplement comes under investigation 

due to a product complaint. 

(Response) We agree with this 

comment. Therefore, the final rule 

contains no requirement for holding 

reserve samples of components, only 

finished dietary supplements, and, thus, 

proposed § 111.83(a) has no counterpart 

in the final rule. 

H. What Requirements Apply to Holding 

Reserve Samples of Dietary 

Supplements? (Final § 111.465) 

1. Final § 111.465(a) 

Final § 111.465(a) requires you to 

hold reserve samples of dietary 

supplements in a manner that protects 

against contamination and deterioration. 

Under final § 111.465(a)(1) this includes 

holding the reserve sample under 

conditions consistent with product 

labels or, if no storage conditions are 

recommended on the label, under 

ordinary storage conditions. Final 

§ 111.465(a)(1) derives from proposed 

§ 111.83(b)(1) which would require you 

to hold reserve samples under 

conditions of use recommended or 

suggested in the label of the dietary 

supplement and, if no conditions of use 

are recommended or suggested in the 

label, then under ordinary conditions of 

use. 

Final § 111.465(a)(1) refers to 

‘‘conditions consistent with product 

labels’’ rather than to ‘‘conditions of use 

recommended or suggested in the label 

of the dietary supplement’’ and refers to 

‘‘storage conditions’’ rather than 

‘‘conditions of use.’’ This change is to 

reflect that the ‘‘conditions of use’’

referenced in the 2003 CGMP Proposal 

referred to the typical storage of the 

dietary supplement and not the 

consumption of the product by the 

consumer. 

We did not receive comments specific 

to proposed § 111.83(b)(1). 

Under final § 111.465(a)(2) the 

manner in which you hold reserve 

samples of dietary supplements 


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includes using the same containerclosure system in which the packaged 

and labeled dietary supplement is 

distributed, or if distributing dietary 

supplements to be packaged and 

labeled, using a container-closure 

system that provides essentially the 

same characteristics to protect against 

contamination or deterioration as the 

one in which you distribute the dietary 

supplement for packaging and labeling 

elsewhere. Final § 111.465(a)(2) derives 

from proposed § 111.83(b)(2) which 

would require that the manner in which 

you hold reserve samples of dietary 

supplements include using the same 

container-closure system in which the 

dietary supplement is marketed or in 

one that provides the same level of 

protection against contamination or 

deterioration. 

(Comment 309) One comment states a 

substantial amount of its product is 

shipped in bulk for packaging 

elsewhere. As a result, one often does 

not know the packaging being used to 

market the dietary supplement or how 

the packaged product is being stored. 

This comment recommends we revise 

the proposed regulation to require using 

the same container-closure system in 

which the dietary supplement is 

marketed ‘‘if known and if not in a 

typical market container-closure 

system.’’

(Response) We acknowledge that 

some manufacturers of dietary 

supplements will distribute product in 

bulk and will not know the packaging 

used to market the dietary supplement. 

In addition, if you ship products in 

bulk, any commitment you make to your 

customer about the quality of the 

product you shipped would relate to the 

container you used to ship the bulk 

product. To address these points we 

provide in final § 111.465(a)(2) that you 

have the flexibility to use a containerclosure system that provides essentially 

the same characteristics to protect 

against contamination or deterioration 

as the one in which it is distributed for 

packaging and labeling elsewhere. For 

example, if you distribute product in 

bulk using a polyethylene bottle that 

can hold 50 kilograms of the product, 

and there is an air space above the 

product, you would hold the reserve 

samples in a polyethylene bottle with an 

air space. However, you would use a 

bottle that is sized to fit the amount that 

you are holding in reserve. 

2. Final § 111.465(b) 

Final § 111.465(b) requires you to 

retain reserve samples for 1 year past 

the shelf life date (if shelf life dating is 

used), or for 2 years from the date of 

distribution of the last batch of dietary 

supplements associated with the reserve 

samples, for use in appropriate 

investigations. Final § 111.465(b) 

derives from proposed § 111.37(b)(12), 

which proposed, in part, that you must 

keep reserve samples for 3 years from 

the date of manufacture. Proposed 

§ 111.37(b)(12) is now final 

§ 111.83(b)(3) with a change to 2 years 

for the retention period and with 

changes that we are making consistent 

with comments that requested that the 

time frame for retaining reserve samples 

be linked to a shelf life date (or other 

form of expiration dating) when such a 

date is established. We discuss the 

reasons for the change from 3 years to 

2 years and the change from ‘‘date of 

manufacture’’ to ‘‘the date of 

distribution’’ in section XXI of this 

document. In essence, final § 111.465(b) 

duplicates final § 111.83(b)(3) because 

we believe it will be useful to include 

the length of time you must hold reserve 

samples in each place in the codified 

where it is logical to look for this 

information. 

I. What Requirements Apply to 

Distributing Dietary Supplements? 

(Final § 111.470) 

Final § 111.470 requires you to 

distribute dietary supplements under 

conditions that will protect the dietary 

supplements against contamination and 

deterioration. Final § 111.470 derives 

from proposed § 111.90. 

We did not receive comments specific 

to proposed § 111.90. 

J. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.475) 

In the 2003 CGMP Proposal, we 

invited comment on whether we should 

require you to make and keep records 

on the distribution of dietary 

supplements that you manufacture, 

package, or hold. 

(Comment 310) Some comments 

assert that written records of product 

distribution would provide the ability to 

trace the shipment of each finished 

batch in the event of a product recall. 

One comment expresses the view that 

the ability to quickly and efficiently 

recall a product is an important 

safeguard in ensuring public health in 

the event of a serious problem. Another 

comment points out that the scope of 

recall would likely be much broader if 

records of product distribution were not 

available to pinpoint distribution. 

(Response) We agree with these 

comments. Therefore, final § 111.475 

requires you to make and keep records 

of product distribution in accordance 

with subpart P. In addition, we are 

adding a provision to complement final 

§ 111.453 to ensure that records are 

maintained of the written procedures 

you establish for holding and 

distributing operations. As discussed, 

comments stressed that such procedures 

must be available to us during the 

course of an inspection. 

(Comment 311) One comment asserts 

that the final rule should not include a 

requirement for records of product 

distribution, because such records are 

already common industry practice. This 

comment also points out that neither the 

food CGMPs in part 110 nor the 

agency’s 1997 ANPRM have 

requirements for records of product 

distribution. 

(Response) To the extent that the 

comment asserts that a practice that is 

a common industry practice should not 

be a requirement in the final rule, we 

disagree. CGMP includes those practices 

that may be commonly used in industry. 

In fact, the reason that such practices 

may be common in industry is because 

they are already considered to be CGMP. 

As we noted in the preamble to the 2003 

CGMP Proposal (68 FR 12157 at 12221), 

however, not all dietary supplement 

establishments follow CGMP and, 

therefore, may not be keeping records of 

product distribution. Thus, in this final 

rule we do not exclude practices we 

consider to be CGMP and already may 

be used by some in industry. 

The industry outline we published in 

the 1997 ANPR suggested (under 

Warehousing, Distribution, and PostDistribution Procedures) that the CGMP 

rule require adequate distribution 

records to be maintained and retained 

for at least 1 year beyond the expected 

product shelf life, whereby an effective 

product recall can be achieved should 

one become necessary. Therefore, we 

disagree that the 1997 ANPRM did not 

suggest a requirement to make and 

retain records of product distribution. 

XIX. Comments on Returned Dietary 

Supplements (Final Subpart N) 

A. Organization of Final Subpart N 

In the 2003 CGMP Proposal, the 

requirements for returned dietary 

supplements were set forth in proposed 

§ 111.85. As shown in table 15 of this 

document, we are reorganizing 

proposed § 111.85 into a distinct 

subpart (final Subpart N—Returned 

Dietary Supplements). Table 15 lists the 

sections in final subpart N and 

identifies the proposed sections that 

form the basis of the final rule. 


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TABLE 15.—DERIVATION OF SECTIONS

IN FINAL SUBPART N 

Final Rule 2003 CGMP 

Proposal 

§ 111.503 What are the 

requirements under 

this subpart N for written procedures? 

N/A 

§ 111.510 What requirements apply when a 

returned dietary supplement is received? 

§ 111.85(a) 

§ 111.515 When must a 

returned dietary supplement be destroyed, 

or otherwise suitably 

disposed of? 

§ 111.85(b) and 

(c) 

§ 111.520 When may a 

returned dietary supplement be salvaged? 

§ 111.37(b)(15) 

§ 111.525 What requirements apply to a returned dietary supplement that quality control personnel approve 

for reprocessing? 

§ 111.50(g) 

§ 111.530 When must an 

investigation be conducted of your manufacturing processes 

and other batches? 

§ 111.85(d) 

§ 111.535 Under this 

subpart N, what 

records must you 

make and keep? 

§ 111.50(g) 

§ 111.85(e) and 

(f) 

B. Highlights of Changes to the 

Proposed Requirements for Returned 

Dietary Supplements 

1. Revisions 

The final rule includes: 

• Revisions that reflect that the final 

rule applies to persons who 

manufacture, package, label, or hold 

dietary supplements unless subject to an 

exclusion in § 111.1. 

• A provision (final § 111.520) that 

we are adding for consistency, so that 

the final rule for returned dietary 

supplements clearly sets forth the 

requirements for a positive outcome 

(i.e., when you may salvage a returned 

dietary supplement) as well as a 

negative outcome (i.e., when you must 

destroy or otherwise suitably dispose of 

a returned dietary supplement); and 

• A provision (final § 111.525) we are 

adding for consistency, so that the final 

rule for returned dietary supplements 

clearly sets forth the requirements for 

reprocessed materials. 

2. Changes After Considering Comments 

The final rule: 

• Includes a new requirement to 

establish and follow written procedures 

to fulfill the requirements for returned 

dietary supplements; 

• Includes a revised description of 

the conditions that preclude you from 

salvaging a returned dietary 

supplement; and 

• Provides flexibility for firms to 

salvage a returned dietary supplement 

without conducting tests to demonstrate 

that the dietary supplement meets all 

specifications, provided that quality 

control personnel conduct a material 

review and make a disposition decision 

to approve the salvage. 

C. General Comments on Proposed 

§ 111.85 

(Comment 312) Several comments 

request we clarify the roles of the 

various parties in the ‘‘pre-consumer 

supply chain’’ for dietary supplements. 

(Response) We have discussed, in 

section VI of this document, who is 

subject to the final rule in what the 

comment describes as the ‘‘preconsumer supply chain’’ and do not 

repeat that discussion here. The 

requirements for returned dietary 

supplements do not distinguish between 

those returned to a person who 

manufactures a finished batch and those 

returned to a person whose role in the 

manufacturing process is limited to 

operations such as packaging, labeling, 

or holding. 

Any reprocessing operations, other 

than repackaging or relabeling, by a 

packager or labeler who receives a 

product for packaging or labeling as a 

dietary supplement would make that 

packager or labeler subject to all 

relevant regulatory requirements under 

this final rule, as explained in section VI 

of this document. A packager or labeler 

that only conducts repackaging or 

relabeling operations may conclude that 

a product was returned for reasons 

related to a problem with the 

manufacture of the product it received 

for packaging or labeling, and therefore 

cannot be salvaged. In such a case, 

under final § 111.515 the packager or 

labeler would have to destroy or 

otherwise suitably dispose of the dietary 

supplement. Under final § 111.515, the 

packager or labeler may contact the 

manufacturer to determine if the 

packager or labeler could suitably 

dispose of the dietary supplement by 

sending it back to the manufacturer for 

possible reprocessing (see discussion of 

final § 111.515 in this section). A 

manufacturer who receives a dietary 

supplement returned by a packager or 

labeler would be required to comply 

with the requirements of final subpart N 

for returned dietary supplements, 

including requirements for any 

reprocessing of the returned dietary 

supplements. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.503) 

We received many comments that 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

Final § 111.503 requires you to 

establish and follow written procedures 

to fulfill the requirements of subpart N. 

Under final § 111.535(b)(1) we are 

requiring you to make and keep records 

of such written procedures. Such 

records would be available to us under 

the requirements in subpart P. 

E. What Requirements Apply When a 

Returned Dietary Supplement is 

Received? (Final § 111.510) 

Final § 111.510 requires you to 

identify and quarantine returned dietary 

supplements until quality control 

personnel conduct a material review 

and make a disposition decision. Final 

§ 111.510 is similar to proposed 

§ 111.85(a). 

We did not receive comments specific 

to proposed § 111.85(a). 

F. When Must a Returned Dietary 

Supplement Be Destroyed, or Otherwise 

Suitably Disposed Of? (Final § 111.515) 

Final § 111.515(a) requires that you 

destroy, or otherwise suitably dispose 

of, any returned dietary supplement, 

unless the outcome of a material review 

and disposition decision is that quality 

control personnel either: (1) Approve 

the salvage of the returned dietary 

supplement for redistribution or (2) 

approve the returned dietary 

supplement for reprocessing. Final 

§ 111.515(a) derives from the following 

proposed sections: 

• Proposed § 111.85(b) which would 

require that you not salvage returned 

dietary supplements unless: (1) 

Evidence from their packaging (or, if 

possible, an inspection of the premises 

where the dietary ingredients and 

dietary supplements were held) 

indicates that the dietary ingredients 

and dietary supplements were not 

subjected to improper storage 

conditions and (2) tests demonstrate 

that the dietary ingredients or dietary 

supplements meet all specifications for 

identity, purity, quality, strength, and 

composition; and 

• Proposed § 111.85(c) which would 

require that you destroy or suitably 

dispose of the returned dietary 


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ingredients or dietary supplements if 

such dietary ingredients and dietary 

supplements do not meet specifications, 

unless the quality control unit conducts 

a material review and makes a 

disposition decision to allow 

reprocessing. 

Final § 111.515(a) includes editorial 

changes and other changes made after 

considering comments. 

(Comment 313) Several comments 

assert it is unnecessary to conduct 

testing for all specifications for every 

returned product because products may 

be returned for reasons unrelated to 

product quality. For example, products 

may be returned due to overstocking, 

ordering the wrong quantity, going out 

of business, or failing to pay for the 

product on time. In addition, several 

comments assert that many returned 

products are intact, show no signs of 

mishandling, and are within the time 

limits for shelf life. These comments 

assert that a material review and 

disposition decision by the quality 

control unit to restock the material 

without retesting may be acceptable in 

these types of situations. Some 

comments assert that proposed 

§ 111.85(b) is more restrictive than 

CGMP requirements for drug products, 

and suggest that testing need be 

conducted only when some doubt has 

been cast upon the identity, purity, 

quality, strength, or composition of the 

product, or if the product was returned 

for some other GMP-related problem. 

Some comments contend that 

proposed §§ 111.35(i)(3)(v) and 111.85 

would make it difficult to salvage any 

returned product because companies 

receiving returns often cannot verify the 

conditions under which such products 

were held. One comment refers to a 

stakeholder meeting when we indicated 

that the extent of testing requirements 

would depend upon the reason such 

products were returned. The comments 

state that the rule should allow 

flexibility as to when returned products 

must be tested. 

Some comments specifically suggest 

the approach used in the USP (revised 

in 2nd supplement USP 26). These 

comments suggest that proposed 

§ 111.85(b) be revised as follows: ‘‘If the 

conditions under which returned 

products have been held, stored, or 

shipped before or during their return, or 

if the condition of the product, its 

container, carton or labeling, as a result 

of storage or shipping, cast doubt on the 

safety, identity, strength, quality, or 

purity of the product, the returned 

product should be destroyed unless 

examination, testing or other 

investigations prove the product meets 

appropriate standards of safety, identity, 

strength, quality, or purity.’’

These comments assert that 

inspection of the condition of the 

returned product could be used to 

determine that a product can be 

returned to inventory, and this 

inspection could be covered by internal 

procedures and based on experience in 

testing product stored under conditions 

that include extremes in heat and 

humidity without affecting the 

container or closure system. 

(Response) As already discussed in 

this section, the final rule includes a 

new requirement that you establish and 

follow written procedures for handling 

returned dietary supplements. The final 

rule also retains the requirement that 

quality control personnel (formerly 

‘‘unit’’ in the proposed rule) conduct a 

material review and make a disposition 

decision regarding all returned dietary 

supplements (see discussion of final 

§ 111.113(a)(5) in section XI of this 

document). We agree with the 

comments that it is not necessary to 

conduct testing for all specifications for 

every returned product, because 

products may be returned for reasons 

unrelated to the quality of the dietary 

supplement. Final § 111.130 provides 

for quality control personnel to 

determine whether tests or 

examinations are necessary for returned 

dietary supplements to determine 

compliance with product specifications. 

Therefore, final § 111.515 does not 

include a testing requirement. We 

believe the combination of written 

procedures and oversight by quality 

control personnel is adequate to 

determine the appropriate disposition of 

a returned dietary supplement, without 

requiring a test in every case to 

demonstrate that the dietary supplement 

meets specifications for identity, purity, 

strength, and composition. 

In final § 111.515(a) we generally 

accept the comments’ suggestions and 

reflect the approach of the USP for 

returned products. Thus, you must 

destroy or otherwise suitably dispose of 

the returned dietary supplement, unless 

the outcome of the material review and 

disposition decision is that quality 

control personnel approve the salvage of 

the returned dietary supplement for 

redistribution or approve the 

reprocessing of the returned dietary 

supplement. We provide flexibility on 

how quality control personnel may 

conduct a material review and make a 

disposition decision and do not require 

testing in every case. We respond in 

section V of this document to the 

comment asserting that the proposed 

CGMPs exceed the drug CGMPs. 

G. When May a Returned Dietary 

Supplement Be Salvaged? (Final 

§ 111.520) 

Final § 111.520 permits the salvage of 

a returned dietary supplement only if 

quality control personnel conduct a 

material review and make a disposition 

decision to allow the salvage. Final 

§ 111.520 is a conforming provision we 

are adding for consistency, so that the 

final requirement for returned dietary 

supplements clearly sets forth a positive 

outcome (i.e., when you may salvage a 

returned dietary supplement) as well as 

a negative outcome (i.e., when you must 

destroy or otherwise suitably dispose of 

a returned dietary supplement). Final 

§ 111.520 is consistent with final 

§ 111.130 (proposed § 111.37(b)(15)) 

which requires quality control 

personnel to approve the distribution of 

returned dietary supplements. 

H. What Requirements Apply to a 

Returned Dietary Supplement That 

Quality Control Personnel Approve for 

Reprocessing? (Final § 111.525) 

Final § 111.525(a) requires you to 

ensure that any returned dietary 

supplements that are reprocessed meet 

all product specifications established in 

accordance with final § 111.70(e). Final 

§ 111.525(b) requires quality control 

personnel to approve or reject the 

release for distribution of any returned 

dietary supplement that is reprocessed. 

As with final § 111.520, final § 111.525 

is a provision we are adding for 

consistency. Final § 111.525 is 

consistent with final § 111.90(c). 

I. When Must an Investigation Be 

Conducted of Your Manufacturing 

Processes and Other Batches? (Final 

§ 111.530) 

Final § 111.530 requires that, if the 

reason for a dietary supplement being 

returned implicates other batches, you 

must conduct an investigation of your 

manufacturing processes and each of 

those other batches to determine 

compliance with specifications. Final 

§ 111.530 derives from proposed 

§ 111.85(d) which would require that if 

the reason for a dietary supplement 

being returned implicates associated 

batches, you must conduct an 

investigation of your manufacturing 

processes and those other batches to 

determine compliance with 

specifications. Final § 111.530 includes 

a nonsubstantive editorial change of 

‘‘associated’’ to ‘‘each of those other 

batches’’ for clarity. 

We did not receive comments specific 

to proposed § 111.85(d). 


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J. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.535) 

Final § 111.535 sets forth the 

requirements to make and keep records 

for returned dietary supplements. Final 

§ 111.180 derives from proposed 

§ 111.85(e) and (f). 

We did not receive comments specific 

to proposed § 111.85(e) or (f). 

1. Final § 111.535(a) 

Final § 111.535(a) requires you to 

make and keep records required under 

subpart N in accordance with subpart P. 

Final § 111.535(a) derives from 

proposed §111.85(f) and includes 

changes associated with the 

reorganization. 

2. Final § 111.535(b)(1) 

As discussed in this section, the final 

rule includes a new requirement (final 

§ 111.503) that you establish and follow 

written procedures to fulfill the 

requirements of subpart N. Those 

written procedures are records. 

Therefore, final § 111.535(b)(1) requires 

you to make and keep a record of the 

written procedures for fulfilling the 

requirements of subpart N. 

3. Final § 111.535(b)(2) 

Final § 111.535(b)(2) requires you to 

make and keep a record of any material 

review and disposition decision on a 

returned dietary supplement. Final 

§ 111.535(b) derives from proposed 

§ 111.85(e), with revisions associated 

with the reorganization. 

4. Final § 111.535(b)(3) 

Final § 111.535(b)(3) requires you to 

make and keep a record of the results of 

any testing or examination conducted to 

determine compliance with product 

specifications established under 

§ 111.70(e). Final § 111.535(b) derives 

from proposed § 111.85(e) which would 

require you to establish and keep 

records on any testing conducted to 

determine compliance with established 

specifications in the master 

manufacturing record for the type of 

dietary supplement that was returned. 

Final § 111.535(b)(3) includes the 

following revisions: 

• Consistent with final § 111.70(e), 

final § 111.535(b)(3) substitutes 

‘‘product specifications established 

under § 111.70(e)’’ for ‘‘established 

specifications in the master 

manufacturing record for the type of 

dietary ingredient or dietary supplement 

that was returned.’’

• Consistent with final § 111.75(c), 

final § 111.535(b)(3) provides flexibility 

to use either tests or examinations to 

determine whether specifications are 

met. 

5. Final § 111.535(b)(4) 

Final § 111.535(b)(4) requires you to 

make and keep a record of 

documentation of the re-evaluation by 

quality control personnel of any dietary 

supplement that is reprocessed and the 

determination by quality control 

personnel of whether the reprocessed 

dietary supplement meets product 

specifications established in accordance 

with § 111.70(e). Final § 111.535(b)(4) is 

related to final § 111.525. Under final 

§ 111.525, you must ensure that any 

returned dietary supplements that are 

reprocessed meet all product 

specifications you established under 

§ 111.70(e) and quality control 

personnel must approve or reject the 

release for distribution of any returned 

dietary supplement that is reprocessed. 

XX. Comments on Product Complaints 

(Final Subpart O) 

A. Organization of Final Subpart O 

In the 2003 CGMP Proposal, the 

requirements for consumer complaints 

were set forth in § 111.95. As shown in 

table 16 of this document, we are 

reorganizing proposed § 111.95 into 

three provisions in a new subpart (final 

Subpart O—Product Complaints). Table 

16 lists the sections in final subpart O 

and identifies the provisions that form 

the basis for the final rule. 

TABLE 16.—DERIVATION OF SECTIONS

IN FINAL SUBPART O 

Final Rule 2003 CGMP 

Proposal 

§ 111.553 What are the 

requirements under 

this subpart O for written procedures? 

N/A 

§ 111.560 What requirements apply to the review and investigation 

of a product complaint? 

§ 111.95(a), (b), 

(c), and (d) 

§ 111.570 Under this 

subpart O, what 

records must you 

make and keep? 

§ 111.95(e) and 

(f) 

B. Highlights of Changes to the 

Proposed Requirements for Product 

Complaints 

1. Revisions 

The final rule: 

• Includes changes that reflect the 

final rule applies to persons who 

manufacture, package, label, or hold 

dietary supplements unless subject to an 

exclusion in § 111.1. 

• Uses the term ‘‘product complaint’’

rather than ‘‘consumer complaint,’’ and 

the definition of ‘‘product complaint’’

does not include an explanation about 

the types of complaints that may or may 

not be covered by the CGMP 

regulations. The definition does, 

however, include examples of product 

complaints. 

2. Changes After Considering Comments 

The final rule modifies the process for 

handling product complaints as follows: 

• A qualified person investigates any 

product complaint that involves a 

possible failure of a dietary supplement 

to meet any requirements of part 111, 

without an intermediate step of having 

quality control personnel first determine 

whether the complaint should be 

investigated; 

• Quality control personnel review 

and approve all decisions made by a 

qualified person about whether to 

investigate a product complaint and the 

findings and followup action of any 

investigation performed rather than 

conduct the investigation and followup; 

and 

• The review and investigation of the 

product complaint extends to all 

relevant batches and records, without 

identifying specific records, and specific 

batches, that must be included in the 

review and investigation. 

C. General Comments on Proposed 

§ 111.95 (Final Subpart O) 

(Comment 314) Some comments 

express general support for the 

proposed procedures for consumer 

complaints. Other comments request 

proposed § 111.95 be deleted. Most of 

these comments point out that we had 

announced the development of 

CFSAN’s Adverse Event Reporting 

System (CAERS) for reporting to FDA 

adverse events attributed to food 

products and suggest that this new 

system would be the appropriate 

mechanism for handling complaints 

about dietary supplements. 

(Response) We disagree with these 

comments. Because the problem giving 

rise to the complaint may be associated 

with a failure in manufacturing, 

packaging, labeling, or holding, it is 

CGMP for a firm that receives a product 

complaint to review it and investigate, 

if necessary, regardless of whether we 

are notified about the complaint. An 

important goal of the firm’s review and 

investigation is to determine whether 

there is a problem with the production 

and process control system for the 

manufacture, packaging, labeling, or 

holding of the dietary supplement. That 


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goal would not be achieved merely by 

notifying us. A firm subject to any of the 

requirements of this final rule, whether 

such firm is a manufacturer, packager, 

labeler, or holder, is responsible for the 

requirements in subpart O for a product 

complaint it receives. 

(Comment 315) Some comments 

assert that the proposed requirements 

for consumer complaints do not go far 

enough and urge that any final rule 

require any complaints that involve an 

adverse event be referred to us. The 

comments stress accurate reporting of 

adverse events is essential to long term 

evaluations of a product’s safety. 

(Response) Mandatory reporting 

requirements to us regarding adverse 

events related to dietary supplements 

are outside the scope of this rulemaking. 

This final rule addresses the internal 

processes and controls that persons who 

manufacture, package, label, or hold 

dietary supplements must follow. 

Mandatory reporting to FDA of serious 

adverse events, however, is now 

required as a result of the enactment of 

the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection 

Act’’ (Public Law 109–462) signed into 

law on December 22, 2006. The new law 

requires manufacturers, packers, or 

distributors of such products to submit 

reports to FDA about serious adverse 

events involving such products based 

on specific information that they receive 

from the public. Serious adverse events 

are defined in the law as those events 

that result in death, a life-threatening 

situation, an inpatient hospitalization, a 

persistent or significant disability or 

incapacity, or a congenital anomaly or 

birth defect or one that requires medical 

or surgical intervention to prevent such 

serious outcomes (based on reasonable 

medical judgment). 

As discussed in the preamble to the 

2003 CGMP Proposal (68 FR 12157 at 

12217), however, we continue to 

strongly recommend that firms that 

receive product complaints, that are not 

‘‘serious adverse events,’’ notify us 

about any illness or injury, because, for 

example, we may have additional 

expertise or data that may be helpful in 

investigating the complaint or 

determining whether the problem 

applies to more than one product. In 

light of the requirement in the final rule 

to establish and follow written 

procedures for handling product 

complaints, we encourage you to 

include our recommendations in the 

written procedures that you develop for 

handling product complaints (see 

discussion of final § 111.553 in this 

section). 

(Comment 316) Some comments raise 

questions about who would be subject 

to the proposed requirements regarding 

consumer complaints. Some comments 

state the section should apply only to 

manufacturers of dietary supplements, 

not to manufacturers of dietary 

ingredients. Other comments are 

concerned that distributors who merely 

put their label on the finished product 

may be held responsible for keeping 

records of adverse events caused by 

failures to follow CGMPs during the 

manufacture of the supplements. 

(Response) The final rule only applies 

to persons who manufacture, package, 

label, or hold a dietary supplement. We 

discuss the scope of this final rule in 

detail in section VI of this document. 

In most cases, the person who 

receives a product complaint from a 

consumer will be the manufacturer, 

packager, or distributor of the dietary 

supplement. A distributor (also a 

‘‘holder’’ under this final rule) who 

receives a product complaint must 

review and investigate that complaint to 

determine whether the complaint relates 

to a failure of the processes under the 

control of the distributor, such as 

conditions of temperature, humidity, 

and light that could affect the identity, 

purity, strength, or composition of the 

dietary supplement. If the distributor 

concludes the problem is unrelated to 

any process under the control of the 

distributor, the distributor should 

contact the manufacturer. Under the 

final rule, any person in the 

manufacturing chain who receives a 

product complaint—regardless of the 

source—must comply with the 

requirements in this subpart O. 

(Comment 317) One comment 

suggests proposed § 111.95, which 

describes requirements for consumer 

complaints, could be combined with 

proposed § 111.85 which describes 

requirements for returned dietary 

supplements. 

(Response) We decline to adopt this 

suggestion. In this final rule, we are 

incorporating the requirements for 

returned dietary supplements into a 

distinct subpart (final subpart N) that 

sets forth requirements for returned 

dietary supplements. The procedures 

described in final subpart O, which 

relate solely to the handling of product 

complaints rather than returned dietary 

supplement products, are quite different 

from those described in final subpart N, 

which addresses the handling, review, 

and possible reprocessing of returned 

product. 

(Comment 318) Some comments 

assert the proposed requirements for 

complaints are different from those for 

food CGMPs. 

(Response) We are making no changes 

to the requirements after considering 

these comments. We responded in 

section V of this document to similar 

comments asserting that certain aspects 

of the proposed regulations are different 

from those for other food CGMP 

requirements. 

D. What Are the Requirements Under 

This Subpart for Written Procedures? 

(Final § 111.553) 

We received many comments which 

recommended written procedures for 

various provisions. We address the need 

for written procedures generally in 

section IV of this document. We also 

respond to individual comments on 

specific provisions in the same section. 

Final § 111.553 requires that you 

establish and follow written procedures 

to fulfill the requirements of this 

subpart O. Under final § 111.570(b)(1) 

we require you to make and keep 

records of such procedures. Such 

records would be required to be made 

available to us under the requirements 

in subpart P. 

We encourage you to include in your 

written procedures the recommendation 

made in the 2003 CGMP Proposal for 

you to consult with a health care 

provider if you receive complaints that 

involve serious illness or injury. Even if 

the complaints are not required to be 

submitted to FDA under the newly 

enacted ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection 

Act’’ (Public Law 109–462), we 

encourage your company to notify us 

about the product complaints. 

Manufacturers and distributors should 

be aware that this newly enacted law, 

which requires reporting to FDA of 

‘‘serious adverse events,’’ contains new 

mandatory provisions that require 

record retention of adverse event reports 

separate from the requirements in this 

CGMP final rule concerning product 

complaints. 

E. What Requirements Apply to the 

Review and Investigation of a Product 

Complaint? (Final § 111.560) 

1. Final § 111.560(a)(1) 

Final § 111.560(a)(1) requires a 

qualified person to review all product 

complaints to determine whether the 

product complaint involves a possible 

failure of a dietary supplement to meet 

any of its specifications, or any other 

requirements of part 111, including 

those specifications and other 

requirements that, if not met, may result 

in a risk of illness or injury. Final 

§ 111.560(a)(1) derives from proposed 

§ 111.95(a). 

We did not receive comments specific 

to proposed § 111.95(a). 


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

Final § 111.560(a)(2) requires a 

qualified person to investigate any 

product complaint that involves a 

possible failure of a dietary supplement 

to meet any of its specifications, or any 

other requirements of part 111, 

including those specifications and other 

requirements that, if not met, may result 

in a risk of illness or injury. Final 

§ 111.560(b) requires that quality control 

personnel review and approve decisions 

by the qualified person about whether 

or not to investigate a product 

complaint and the findings and 

followup action of any investigation 

performed. Final § 111.560(c) requires 

that the review and investigation extend 

to all relevant batches and records. 

(Comment 319) Some comments 

characterize the requirements of 

proposed § 111.95 as a confusing and 

difficult scheme to review, investigate, 

and resolve customer complaints. These 

comments state the 2003 CGMP 

Proposal would require extensive 

human resources, recordkeeping, and 

decisionmaking. 

(Response) We disagree that the 2003 

CGMP Proposal would require extensive 

human resources, recordkeeping, or 

decisionmaking. The comments 

provided no rationale for such 

assertions. The 2003 CGMP Proposal 

sets forth basic steps, i.e., review, 

evaluation, and followup, that one 

would need to take to appropriately 

address a product complaint. For those 

product complaints for which there is a 

reasonable possibility of a relationship 

to an adverse event, the 2003 CGMP 

Proposal would require that an 

investigation be done by the quality 

control unit because we believe such an 

event would need more careful review 

and followup. 

To address the comments that found 

proposed § 111.90 confusing, we have 

made the following changes in the final 

rule to simplify the procedures for 

handling product complaints: 

• We replaced the proposed 

procedure in which a qualified person 

determines whether a complaint should 

be investigated by the quality control 

unit with a procedure in which a 

qualified person investigates any 

product complaint that involves a 

possible failure of a dietary supplement 

to meet any requirements of part 111. 

• We require an oversight function by 

quality control personnel for the review 

and evaluation of product complaints, 

but do not require that quality control 

personnel do any investigations. This is 

consistent with other changes that we 

are making in response to comments 

that requested that the quality control 

unit focus on reviewing tasks performed 

by others rather than on performing the 

tasks itself. 

• We refer to ‘‘any product complaint 

that involves a possible failure of a 

dietary supplement to meet any of its 

specifications, or any other 

requirements of this part [part 111], 

including those specifications and other 

requirements that, if not met, may result 

in a risk of illness or injury’’ rather than 

to ‘‘a reasonable possibility of a 

relationship between the quality of a 

dietary supplement and an adverse 

event.’’ This is consistent with changes 

that we are making to the definition of 

the term ‘‘product complaint’’ in final 

§ 111.3 (see section VI of this 

document). 

• We continue to require that the 

review and investigation of the product 

complaint extend to all relevant batches 

and records but simplify the language of 

the requirement by removing the details, 

i.e., that the investigation must include 

the batch records associated with the 

dietary supplement involved in the 

consumer complaint and not specifying 

that the investigation must extend to 

other batches of dietary supplement. 

Rather, we require that the investigation 

must extend to all relevant batches and 

records. 

The final rule provides firms 

flexibility on how to use its human 

resources. Nothing in subpart O would 

preclude a qualified person among 

designated quality control personnel to 

be designated to actually review product 

complaints and conduct investigations 

of any product complaint. If an 

individual is so designated and 

conducts the investigation, reviews and 

approves the findings, and conducts 

followup actions of any investigation 

performed, final § 111.560(b) would not 

apply. 

(Comment 320) Some comments 

object to the requirement in proposed 

§ 111.95(c) that consumer complaints 

are to be investigated only when there 

may be a relationship between product 

quality and an adverse event. These 

comments suggest this provision be 

extended to any possible relationship 

between dietary supplements and 

adverse events, including those that 

might be independent of whether the 

product is produced under CGMPs. 

These comments consider there should 

be consistent procedures for handling 

product complaints, regardless of 

whether the complaints relate to 

product quality. 

(Response) The action requested in 

these comments is outside the scope of 

this rule, which specifically addresses 

CGMP requirements to ensure the 

quality of the dietary supplement 

product. However, we encourage firms 

to investigate all product complaints in 

a consistent way, regardless of whether 

the complaints relate to the quality of 

the dietary supplement. 

(Comment 321) Some comments 

request clarification of statements made 

or terms used in the preamble to the 

2003 CGMP Proposal regarding the 

handling of product complaints. In the 

preamble discussion of proposed 

§ 111.95(c), we stated a consumer 

complaint about adverse effects ‘‘after 

consuming several dietary 

supplements’’ is worthy of quality 

control unit investigation. One comment 

asks about the meaning of ‘‘several’’ and 

whether this example means that a 

manufacturer is responsible for 

consumers who take more than the 

recommended dosage. 

(Response) In our discussion of 

proposed § 111.95(c) we addressed a 

situation where a consumer had 

symptoms on more than one occasion 

rather than a situation where a 

consumer took more than the 

recommended dosage. However, firms 

must investigate any complaint of 

illness or injury even if a consumer 

reports that he/she has consumed more 

than the amount recommended on the 

product label to determine if the 

complaint is related to CGMP. 

F. Under This Subpart, What Records 

Must You Make and Keep? (Final 

§ 111.570) 

1. Final § 111.570(a) 

Final § 111.570(a) requires you to 

make and keep the records required 

under subpart O in accordance with 

subpart P. Final § 111.570(a) derives 

from proposed § 111.95(f)(2) with 

changes associated with the 

reorganization. 

We did not receive comments specific 

to proposed § 111.95(f)(2). 

2. Final § 111.570(b)(1) 

Final § 111.570(b)(1) requires you to 

make and keep a record of the written 

procedures for fulfilling the 

requirements of subpart O. Final 

§ 111.553 requires written procedures 

for fulfilling the requirements of subpart 

O. Those written procedures are 

considered a record under final 

§ 111.570(b)(1). 

3. Final § 111.570(b)(2) 

Final § 111.570(b)(2) requires you to 

make and keep a written record of every 

product complaint that is related to 

CGMP. Final § 111.570(b)(2) derives 

from proposed § 111.95(e) which would 

require that you ‘‘* * * make and keep 

a written record of every consumer 


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complaint that is related to good 

manufacturing practices. For the 

purposes of the regulations in this part, 

a consumer complaint about product 

quality may or may not include 

concerns about a possible hazard to 

health. However, a consumer complaint 

does not include an adverse event, 

illness, or injury related to the safety of 

a particular dietary ingredient 

independent of whether the product is 

produced under good manufacturing 

practices.’’

As a revision for consistency with the 

definition of ‘‘product complaint’’ in 

final § 111.3, final § 111.570(b)(2) does 

not include the two full sentences from 

proposed § 111.95(e), as quoted in the 

previous paragraph. 

4. Final § 111.570(b)(2)(i) 

Final § 111.570(b)(2)(i) requires that 

the person who performs the 

requirements of subpart O, at the time 

of performance, document and record 

the performance. Final § 111.570(b)(2)(i) 

is similar to proposed § 111.95(f)(1) with 

changes associated with the 

reorganization. 

5. Final § 111.570(b)(2)(ii) 

Final § 111.570(b)(2)(ii) requires that 

the written record of the product 

complaint include: (1) The name and 

description of the dietary supplement; 

(2) the batch, lot, or control number of 

the dietary supplement, if available; (3) 

the date the complaint was received and 

the name, address, or telephone number 

of the complainant, if available; (4) the 

nature of the complaint including, if 

known, how the product was used; (5) 

the reply to the complainant, if any; and 

(6) findings of the investigation and 

followup action taken when an 

investigation is performed. Final 

§ 111.570(b)(2) is similar to proposed 

§ 111.95(e)(1) through (e)(6) and 

includes a change we are making after 

considering comments to proposed 

§ 111.95(e)(4) (discussed in the 

following paragraphs) which would 

have required that the consumer 

complaint written record include ‘‘The 

nature of the complaint including how 

the consumer used the product.’’ On our 

own initiative, we also made a change 

to include the date the complaint was 

received. 

(Comment 322) One comment notes 

proposed § 111.95(e)(4) would require 

the written record of consumer 

complaints to include ‘‘how the 

consumer used the product.’’ The 

comment notes this information may 

not always be available and suggests the 

words ‘‘where known’’ should be added. 

(Response) We agree that there can be 

circumstances where the firm that 

receives the product complaint may not 

know how the product was used. For 

example, a consumer may make a 

complaint by leaving a telephone 

message before or after business hours 

and neither describe how the product 

was used, nor leave contact information 

so that the firm could followup with the 

consumer. To address this comment, we 

provide in the final rule that the written 

record of the product complaint include 

‘‘the nature of the complaint including, 

if known, how the product was used.’’

(Comment 323) Some comments 

request clarification of statements made 

or terms used in the preamble to the 

2003 CGMP Proposal regarding the 

handling of product complaints. In our 

discussion of proposed § 111.95(e) we 

recommended that consumer 

complaints and investigations be 

reported to us when consumption of a 

dietary supplement may be related to ‘‘a 

serious adverse event.’’ Some comments 

note that ‘‘serious’’ is not defined. 

(Response) The term ‘‘serious adverse 

event’’ is widely used in the industries 

we regulate. Our current forms for 

reporting ‘‘serious adverse events’’ via 

the MedWatch program do not define 

the term, but instead list outcomes that 

were attributed to an adverse event. 

These outcomes include death, lifethreatening, hospitalization (initial or 

prolonged), disability, congenital 

anomaly, required intervention to 

prevent permanent impairment/damage, 

and ‘‘other.’’ As discussed in this 

section, however, there is a new 

statutory requirement for mandatory 

reporting to FDA of serious adverse 

events enacted in the ‘‘Dietary 

Supplement and Non-Prescription Drug 

Consumer Protection Act’’ (Public Law 

109–462). The new law does define 

‘‘serious adverse events’’ as those events 

that result in death, a life-threatening 

situation, an inpatient hospitalization, a 

persistent or significant disability or 

incapacity, or a congenital anomaly or 

birth defect or one that requires medical 

or surgical intervention to prevent such 

serious outcomes (based on reasonable 

medical judgment). The law also has 

specific provisions for how these 

serious adverse events are to be 

submitted to FDA and record retention 

for records relating to these and other 

adverse event reports. We anticipate 

issuing guidance on implementation of 

the new statutory provisions. We 

encourage firms who are unsure as to 

whether the nature of a reported adverse 

event should be reported to FDA to 

contact us for assistance. 

XXI. Comments on Records and 

Recordkeeping (Final Subpart P) 

A. Organization of Final Subpart P 

In the 2003 CGMP Proposal, the 

requirements for records and 

recordkeeping were set forth in 

proposed § 111.125. As shown in table 

17 of this document, we are 

reorganizing the requirements for 

records and recordkeeping into a 

distinct subpart (final Subpart P—

Records and Recordkeeping). Table 17 

lists the sections in final subpart P and 

identifies the proposed provisions that 

form the basis for the final rule. 

TABLE 17.—DERIVATION OF SECTIONS

IN FINAL SUBPART P 

Final Rule 2003 CGMP 

Proposal 

§ 111.605 What requirements apply to the 

records you make and 

keep? 

§ 111.125(a) 

and (b) 

§ 111.610 What records 

must be made available to FDA? 

§ 111.125(b) 

and (c) 

B. Highlights of Changes to the 

Proposed Requirements for Records and 

Recordkeeping 

1. Revisions 

The final rule reflects that it applies 

to persons who manufacture, package, 

label, or hold a dietary supplement 

unless subject to an exclusion in 

§ 111.1. 

2. Changes After Considering Comments 

This final rule requires you to keep 

written records required by this subpart 

for either 1 year past the shelf life date, 

if shelf life dating is used, or 2 years 

beyond the date of distribution of the 

last batch of dietary supplements 

associated with those records (final 

§ 111.605(a)). 

C. General Comments on Proposed 

§ 111.125 

(Comment 324) Some comments 

support the requirements in proposed 

§ 111.125 because documentation helps 

to ensure CGMPs are consistently 

followed and retention of records 

provides an effective trail when 

subsequent problems need to be 

identified and corrected. 

Another comment asserts the 

recordkeeping requirements would 

represent a large burden for companies 

that manufacture vitamin and mineral 

supplements with a large number of 

active ingredients. 


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(Response) We agree that records are 

useful in identifying manufacturing 

problems and tracking the source of 

failures in CGMPs. 

We understand the burden on 

manufacturers may be heavier for 

manufacturers who use many dietary 

ingredients and discuss the burden of 

the recordkeeping requirements in 

sections XXVIII and XXIV of this 

document. However, we do not believe 

that a manufacturer who elects to put 

several components into one finished 

batch of dietary supplement would 

necessarily have a larger burden than 

one who, instead, elects to manufacture 

multiple dietary supplements each 

containing one component. We believe 

that the requirements, for example, for 

ensuring the identity, purity, strength, 

and composition of each component in 

a dietary supplement need to be the 

same for a dietary supplement 

containing one ingredient or component 

and one containing multiple ingredients 

or components. To the extent the 

comment is suggesting that the 

recordkeeping requirements for those 

who manufacture multivitamin/mineral 

dietary supplements (containing 

components) are too large and should be 

less, the comment provided no basis for 

such a change. 

D. What Requirements Apply to the 

Records That You Make and Keep? 

(Final § 111.605) 

1. Final § 111.605(a) 

Final § 111.605(a) requires you to 

keep written records for 1 year past the 

shelf life date, if shelf life dating is used, 

or 2 years beyond the date of 

distribution of the last batch of dietary 

supplements associated with those 

records. Final § 111.605(a) derives from 

proposed § 111.125(a). 

(Comment 325) Several comments 

suggest that the requirement in 

proposed § 111.125(a) to keep records 

for 3 years beyond the date of 

manufacture should be modified. One 

comment favors record retention for 3 

years beyond the date of manufacture or 

for the shelf life of the product, 

whichever is longer. Some comments 

state the rule should require 

establishment of an expiration date and 

that the manufacturer should have the 

option of retaining records for 1 year 

beyond the expiration date, when an 

expiration date has been established by 

the manufacturer. Some comments 

point out that under section 306(a) of 

the Bioterrorism Act, FDA is authorized 

to issue recordkeeping regulations with 

a record retention period of ‘‘not longer 

than two years.’’ One comment, 

therefore, asserts CGMP records should 

not be kept for more than 2 years. 

(Response) We believe a record 

retention period for records related to 

CGMP requirements should correlate 

generally with the length of time that 

product complaints are likely to arise 

related to the manufacture of a dietary 

supplement. Such correlation will 

increase the likelihood that, if a problem 

with a dietary supplement is identified 

that may be associated with a violation 

of CGMP, the dietary supplement 

manufacturer, packager, labeler, or 

holder will have access to the CGMP 

records associated with that dietary 

supplement. In addition, we will have 

access to such records at inspection. 

We have modified the final rule to 

require a record retention period of 2 

years beyond the date of distribution of 

the last batch of dietary supplements 

associated with those records or 1 year 

past the shelf life date, if shelf life 

dating is used. 

A significant portion of the dietary 

supplement industry use shelf life 

dating. It is likely that if there are 

product complaints related to a product 

these will arise during the shelf life of 

these products. To ensure there is 

adequate time to examine the records, 

determine if there are related 

manufacturing problems, and 

implement corrective actions, it is 

necessary to require the retention of 

records for 1 year past the shelf life date. 

This will help ensure that 

establishments have access to such 

records to perform the necessary CGMP 

actions. 

For those dietary supplements 

without shelf life or expiration dating, 

we believe that 2 years from the date of 

distribution is a reasonable estimate of 

the time needed to retain records in 

order to address CGMP problems 

identified in product complaints. 

It is important to note that, as 

discussed in this section, the term 

‘‘shelf life dating,’’ includes shelf life 

dating as well as expiration dating and 

‘‘best if used by’’ dating. 

We disagree with the comment that 

suggests we require an expiration date 

on all products. Many products will not 

have a determinable expiration date due 

to the state of knowledge about these 

products. We believe the manufacturer 

is in the best position to determine if its 

product requires an expiration date. 

(Comment 326) One comment 

requests clarification of the ‘‘date of 

manufacture.’’ The comment asserts if 

an expiration date is shown on the label 

of a product, the date of manufacture 

should be considered to be the date on 

which the expiration date is based. The 

comment gives an example of vitamin C 

tablets having a 2-year shelf life. The 

comment explains if the tablets are 

compressed, tested, and approved for 

packaging in August 2003, they would 

generally be assigned an expiration date 

of August 2005 regardless of the date of 

packaging. The comment argues if the 

tablets are held and later packaged in 

February 2004, records for this batch 

should only have to be kept for 1 year 

beyond the expiration date (i.e., August 

2006), rather than 3 years beyond the 

packaging date (i.e., February 2007). 

(Response) In the scenario described 

in the previous paragraph, where an 

expiration date (shelf life) has been 

determined, records for this batch must 

only be kept for 1 year beyond the 

expiration date (i.e., shelf life date). The 

packaging date in the scenario has no 

effect on the amount of time records 

must be kept. However, in the final rule, 

we have decided that it is more 

appropriate to determine the record 

retention period from the date of 

distribution rather than the ‘‘date of 

manufacture.’’ The date on which the 

manufacturer completes the 

manufacture of a batch of a dietary 

supplement (the date of manufacture) 

does not necessarily indicate the 

availability of the dietary supplement 

product in the marketplace. It is 

possible that such product could be 

held for a period of time before entry 

into the marketplace and possible 

consumer consumption. A more 

accurate time period for entry is 

calculated by the date of distribution. 

Final § 111.605(a)(2) requires that 

manufacturers, packagers, labelers, and 

holders keep their records for 2 years 

from the date of distribution of the last 

batch of dietary supplement associated 

with those records. For products with a 

shelf life date, the records associated 

with those dietary supplements are 

required to be kept for 1 year past the 

shelf life date of that particular dietary 

supplement. Packagers and labelers that 

return the product to the manufacturer 

for distribution are not required to keep 

separate records under this subpart. 

2. Final § 111.605(b) 

Final § 111.605(b) requires you to 

keep records as original records, true 

copies (such as photocopies, microfilm, 

etc.), or as electronic records. Final 

§ 111.605(b) derives from proposed 

§ 111.125(b). 

We did not receive comments specific 

to proposed § 111.125(b). 

3. Final § 111.605(c) 

Final § 111.605(c) requires that all 

electronic records comply with part 11 

(21 CFR part 11). Final § 111.605(c) 

derives from proposed § 111.125(b). 


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(Comment 327) One comment 

believes part 11 should only apply to 

records that do not have paper 

counterparts. 

(Response) This comment is beyond 

the scope of this CGMP rulemaking. 

(Comment 328) One comment 

suggests the proposed requirement that 

CGMP electronic records must comply 

with part 11 should be deleted because 

the FDA guidelines on part 11 have not 

yet been finalized. 

(Response) Part 11 applies to 

electronic CGMP records. Therefore, 

final § 111.605(c) requires that all 

electronic records, including electronic 

signatures, must comply with part 11. 

We have finalized guidance for 

industry. The guidance entitled ‘‘Part 

11, Electronic Records; Electronic 

Signatures Scope and Application,’’ sets 

out our enforcement policies with 

respect to certain aspects of part 11 (Ref. 

33). The guidance is available at http:// 

www.fda.gov/cder/guidance/ 

5667fnl.htm. The guidance applies to 

any CGMP electronic records and 

signatures. 

E. What Records Must Be Made 

Available to FDA? (Final § 111.610) 

1. Final § 111.610(a) 

Final § 111.610(a) requires you to 

keep records, or copies of such records, 

required by this final rule, readily 

available during the retention period for 

inspection and copying by FDA when 

requested. Final § 111.610(a) derives 

from proposed § 111.125(c). We 

responded in section V of this document 

to comments that we received on FDA’s 

statutory authority to inspect and copy 

records. We made one editorial, 

nonsubstantive change from the 

language in proposed § 111.125(c). We 

removed the word ‘‘authorized’’ to 

prevent any confusion regarding 

whether some authorization other than 

the statutory authority that provides the 

legal basis for this final rule is necessary 

for our access to inspect and copy 

records. 

2. Final § 111.610(b) 

Final § 111.610(b) requires that if you 

use reduction techniques, such as 

microfilming, you must make suitable 

reader and photocopying equipment 

readily available to us. Final 

§ 111.610(b) derives from proposed 

§ 111.125(b). 

We did not receive any comments 

specific to proposed § 111.125(b) and 

final § 111.610(b). 

XXII. Other Comments and 

Miscellaneous 

A. Comments on Guidance Documents 

To Be Used With the Final Rule 

In the 2003 CGMP Proposal, we 

invited comment on the usefulness of 

guidance documents, education, 

training, or other approaches and 

potential sources of education and 

training that would assist industry 

efforts to implement the 2003 CGMP 

Proposal, if finalized as proposed (68 FR 

12157 at 12163). 

(Comment 329) A few comments state 

booklets, videos, seminars, and other 

training would be useful on topics such 

as sanitation, recordkeeping, quality 

assurance methods, microbiological 

testing, and botany. Another comment 

states a subset of CGMPs that focuses on 

plant authenticity, purity, proper 

handling, and hygiene should be 

developed for parties who exclusively 

deal with bulk raw agricultural 

commodities (with the exception of 

individual wildcrafters). If such CGMPs 

are not developed, the comment 

requests we develop guidance 

documents on the identification, 

cultivation, and handling of botanicals. 

The same comment also notes guidance 

specifically is needed on the use of 

microscopy to identify plants. 

(Response) We acknowledge these 

comments and, in the future, we may 

issue guidance that relates to certain 

dietary supplement CGMP 

requirements. 

B. Comments on Consideration for 

Other CGMP Programs 

(Comment 330) One comment asserts 

several existing dietary supplement 

CGMP programs (e.g., those developed 

by the NNFA, NSF International, ANSI, 

and USP) are well designed and 

represent useful examples for us to 

follow. The comment notes section 

12(d) of the National Technology 

Transfer and Advancement Act directs 

Federal agencies to use such voluntary 

consensus standards whenever possible, 

as long as the standards are consistent 

with Federal law and are practical. The 

comment recommends we include 

standards from these existing CGMP 

programs where suitable in the final 

rule. 

(Response) In the development of the 

2003 CGMP Proposal and this final rule, 

we carefully considered the comments 

that recommended aspects of other 

CGMP programs. For example, as 

discussed previously, the 1997 ANPRM 

for this rule contained the entire text of 

an outline presented to us by 

representatives of the dietary 

supplement industry. Furthermore, 

where comments recommended aspects 

of other CGMP programs, we considered 

those recommendations and, in some 

cases, incorporated certain 

recommendations into requirements in 

this final rule (e.g., the use of a 

certificate of analysis). 

In 2006, ANSI updated its Standard 

173 (ANSI Standard 173) regarding 

dietary supplements (Ref. 35). ANSI 

Standard 173 contains provisions for 

dietary supplement CGMP that are 

based, in part, on the industry 

submission to FDA in November 1995, 

which the agency published as part of 

its 1997 ANPRM. We considered 

comments to the 1997 ANPRM, many of 

which commented on the provisions of 

the industry submission, and the 

comments to the 2003 CGMP Proposal 

in the course of developing this CGMP 

final rule. We have considered the 

provisions contained in the updated 

ANSI Standard 173 and many of the 

specific provisions contained in ANSI 

Standard 173 are similar to provisions 

adopted in this final rule. For example, 

both the ANSI standard and this CGMP 

final rule have similar requirements on 

written procedures, personnel 

qualifications, record retention, and 

quality control. However, we 

determined that adopting the entire 

ANSI Standard 173 would be 

impracticable. There are key provisions 

which reflect major differences between 

the latest ANSI Standard 173 and the 

CGMP final rule. Many of these 

differences are in the product testing 

environment. For example, the ANSI 

standard contains different product 

testing frequency and production stage 

requirements. We have extensively 

discussed the justification for the 

particular testing requirements adopted 

in this CGMP final rule, which we 

believe are no more burdensome than 

the ANSI Standard 173 requirements. 

For example, the ANSI Standard 173 

contains testing methods for metal or 

microbiological contaminants not 

included in the final rule. We found that 

providing flexibility for manufacturers 

to choose their own specific test 

methods was a more efficient way of 

reaching the goals of the CGMP final 

rule than specifying and requiring 

particular tests. We support, however, 

the use of the ANSI Standard 173 testing 

methods by manufacturers, where 

appropriate, in complying with the 

requirements of this rule. 

(Comment 331) Another comment 

states CGMPs that reflect common 

elements and areas of uniqueness 

should be placed in subcategories of 

CGMPs as is the case with the current 

food CGMP model. The comment 

recommends we follow a similar 


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approach and establish subcategories of 

CGMPs for dietary supplements (e.g., for 

vitamin-mineral and probiotic tablets). 

(Response) In the 1997 ANPRM, we 

asked for comment about whether broad 

CGMP regulations would be adequate, 

or whether it would be necessary to 

address the operations of particular 

segments of the dietary supplement 

industry (68 FR 12157 at 12174). Based 

on the comments received to the 1997 

ANPRM, we were persuaded that a 

broad final rule is preferable to multiple 

regulations focused on particular 

segments of the dietary supplement 

industry, or to general CGMP provisions 

plus subcategories applicable to 

segments of the dietary supplement 

industry. We stated in the 2003 CGMP 

Proposal that we would consider 

whether we needed to re-evaluate our 

decision to establish one set of 

requirements for all dietary 

supplements (id.). This comment did 

not provide any basis to persuade us to 

re-evaluate the decision we made that a 

broad CGMP rule was appropriate. 

Thus, in this final rule, we are 

establishing one set of requirements for 

all persons who manufacture, package, 

label, or hold dietary supplements and 

not subject to an exclusion under final 

§ 111.1. 

C. Comments on Public Involvement 

1. Public Involvement 

(Comment 332) Several comments 

express general concerns with our 

public involvement process. Several 

comments state additional public 

meetings and workshops are necessary 

to permit FDA, industry, and other 

stakeholders to work together to seek a 

more workable solution to dietary 

supplement CGMPs and to resolve 

differences of opinion. One comment 

states the differences of opinion 

identified by the comment process will 

not be meaningfully resolved without 

active and forthright communication 

with stakeholders. According to the 

comment, we should establish a forum 

prior to the publication of the final rule 

to communicate our perception of these 

differences of opinion. In another 

comment, a trade association expresses 

disappointment that our 2003 CGMP 

Proposal disregards industry efforts to 

draft CGMPs over the last decade. 

Another comment contends the 

proposal was rushed and the comment 

period was established without 

publication of a core economic analysis 

to support it. 

(Response) We disagree with these 

comments. We believe there has been 

sufficient public involvement given the 

public meetings that were held and the 

opportunity for comment during the 

comment periods provided. We discuss 

the public involvement in section I of 

this document. Further, the 2003 CGMP 

Proposal did contain an economic 

analysis. We received extensive 

comments on the economic analysis in 

the 2003 CGMP Proposal. We have 

made several changes to the economic 

analysis of this final rule in response to 

these comments as discussed in section 

XXIV of this document. Furthermore, 

we have made various changes in 

response to comments to the CGMP 

requirements in this final rule. 

D. Comments on Implementation and 

Enforcement 

(Comment 333) Several comments 

suggest postponing the effective date of 

the rule for 24 months to allow a 

voluntary inspection and compliance 

program to take effect in the interim. 

One comment recommends adoption of 

a voluntary program similar to that of 

OSHA regulations in Title 29 of the 

Code of Federal Regulations, where 

companies would invite FDA inspection 

without penalty or cost unless a serious 

violation occurs. In cases of serious 

violation, companies would have the 

option to voluntarily correct the 

problem and inform the public before 

the effective date of the rule. 

(Response) We disagree with these 

comments regarding the establishment 

of a voluntary compliance period. The 

effective date of this final rule is 60 days 

after the date of its publication in the 

Federal Register. However, as discussed 

in sections VI and XXIV of this 

document, we have staggered 

compliance dates to 12 months, 24 

months, and 36 months, respectively, 

after the final rule’s publication date for 

businesses of over 500 employees, 

businesses with under 500 employees 

but 20 or more employees, and 

businesses with less than 20 employees. 

(Comment 334) Several comments 

indicate they want differential treatment 

under the final rule based on the 

seriousness of a violation, others ask for 

strict enforcement, and others ask how 

FDA would enforce against those who 

continually adulterate dietary 

supplements. 

(Response) We consider these 

comments to be outside the scope of this 

final rule. In general, we would provide 

guidance on our enforcement policy 

through the issuance of guidance 

documents if we determine that any 

variance from full enforcement is 

warranted. 

(Comment 335) Another comment 

expresses concern the 2003 CGMP 

Proposal works at ‘‘cross purposes’’

with recent regulations associated with 

bioterrorism. The comment 

recommends these rules be harmonized 

to reduce costs and increase efficiencies 

for manufacturers. 

(Response) It is not clear what the 

comment means when it states the 2003 

CGMP Proposal works at ‘‘cross 

purposes’’ with the regulations issued 

under the Bioterrorism Act or that we 

should ‘‘harmonize’’ the regulations 

issued under the Bioterrorism Act with 

the final rule establishing dietary 

supplement CGMP requirements. We 

have made every effort to consider the 

regulations issued under the 

Bioterrorism Act and their relationship 

to this final rule. There are different 

purposes to the Bioterrorism Act and 

these CGMP requirements; however, we 

have harmonized to the extent possible. 

(Comment 336) One comment states 

the 1-year compliance period for large 

firms is reasonable as long as we modify 

the rule to better reflect existing CGMPs 

already in practice among responsible 

companies. The comment also notes the 

3-year compliance period for small 

firms may be reasonable, but urges us to 

enforce compliance of basic food GMP 

requirements, which some of these firms 

may not be observing. 

(Response) The effective date for this 

final rule is 60 days after its date of 

publication in the Federal Register, 

though we are staggering the 

compliance dates as described in 

sections VI and XXIV of this document. 

Dietary supplement products in the 

marketplace must already be in 

compliance with all other statutory and 

regulatory provisions that affect dietary 

supplements. 

E. Removal of References to Part 112 

The 2003 CGMP Proposal (68 FR 

12157 at 12175) had proposed the 

heading and table of contents for part 

112. Proposed part 112 had the heading 

‘‘Restrictions for Substances Used in 

Dietary Supplements.’’ At the time, we 

said that it was necessary to amend part 

112 because at that time the proposed 

rule for dietary supplements containing 

ephedrine alkaloids (62 FR 30678, June 

4, 1997) had not been finalized and 

included proposed revisions to part 111. 

The 2003 CGMP Proposal for dietary 

supplement CGMPs proposed using part 

111 and proposed the relocation of the 

‘‘Restrictions for Substances Used in 

Dietary Supplements’’ to part 112. Since 

the issuance of the 2003 CGMP 

Proposal, the final rule for dietary 

supplements containing ephedrine 

alkaloids has been finalized (69 FR 

6788, February 11, 2004) and has been 

included in 21 CFR part 119. Thus, 

there is no need to reserve part 112 in 

this final rule. The references to part 


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112 have been removed from the final 

rule. 

XXIII. Paperwork Reduction Act of 

1995 

This final rule contains information 

collection requirements that are subject 

to review by the Office of Management 

and Budget (OMB) under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501–

3520). The title, description, and 

respondent description of the 

information collection requirements are 

given in the following paragraphs, with 

estimates of the one-time burden of 

establishing written procedures and the 

annual recordkeeping burden. Included 

in the burden estimates are the time for 

reviewing instructions, searching 

existing data sources, gathering and 

maintaining the data needed, and 

completing and reviewing each 

collection of information. 

Title: Current Good Manufacturing 

Practice in Manufacturing, Packaging, 

Labeling, or Holding Operations for 

Dietary Supplements 

Description: Section 402(g) of the act 

gives us explicit authority to issue a rule 

establishing current good manufacturing 

practice requirements for dietary 

supplements. Section 402(g)(1) of the 

act states that a dietary supplement is 

adulterated if ‘‘it has been prepared, 

packed, or held under conditions that 

do not meet current good manufacturing 

practice regulations.’’ Section 402(g)(2) 

of the act authorizes us to, by regulation, 

‘‘prescribe good manufacturing practices 

for dietary supplements.’’ Under section 

701(a) of the act (21 U.S.C. 371), FDA 

may issue regulations necessary for the 

efficient enforcement of the act. Other 

relevant legal authority is discussed in 

section V of this document. 

We did not receive any direct 

comments on the Paperwork Reduction 

Act analysis of the 2003 CGMP 

Proposal. Many comments on the 

estimated costs of the 2003 CGMP 

Proposal stated that we underestimated 

the annual number of batches of dietary 

supplements produced. Due to a 

contractor’s error, we did underestimate 

the number of batches produced. This 

final paperwork reduction analysis 

corrects for this error. The final analysis 

also has been revised from the analysis 

of the 2003 CGMP Proposal in order to 

incorporate the effects of revisions to 

the proposed regulation, including 

reorganization. 

Records are an indispensable 

component of CGMP. The records 

required by this final rule provide the 

foundation for the planning, control, 

and improvement processes that 

constitute a quality control system. 

Implementation of these processes in a 

manufacturing operation serves as the 

backbone to CGMP. The records will 

show what is to be manufactured; what 

was, in fact, manufactured; and whether 

the controls that the manufacturer put 

in place to control the identity, purity, 

strength, and composition and limits on 

contaminants and to prevent 

adulteration were effective. Further, 

records will show whether and what 

deviations from control processes 

occurred, facilitate evaluation and 

corrective action concerning these 

deviations (including, where necessary, 

whether associated batches of product 

should be recalled from the 

marketplace), and enable a 

manufacturer to assure that the 

corrective action was effective. Further, 

records will show whether and what 

deviations from control processes 

occurred, facilitate evaluation and 

corrective action concerning these 

deviations (including, where necessary, 

whether associated batches of product 

should be recalled from the 

marketplace), and enable a 

manufacturer to assure that the 

corrective action was effective. In 

addition, by requiring records, we will 

be able to ensure that you follow CGMPs 

so that you ensure the quality of your 

dietary supplements during 

manufacturing, packaging, labeling, or 

holding operations. The final rule 

establishes the minimum manufacturing 

practices necessary to ensure that 

dietary supplements are manufactured, 

packaged, labeled, or held in a manner 

that will ensure the quality of the 

dietary supplements during 

manufacturing, packaging, labeling or 

holding operations. 

The records requirements of this final 

rule include written procedures and 

records pertaining to: (1) Personnel; (2) 

sanitation; (3) calibration of instruments 

and controls; (4) calibration, inspection, 

or checks of automated, mechanical, or 

electronic equipment; (5) maintaining, 

cleaning, and sanitizing equipment and 

utensils and other contact surfaces; (6) 

water used that may become a 

component of the dietary supplement; 

(7) production and process controls; (8) 

quality control; (9) components, 

packaging, labels and product received 

for packaging and labeling; (10) master 

manufacturing and batch production; 

(11) laboratory operations; (12) 

manufacturing operations; (13) 

packaging and labeling operations; (14) 

holding and distributing operations; (15) 

returned dietary supplements; and (16) 

product complaints. 

Description of Respondents: 

Manufacturers, dietary supplement 

manufacturers, packagers and repackagers, labelers and re-labelers, 

holders, distributors, warehousers, 

exporters, importers, large businesses, 

and small businesses. 

The recordkeeping requirements of 

the final rule are set forth in each 

subpart. In table 18 of this document we 

list the one-time burdens associated 

with establishing written procedures. In 

table 19 of this document we list the 

annual burdens associated with 

recordkeeping. In each table, where the 

same records are mentioned in more 

than one provision of a subpart, we list 

the burden under the provisions 

corresponding to the heading, ‘‘Under 

this subpart, what records must you 

make and keep?’’ For some provisions 

listed in table 19, we did not estimate 

the annual frequency of recordkeeping 

because recordkeeping occasions consist 

of frequent brief entries of dates, 

temperatures, monitoring results, or 

documentation that specific actions 

were taken. Information might be 

recorded a few times a day, week, or 

month. When the records burden 

involves frequent brief entries, we 

entered one as the default for the annual 

frequency of recordkeeping. For 

example, many of the records listed 

under final § 111.35 in table 19, such as 

final § 111.35(b)(2) (documentation, in 

individual equipment logs, of the date 

of the use, maintenance, cleaning, and 

sanitizing of equipment), involve many 

short sporadic entries over the course of 

the year, varying across equipment and 

plants in the industry. We did not 

attempt to estimate the actual number of 

recordkeeping occasions for these 

provisions, but instead entered an 

estimate of the average number of hours 

per year. We entered the default value 

of 1 as the annual frequency of 

recordkeeping for these and similar 

provisions. For final § 111.35, the entry 

for annual frequency is 1 as a default 

representing a large number of brief 

recordkeeping occasions. 

In many rows of tables 18 and 19 of 

this document, we list a burden under 

a single provision that covers the 

written procedures or records described 

in several provisions. The burden of the 

master manufacturing record listed in 

table 18 under final § 111.210 includes 

the burden for final § 111.205 because 

the master manufacturing record must 

include those written procedures. 

Similarly, the burden of the batch 

production records listed in table 19 

under final § 111.260 includes the 

burden for records listed under final 

§ 111.255 because the batch production 

records must include those records. 

The annual frequency for batch 

production records (and other records 

kept on a batch basis in table 19 of this 

document) equals the annual number of 


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batches. The estimated burden for 

records kept by batch includes both 

records kept for every batch and records 

kept for some but not all batches. We 

use the annual number of batches as the 

frequency for records that will not 

necessarily be kept for every batch, such 

as test results or material review and 

disposition records, because such 

records are part of records, if they are 

necessary, that will be kept for every 

batch. 

We estimate the burden of this 

collection of information as follows: 

TABLE 18.—ESTIMATED ONE-TIME BURDEN TO ESTABLISH WRITTEN PROCEDURES1

21 CFR Section Number of 

Recordkeepers 

Annual Frequency 

per Recordkeeping Total Records Hours per Record Total Hours 

111.14 15,000 1 15,000 3 .6 54,000 

111.23 15,000 1 15,000 1 15,000 

111.35 400 1 400 36 14,400 

111.95 250 1 250 68 17,000 

111.140 300 1 300 10 .7 3,210 

111.180 200 1 200 10 2,000 

111.210 250 1 250 12 3,000 

111.325 150 1 150 45 6,750 

111.375 260 1 260 9 2,340 

111.430 250 1 250 12 .6 3,150 

111.475 15,000 1 15,000 2 .1 31,500 

111.535 200 1 200 6 1,200 

111.570 240 1 240 12 2,880 

Total 156,430 

1There are no capital costs or operating costs associated with the collection of information under this final rule. 

TABLE 19.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

21 CFR Section Number of 

Recordkeepers 

Annual Frequency 

per Recordkeeping 

Total Annual 

Records 

Hours per 

Record Total Hours 

111.14 15,000 4 60,000 1 60,000 

111.23 15,000 1 15,000 0 .2 3,000 

111.35 400 1 400 12 .5 5,000 

111.95 250 1 250 45 11,250 

111.140 240 1,163 279,120 1 279,120 

111.180 240 1,163 279,120 1 279,120 

111.210 240 1 240 2 .5 600 

111.260 145 1,408 204,160 1 204,160 

111.325 120 1 120 15 1,800 

111.375 260 1 260 2 520 

111.430 50 1 50 12 .6 630 

111.475 15,000 1 15,000 0 .4 6,000 

111.535 110 4 440 13 .5 5,940 

111.570 240 600 144,000 0 .5 72,000 

Total 929,140 

1There are no capital costs or operating costs associated with the collection of information under this final rule. 


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The burden estimates in tables 18 and 

19 of this document are based on our 

institutional experience with other 

CGMP requirements and on data 

provided by Research Triangle Institute 

(RTI) in the ‘‘Survey of Manufacturing 

Practices in the Dietary Supplement 

Industry,’’ OMB Control Number 0910–

0422, expiration date April 4, 2000 

(Refs. E1 and E2). 

The estimates in both tables of the 

number of firms affected by each 

provision of the rule are based on the 

percentage of manufacturers, packagers, 

labelers, holders, distributors, and 

warehousers that reported in the survey 

that they have not established written 

SOPs or do not maintain records that 

would be required under the final rule. 

Because we do not have survey results 

for general warehouses, we entered the 

approximate number of facilities in that 

category for those provisions covering 

general facilities. For the dietary 

supplement industry, the survey 

estimated that 1,460 firms would be 

covered by this final rule, including 

manufacturers, packagers, labelers, 

holders, distributors, and warehousers. 

The time estimates include the burden 

involved in documenting that certain 

requirements are performed and in 

recordkeeping. We used an estimated 

annual batch production of 1,408 

batches per year to estimate the burden 

of requirements that are related to the 

number of batches produced annually, 

such as final § 111.260, ‘‘What must the 

batch production record include?’’ The 

estimate of 1,408 batches per year is 

near the midpoint of the number of 

annual batches reported by survey 

firms. 

The length of time that CGMP records 

must be maintained is set forth in final 

§ 111.605. Tables 18 and 19 of this 

document reflect the estimated burdens 

for written procedures, record 

maintenance, periodically reviewing 

records to determine if they may be 

discarded, and for any associated 

documentation for that activity for 

records that will be required under part 

111. We have not included a separate 

estimate of burden for those sections 

that require maintaining records in 

accordance with final § 111.605, but 

have included those burdens under 

specific provisions for keeping records. 

For example, final § 111.255(a) requires 

that the batch production records be 

prepared every time a batch is 

manufactured, and final § 111.255(d) 

requires that batch production records 

be kept in accordance with final 

§ 111.605. The estimated burdens for 

both § 111.255(a) and (d) are included 

under final § 111.260 (what the batch 

record must include). 

The information collection provisions 

of this final rule have been submitted to 

OMB for review. 

Prior to the effective date of this final 

rule, we will publish a document in the 

Federal Register announcing OMB’s 

decision to approve, modify, or 

disapprove the information collection 

provisions in this final rule. An agency 

may not conduct or sponsor, and a 

person is not required to respond to, a 

collection of information unless it 

displays a currently valid OMB control 

number. 

XXIV. Analysis of Impacts 

A. Introduction 

FDA has examined the impacts of this 

final rule under Executive Order 12866. 

Executive Order 12866 directs agencies 

to assess all costs and benefits of 

available regulatory alternatives and, 

when regulation is necessary, to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). 

Executive Order 12866 classifies a rule 

as significant if it meets any one of a 

number of specified conditions, 

including: Having an annual effect on 

the economy of $100 million, adversely 

affecting a sector of the economy in a 

material way, adversely affecting 

competition, or adversely affecting jobs. 

A regulation is also considered a 

significant regulatory action if it raises 

novel legal or policy issues. FDA has 

determined that this final rule will be an 

economically significant regulation 

under Executive Order 12866 because it 

will have an annual effect on the 

economy of more than $100 million. 

The Small Business Regulatory 

Enforcement Fairness Act of 1996 

(Public Law 104–121) defines a major 

rule for the purpose of congressional 

review as being likely to cause one or 

more of the following: An annual effect 

on the economy of $100 million; a major 

increase in costs or prices; significant 

adverse effects on competition, 

employment, productivity, or 

innovation; or significant adverse effects 

on the ability of U.S.-based enterprises 

to compete with foreign-based 

enterprises in domestic or export 

markets. In accordance with the Small 

Business Regulatory Enforcement 

Fairness Act, OMB has determined that 

this final rule will be a major rule for 

the purpose of congressional review. 

FDA has examined the impacts of this 

final rule under the Regulatory 

Flexibility Act (5 U.S.C. 601–612). If a 

rule has a significant economic impact 

on a substantial number of small 

entities, the Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would lessen the economic 

effect of the rule on small entities. FDA 

finds that this final rule will have a 

significant economic impact on a 

substantial number of small entities. 

The Unfunded Mandates Reform Act 

of 1995 (Public Law 104–4) requires 

cost-benefit and other analyses for rules 

that would cost more than $100 million 

in a single year. The current (2005) 

inflation-adjusted statutory threshold is 

$122 million. This final rule qualifies as 

a significant rule under the statute. 

1. Summary of the Economic Analysis 

We carry out the cost-benefit analyses 

required for significant rules in the 

Final Regulatory Impact Analysis, in 

section XXIV.B of this document. We 

perform the Final Regulatory Flexibility 

Analysis of the effects on the final rule 

on small businesses in section XXIV.C 

of this document. We estimate that, 

once it is fully implemented 36 months 

after the date of publication, the 

quantifiable annual benefits from the 

final rule will be about $44 million. The 

benefits able to be quantified are 

generated by more consistently 

produced dietary supplements which 

will increase product safety, which 

reduces the number of acute illnesses 

and product recalls. In addition, the 

final rule may generate benefits that we 

lack sufficient data to quantify. These 

benefits we cannot quantify arise from 

dietary supplements manufactured 

under a system to ensure quality, which 

leads to a reduction in the number of 

chronic illnesses and conditions. 

The final rule will lead to quantifiable 

costs of $16 million in the first year it 

takes effect, $120 million in the second 

year, and $190 million in the third year. 

After 3 years, the annual costs will be 

about $164 million. If we annualize the 

benefits and costs over 20 years at a 3 

percent rate of discount, the annualized 

quantifiable benefits are $40 million and 

annualized quantifiable costs are $153 

million. These annualized benefits 

include only those that we are able to 

quantify. The total annualized benefits 

may be larger than our estimate of $40 

million in quantifiable benefits because 

of the benefits that we are not able to 

quantify. 

We have determined, based on 

information contained in this regulatory 

impact analysis as well as information 

contained elsewhere in the preamble, 

that the benefits of this final rule justify 

the costs. 

The final rule will have a significant 

economic effect on small businesses. We 

estimate that the annual costs will be 

about $46,000 for an establishment with 


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12An experience good is a product or service 

where product characteristics such as quality or 

price are difficult to observe in advance, but these 

characteristics can be ascertained upon 

consumption. A credence good is a good whose 

utility impact is difficult or impossible for the 

consumer to ascertain even after consumption of 

the good. 

fewer than 20 employees and $184,000 

for an establishment with 20 to 499 

employees. 

2. Summary of Comments on the 

Economic Analysis 

We received numerous substantive 

comments on the economic analysis of 

the 2003 CGMP Proposal. In general, 

comments from the dietary supplement 

industry state that we underestimated 

the cost of the 2003 CGMP Proposal. 

Specific comments from the industry 

target the 2003 CGMP Proposal’s testing 

requirements, which the comments 

characterize as ‘‘burdensome.’’ Many 

comments address our estimate of the 

number of batches of dietary 

supplements firms produce in a year. 

Many comments express the fear that, as 

a result of this 2003 CGMP Proposal, the 

prices consumers pay for dietary 

supplements would increase 

dramatically. Nearly all economic 

comments mention potential adverse 

effects of the 2003 CGMP Proposal on 

small businesses, stating that many 

firms would have to stop 

manufacturing. A few comments state 

that, if made final, the 2003 CGMP 

Proposal would make dietary 

supplements more expensive than 

pharmaceuticals. Other comments 

address the following topics: 

• FDA’s other assumptions, including 

the number of tests required for each 

batch and the number of tests already 

being performed. 

• Development of analytical methods. 

• Equipment and capital investment 

costs. 

• Recordkeeping costs. 

• FDA’s estimation of benefits. 

We will summarize comments on 

individual substantive issues under the 

appropriate subject headings and 

respond. 

B. Final Regulatory Impact Analysis 

1. The Need for the Final Current Good 

Manufacturing Practice Rule 

The final rule is needed because 

establishments that manufacture, 

package, label, or hold dietary 

supplements may not have sufficient 

market incentives to use controls to 

ensure that the characteristics of the 

supplements are what consumers would 

choose to buy if they had full or 

adequate information. Dietary 

supplements have the characteristics of 

both experience goods and credence 

goods.12 In terms of the acute illnesses 

discussed below, it may be difficult for 

consumers to identify the attributes of 

dietary supplements before the actual 

consumption of the good. Therefore, it 

may be difficult, in the absence of some 

regulation of dietary supplement 

manufacturing practices, for consumers 

to differentiate between products 

produced under good manufacturing 

practices, and those that are not, at the 

point of purchase in the marketplace. In 

terms of dietary supplements as 

credence goods, consumers may never 

have adequate information on product 

characteristics even after the 

consumption of the good, making it 

difficult for consumers to determine 

what benefits each product offers. 

Because problems can be undetectable, 

establishments may not adopt the 

necessary practices to ensure product 

attributes are as they are intended 

unless required to do so by regulation. 

Of course, the characteristics of 

dietary supplements, as a type of food 

product, argue for some sort of 

Government intervention in this market 

in order to alleviate the specific market 

failures that lead to the types of 

problems with dietary supplements that 

this rule addresses. There are many 

types of interventions that may be used 

to address market failure; FDA has 

examined the options and has 

determined that specific CGMPs are 

necessary for dietary supplements. The 

rest of this regulatory impact analysis, 

and particularly section III.A of this 

document, discusses why FDA has 

concluded that specific CGMPs are 

necessary for dietary supplements. 

(Comment 337) We received several 

comments on the need for the 2003 

CGMP Proposal. Four comments 

specifically support the proposal, 

stating, in part, that they are pleased we 

are addressing the issue of dietary 

supplement manufacturing. In addition, 

one comment states that the 2003 CGMP 

Proposal was a good step toward 

providing assurance that dietary 

supplements are as safe as prescription 

and OTC drugs. 

Other comments express concern 

about the 2003 CGMP Proposal. One 

comment generally supports it, but 

expresses concern that the statements 

we make regarding market incentives to 

prevent adulteration and misbranding 

are inaccurate and misleading. The 

comment points out that the incentive 

exists for firms to prevent adulterated 

products from entering the marketplace 

because of their desire to avoid damage 

to their reputations. In addition, 

adulterated products are already illegal 

to market. Two other comments support 

the 2003 CGMP Proposal only with 

modifications, and another comment 

supports CGMP regulations, provided 

they reflect the current ‘‘best practices 

of leading manufacturers.’’ Two 

comments assert that a ‘‘more rigorous’’

enforcement program would be more 

effective than dietary supplement CGMP 

requirements in preventing adulteration. 

Two comments state that a regulation 

would serve no useful purpose because 

of the ‘‘low level of harm identified in 

the industry.’’

One comment states that the 2003 

CGMP Proposal spells out design 

standards rather than performance 

standards. According to the comment, 

the 2003 CGMP Proposal spells out 

procedures a firm must follow rather 

than defining a specific outcome, such 

as a specified level of contamination. 

This comment maintains that we should 

set a performance standard and then 

allow manufacturers flexibility in how 

that standard is reached. Another 

comment states that, although certain 

dietary supplement ingredients may 

cause concern, this concern did not 

justify imposing ‘‘overbearing’’ and 

‘‘broad’’ CGMP regulations for an entire 

industry. Another comment asserts that 

the CGMPs as presented in the 2003 

CGMP Proposal would serve as an anticompetitive tool by allowing dominant 

manufacturers to increase their 

dominance and make it more difficult 

for new firms to enter the industry. 

(Response) Those comments that 

disagreed with our analysis provided no 

data or evidence to support the 

comment. Without such data or 

evidence, we have no basis upon which 

to revise our analysis and continue to 

use the analysis. Thus, we have not 

made any changes based on these 

comments. 

Whether or not these provisions are 

performance or design standards is a 

theoretical issue. Instead of specifically 

choosing either design or performance 

standards for all provisions of the rule, 

FDA has chosen to provide flexibility to 

manufacturers whenever possible. For 

example, providing for the use of ‘‘safe 

and sanitary’’ water sources gives 

manufacturers flexibility in deciding the 

best way to assure that ‘‘safe and 

sanitary’’ water is used in the 

manufacture of their products. There are 

many areas of the rule where more than 

one way is given to comply with a 

particular provision. This flexibility 

allows manufacturers to choose the 

appropriate means to comply with the 

provision that is the most cost-effective 

for them. 


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Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 34919 

13Options 1 through 6 were discussed in detail in 

the 2003 CGMP Proposal (68 FR 12157 at 12221 

through 12223; March 13, 2003) and analyses of 

costs were provided when possible. The principles 

of the options discussion have not changed and are 

still relevant for purposes of the requirements of the 

final rule. The 2003 CGMP proposal also included 

an Analysis of Impacts which contained some 

errors from a contractor’s report. We have corrected 

the analysis and have recalculated the costs of the 

2003 CGMP Proposal. These corrections and 

recalculations are discussed in section XXIV.B.9 of 

this document. 

We agree with the comments that 

point out that existing statutes and 

regulations, concern for brand names, 

and voluntary industry standards 

provide some product safety and 

quality. Nonetheless, continuing 

problems in the industry provide 

evidence for the need for this final rule. 

From 2000 through 2005, there were a 

total of 75 recall actions in the dietary 

supplement industry, including class 1, 

2, and 3 recalls of vitamins and minerals 

and herbal and botanical supplements. 

We will discuss these recalls, which 

accounted for about 4 percent of the 

1,937 FDA food recall actions in 2000 

through 2005, later in this document. 

Most of these recalls occurred because 

establishments failed to adhere to 

product manufacturing or labeling 

specifications. 

For a class 1 recall, there is a 

reasonable probability of serious 

adverse health consequences or death; 

for a class 2 recall, exposure to the 

product may cause temporary or 

medically reversible adverse health 

consequences; for a class 3 recall, 

exposure to the product is not likely to 

cause adverse health consequences. Full 

compliance with the provisions of this 

final rule could have prevented most of 

the recalls. We note also recall 

classifications only track acute hazards, 

not long-term quality problems. Results 

from ConsumerLab.com and other 

independent laboratory results provide 

further evidence of a need for this final 

rule (Refs. E3 through E6). Statistical 

sampling methods were not used to 

collect the data reported in these 

analyses. Therefore, although this 

information provides anecdotal 

evidence of problems, the data may not 

be representative of overall industry 

practices. The information serves as 

additional evidence of the existence of 

problems. 

Although the final rule will increase 

the monetary cost of entering the dietary 

supplement industry, the industry will 

remain highly competitive with more 

than a thousand competing producers 

and thousands more potential entrants. 

2. Regulatory Options 

We considered several regulatory 

options for dealing with current 

manufacturing, packaging, labeling, and 

holding practices that may not ensure 

the quality of the dietary supplement. 

The options considered include: (1) No 

new regulatory action, (2) fewer 

requirements for vitamins and minerals, 

(3) more restrictive regulations than the 

final rule, (4) HACCP without the other 

elements of the final rule, (5) final 

product testing only, (6) a final rule for 

high-risk products or hazards only, and 

(7) the 2003 CGMP Proposal.13 As a 

result of comments on the 2003 CGMP 

Proposal and our reconsideration of our 

position on several provisions, this final 

rule differs from the 2003 CGMP 

Proposal. 

(Comment 338) We received few 

comments on the option of fewer 

requirements for vitamins and minerals, 

and the comments submitted did not 

support this option. One comment 

supports one set of CGMPs that would 

apply to the entire industry rather than 

fewer requirements for vitamins and 

minerals than for botanicals. Another 

comment states that having fewer 

requirements for vitamins and minerals 

would not be wise because of the large 

number of people who take 

multivitamin or mineral supplements. 

One comment supports more 

restrictive CGMP requirements, 

including further testing and quality 

assurance requirements. 

We received two comments that 

support HACCP without other elements 

of the final rule. One comment echoes 

an earlier comment made about 

stressing outcomes and points to the 

HACCP systems in the juice and seafood 

industries as a way of ensuring effective 

quality control design. The comment 

asserts that the detailed manufacturing 

controls and testing requirements 

spelled out in the 2003 CGMP Proposal 

may actually stifle innovation. Another 

comment echoes these thoughts, adding 

that a HACCP approach could work in 

tandem with a more traditional 

specification and test approach. 

We received one comment that 

specifically discusses requiring only 

final product testing, but received 

numerous comments on final product 

testing in general. The specific comment 

did not support reliance on final 

product testing only, stating it is not the 

best or most appropriate control. In 

addition, the comment claims it is not 

technically feasible in many cases and 

is economically burdensome, a point 

repeated in other general comments 

about final product testing. In addition, 

numerous comments point out that a 

firm cannot ‘‘test in quality,’’ meaning 

that ensuring the quality of the dietary 

supplement will not be achieved 

through rigorous end-product testing, 

which emphasizes the wrong stage of 

production, but by ensuring quality 

through an effective process control 

system. 

Few comments discuss regulation of 

only high-risk products. Those that did 

note that some ingredients would be of 

public health concern and it would be 

preferable to test these ingredients only 

rather than all ingredients. 

(Response) The comments on the 

regulatory options did not provide 

evidence to directly support or oppose 

those options but instead addressed 

particular issues such as testing or 

coverage. 

We took the comments on specific 

issues into account in the analysis of 

this final rule. We discuss them below 

in the relevant parts of the analysis. 

One comment supporting HACCP 

stated that the detailed manufacturing 

and testing requirements of the 2003 

CGMP Proposal would, compared with 

HACCP, stifle innovation. Although 

regulations that impose costs can divert 

resources away from innovation, the 

costs of this final rule represent less 

than 1 percent of industry revenues (see 

table 35 of this document). Because 

research and development expenditures 

account for a small fraction of total 

expenditures, any reduced expenditures 

on research and development associated 

with this final rule will be a small 

fraction of 1 percent of revenues. Thus, 

it seems unlikely that this rule would 

have the effect of stifling innovation. As 

we explained in the economic analysis 

of the 2003 CGMP Proposal, the HACCP 

option would not specify detailed 

manufacturing requirements but would 

also fail to ensure product quality (68 

FR 12157 at 12222). In section X.I of this 

document, we discuss why HACCP is 

not appropriate for dietary supplements. 

The comment supporting HACCP failed 

to provide any data or any evidence to 

support its conclusion. Without such 

data or evidence, we have no basis upon 

which to revise our analysis and 

continue to use the analysis. 

3. Coverage of the Final Rule 

The final rule applies to 

establishments that manufacture, 

package, label, or hold dietary 

supplements. Tables 20 and 21 of this 

document list the estimated number of 

covered manufacturers, packagers, 

labelers, holders, and other 

establishments subject to the final rule. 

Table 20 shows the number of 

establishments categorized as 

manufacturers, repackagers or 

relabelers, holders whose primary 

business is dietary supplements, and 

other (although not including other 


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34920 Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 

holders and distributors). Table 21 

shows our estimate of the number of 

general warehouses, wholesalers, and 

others that hold dietary supplements, 

but are not otherwise involved in the 

industry. 

TABLE 20.—COVERED ESTABLISHMENTS BY TYPE OF OPERATION FROM THE DIETARY SUPPLEMENT ENHANCED

ESTABLISHMENT DATABASE (DS–EED) 

Establishment Type No. of 

Establishments 

Percent of 

Establishments 

Manufacturer 1,228 84.1 

Repackager; relabeler 26 1.8 

Holder 114 7.8 

Establishments not already classified 92 6.3 

Total 1,460 100.0 

TABLE 21.—COVERED ESTABLISHMENTS THAT HOLD DIETARY SUPPLEMENTS

Type of Holders NAICS Code No. of 

Establishments 

General grocery wholesalers or drug wholesalers 424410 4,036 

General warehouse 493110 4,415 

Drug wholesalers 42420 7,418 

Total 15,869 

We consulted several sources to 

estimate the number of establishments 

reported in this document. The number, 

1,460, is the estimated number of 

establishments in the DS-EED that 

manufacture, package, label, or hold 

dietary supplement products in the 

United States. In the analysis of the 

2003 CGMP Proposal, we included an 

additional 106 U.S. establishments that 

supplied dietary ingredients. Because 

those establishments are not covered in 

this final rule, we exclude them from 

the total. RTI developed the DS-EED 

using FDA’s Official Establishment 

Inventory and supplemented that source 

with information from trade 

organizations, trade shows, and 

electronic databases (Refs. E1 and E2). 

To estimate the total number of 

establishments that could hold dietary 

supplements but do not consider dietary 

supplements as their primary business, 

we first looked for a count of 

establishments that had North American 

Industrial Classification System 

(NAICS) codes for wholesalers of 

groceries or drugs. Next we looked for 

a count of firms that met the description 

of warehouses for groceries or drugs. We 

did not find a category devoted 

exclusively to food and drug 

warehousing, so we concluded that 

general warehousing most closely 

corresponded to the set of 

establishments that would hold dietary 

supplements. The results are shown in 

table 21 of this document. This total 

differs from the total reported in the 

analysis of the 2003 CGMP Proposal 

because the new classification system 

allows us to identify more 

establishments that would not hold 

dietary supplements and therefore 

exclude them from the total. 

Foreign firms that export dietary 

supplements to the United States must 

satisfy the requirements of this final 

rule. We do not have data on the 

number of foreign firms that export 

dietary supplements to the United 

States. The small number of foreign 

products in the FDA dietary supplement 

sales database suggests that relatively 

few foreign firms export dietary 

supplements to the United States (Ref. 

E7). The foreign firms that will be most 

affected by the final rule are suppliers 

of dietary ingredients. Although 

suppliers of dietary ingredients are not 

directly covered by the final rule, the 

need of manufacturers to meet the 

ingredient specifications required by the 

final rule will indirectly affect foreign 

suppliers (as well as domestic 

suppliers). 

No comments were received on the 

economic analysis of the coverage of the 

2003 CGMP Proposal. 

4. Baseline Practices 

a. Consumption. Baseline risks 

depend on baseline consumption of 

dietary supplements. Total sales in 2004 

were about $20 billion (Ref. E8). 

Vitamins and minerals accounted for 

about 42 percent of sales. Sales of herbal 

supplements, which have not grown in 

recent years, were half as large as sales 

of vitamin and minerals, accounting for 

about 21 percent of the total. Amino 

acids, proteins, animal extracts, tea-like 

supplements, and other supplements 

not otherwise classified accounted for 

the remainder of sales. 

There were no comments on the 

consumption baseline. 

b. Manufacturing. We contracted with 

RTI to conduct a survey of the dietary 

supplement industry to learn about both 

baseline (existing) manufacturing 

practices and the existing standards 

used for manufacturing dietary 

ingredients and dietary supplements 

(Ref. E2). A sample of 966 dietary 

supplement establishments from the DSEED database was selected from an 

estimated eligible population of 1,566 

firms in the industry (the total number 

of dietary supplement establishments 

included 106 ingredient manufacturers, 

who are now excluded from the 

requirements of the final rule). The 

eligibility criteria and the response rate 

for the survey are fully explained in the 

final report on the survey (Ref. E2). We 

further classified the target firms by 

product and by size. The product 

categories were: (1) Vitamins and 

minerals; (2) amino acids and proteins; 

(3) herbals and botanicals, including 


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Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 34921 

14Mandatory reporting to FDA of serious adverse 

events is now required as a result of the enactment 

of the ‘‘Dietary Supplement and Non-Prescription 

Drug Consumer Protection Act’’ (Public Law 109–

462), signed into law on December 22, 2006. The 

new law requires manufacturers, packers, or 

distributors of such products to submit reports to 

FDA about serious adverse events involving such 

products based on specific information that they 

receive from the public. 

extracts; and (4) supplements not 

already classified. 

The Small Business Administration 

classifies companies as ‘‘small’’ based 

on the size of the entire company, 

including both parent and subsidiaries. 

If firms that manufacture dietary 

supplements have fewer than 500 

employees, they are classified as small. 

In addition, for purposes of this 

analysis, we classify firms with fewer 

than 20 employees as very small. 

We received 238 completed surveys. 

Table 22 of this document shows the 

number of completed surveys by 

product and by size of establishment. 

TABLE 22.—NUMBER OF COMPLETED SURVEYS BY SAMPLING STRATA

Size 

Very Small (fewer 

than 20 employees) 

Small (20 to 499 

employees) 

Large (500 or more 

employees) Unknown Total 

Vitamins and minerals 19 39 13 1 72 

Amino acids, proteins 8 7 0 5 20 

Herbals and botanicals, including extracts 58 25 0 30 113 

Supplements not already 

classified 14 13 2 4 33 

Total 99 84 15 40 238 

(Comment 339) We received two 

comments on manufacturers’ baseline 

practices. One comment expresses 

concern that, as the information is over 

3 years old, it may no longer represent 

current industry practices. The second 

comment questions the way we 

calculated the number of dietary 

supplement establishments that do not 

follow any CGMP models. In the 2003 

CGMP Proposal, we state that survey 

data reflect that 36 percent of surveyed 

establishments do not follow any CGMP 

models. The comment points out that 

26.5 percent of firms responded ‘‘no’’ to 

the question, ‘‘Does this plant follow a 

published GMP model for the dietary 

supplement products produced at this 

plant?’’ Furthermore, of the 63 that 

answered ‘‘no,’’ ‘‘at least’’ 29 of the 

firms provided responses indicating the 

reason they do not follow a published 

GMP is that they did not manufacture 

dietary supplement products. 

(Response) Although the survey 

responses are now over 6 years old, they 

represent the best information we have 

on the industry and its practices. We 

have, however, adjusted our estimated 

costs to reflect the correction of the 

results from the original survey. 

5. Baseline Risk 

The current number of illnesses 

caused by poor dietary supplement 

manufacturing practices requires data 

linking illnesses to poor practices. 

Because these data do not exist, we 

looked for other information to provide 

indirect evidence on the problem. We 

looked at many sources for information, 

including medical and other literature 

on adverse events, information from 

poison control centers, reports to the 

agency, newspaper and magazine 

articles, and surveys of users. The 

literature review was conducted using 

Medline, Healthstar, Aidsline, Cancerlit, 

and OldMedline (Ref. E9). We found 

evidence of many adverse events 

associated with dietary supplements. 

For example, in 2003, the American 

Association of Poison Control Centers 

received 24,412 reports on events 

associated with herbal dietary 

supplements and 57,801 reports on 

events associated with vitamin and 

mineral supplements, with 8,653 of the 

herbal and 5,669 or the vitamin and 

mineral reports treated in health care 

facilities (Ref. E10). In addition, we have 

received many voluntary reports of 

illnesses caused by dietary supplements 

(Ref. E11).14

The vast majority of these events and 

those described in other sources we 

consulted, however, are reported as 

associated with the ingredients used in 

the products themselves, not with 

contamination or other results of poor 

manufacturing processes. Most of the 

reports from poison control centers on 

vitamins and minerals, for example, 

involved inappropriate ingestion by 

children (Ref. E10). We have no direct 

evidence on how many illnesses can be 

attributed to manufacturing processes. 

The anecdotal evidence described 

elsewhere in the preamble suggests that 

many illnesses could have been caused 

by poor manufacturing processes, but 

there are only a few examples of 

evidence that explicitly link illnesses to 

manufacturing processes. Examples of 

illness that were linked directly to poor 

manufacturing practices include 

vitamin D toxicity from excessive 

vitamin D in multivitamins and cardiac 

glycoside poisoning from botanical 

dietary supplements contaminated with 

Digitalis lanata (Ref. E12). 

With no direct evidence on the 

number of illnesses caused by poor 

manufacturing practices, we had to use 

an indirect approach. We based the 

approach on our recall records. Class 1 

and class 2 recalls all involve defective 

products that could have caused illness 

if ingested. Although the recall data 

cannot be linked directly to illness data, 

we have found anecdotes, surveys, and 

some medical literature on illnesses that 

could be caused by avoidable dietary 

supplement manufacturing mistakes. 

We have recall data that show that 

manufacturing mistakes exist, so we can 

construct a plausible link between 

manufacturing mistakes and potential 

illnesses or injuries. The number of 

illnesses associated with a 

manufacturing problem leading to a 

recall is both variable and uncertain, 

and could be anything from zero to 

quite large. Based on data from FDA 

food and dietary supplement recalls, we 

concluded that one reported illness per 

recall is a plausible average, so we 

assumed that a recall could be a proxy 

for a single reported illness associated 

with a defective product. 


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34922 Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 

15Mandatory reporting to FDA of serious adverse 

events is now required as a result of the enactment 

of the ‘‘Dietary Supplement and Non-Prescription Drug Consumer Protection Act’’ (Public Law 109–

462), signed into law on December 22, 2006. 

Because there are no active 

surveillance systems for identifying 

adverse health events related to dietary 

supplements, we assume that the total 

number of illnesses caused by poor 

manufacturing practices is substantially 

greater than the number reported.15

Based on data for drug and vaccine 

reporting rates in other studies, one 

study concluded that for dietary 

supplements, reported illnesses 

represent approximately 1 percent of 

total illnesses (Ref. E13). We use the 

associated multiplier, 100, in our 

baseline estimate and assume that 

reporting adverse health events due to 

poorly manufactured dietary 

supplements occurs at the same rate as 

reporting adverse health events caused 

for other reasons by dietary 

supplements. Other reporting rates and 

associated multipliers are, however, 

plausible. For some hazards that lead to 

severe events only, we have used a 

multiplier of 10; the Centers for Disease 

Control and Prevention have used a 

multiplier of 38 for Salmonella 

infections and similar food-related 

illnesses. We show the sensitivity of 

benefits to the choice of multiplier 

below. 

From 1990 through 1999, we received 

reports on an annual average of 11.8 

class 1 and class 2 recalls of dietary 

supplements related to manufacturing 

problems. If we assume that each recall 

is a proxy for a reported illness, then the 

total number of illnesses per year is 

approximately 1,180. We recognize that 

our procedure generated uncertain 

estimates of the number of illnesses. 

With a multiplier of 10, the estimated 

number of illnesses per year is 118; with 

a multiplier of 40, the total number of 

illnesses per year is 472. 

We estimate that the monetary value 

of the health losses for the hazards 

listed in table 23 of this document as a 

weighted average of the values attached 

to the different health outcomes 

associated with each hazard. We 

estimate the health losses or fatal cases 

as the monetary value of a statistical 

life, defined as the willingness to pay 

for a small change in the probability of 

death. We estimate the health losses for 

non-fatal illnesses as the sum of: (1) The 

imputed value of lost productivity, (2) 

the imputed value of pain and suffering, 

and (3) actual expenditures on medical 

treatment. We measured lost 

productivity (defined to include 

household and market productivity) 

indirectly with measures of functional 

state, which includes measures of 

physical function. We estimated the 

losses caused by pain and suffering with 

a symptom-problem index. We combine 

the functional losses with the pain and 

suffering into a single index of lost 

quality-adjusted life years (measured by 

the Quality of Well-Being Index). We 

then convert the quality-adjusted life 

years to dollars by multiplying the 

index numbers by the dollar value of a 

quality-adjusted life year. We used 

direct measures of medical costs, such 

as payments to physicians and 

hospitals. We obtained data on the cost 

of a hospital day and other medical 

costs from the Health Care Cost and 

Utilization Project’s Nationwide 

Inpatient Sample, administered by the 

HHS Agency for Healthcare Research 

and Quality (Ref. E14). 

Table 23 of this document contains 

summaries of our measures of the health 

costs potentially caused by known 

instances of hazards associated with 

poor dietary supplement manufacturing 

processes for the decade 1990 through 

1999. We estimated the health loss per 

day for the different levels of illness 

severity by summing the lost 

productivity (as measured by functional 

state) and the loss from pain and 

suffering (as measured by the symptomproblem index). These losses per day 

can be interpreted as the difference 

between a day of normal health and a 

day of suffering from the health 

conditions caused by these defective 

products. The numerical scale is a 

relative baseline that rests on the notion 

of a quality-adjusted life day (QALD). 

The QALD for a day of normal health 

equals 1; the QALD for death equals 0. 

The loss of QALDs per illness equals the 

daily loss multiplied by the number of 

days the illness lasts. We converted 

QALDs to dollars by multiplying the 

index numbers by the dollar value of a 

QALD. We computed the monetary 

value of a QALD using three values 

derived from three different values for a 

quality-adjusted life year: $100,000, 

$300,000, and $500,000. These yield 

values per day of $274, $822, and 

$1,370. Our base measures use $822; we 

show the effects of using other values in 

the sensitivity analysis. 

TABLE 23.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990 

AND 1999 

Recall Class Number of 

Recalls 

Expected Value 

of Illness 

Expected Value of Illness Times 

Number of Recalls 

Chemical 

Copper salts 2 1 $489 $489 

Digitalis 1 33 $37,442 $1,235,599 

Ephedra 1 1 $177,237 $177,237 

Hypervitaminosis A 1 2 $1,264 $2,528 

Hypervitaminosis D 2 1 $1,366 $1,366 

Lead poisoning (class 1) 1 1 $15,591 $15,591 

Lead poisoning (class 2) 2 40 $10,436 $417,451 

Niacin 2 2 $5,802 $11,603 

Pyridoxine (Vitamin B6) 2 1 $12,085 $12,085 


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Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 34923 

TABLE 23.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990 

AND 1999—Continued 

Recall Class Number of 

Recalls 

Expected Value 

of Illness 

Expected Value of Illness Times 

Number of Recalls 

Selenium poisoning (class 1) 1 1 $755,338 $755,338 

Selenium poisoning (class 2) 2 6 $1,288 $7,731 

Stannous fluoride 1 1 $1,266 $1,266 

Superpotent zinc 2 1 $389 $389 

Biological 

Botulism (class 1) 1 1 $494,683 $494,683 

Botulism (class 2) 2 1 $2,044 $2,044 

Klebsiella Pneumonia 1 1 $774,178 $774,178 

Salmonella (class 1) 1 4 $15,298 $61,191 

Salmonella (class 2) 2 4 $778 $3,110 

Allergenic 

Lactose intolerance 2 1 $396 $396 

Undeclared sulfites 1 1 $723 $723 

Yellow #5 sensitivity 2 5 $723 $3,616 

Yellow #6, red #40, blue #2 2 1 $1,595 $1,595 

Physical 

Glass fragments 2 1 $4,241 $4,241 

Other 

L-tryptophan (Eosinophilia-Myalgia Syndrome 

(EMS)) 1 7 $1,135 $7,946 

Total 118 $3,992,397 

The hazards that occurred between 

1990 and 1999 are not necessarily the 

same hazards that would occur today. 

For example, botulism is rare and may 

no longer be a hazard associated with 

dietary supplements, but recalls 

involving botulism represent generic 

examples of adulteration that could 

occur with other substances in the 

absence of good manufacturing 

practices. Also, we base our cost 

estimates on information from 1999, so 

it is appropriate to estimate benefits 

from the same time. 

(Comment 340) We received a 

comment that took issue with the way 

the recalls are counted. The comment 

asserts it is more appropriate to count 

each recall action as a separate recall, 

regardless of the number of different 

products affected. 

The same comment criticizes the 

inclusion of the outbreak of 

Eosinophilia-Myalgia Syndrome (EMS) 

in the table of what is characterized as 

‘‘ordinary’’ recalls, since this case is 

analyzed separately as an example of a 

‘‘rare catastrophic event.’’ The comment 

states that the outbreak of Digitalis 

should also have not been included in 

the recall list because it also was a rare 

event. The comment asserts that FDA 

announcements and media attention 

should have led to full reporting of any 

adverse events. 

Other comments generally refer to risk 

associated with dietary supplements. 

One comment states that botanical 

supplements pose minimal risk if 

dispensed directly to a patient rather 

than used in an unsupervised setting, 

and that toxicology and adverse event 

reports indicate that end-of-process 

adulteration in herbal clinics is rare. By 

contrast, another comment states that 

adverse events related to dietary 

supplement use led to hospital 

admissions at one location and that 

reports of misbranded and adulterated 

dietary supplements are common. 

(Response) We are not changing the 

way we count recalls. Each different 

recall will continue to be counted as a 

separate recall. How recalls are counted, 

however, does not affect the analysis. 

The method used in this analysis 

corresponds to an average of about one 

reported illness per recall action. A 

particular event can lead to many recall 

actions. If we changed the way we 

counted recalls so as to reduce the 

number of baseline recalls to correspond 

to events, the average reported illnesses 

per recall would rise in proportion. The 

estimated benefits would not change. 

We are no longer including the 

outbreak of EMS in our analysis of 

benefits. The product recalls associated 

with EMS occurred several years after 

the outbreak that we are now excluding. 

The continued benefit associated with 

preventing EMS is associated with 


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34924 Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 

incorporating quality controls aimed at 

such hazards. 

6. Benefits 

The benefits of this final rule come 

from ensuring the quality of dietary 

supplements. Dietary supplements 

should contain the listed ingredients in 

the listed amounts in product forms that 

disintegrate and dissolve. Dietary 

supplements should not contain any 

contaminants that would adulterate the 

product under section 402(a)(1), (a)(2), 

(a)(3), or (a)(4) of the act. 

Estimating the benefits of preventing 

adulteration and contamination is 

straightforward, at least in theory. These 

benefits are the value of reducing the 

risk of the acute illnesses and longerterm complications associated with 

physical, chemical, and microbiological 

contamination (see table 23 of this 

document). The direct value of 

preventing recalls is another source of 

benefits from preventing adulteration 

and contamination. We estimate the 

benefits of preventing adulteration and 

contamination by first estimating (based 

on recall data) the number and kinds of 

illnesses prevented, and then placing a 

value on preventing those illnesses. We 

include the recall costs avoided by 

industry as additional benefits of 

preventing adulteration and 

contamination. 

Estimating the value of ensuring the 

quality of the dietary supplements and 

that they are manufactured according to 

their specifications is difficult in 

practice because we lack the necessary 

data on what is missing and how what 

is missing affects public health. Some 

dietary supplements have authorized 

health claim labeling that allows them 

to state their products may reduce the 

risk of chronic illnesses or conditions. 

Ensuring that those supplements are 

manufactured consistently according to 

the appropriate specifications will 

increase their effectiveness in reducing 

the risk of chronic illnesses. In this 

analysis, we describe those benefits but 

are not able to quantify them. 

The benefits from the final rule, then, 

will be: 

• Reduced health costs associated 

with a reduced number of acute 

illnesses (quantified), 

• Fewer product recalls (quantified), 

and 

• Reduced health costs associated 

with a reduced number of chronic 

illnesses and conditions (not 

quantified). 

This final rule could also enhance the 

benefits of the ‘‘Dietary Supplement and 

Non-Prescription Drug Consumer 

Protection Act’’ (Public Law 109–462), 

which requires mandatory reporting to 

FDA of serious adverse events. This 

final rule includes requirements that 

will provide the information needed to 

quickly and accurately conduct a 

sufficient traceback in the case of an 

adverse event. This enhanced ability to 

track information related to serious 

adverse events will increase both the 

accuracy and the speed of the response 

to such events, which may in many 

cases reduce the number of illnesses or 

deaths associated with unsafe dietary 

supplements. 

(Comment 341) We received many 

comments on the estimated benefits. 

Although we did receive comments that 

stated the rule would benefit consumers 

by enhancing public confidence in 

dietary supplements, many comments 

state that the estimated benefits in the 

2003 CGMP Proposal were overstated. 

In addition, one comment states that our 

estimates of benefits are double 

counted, because the outbreak of EMS 

was included in the measure of benefits 

from preventing a large catastrophic 

event as well as total benefits of 

reduction of illnesses measured by 

recalls. Furthermore, comments critical 

of the benefits state the search cost 

model used in the analysis is not 

applicable or the benefits of reduced 

search costs do not exist, we lack 

evidence with which to base the 

estimate of reduced health care costs 

from elimination of rare catastrophic 

events, and recalls will not fall to zero 

as a result of implementing CGMPs. 

(Response) We agree with the 

comment that benefits were overstated 

because of the inclusion of the outbreak 

of EMS. We no longer include the value 

of preventing that or similar outbreaks 

in our estimate of benefits. Although we 

do not agree with the comments on the 

applicability of the search model as a 

measure of benefits, the empirical 

difficulties associated with quantifying 

those benefits have led us to replace the 

search model with a qualitative 

description. 

We now explain each of the three 

sources of benefits: Reduced acute 

illnesses, fewer recalls, and reduced 

chronic illnesses and conditions. 

a. Reduced health costs associated 

with a reduced number of acute 

illnesses. The final rule will help ensure 

the quality of dietary supplements, 

which will lead to improved safety of 

dietary supplements, reducing the 

probability of acute illness or deaths 

caused by manufacturing problems. We 

estimated the reduction of acute 

illnesses by using our recall records as 

evidence of possible illnesses; class 1 

and class 2 recalls of dietary 

supplements all involved adulterated 

products that could have caused illness 

if ingested. In the 2003 CGMP Proposal, 

we estimated the reduction of illnesses 

from preventing catastrophic events by 

using the public health effects of the 

outbreak of EMS that resulted from 

consumption of contaminated Ltryptophan. We agree with comments 

questioning the applicability of this 

outbreak to CGMP, so we are no longer 

including the value of preventing this 

outbreak as a benefit of this rule. 

We estimated the annual expected 

health benefits for acute illnesses 

prevented by taking the values of 

preventing particular illnesses and 

weighing them by their likely incidence 

as indicated by recall data. The acute 

illnesses prevented that we use to 

estimate benefits are not actual 

illnesses, but statistical illnesses 

(defined as the probability of illness 

multiplied by the population at risk) 

prevented by the reduction in risk 

associated with this final rule. These 

recalls indicate recurring failures to 

ensure the quality of dietary 

supplements. Although each class 1 and 

2 recall is estimated to have resulted in 

some illnesses (which may have 

triggered the recall), there may also be 

other manufacturing problems that did 

not lead to recalls but that did lead to 

illness. Both situations are part of the 

baseline number of illnesses and deaths 

estimated. 

We computed the expected health 

benefits from preventing a single illness 

(of any type) associated with a recall as 

a weighted average of all potential 

illnesses. We then calculated the 

average health benefits of preventing a 

single illness associated with a non-fatal 

class 1 or a class 2 recall as: 

Health costs prevented = (QALY x value 

per QALY) + medical costs 

We define QALY as the average qualityadjusted life year per illness; as 

explained earlier, we computed the 

average by weighting the quality 

adjusted life years lost for the 

probability of each health outcome by 

the expected frequency of that outcome. 

To estimate the number of acute 

illnesses prevented, we started with the 

average number of recalls per year for 

the decade 1990 through 1999. The 

yearly averages for the decade were six 

class 1 recalls and seven class 2 recalls. 

As discussed previously, we then 

assumed that these recalls represented 

about 1 percent of all acute illnesses 

caused by the manufacturing problems 

leading to the recalls. With that 

assumption, we estimated that the 

recalls represented about 530 acute 

illnesses from class 1 recalls and 650 


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16In the uncertainty analysis in section XXIV.B.11 

of this document, we used a probability distribution 

to represent the uncertainty associated with the 

number of illnesses. We modeled the number of 

illnesses prevented for each class as the average 

number of recalled products plus a negative 

binomial distribution representing unknown cases. 

The negative binomial distribution estimates the 

number of failures (unknown cases) that will occur 

before some number of successes (known cases) for 

a given probability of success. In the negative 

binomial distribution, we assumed that the 

numbers of recalls represented reported cases and 

that the probability of reporting equaled 1 percent 

(Ref. E13). The mean estimated number of illnesses 

is 100 times the reported number of recalls. 

acute illnesses from class 2 recalls.16

The illnesses used to estimate the 

benefits of the final rule represent a 

sample of acute illnesses that could 

occur without this final rule. We assume 

that the benefits computed for the 

average year from the decade 1990 

through 1999 represent the annual 

average benefits we should expect in the 

future. We do not assume that the acute 

illnesses prevented in the future will be 

identical to those that occurred during 

1990 through 1999. 

TABLE 24.—HEALTH BENEFITS ESTIMATED USING RECALL DATA

FROM 1990 THROUGH 1999 

Estimated annual number 

of acute illnesses prevented (530 class 1 and 

650 class 2 recalls) 

1,180 

Dollar estimate of average 

health benefit for preventing an acute illness 

associated with a class 

1 or class 2 recall 

$33,800 

Estimated dollar estimate 

of annual health benefits 

$40 million 

The estimated benefits are indeed 

sensitive to the choice of years. For 2000 

through 2005, there were 75 recalls: 29 

class 1, 25 class 2, and 21 class 3. The 

annual averages for 2000 through 2005 

are therefore 4.8 class 1, 4.2 class 2, and 

3.5 class 3 recalls. We estimate that 

about 80 percent of the class 1 and class 

2 recalls were related to manufacturing 

problems (for 1990 through 1999 over 

95 percent of class 1 and class 2 recalls 

stemmed from manufacturing 

problems). With an average of 9 class 1 

and class 2 recalls per year, our baseline 

estimate of total associated illnesses 

using 2000 through 2005 data is 900 (9 

x 100). If this final rule prevents 80 

percent of these events, then 720 

illnesses will be prevented. We do not 

use this estimate to calculate baseline 

benefits for this final rule because we do 

not have a comparably recent estimate 

of costs. If the reduced number of recalls 

reflects increased controls in the 

industry, then the benefits and costs of 

this final rule will be lower than what 

we have estimated. 

(Comment 342) We received 

comments critical of the estimates of 

reduced illness due to recalls. One 

comment points out that drugs, despite 

having stringent CGMP requirements, 

have a higher rate of recalls than dietary 

supplements, thus providing evidence 

that such requirements do not 

necessarily reduce recalls. Expanding 

on this thought, other comments state 

that we seem to assume that new CGMP 

requirements will reduce human error 

to zero and no more recalls will occur, 

which is said to be unrealistic. 

Other comments express concern 

about the 100-fold multiplier used to 

estimate the costs related to recallassociated illnesses. The comment states 

that we, besides referencing Walker 

(2000) (Ref. E13 of this document (Ref. 

E16 in the 2003 CGMP Proposal)), 

provided no other information to 

substantiate the use of the 100-fold 

multiplier and therefore are being 

arbitrary. Any other number could be as 

accurate. In addition, other comments 

state that it is difficult to believe that the 

multiplier would be applicable to 

recalls associated with Klebsiella 

pneumonia and selenium poisoning, 

and L-tryptophan, because the severity 

of the illnesses would certainly have 

been associated with the highly 

publicized recalls; that is, they would 

not have gone unreported. 

Some comments present recalculated 

benefits. One comment estimates 

benefits from fewer illnesses as a result 

of the 2003 CGMP Proposal to be $10.9 

million, rather than our estimate in the 

analysis of the 2003 CGMP Proposal of 

$39 million. This new estimate was 

arrived at by taking into account what 

was characterized as double-counted 

benefits which, as mentioned earlier, 

were characterized as the inclusion of 

EMS in the measure of benefits from 

preventing a large catastrophic event as 

well as total benefits of reduction of 

illnesses measured by recalls. Another 

comment re-estimates the benefits as 

$16 million. This estimate was 

calculated assuming 100 percent of 

potential illnesses related to Klebsiella 

pneumonia were classified as severe 

(with none classified as deaths), and 50 

percent of illnesses associated with the 

selenium recall were classified as 

serious and none were classified as 

deaths. This comment also disagrees 

with the assumption that 3 percent of 

the 100 potentially ill from the recall 

associated with undeclared ephedra 

would have died. Furthermore, this 

comment adjusts the benefits to take 

into account recalls that this comment 

felt were erroneously included in the 

calculation of benefits from reduced 

illnesses. 

(Response) We have not seen any new 

data or other information that would 

lead us to change the 100-fold 

multiplier for our basic estimate. We 

recognize that the multiplier is 

uncertain; different multipliers lead to 

different estimated numbers of illnesses 

and different estimated benefits. With a 

multiplier of 10, estimated benefits are 

10 percent of our baseline; with a 

multiplier of 40, estimated benefits are 

40 percent of our baseline. The 

estimated benefits of this final rule, 

thus, move in proportion to the assumed 

multiplier. We recognize this 

uncertainty and show how it affects the 

estimated benefits in the sensitivity 

analysis. The multiplier implicitly 

assumes that the more severe illnesses 

are more likely to be reported; the 

average reporting rate for all adverse 

events is assumed to be about 1 percent. 

The average incorporates higher 

reporting rates for more severe illnesses, 

and lower reporting rates for less severe 

illnesses. 

The comments on the severity weights 

for Klebsiella pneumonia and ephedra 

did not persuade us to change these 

estimates. We based the estimates on the 

outcomes for severe events associated 

with these hazards. The Klebsiella 

weights come from the medical 

literature (Ref. E9); the ephedra weights 

are based on adverse events involving 

ephedrine alkaloids. 

The comparison of drug recalls to 

dietary supplement recalls does not 

provide data that would cause us to 

change our analysis. The drug industry 

is far larger than the dietary supplement 

industry and any such comparison 

would have to account for that 

difference as well as other differences. 

Expenditures on prescription drugs 

exceeded $200 billion in 2004. 

(Comment 343) We received many 

comments regarding the use of the 

outbreak of EMS in 1989 as a basis for 

estimating health benefits from 

preventing a catastrophic event. The 

majority of the comments assert that 

CGMPs would not have prevented the 

outbreak. One comment expands this 

assertion by stating our claim that 

testing requirements would reduce the 

probability that contaminated 

ingredients would be released to the 

public is incorrect, because it was not 

known what, if any, contaminants 

caused the outbreak. Secondly, the 

comment states that our claim that 

complaint files would allow for fast 

identification of an adverse health event 

is also incorrect because the victims of 


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34926 Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 

17We recognize, however, that the presence of Ltrypotophan only indicates a small probability of 

EMS. The estimates in table 23 of this document assume that L-trypotophan represents a 0.1 percent 

probability of EMS. 

EMS did not know the L-tryptophan 

was the cause of their illnesses. 

Two other comments question the 

periodicity for a cycle of potential 

catastrophic events due to dietary 

supplements. One comment suggests a 

period of 70 years rather than our 30 

years. The other comment does not 

suggest a period but rather states that, 

since we have no data to support the 

cycle of 30 years, and we admit it is 

difficult to know how likely rare events 

are, it is possible that the total projected 

benefit could be zero. 

Lastly, other comments state that the 

benefits from preventing a rare 

catastrophic event are double-counted. 

These comments state these benefits are 

double-counted because they are also 

included in the estimation of benefits 

from reduced recalls. 

(Response) As stated previously, we 

are no longer including estimated 

benefits from preventing a rare 

catastrophic event in the analysis of 

benefits. We continue to include the 

benefits of preventing statistical cases of 

EMS in the annual health benefits, 

because several recalls of L-tryptophan, 

which could be associated with EMS 

took place during the 1990 through 1999 

period.17

b. Fewer products recalled. 

Implementation of the final rule will 

reduce the number of adulterated 

products distributed to the public, 

which will reduce the number of 

products recalled. Process controls and 

better recordkeeping will increase the 

ability of establishments to produce 

dietary supplements according to 

specifications and to identify problems 

before distribution. If adulterated 

products are caught before they are 

distributed or earlier in the production 

process, they will not need to be 

recalled. 

To estimate the direct benefits from 

fewer recalled adulterated dietary 

supplements, we estimate the number of 

annual recalls of dietary supplements 

that would be prevented by adherence 

to CGMP requirements in the final rule. 

From 1990 to 1999, FDA received 

reports on 195 recalls related to 

manufacturing problems, an average of 

19.5 recalls per year (Ref. E9). The 

average figure reported here includes 

class 3 recalls. The number of units of 

dietary supplements for each recalled 

product varied, so we used a 

distribution per recall of 1,000 units to 

34,000 units (Ref. E9). Product price 

(updated to 2004) also varies, with most 

prices falling between $6 per unit and 

$11 per unit; we used a most likely 

price of $8.50 per unit. We include an 

adjustment for the goodwill lost by the 

establishment as a result of the recall. 

We multiply the direct cost of the recall 

by two in order to include the lost 

goodwill. We also adjust for recalls that 

would likely not be prevented by the 

final rule. The result is an estimated 

savings of $1.8 million in direct costs 

and $1.8 million in goodwill, for a total 

savings of about $3.6 million per year. 

(Comment 344) We received several 

comments on our estimates of the 

reduction in recalls. As noted 

previously, a comment generally states 

that drugs, despite having stringent 

CGMP requirements, have a higher rate 

of recalls than dietary supplements, 

thus providing evidence that CGMPs do 

not necessarily reduce recalls. Again, 

other comments state that we seem to 

hold the unrealistic assumption that the 

final rule will reduce human error to 

zero and no more recalls will occur. 

Another comment points out that the 

assumption that the final rule would 

cause the discovery of all adulteration is 

inconsistent with the requirement that 

firms keep complaint files. If the rule 

eliminates adulteration, the comment 

states, then there should be no 

complaints to report. 

(Response) We do not believe that 

recalls will fall to zero. We assume that 

the recalls identified as being 

preventable by this final rule will fall to 

zero, but that mistakes and other 

hazards will continue to generate 

recalls. In the sensitivity analysis, 

however, we show the effects of a lower 

level of effectiveness in preventing 

recalls associated with manufacturing 

problems. 

c. Reduced health costs associated 

with a reduced number of chronic 

illnesses and conditions. We cannot 

quantify the value of ensuring that 

dietary supplements contain everything 

in the established specifications (and 

nothing that is not in the specifications) 

because we lack the necessary data on 

what is missing and how what is 

missing affects public health. The 

public health benefits are derived from 

the reduced number of chronic illnesses 

and conditions. These benefits may 

arise from known nutritional effects or 

from uncertain nutritional effects. 

d. Benefits from known nutritional 

effects. Many of the nutritional benefits 

of vitamins and minerals are known and 

well-documented. For example, the 

Dietary Guidelines for Americans, 2005 

states that dietary supplements can be 

used to help meet the recommended 

intakes of vitamin B12, folic acid, and 

vitamin D (Ref. E15). The Institute of 

Medicine’s Dietary Reference Intakes 

include statements that supplements 

can be sources of several vitamins and 

minerals (Ref. E16). We have recognized 

the use of supplements in authorized 

health claims for calcium and 

osteoporosis (§ 101.72) and folic acid 

and neural tube defects (§ 101.79). 

In table 25 of this document, we list 

some of the health benefits associated 

with the consumption of various dietary 

supplements. 

TABLE 25. SELECTED HEALTH BENEFITS FROM CERTAIN DIETARY SUPPLEMENTS

Dietary Supplement User Benefit 

Folic acid Women of child-bearing age Reduces the risk of neural tube defects 

Calcium Children and adults Reduces the risk of osteoporosis 

Iron Adolescent females and women of child-bearing age Reduces the risk of anemia 

Vitamin D Children and adults; persons with dark skin, or with too little 

exposure to sunlight 

Reduces the risk of osteoporosis 

Vitamin B12 Persons over the age of 50 Reduces the risk of anemia 


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e. Benefits from uncertain nutritional 

effects. We do not know the full range 

of effects (or lack of effects) of most 

dietary supplements. Vitamins and 

minerals with known nutritional effects 

in supplement form may have other 

effects that we have yet to discover. Our 

uncertainty is particularly large with 

respect to the nutritional effects of 

herbal and botanical supplements. The 

evidence is still too mixed and 

incomplete to determine the effects of 

most of these substances. If, however, 

herbal dietary supplements do indeed 

have significant beneficial effects on the 

risk of chronic illnesses and conditions, 

then if the final rule ensures that the 

supplements consistently meet their 

specifications, we should add those 

benefits to those from supplements 

having known nutritional effects. 

The benefits of this final rule that we 

can identify are those associated with 

the known effects. The product 

deficiency might be, for example, that 

packages contain some percentage less 

or more of the necessary ingredient 

(such as calcium) than what is listed on 

the label. The relationship between the 

shortage or excess amount of the 

ingredient and the probability of 

chronic illness would also have to be 

taken into account in order to determine 

the risk associated with the product 

deficiencies. The increase in the 

probability of chronic illnesses may be 

negligible, less than, the same, or more 

than the shortage or excess in the 

amount of the ingredient. The increase 

in the probability of chronic illness 

would also depend on how long the 

supplement contained a shortage or 

excess amount of the ingredient. 

Suppose, for example, that a calcium 

supplement contains 10 percent less 

calcium than it should for 1 year. If the 

average consumer takes calcium 

supplements for 20 years, would the 1- 

year deficiency of 10 percent increase 

the probability of osteoporosis by more 

or less than 0.5 percent (10 percent x (1/ 

20))? 

If we could determine the change in 

the number of chronic illnesses 

prevented by dietary supplements as a 

result of this final rule, we could 

estimate benefits by multiplying the 

additional number of chronic illnesses 

prevented by the value of preventing 

those illnesses. The values consumers 

place on preventing illness differ across 

illnesses and across consumers, and are 

related to the reasons they use dietary 

supplements. We will illustrate the 

method with two examples: Calcium 

and osteoporosis and folic acid and 

neural tube defects. 

Calcium and osteoporosis. Many 

consumers take calcium supplements to 

reduce the probability of osteoporosis, 

which afflicts as many as 10 million 

people over age 50 (about 8 million 

women and 2 million men). An 

additional 34 million men and women 

may be at risk for developing 

osteoporosis (Ref. E17). If ensuring that 

calcium supplements contain what they 

should reduces the risk of osteoporosis, 

the total osteoporosis health benefits 

associated with the final rule will be the 

number of cases prevented multiplied 

by the health costs per case. We 

estimated the health costs per case as 

the sum of the direct medical costs, the 

value of functional disability, and the 

value of the pain and suffering 

associated with the illness. Cases range 

in severity from mild to severe. A mild 

case, for example, might lead to a loss 

of utility (measured as quality-adjusted 

life years—a year of life adjusted for the 

individual’s health status) of 0.14 per 

year for 9 years. If we apply a discount 

rate of 7 percent to the years the 

condition lasts, the loss of qualityadjusted life years is about 0.9 (6.5 

discounted years x 0.14 lost utility per 

year). In other rulemakings we have 

used a range of values for a qualityadjusted life year; the range has been 

from $100,000 to $500,000, with a 

medium monetary value of $300,000 (68 

FR 41434, July 11, 2003). With a value 

per year of $300,000, the value of 

preventing a mild case is about 

$270,000 (0.9 x $300,000). 

A severe case, by contrast, can lead to 

fractures and permanent disability. 

Also, osteoporosis in women can occur 

at early ages and last decades. If 

someone suffers from osteoporosis for 

30 years, the discounted quality 

adjusted life years lost would be 6.9 

(12.4 discounted years x 0.56 lost utility 

per year). We estimate that medical 

costs for a severe case can be over 

$17,000. The value of preventing a 

severe, long-lasting case is therefore 

about $2.1 million ((6.9 x $300,000) + 

$17,000). 

Folic acid and neural tube defects. 

Many women of child-bearing age take 

dietary supplements to help ensure their 

own health, and the health of their 

children should they become pregnant. 

For example, 40 percent of women aged 

18 to 45 take supplements containing 

folic acid, which may reduce the 

probability that children will be borne 

with neural tube defects (Ref. E18). 

Neural tube defects affect the spine 

(spina bifida) and the brain 

(anencephaly). About 3,000 pregnancies 

are affected each year (Ref. E18). 

The benefit of ensuring that folic acid 

supplements contain what they should 

equals the population at risk multiplied 

by the reduction in the probability of 

neural tube defects, multiplied by the 

value of preventing a neural tube defect. 

Neural tube defects involve large 

medical expenses, and either early 

death or permanent disability. The 

lifetime medical costs alone are between 

$400,000 and $500,000 for spina bifida 

(Ref. E19, with values updated). In 

recent rulemakings, we have used $5 

million as the value of a statistical life, 

defined as the willingness to pay for 

reductions in small risks of premature 

death. Preventing a statistical death 

from anencephaly would therefore 

generate benefits of $5 million to $6.5 

million. For spina bifida, one estimate is 

that an average case leads to a loss of 

more than 15 quality-adjusted life years, 

for a monetized loss of close to $5 

million for a non-fatal case if valued at 

$300,000 per quality adjusted life year 

(Ref. E20). The value of preventing a 

case of spina bifida, then, is the sum of 

medical costs and the value of a saving 

the quality-adjusted life years, or about 

$5 million ($450 million value of 

quality adjusted life years + $500,000 

direct medical costs). 

Estimating the total benefits of this 

final rule requires estimates of the 

numbers of chronic illnesses and 

conditions whose incidence can be 

further reduced by ensuring that dietary 

supplements contain what they should. 

Because we have no information on the 

baseline number of chronic illnesses 

caused by deficient or excessive 

ingredients, or on the change in the 

likelihood of chronic illness that will 

occur as a result of the provisions of this 

final rule, we cannot estimate the full 

benefits of ensuring that dietary 

supplements contain what they should. 

Our quantified benefits for this final 

rule must therefore consist entirely of 

the benefits from reducing the risks of 

acute illnesses and reducing the number 

of product recalls. The total benefits 

will be larger by an amount we are not 

able to quantify. 

(Comment 345) We received many 

comments about the estimated benefits 

as measured by the value of 

hypothetical search time. 

(Response) We are no longer using the 

search model. 

f. Total benefits. The total benefits 

from the final rule are the sum of the 

value of health benefits from fewer 

acute illnesses, the value of fewer 

product recalls, and the value of the 

health benefits from fewer chronic 

illnesses. Table 26 of this document 

shows the total benefits. 

(Comment 346) One comment states 

that our total estimated benefits could 

be as little as $21 million. 

(Response) Our current estimate of 

total quantified benefits is $44 million 


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per year, once the final rule takes full 

effect. In addition, as discussed 

previously, there are benefits to this rule 

that have not been quantified. The 

unqualified benefits estimate is the 

mean of a range of estimates based on 

assumptions about reporting rates and 

the effectiveness of the final rule. 

In the analysis of benefits for this rule 

there are two large uncertainties: 

Quantified underreporting of acute 

illnesses and injuries and nonquantified 

benefits associated with chronic 

illnesses. Despite the best efforts by 

public health authorities, there will 

always be underreporting of illness and 

injuries. Where fatalities are concerned, 

unless there are litigation problems or 

the potential for the spread of infectious 

disease, there is no incentive to do 

extensive forensic work to determine 

whether a fatality is related to the 

ingestion of a dietary supplement. This 

leads to reporting most fatalities under 

the most general International 

Classification of Diseases codes. We 

acknowledge the large uncertainties in 

our estimate because of these factors. 

The degree of prevention of chronic 

illnesses due to preventing super- or 

subpotent dietary supplements depends 

on two factors, both of which are highly 

uncertain. The first factor concerns 

product benefit: How many dietary 

supplements have any beneficial effect 

on chronic illnesses and how strong are 

those effects? Recent work in this area 

so far has examined only a few dietary 

supplements, with mixed results. Of 

course, ensuring the potency of an 

ingredient that has adverse effects or has 

adverse interactions with drugs would 

subtract from the benefits. The second 

factor is the incidence and effects of 

subpotency and superpotency across 

products and over time: How much of 

a difference in the product need there be 

to generate a substantial adverse health 

effect? Because of these uncertainties, it 

is virtually impossible to make any sort 

of quantitative statement about likely 

effects of a regulation ensuring against 

superpotency and subpotency. 

Because of the uncertainties in 

estimating the benefits associated with 

both chronic and acute illnesses 

associated with manufacturing practices 

for dietary supplements, the decision to 

implement regulatory requirements 

becomes an exercise in weighing 

quantitative and qualitative benefits to 

public health against expenditure of 

scarce resources. By choosing to go 

forward with this rule, FDA is 

exercising precaution with respect to 

uncertain risks. 

In the uncertainty and sensitivity 

analyses in section XXIV.B.11 of this 

document, we show how uncertainty 

and different assumptions generate 

higher or lower quantifiable benefits. 

Using plausible assumptions about the 

uncertain variables, we estimate that 

total quantified benefits (using 1990 

through 1999 data) most likely fall 

within a range of $8 million to $64 

million per year. 

TABLE 26.—SUMMARY OF ANNUAL

BENEFITS

Benefits Mean 

Fewer acute illnesses $40 million 

Fewer product recalls $4 million 

Fewer chronic illnesses Not quantified 

Total quantified benefits $44 million 

7. Costs 

The same changes in manufacturing 

practices that produce benefits also have 

opportunity costs. Due to the increased 

expenditures of complying with this 

final rule, firms may spend fewer 

resources on potentially costly activities 

such as worker safety, product 

development and marketing, or 

voluntary testing of the efficacy of their 

products. The final rule will require 

dietary supplement establishments to 

adopt some new practices in order to 

manufacture, package, label, or hold 

their products in compliance with 

CGMP requirements. In some cases, 

establishments will make capital 

improvements to the physical plant, add 

or replace equipment or controls, 

perform additional maintenance, 

establish written procedures, keep 

records, carry out tests, monitor 

production and process controls, or 

execute a variety of additional tasks that 

they may not have previously 

performed. Not all firms will comply; 

some will go out of business or move 

their plants to other countries and not 

sell their product in the United States. 

We estimated the additional costs of 

production associated with the final 

rule and the leading regulatory options 

using the survey to estimate baseline 

manufacturing practices (Ref. E2). 

a. Description of the costs. To estimate 

costs for the dietary supplement 

industry, we initially divided the 

industry into four product categories 

and three size categories. Because the 

survey showed that there were only a 

few establishments in some categories, 

we consolidated the size and product 

into three size categories. The size 

categories were: 

• Very small (fewer than 20 

employees), 

• Small (20 to 499 employees), and 

• Large (500 or more employees). 

Although this consolidation glosses 

over the important differences across 

products, the purpose is to estimate the 

broad average costs of the rule. 

For each size category, we constructed 

a cost model that included every 

provision of the final rule. We then 

attached a cost to each provision that 

had an additional activity associated 

with it. Most provisions did not have 

costs attached to them, because they 

were either descriptive or the costs were 

included elsewhere. 

The costs will be the marginal, or 

additional, costs of the activities 

producers undertake in response to the 

provisions of the final rule. In the cost 

model, we expressed the cost as cost per 

unit, with the unit being the 

establishment, the number of 

employees, or the annual number of 

batches produced or affected. 

b. Summary of general comments on 

costs. We received many comments on 

the costs of the 2003 CGMP Proposal. 

Many of the comments were general in 

nature and addressed the belief that our 

economic analysis underestimated the 

total costs of the 2003 CGMP Proposal, 

both first year costs and annual costs. 

Numerous comments point to the rule’s 

testing requirements as the main cause 

of the high costs. Comments also state 

that the analysis underestimates costs of 

hiring new workers, capital equipment, 

and holding and distributing costs. In 

addition, some comments point out that 

the economic analysis did not include 

estimates of costs of holding reserve 

samples and tracking product 

complaints. 

As a result of the 2003 CGMP 

Proposal, comments assert, product 

choice would decline, prices of existing 

products would increase, and many 

businesses, particularly small 

businesses, would be forced to shut 

down. One comment states there could 

be a decrease in spending on research 

and development. Some comments state 

that the burden on business could be 

alleviated by allowing the use of 

certificates of analysis for incoming raw 

materials and using a statistical, or more 

flexible, testing regime instead of 

requiring final product testing on all 

batches. 

A comment from a trade association 

representing ingredient suppliers and 

manufacturers in the dietary 

supplement industry accepts our 

assumptions on the following variables: 

• The number of control points, 

• The average number of ingredients 

per product, and 

• The average cost per test. 

Other comments, however, state that 

the average number of ingredients is 


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higher than estimated and that the 

average cost per test is higher than 

estimated; one comment from a 

manufacturer states that its average cost 

was 2.5 times our estimate. These 

comments came from self-described 

small firms. 

(Comment 347) One comment states 

that we failed to consider start-up costs. 

(Response) We include start-up costs 

(also referred to as set-up or one-time 

costs) throughout this analysis. 

(Comment 348) Many comments on 

the regulatory impact analysis targeted 

our estimates of firms’ batches per year. 

Nearly all comments about batches state 

that our batch estimates are too low. For 

example, an industry trade groups 

claims our estimate of 309 batches per 

year for large firms is ‘‘implausibly 

low.’’ The same comment states that the 

distribution of the number of batches 

per firm of 309, 554, and 223 for large, 

small, and very small firms is ‘‘illogical’’

because it does not make sense that 

large firms would have fewer batches 

per year than small firms. 

(Response) Due to a contractor’s error, 

we used an inaccurate estimate of the 

annual number of batches in the 

analysis of the 2003 CGMP Proposal. 

The analysis of the final rule corrects for 

this error. The corrected mean numbers 

of batches per firm are 444 for very 

small, 2,436 for small, and 1,164 for 

large firms. The corrected estimates of 

the number of batches continue to show 

that small firms produce more batches 

than large firms. Comments from selfdescribed small firms suggest that this 

distribution of batches is reasonable. 

These comments state that small firms 

produce many small batches of product 

using machinery with smaller capacity 

than that used by large firms. Very small 

firms produce the fewest number of 

batches per firm of the three size 

categories because of their much lower 

output. 

(Comment 349) One comment states 

that we used faulty data in the economic 

analysis. 

(Response) In accordance with our 

information quality guidelines, we have 

used the best available data in this 

analysis. As explained in the response 

to comment 348, the survey results used 

in the analysis of the 2003 CGMP 

Proposal included an inaccurate 

estimate of the number of batches of 

dietary supplements produced. We use 

the corrected estimate in the analysis of 

this final rule. 

(Comment 350) Some comments 

dispute the estimated testing costs. In 

particular, comments question our 

assumptions on: 

• The number of tests required per 

batch, 

• The number of tests already being 

performed, 

• The costs to perform specific 

analytical tests, and 

• The development of analytical 

methods. 

(Response) The final rule reduces the 

number of required tests. In the final 

rule, we account for tests where no 

analytical methods have been 

developed. We now require fewer tests, 

although we anticipate that some testing 

will take place associated with the 

creation of certificates of analysis 

required for component specifications 

and as verification for process controls. 

We now assume that the tests will be: 

• One identity test for each shipment 

lot of incoming dietary ingredients (e.g., 

vitamin C); 

• Tests of subsets of shipment lots by 

supplier firms to create certificates of 

analysis for identity of other 

components (e.g., sugar); 

• Tests of subsets of shipment lots for 

other specifications in the certificates of 

analysis; 

• Tests of subsets of batches of 

dietary supplements for microbial, 

chemical, or physical contaminants; 

• Tests of subsets of batches of 

dietary supplements for specifications; 

and 

• Tests for meeting requirements that 

water used to manufacture dietary 

supplements complies with Federal, 

State, and local requirements and does 

not contaminate the dietary supplement. 

We are not changing our estimate of 

the current prevalence of testing, which 

is based on the survey of manufacturers 

(Ref. E2). We would only revise this 

estimate in light of new data of 

comparable quality to that provided by 

the survey. 

(Comment 351) We did receive two 

comments favorable to recordkeeping, 

stating that master and production batch 

records were good to adopt and that 

associated costs will be minimal. One of 

the comments states that the level of 

detail may be unrealistic for a small 

firm, but also states that any final 

regulation could be made more flexible 

for small manufacturers. 

Although there were favorable 

comments, we received several 

comments critical of the recordkeeping 

requirements. These comments make 

general statements that the economic 

analysis underestimates the 

recordkeeping burden and some added 

that these requirements go beyond the 

CGMPs for food. In addition, several of 

the comments include firms’ own 

estimates of costs of complying with the 

recordkeeping requirement. Comments 

estimate costs in the range of $11,000 to 

$64,000. 

(Response) The recordkeeping 

requirements in the final rule differ 

from the 2003 CGMP Proposal; revised 

estimates are included in this final 

regulatory impact analysis and 

paperwork reduction analysis. 

(Comment 352) We received a 

favorable comment regarding the 

requirements for physical plant and 

equipment, saying that, although the 

costs would be moderate, the result 

would be higher quality products. 

Another comment states that, although 

not unrealistic, the provision would be 

very costly. 

Other comments are more critical. 

One comment estimates that renovation 

expenses would amount to 

approximately $600 million over the 

entire industry, as opposed to our 

estimate of $45 million. This comment 

states that the reason our estimates in 

the 2003 CGMP Proposal were too low 

is that we apply a reduction factor 

which assumes that 18 percent of very 

small firms, 10 percent of small firms 

and 1 percent of large firms will have to 

make capital improvements. It is more 

appropriate, the comment states, to 

assume that most facilities will need to 

renovate about 10 percent of their plant, 

regardless of firm size. In addition, the 

requirement that plants have smooth, 

hard surfaces on all floors, walls, and 

ceilings is unrealistic and would add 

quite a bit of cost. The comment asserts 

no company will have such surfaces 

throughout the plant and this is not a 

requirement in either the food or drug 

CGMP requirements. Other comments 

echo the belief that capital expenditures 

would be greater than our estimates and 

would be excessively burdensome. One 

comment estimates this cost at 

approximately $83,000 per facility. 

The comment also estimates that a 

large firm that needs to expand its 

capacity could expect to incur costs of 

$240,000, as opposed to the $2,000 that 

the comment says we estimated for large 

firms. In addition, it is pointed out that 

equipment costs could be burdensome 

to small firms, which likely do not have 

well-equipped labs. This thought is 

affirmed by other comments that 

estimate that new equipment could cost 

anywhere from $50,000 to $1 million, 

with annual costs estimated between 

$15,000 and $100,000. In addition, 

expansion of laboratory space is 

estimated at $200 per square foot, as 

opposed to the agency’s estimate of $50 

per square foot. Lastly, one comment 

suggests we work with the Internal 

Revenue Service to allow for more rapid 

depreciation of facility costs to help 

small businesses make facility upgrades. 

(Response) In the analysis of the 2003 

CGMP Proposal, we estimated the 


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number of firms needing to make capital 

expenditures associated with the rule as 

a distribution, with the parameters of 

the distribution determined by the size 

of the facility. We assume that if a firm 

does make a capital investment in 

response to the rule, it would affect 

about 10 percent of the plant. With an 

estimated cost of $50 per square foot, 

and the average size of a very small 

plant of about 25,000 square feet, the 

cost per very small establishment 

making a capital investment would be 

about $125,000. With the average size of 

a small plant of about 70,000 square 

feet, the cost per small establishment 

making a capital investment would be 

about $350,000. With the average size of 

a large plant of about 600,000 square 

feet, the cost per large establishment 

making a capital investment would be 

about $3 million (Ref. E2). We assume 

that most facilities will not need to 

make capital investments to meet the 

sanitation requirements of this final rule 

as, according to the survey results, most 

establishments already meet the 

sanitation standards of this final rule. 

This would not be possible if their 

facilities were inadequate. We note that 

the final rule does not require smooth 

and hard surfaces throughout the plant. 

We estimated the capital costs as the 

costs of minor renovations to help meet 

sanitation requirements, not as the cost 

of, for example, expanding the size of a 

laboratory or some other technically 

sophisticated change. Although some 

facilities may choose to expand 

laboratories, the testing requirements of 

this final rule should be able to be met 

by existing laboratory facilities within 

or outside of the manufacturing 

facilities. 

Working with the Internal Revenue 

Service on depreciation is beyond the 

scope of our authority. We will provide 

advice on financing capital 

improvements through our small 

business representatives in the Office of 

Regulatory Affairs. 

(Comment 353) Many comments 

address costs resulting from what 

industry describes as the exhaustive 

testing requirements outlined in the 

2003 CGMP Proposal. Comments point 

out that the requirement to test every 

ingredient would be very costly for 

firms large and small, with many firms 

stating that they risk going out of 

business. In addition, several comments 

add that the testing requirements would 

do little to enhance product quality. 

Many comments assert that allowing the 

use of a certificate of analysis would 

reduce the amount of tests performed on 

a shipment of incoming raw materials, 

reducing redundant testing, and also 

reducing the risk that a firm may go out 

of business. Other comments state that 

allowing statistical testing regimes 

would also cut down on testing costs. 

(Response) As we already have 

discussed in this section, we have 

reduced the amount of required testing 

in this final rule. The final rule requires 

testing the identity of every incoming 

dietary ingredient. However, the final 

rule allows for use of certificates of 

analysis in place of identity tests of 

other components and other tests of 

incoming dietary ingredients and other 

components. The final rule also allows 

sound statistical testing regimes for 

finished products. We recognize, 

however, that it may be possible for a 

manufacturer to demonstrate, through 

various methods and processes in use 

over time for its particular operation, 

that a system of less than 100 percent 

identity testing would provide no 

material diminution of assurance of the 

identity of the dietary ingredient as 

compared to the assurance provided by 

100-percent identity testing. To provide 

an opportunity for a manufacturer to 

make such a showing and reduce the 

frequency of identity testing of 

components that are dietary ingredients 

from 100 percent to some lower 

frequency, we decided to provide, in an 

interim final rule published elsewhere 

in this issue of the Federal Register, a 

procedure that allows for submission to, 

and review by, FDA of an alternative to 

the required 100-percent identity testing 

of components that are dietary 

ingredients, provided certain conditions 

are met. 

(Comment 354) One comment states 

that our cost estimates are based on the 

assumption of only two ingredient tests, 

an assumption which the comment calls 

into question. For multivitamins, one 

comment estimates about 8 separate 

tests and 16 separate assays, depending 

on the nutrients present. 

(Response) In the analysis of this final 

rule, we assume one identity test per 

incoming shipment lot of dietary 

ingredients based on the revisions made 

to the final rule compared with the 2003 

CGMP Proposal. 

(Comment 355) Many comments 

include individual estimates of testing 

costs. For example, two comments 

estimate an average cost of about $100 

per test, and other comments estimate 

averages as high as $360, as opposed to 

our estimate of about $60 per test. 

Several other comments claim that the 

costs of finished product testing alone 

would be ‘‘at least 100 times’’ greater 

than our estimates; other comments 

state that testing costs would almost 

equal the costs of manufacturing. One 

comment estimates testing costs for 

firms of all sizes at $245 million, as 

opposed to our estimate of $24 million, 

although another contains estimates as 

high as $13.6 million annually for one 

firm. Two comments concede that some 

finished product testing may be 

necessary. 

In addition, some comments state that 

our estimate of finished and raw 

material testing is off by a multiple of 

three to six. One comment states that, 

for companies that have products which 

contain a large number of ingredients 

expensive to test, very large costs will 

be incurred. This comment also states 

that our cost estimates do not include 

in-process testing, which they claim the 

rule would clearly require. Specifically, 

our analysis suggests that an average of 

2.5 in-process tests per batch are likely 

to be needed at critical control points. 

In addition, the comment maintains that 

our analysis showed that additional 

testing may be required for an average 

of 2.5 components of herbal products 

and 7.5 components of vitamin 

products, but our estimates do not 

include costs of the tests. Finally, 

comments point out that, if the 

production system is properly 

controlled, then a ‘‘reduced schedule’’

of final product testing is justified and 

that focusing excessive resources on 

end-product testing does not constitute 

GMP. Quality controls should be built 

into the production and process system 

from the beginning of the manufacturing 

process. 

A comment also states that our 

estimates of firms that already test are 

inaccurate. The comment asserts that 

our estimates are overstated and they 

also think we have understated that 

proportion of finished batches not 

currently being tested. In addition, the 

comment claims that ‘‘even large firms 

that are testing 90 percent of their 

products are unlikely to be performing 

the exhaustive level of testing required 

by the 2003 CGMP Proposal, namely 

testing every component of every batch 

of finished product.’’

The comments point out that our cost 

estimates do not include estimates for 

the cost of developing methods of 

analysis for ingredients. At a minimum, 

one comment states this estimate should 

be $2 million (the cost of 100 methods 

at a minimum of $20,000 each). Several 

comments point out that often there are 

no existing scientifically valid analytical 

methods to test finished products, 

especially botanical products. Another 

comment states that costs of analytical 

testing are at least three times our 

estimate, and could be as high as eight 

times our estimate. Because of this, 

many comments call for the use of a 

certificate of analysis in place of 

analytical testing. 


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Another comment states some 

unintended consequences could occur 

in the industry due to the testing 

requirements, including stress on the 

current contract laboratory facilities and 

in-house laboratories, and also increases 

in holding costs, due to changes in turnaround time at outside labs. Other 

comments point to the loss of product 

choice that could occur if the testing 

requirements force manufacturers to go 

out of business or discontinue certain 

products. 

(Response) In response to comments, 

we have revised the testing 

requirements in the final rule. We also 

have revised our estimates of the costs 

of testing. In what follows, we describe 

the estimated number and costs of tests 

required by this final rule. 

The final rule requires tests for 

identity for each incoming shipment lot 

of dietary ingredient. Estimating the 

number of tests per batch is 

complicated, because the tests are 

required on the shipment lots and we 

have data only on the number of batches 

of dietary supplements produced. For 

example, if a shipment lot of some 

dietary ingredient is used in six batches 

of final products, it would need to be 

tested for identity only once. The 

number of required identity tests per 

batch of final product will equal the 

number of dietary ingredients per batch, 

divided by the average number of 

batches per shipment lot (to account for 

the production of multiple batches of 

dietary supplements from single lots of 

components). In addition to the required 

identity tests, a subset of other 

components will be tested for identity 

(these tests are likely to be the 

responsibility of suppliers and need 

only be done once per batch no matter 

how many recipients of those batches). 

The quantity and quality of evidence 

on the variables used to estimate the 

number of tests varies greatly. In this 

section, we explain the evidence and 

assumptions we used to construct the 

formulas for the number of tests. 

Number of dietary ingredients. We 

based our measure of the number of 

dietary ingredients per product on a 

sample of almost 3,000 dietary 

supplement labels (Ref. E7). Although 

some ingredients may be missing from 

the labels and some listed ingredients 

may be missing from the products, the 

ingredient list represents the best 

evidence we have on what ingredients 

are used in dietary supplements. 

Although comments claimed that we 

underestimated the number of 

ingredients, they offered no evidence 

that would persuade us to change our 

estimates, which are based on a sample 

representing at least 10 percent of the 

products in the market. 

According to the sample of listed 

ingredients, vitamin and mineral 

products contain about 13 listed dietary 

ingredients. Other dietary supplements, 

mainly herbals, contain about four listed 

dietary ingredients (Ref. E7). 

Number of unlisted components. 

Dietary supplements are manufactured 

using solvents, binders, and lubricants 

that may not show up in the final 

product. An industry source (Ref. E21) 

says that four to six unlisted 

components are typical per product, 

although fewer are certainly possible. 

The minimum number is zero. Based on 

industry data, we assume that the 

number of unlisted components would 

be zero to six for vitamins and minerals, 

and zero to four for herbal and other 

products. 

Number of shipments (i.e., shipment 

lots) of ingredients and unlisted 

components. We have no direct 

information on the number of shipment 

lots of dietary ingredients and other 

components. We also have no 

information on the number of shipments 

per lot or on the number of shipments 

per batch. It is costly to store 

components, so some establishments 

may buy many small lots of dietary 

ingredients and other components 

rather than a few large lots. Crude 

botanical and other ingredients are 

inherently unstable and may lose their 

stability in even a short time unless 

costly temperature, humidity, and light 

controls are in place. We also know, 

however, that some dietary ingredient 

suppliers produce and ship ingredients 

in large lots. For dietary supplements 

produced using part of a large 

production run of a dietary ingredient, 

the number of batches per shipment lot 

could be large. Also, some producers 

buy a single large shipment lot of a raw 

material and use it in many batches. We 

assume that as many as 12 batches per 

shipment lot of dietary ingredient is a 

plausible maximum. Based on 

consultation with industry (Ref. E21), 

we assumed, in the cost calculation, that 

1 was the minimum and 12 the 

maximum number of batches produced 

per lot, with 6.5 the average. We 

received no comments on our use of the 

assumption in the analysis of the 

proposed rule and continue to use it in 

our analysis of the final rule. In the 

sensitivity analysis, we show how costs 

change when we change the 

assumption. 

Number of batches produced. We 

have survey results on the number of 

batches produced per establishment 

(Ref. E2). Several comments stated that 

we underestimated the number of 

batches produced, which we found to be 

the case because of an erroneous 

calculation in the contractor’s report. In 

the revised contract survey results, very 

small establishments produce an 

average of 444 (revised from 223) 

batches per year, small establishments 

produce an average of 2,436 (revised 

from 554) batches per year, and large 

establishments produce an average of 

1,164 (revised from 309) batches per 

year. 

Number of final product tests per 

batch. We have reduced the number of 

tests required for final products. We 

assume that establishments will test a 

representative sample of batches to 

ensure that the final products meet 

specifications. We do not specify any 

particular statistical sampling plan. 

Costs per test. We estimate the costs 

per test partly with published prices of 

independent laboratories as posted on 

the Internet (Refs. E22 and E23), and 

partly from our conversations with FDA 

and industry experts on testing. Testing 

costs vary according to frequency and 

complexity. The more frequently 

technicians perform tests, the lower are 

the costs per test. Many tests require 

sophisticated equipment, such as gas 

chromatography, high pressure liquid 

chromatography, distillation, extraction, 

various spectrophotometers, and other 

types of equipment. Using sophisticated 

equipment requires trained personnel. 

Even simple physical or organoleptic 

testing requires training or experienced 

personnel. The type of ingredient, 

compound, or product can also affect 

the cost because some are easily 

identified using routine or single step 

techniques and others require multiple 

steps or complex techniques, especially 

if there are similar products that can be 

mistaken for the products being 

identified. The type of defect tested for 

affects the cost; some defects can be 

found visually if they are found on the 

surface, but others are latent. Some tests 

require multiple samples or multiple 

steps. In addition, tests require taking 

and preparing samples, whose cost can 

vary. By assuming a single distribution 

for testing costs, we may overestimate 

testing costs for sectors or products with 

below-average costs and underestimate 

testing cost for sectors with aboveaverage costs. In the cost model, for 

example, we distinguish between 

botanical ingredients and nonbotanical 

ingredients in the number of tests, but 

not in average testing costs. If the 

average cost of testing botanical 

products is higher than the average cost 

for vitamins and minerals, the 

distribution of costs may underestimate 

total testing costs for botanical products. 

We do not have sufficient information 


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on the range of testing costs for 

botanical ingredients to determine if the 

average cost of testing is higher or lower 

than for other ingredients. 

The average cost per test is about $60, 

based on a range of costs we found on 

the Internet. This cost represents the full 

cost of carrying out a test, including 

collecting and storing the sample, the 

time for training the personnel who 

carry out the test, and any associated 

records. We assume that $20 per test 

represents a lower bound. Although 

some Internet prices for tests are as high 

as $300, we assumed that, with frequent 

testing, $150 would be a more plausible 

upper bound average cost. The majority 

of listed prices fell into the $20 to $80 

range, so we selected $50 (the midpoint) 

as most likely. 

The number and cost of tests: 

Summary. We estimate the number of 

tests required of the representative 

manufacturer as a weighted average of 

the number of tests required for 

vitamins and minerals and the number 

of tests required for all other 

supplements (which were mainly herbal 

products). The weights, shown as 

follows, differ by size of manufacturer: 

• 24 percent of very small 

manufacturers produce vitamins and 

minerals; 76 percent produce other 

dietary supplements. 

• 42 percent of small manufacturers 

produce vitamins and minerals; 58 

percent produce other dietary 

supplements. 

• 69 percent of large manufacturers 

produce vitamins and minerals; 31 

percent produce other dietary 

supplements. 

Most establishments already conduct 

some tests, or send samples out for 

testing. We therefore adjusted the 

estimated testing costs of the final rule 

to include only required tests and to 

account for the testing costs currently 

borne voluntarily by manufacturers. The 

survey results showed how many 

respondents were conducting various 

types of tests. 

TABLE 27.—VALUES USED TO ESTIMATE TESTING COSTS

Name Value or Distribution Used Source 

Number of dietary ingredients per product 

batch 

Vitamins and minerals—13 

All other categories—4 

Sample from 3,000 dietary supplement labels (Ref. E7) 

Number of identity tests per dietary ingredient 

lot 

1 identity test per ingredient lot Based on requirements of final rule 

Number of identity tests per other component 

lot 

1 identity test per subset of component lots Assumption based on use of certificates of analysis for ingredients 

Number of tests for specifications per ingredient lot 1 to 5 tests per subset of ingredient lots Assumption based on use of certificates of analysis for ingredients 

Number of unlisted components 0 to 6 components for vitamins and minerals, 0 to 4 

for herbal and other products 

Ref. E21 

Number of shipments (lots) of ingredients and 

unlisted components 

1 to 12 batches per shipment lot of dietary ingredients Assumption based on discussions 

with industry 

Number of batches produced per year Very small establishments–444 

Small establishments–2,436 

Large–1,164 

Ref. E2 

Number of final product tests per batch 1 test per subset Based on requirements of the final 

rule 

Costs per test Beta pert distribution skewed rightward between $20 

and $150; $50 most likely; $60 average 

Refs. E22 and E23 

(Comment 356) We received 

comments on labor costs that would be 

incurred as a result of the 2003 CGMP 

Proposal. All comments state that 

personnel costs will increase 

significantly. One comment states that 

the average manufacturing wage we 

used to estimate labor costs, $15.65, 

does not reflect the true cost of 

additional labor, since higher skilled 

employees, such as quality control 

engineers and, as one comment asserts, 

Ph.D.-level employees, will need to be 

hired to comply with the rule. This 

comment states that, including benefits, 

the wage actually ranges between $23.28 

and $72.00 per hour, depending on 

skill. Other comments estimate 

additional annual labor costs ranging 

between $25,000 and $350,000. 

(Response) We used more recent 

estimates to the average manufacturing 

wage cost of $26 per hour to estimate 

the cost of labor (Ref. E24). The 

comment that asserted Ph.D.-level 

employees are needed to comply with 

the rule, provided no basis for this 

assertion. We disagree that Ph.D.-level 

workers are needed for the tasks 

required by this final rule because most 

of the costs estimated as labor costs all 

involved ordinary labor tasks such as 

sanitation, monitoring, and 

recordkeeping. For more difficult or 

complicated tasks, more skilled workers 

may be required, but the overall average 

labor cost represents the best overall 

estimate for valuing the average cost of 

labor in the industry. We assume that 

various tasks required by the final rule 

would take some number of hours per 

year, per batch of product, or per square 

foot of physical plant. 

Estimating costs. We initially gathered 

information and made assumptions 

about the full cost of a provision. We 

then adjusted these estimates to account 

for the many activities already being 

carried out, as well other activities that 

would not have to be carried out by all 

establishments. We used the survey to 

estimate the likelihood that an 

establishment will incur a cost. To get 

an estimate of the average cost of a 

provision (adjusted for baseline 

activities) for each category, we 

multiply the average cost per 

establishment by the probability that the 


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Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 34933 

establishment will need to undertake 

the expense (one minus the probability 

that the establishment is already doing 

it). For each provision of the final rule, 

the simulation carried out the following 

calculation: 

Cost per unit of analysis for each 

provision = 

number of units of analysis per 

establishment x 

probability that establishment incurs 

cost x 

cost per provision per establishment. 

We estimate both a setup cost (a onetime fixed cost) of the provision and an 

annual recurring cost. To get the total 

costs of the rule, we multiply the 

number of establishments in each size 

category (from the survey) by the 

average costs per establishment in that 

category. We then adjust for the 

establishments that did not respond to 

the survey but are believed to be in the 

industry. Two hundred thirty-eight 

establishments responded to the survey; 

we estimate that 1,566 firms are in the 

industry, including ingredient 

suppliers. The number of firms covered 

by most of the provisions will therefore 

be about 1,460. 

We estimate total costs with the 

following calculation: 

(Number of very small establishments x 

costs per very small establishment) + 

(number of small establishments x costs 

per small establishment) + 

(number of large establishments x costs 

per large establishment) + 

(number of warehouses x costs per 

warehouse). 

The rule is complex and the industry 

is made up of very different kinds of 

firms, so cost estimates are averages 

with, in some cases, large variances. The 

cost per unit, number of batches and 

employees, and probability that the 

establishment would incur the cost all 

contain uncertainty. The values in table 

28 of this document are used in the cost 

estimates, and are generated from 

multiple sources. 

TABLE 28.—ADDITIONAL VALUES USED IN COST CALCULATIONS

Name Value or Distribution Used Source 

Average wage per hour $26 Employment Index, Bureau of Labor Statistics 

(Ref. E24) 

Average size of establishments in square feet very small = 24,674 

small = 71,354 

large = 596,000 

Ref. E2 

Average number of employees very small = 7.6 

small = 95 

large = 1,005 

Ref. E2 

Procedures 8 to 16 hours setup time for small firms; 30 to 

40 hours for large firms; annual cost is 10 

percent of setup time per provision 

Ref. E25 

Personnel sanitation 1 hour per week per worker Assumption, based on requirements of final 

rule 

Sanitation time for physical plant 1 hour per week for very small establishments; costs per small and large plants 

scaled in proportion to size of plant 

Assumption, based on difference in average 

physical plant size 

Sanitation supervisor 1 hour per week Assumption, based on requirements of final 

rule 

Pest control setup costs $1,500 to $2,000 for very small establishments; $1,800 to $2,400 for small establishments; $2,600 to $3,400 for large establishments. Average for each size establishment was midpoint ($1,750, $2,100, 

$3,000) 

Ref. E26 

Pest control annual costs $400 to $600 per month for very small establishments; $480 to $720 for small establishments; $700 to $1,000 for large establishments. Average for each size establishment was the midpoint ($500, $600, $850) Ref. E26 

Renovation cost $50 per square foot; with 0 to 20 percent of 

physical plant to be renovated, with 10 percent most likely 

Based on construction costs and square feet 

(Ref. E2) 

Equipment replacement For very small establishments, 0 to $1,000; 

costs per small and large plants scaled in 

proportion to size of plant 

Assumption, based on size of establishments 

(Ref. E2) 

Setup costs for automatic equipment $500 for hardware, 16 hours Software costs and assumptions about labor 

hours 

Annual costs for automatic equipment 10 percent of setup costs Assumption based on requirements of the 

final rule 


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TABLE 28.—ADDITIONAL VALUES USED IN COST CALCULATIONS—Continued 

Name Value or Distribution Used Source 

Sanitation of equipment and surfaces 5 hours per week for very small establishments; costs per small and large plants 

scaled in proportion to size of plant 

Assumption based on average sizes of establishments (Ref. E2) 

Holding products and dietary ingredients: Capital requirements Same as costs of equipment upgrades Based on average sizes of establishments 

(Ref. E2) 

Default probabilities that establishments are 

not currently acting in accordance with a 

provision 

For very small establishments, 0.2; for small 

establishments, 0.05, for large establishments, 0.01 

Based on results of survey for other practices 

(Ref. E2) 

The total setup costs for this final rule 

will be $41 million, spread out over the 

36 months following the publication 

date of the final rule. The annual costs, 

once the final rule is fully implemented, 

will be $164 million, with the two 

largest costs being $52 million for 

testing and $24 million for records. The 

estimated total cost is the mean of a 

range of estimates based on the data and 

assumptions described in tables 27 and 

28 of this document. In the uncertainty 

and sensitivity analyses in section 

XXIV.B.11 of this document, we show 

how uncertainty and different 

assumptions generate higher or lower 

estimated costs. Using plausible 

assumptions about the uncertain 

variables, we estimate that total 

quantified costs most likely will fall 

within a range of $104 million to $322 

million per year. 

8. Summary of Benefits and Costs 

We estimate that, once it is fully 

implemented, the annual quantified 

benefits from the final rule will be $8 

million to $64 million, with a mean 

estimate of $44 million. However, there 

are potentially large benefits of the rule 

that we were not able to quantify. The 

annual costs will be $104 million to 

$322 million, with a mean estimate of 

$164 million. The rule will not be fully 

effective until 36 months after the 

publication date. Table 29 of this 

document shows how the phase-in of 

the final rule will generate the costs and 

quantifiable benefits for the first 4 years. 

Table 30 of this document shows the 

present and annualized values of costs 

and quantifiable benefits over 20 years, 

calculated at discount rates of 3 percent 

and 7 percent. We have determined, 

based in part on the analysis presented 

here, that the benefits, quantified and 

unquantified, of this final rule justify 

the costs. 

TABLE 29.—COSTS AND QUANTIFIABLE BENEFITS BY YEAR

1st year 2nd year 3rd year 4th year 

Costs (in millions) $16 $120 $190 $164 

Benefits (in millions) $3 $29 $44 $44 

TABLE 30. PRESENT AND ANNUALIZED VALUES OF COSTS AND QUANTIFIABLE BENEFITS

Present value at 3 percent 

(in billions) 

Present value at 7 percent 

(in billions) 

Annualized Value over 20 

years at 3 percent (in millions) 

Annualized Value over 20 

years at 7 percent (in millions) 

Costs $2.3 $1.6 $153 $149 

Benefits $0.6 $0.4 $40 $39 

In table 31 of this document we show 

the annual costs for each subpart of the 

regulation. We identify selected costs 

for particular activities for some of the 

subparts. We are unable to estimate 

benefits by subpart, because we estimate 

the benefits by type of benefit rather 

than by provision of the final rule. 

TABLE 31.—COSTS BY SUBPART

Subpart Setup Cost (in millions) Annual Cost (in millions) 

A. General provisions not applicable not applicable 

B. Personnel $1.5 $15.7 

C. Physical plant and grounds $34.0 $17.4 

D. Equipment and utensils $0.9 $2.3 

E. Establish production and process control system $0.5 $66.1 

Subtotal for identity testing negligible $45.0 

Subtotal for all other testing $0.3 $ 6.8 


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TABLE 31.—COSTS BY SUBPART—Continued 

Subpart Setup Cost (in millions) Annual Cost (in millions) 

F. Quality control negligible $2.1 

G. Components, packaging, labels, and dietary supplements received negligible $31.6 

H. Master manufacturing record $0.1 negligible 

I. Batch production record negligible $5.4 

J. Laboratory operations $0.2 negligible 

K. Manufacturing operations negligible $2.2 

L. Packaging and labeling operations $0.1 $10.8 

M. Holding and distributing $2.7 $0.5 

N. Returned dietary supplements negligible $0.2 

O. Product complaints $0.1 $4.5 

P. Records and recordkeeping not applicable not applicable 

Paperwork cost for all subparts $3.7 $24.2 

(Comment 357) We received several 

comments on the summary of the costs 

and benefits. In general, the comments 

state that we overestimated the benefits 

of the 2003 CGMP Proposal and 

underestimated the costs. Other 

comments assert that total estimated 

benefits of the 2003 CGMP Proposal 

would not be $216.6 million, as 

estimated by us, but as low as $13.9 

million. Comments also estimate firstyear costs as high as $629 million, with 

annual costs estimated as high as $860 

million. Other comments predict 

product prices will increase, and 

consumers will decrease consumption 

of dietary supplements. 

(Response) We agree with the 

comments stating that we 

underestimated the costs and 

overestimated the quantified benefits of 

the 2003 CGMP Proposal. We have 

increased our estimate of costs in this 

final rule compared with the estimate in 

the 2003 CGMP Proposal. We have 

decreased our estimate of quantified 

benefits of the final rule compared with 

the estimate in the 2003 CGMP 

Proposal. As explained previously, we 

are unable to quantify all of the benefits 

of the final rule. These changes in the 

estimated benefits and costs of this final 

rule reflect both the changes in the 2003 

CGMP Proposal and the changes in our 

analysis in response to comments. 

We agree with the comment that part 

of the costs of this final rule will be 

passed on to consumers as higher prices 

for dietary supplements. The annual 

costs of this final rule are less than 1 

percent of total spending on dietary 

supplements. We expect that the 

majority of these costs will be borne by 

consumers of dietary supplements, who 

will likely respond to the increase in 

prices by reducing consumption. 

The comments suggesting very high 

costs and very low benefits did not 

persuade us that those extreme values 

were more likely than our estimates. We 

recognize, however, that the 

uncertainties in our analysis make a 

broad range of benefits and costs 

possible. In the analysis of uncertainty, 

we will show the range of predicted 

benefits and costs. We also will show 

the sensitivity of costs and benefits to 

certain key assumptions used in the 

analysis, and how changes in those 

assumptions can generate the extreme 

values cited in some comments. 

9. Benefits and Costs of Regulatory 

Options 

We considered several regulatory 

options, including: (1) No new 

regulatory action, (2) fewer 

requirements for vitamins and minerals, 

(3) more restrictive regulations than the 

final rule, (4) HACCP without the other 

elements of the final rule, (5) final 

product testing only, (6) a final rule for 

high-risk products or hazards only, and 

(7) the 2003 CGMP Proposal. Although 

we received no comments on our 

analysis of the benefits and costs of 

options 2 through 6, we received many 

comments on the estimated benefits and 

costs of the 2003 CGMP Proposal. We 

have now revised the estimated 

quantifiable benefits and costs of the 

2003 CGMP Proposal. The revised 

estimates are based on the comments 

received and the corrections made to the 

data. 

Using the same method as used in this 

final rule to determine benefits, we 

estimate that the quantifiable benefits of 

the 2003 CGMP Proposal would be 

approximately the same as the 

quantifiable benefits of the final rule, 

$44 million per year. 

With the corrected estimated number 

of batches produced, we estimate that 

the setup costs of the 2003 CGMP 

Proposal would be $51 million. If the 

2003 CGMP Proposal had been 

finalized, the annual costs of complying 

with the requirements would be $282 

million, or about $118 million more 

than this final rule. The 2003 CGMP 

Proposal relied more on testing final 

products and other controls closer to the 

end-product. Under the 2003 CGMP 

Proposal, for example, annual testing 

costs would be about $97 million. 

10. Cost Effectiveness Analysis 

Both benefit-cost analysis and costeffectiveness analysis provide a 

systematic framework for identifying 

and evaluating the likely outcomes of 

alternative regulatory choices. OMB 

Circular A–4 requires that major 

rulemakings be supported by both types 

of analysis wherever possible. A costeffectiveness analysis is particularly 

useful when the primary benefits of the 

rulemaking are improved public health 


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18It should be noted that many of the benefits of 

this rule are quality benefits that are not quantified 

and will not be part of this analysis. 

and safety.18 The main advantage of 

measures of effectiveness are that they 

account for a rule’s impact on morbidity 

(nonfatal illness, injury, impairment, 

and quality of life) as well as premature 

death. The inclusion of morbidity 

effects is important because some 

illnesses (e.g., asthma) cause more 

instances of pain and suffering than 

they do premature death. 

The primary benefits expected to 

result from this rulemaking are reduced 

numbers of acute and chronic illnesses 

and reduced number of recalls involving 

dietary supplement products. We were 

not able to quantify chronic illnesses 

that could be avoided as a result of this 

rulemaking. We were able to determine 

that we could avoid about $40 million 

annually in costs of acute illnesses and 

$4 million in avoided recalls as a result 

of improved dietary supplement 

manufacturing. 

We can use the $40 million annually 

in avoided acute illnesses costs to 

calculate a cost-effectiveness measure 

for this rule; $40 million in reduced 

illness costs translates into 48,662 

QALDs saved on an annual basis. Given 

that the annual costs of this final rule 

are expected to be $164 million, the cost 

of each QALD saved is $3,370. This is 

an overestimate of the cost of a QALD 

saved because we were unable to 

quantify the benefits of reduced chronic 

illness as a result of this rulemaking. 

11. Uncertainties in the Analysis 

We used indirect measures of the 

benefits of this final rule which required 

several key assumptions that are critical 

for our estimates. With the exception of 

the recall benefit, which is based 

directly on our recall records, each 

component of the estimated benefits 

involves assumptions that reflect our 

uncertainty. The estimated costs also 

embody key assumptions that reflect our 

uncertainty. 

One assumption that affects both 

estimated costs and estimated benefits is 

that manufacturing practices in the 

industry will persist in the absence of 

additional regulation. If the trend in the 

market is toward the adoption of more 

manufacturing controls than we are 

proposing here, then both the costs and 

benefits of the rule will be less than we 

estimate. If the market trend is toward 

fewer voluntary controls, then both the 

costs and benefits of the regulation will 

be greater than we estimate. 

In addition to the general assumption 

about the effects of the rule, we rely on 

several key assumptions. 

We assume there is an average of one 

reported illness for each class 1 and 2 

recall. 

The frequency of actual illnesses is 

100 times the frequency of reported 

illnesses. We recognize that there is 

considerable uncertainty about the 

factor of 100. 

For the baseline estimates, we assume 

$5 million is the value of a statistical 

life and $300,000 is the value of a 

quality-adjusted life year. The estimated 

health benefits change with changes in 

those valuations. 

Finally, we assume that the reported 

recalls that occurred from 1990 through 

1999 represent the number and type of 

recalls that would have occurred but for 

the implementation of this regulation. 

The cost model also relies on several 

key assumptions. We assume that single 

shipment lots of ingredients and 

unlisted components will be used for 

many batches of final dietary 

supplement products. We assume that 

all testing other than identity testing of 

incoming ingredients will be done on 

representative samples. The number of 

batches or lots tested will be the square 

root of n + 1, with n equal to the total 

number of batches or lots. 

We also assume that the costs per test, 

which include the labor costs of 

selecting the samples and arranging for 

the tests, will be between $20 and $150, 

with $50 most likely. 

We first characterized the 

uncertainties as a probability 

distribution. We ran 5,000 computer 

simulations to estimate both benefits 

and costs. The simulations used 

distributions (given in the tables and the 

text) in place of point estimates. 

TABLE 32.—DISTRIBUTION OF SIMULATION RESULTS FOR ANNUAL BENEFITS AND COSTS

5th Percentile Mean 95th Percentile 

Annual costs (in millions) $109 $164 $260 

Annual quantified benefits (in millions) $36 $44 $54 

The Monte Carlo computer 

simulations give the distributions of 

estimated benefits and costs. If the 

underlying distributions fully capture 

the uncertainty of the estimates, then 

the simulation results give a full picture 

of the uncertainty. With uncertain 

distributions used in the simulations, 

however, the ranges reported in the 

tables may not fully capture the 

uncertainties of the analysis. An 

alternative way to show the uncertainty 

is to see how sensitive the results are to 

plausible changes in certain key 

assumptions. We start with benefits. 

For our baseline estimated benefits of 

this final rule, we use a $5 million value 

for a statistical life (VSL) and a $300,000 

value for a quality-adjusted life year. In 

the sensitivity analysis, we use values of 

$3 million for a statistical life and 

$100,000 for a quality-adjusted life year 

to generate a ‘‘low’’ estimate of health 

benefits and values of $7 million and 

$500,000 to generate a ‘‘high’’ estimate. 

The reporting rate of illnesses 

associated with dietary supplements is 

unknown, which makes our estimate of 

the total number of illnesses highly 

uncertain. We use 1 percent as the 

average reporting rate, which implies 

that total illness are 100 times our 

estimate of reported illnesses. Although 

we assume this reporting rate is the 

most plausible for illnesses associated 

with dietary supplements, the evidence 

supporting it is not strong. We show the 

effects of reporting rates of 2.5 percent 

and 10 percent. 

(Comment 358) Several comments 

questioned our assumption that the final 

rule will eliminate the recalls used to 

estimate benefits. 

(Response) We do not assume that all 

recalls will be eliminated; we only 

assume that the recalls caused by 

manufacturing problems identified 

previously will be eliminated if the rule 

is fully effective. If the rule is not fully 

effective, then the quantified benefits 

will be less than we have estimated. In 

the following discussion we show the 

effects of different assumptions about 

the effectiveness of the final rule. 

The quantified benefits depend on the 

hazards found in recalled products 


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between 1990 and 1999. The 69 recalls 

in 1998 dominate the estimate, 

accounting for 58 percent of class 1 and 

class 2 recalls, and 35 percent of all 

recalls for the decade. In this sensitivity 

analysis we estimate the effect of 

excluding 1998 from the data used to 

estimate average annual benefits. We 

also consider the effects of using the 

annual average number of recalls from 

2000 through 2005 to estimate benefits. 

TABLE 33.—SENSITIVITY OF BENEFITS

Description Estimated Annual Benefits 

(after 3 years) (in millions) 

Final rule $44 

VSL = $3 million and $/QALY = $100,000 (baselines are $5 million and $300,000) $24 

VSL = $7 million and $/QALY = $500,000 (baselines are $5 million and $300,000) $64 

Each recall represents one illness, with reporting rate of 10 percent (baseline is 1 percent) $8 

Each recall represents one illness, with reporting rate of 2.5 percent (baseline is 1 percent) $20 

Final rule reduces manufacturing recalls by 80 percent (baseline is 100 percent) $35 

Exclude 1998 recalls from estimate, so average annual number of manufacturing recalls is 14 (baseline is 

19.5) $27 

Average annual number of manufacturing recalls = 2000–2005 average, so average per year is 10 (baseline 

is 19.5) $26 

In the sensitivity analysis of annual 

costs, we change assumptions about the 

numbers covered by the rule, the 

number of batches produced per 

establishment, the number of lots per 

batch, the average costs per test, and the 

rate of verification testing. 

The number of establishments 

covered is uncertain because we based 

it on voluntary survey responses and 

other evidence from the 1990s. If the 

number of establishments has increased 

or decreased, or if our original data 

overstated or understated the correct 

number, then the estimated costs will be 

either too low or too high. We show the 

effects of different numbers for one 

arbitrarily lower number covered and 

one arbitrarily higher number covered. 

The number of batches produced is 

our basic measure of output. Annual 

costs therefore vary directly with this 

measure and its components. We show 

how the costs depend on the number of 

batches by estimating costs for 50 

percent less and 50 percent more 

batches than estimated from the survey. 

The number of shipment lots and the 

cost per test determine identity testing 

costs, the single largest contributor to 

annual costs. We show how the costs 

vary if the average number of batches 

per lot is 1 or 12. We vary the average 

cost per test from $20 to $100. 

TABLE 34.—SENSITIVITY OF COSTS

Description Estimated Annual Cost 

(after 3 years) (in millions) 

Final rule $164 

Number of covered establishments is 1,300 (baseline is 1,460) $148 

Number of covered establishments is 1,600 (baseline is 1,460) $178 

Number of batches are 50 percent of baseline (baseline is 444, 2,436, and 1,164) $104 

Number of batches are 150 percent of baseline (baseline is 444, 2,436, and 1,164) $224 

1 batch of dietary supplements per shipment lot of a dietary ingredient (baseline is 6.5) $322 

12 batches of dietary supplements per shipment lot of a dietary ingredient (baseline is 6.5) $136 

Average cost per test is $20 (baseline is $60) $129 

Average cost per test is $100 (baseline is $60) $197 

We combine the results of the 

sensitivity analyses to generate overall 

ranges for benefits and costs. We 

estimate that, once it is fully 

implemented, the annual benefits, able 

to be quantified, from the final rule will 

be $8 million to $64 million; the annual 

costs will be $104 million to $322 

million. 

C. Final Regulatory Flexibility Analysis 

1. Introduction 

We have examined the economic 

implications of this final rule as 

required by the Regulatory Flexibility 

Act (5 U.S.C. 601–612). If a rule has a 

significant economic impact on a 

substantial number of small entities, the 

Regulatory Flexibility Act requires 

agencies to analyze regulatory options 

that would lessen the economic effect of 


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the rule on small entities. We find that 

this final rule will have a significant 

economic impact on a substantial 

number of small entities. 

2. Economic Effects on Small Entities 

a. Number of small entities affected. 

The final rule will affect many small 

entities. A small business in this 

industry is any establishment with 

fewer than 500 employees. For purposes 

of the cost-benefit analysis, we also 

looked at the category we call very small 

establishments: Establishments with 

fewer than 20 employees. Based on the 

survey (Ref. E2), we estimated that 774 

establishments, 53 percent of the total 

establishments, could be classified as 

very small (under 20 employees) and 

526 as small (20 to 499 employees), 

which is 36 percent of the total 

establishments. Based on the results of 

the survey (Ref. E2), we estimated the 

total number of warehouses, 

wholesalers, and other holders likely to 

be covered by this regulation to be 

15,689, of which 15,421 are small 

businesses. 

The small establishments that will be 

affected by the final rule are those 

establishments that will have to perform 

the various required activities, and 

would not have done so without the 

rule. We determined estimated baseline 

(pre-CGMP requirements) 

manufacturing practices with the survey 

of the industry (Ref. E2). The survey 

asked representative respondents to 

answer a series of questions, including 

how many employees they had and 

what their existing practices were. From 

the survey, we determined that small 

establishments do not now follow all of 

the provisions of the final rule. Those 

that do not follow all the applicable 

provisions will incur a cost to do so. 

b. Costs to small entities. 

Implementation costs vary across 

establishments depending on current 

practices and the types of products 

manufactured, packaged, labeled, or 

held. We estimated the range of current 

practices using the survey of the 

industry. The cost model, which we 

describe in detail in section XXIV.B.7 of 

this document, divided establishments 

by size, which allowed us to estimate 

the distribution of costs per 

establishment for each size and product 

class. Table 35 of this document shows 

the cost per establishment for very small 

and small establishments. For 

comparison, we include the estimated 

average cost per large establishment and 

the median revenues for each size 

category. As table 35 of this document 

shows, costs per establishment are 

proportionally higher for very small 

than for large establishments. The 

table’s most striking result is that annual 

costs are highest for small (20 to 499 

employees) establishments. 

TABLE 35.—COSTS PER ESTABLISHMENT, BY SIZE

Setup Costs per 

Establishment 

Annual Costs per 

Establishment 

Median Annual Revenue per 

Establishment 

Very small establishments $26,000 $46,000 Under $1 million 

Small establishments $20,000 $184,000 $5 to $10 million 

Large establishments $31,000 $69,000 $10 to $50 million 

Warehouses, wholesalers, and other holders $360 $1,000 Not applicable 

TABLE 36.—TOTAL COSTS BY ESTABLISHMENT SIZE

Setup Costs Percent of Total Setup 

Costs Annual Costs Percent of Total Annual Costs 

Very small establishments $20 million 49 percent $38 million 23 percent 

Small establishments $10 million 24 percent $98 million 60 percent 

Large establishments $5 million 12 percent $11 million 7 percent 

Warehouses, wholesalers, and other holders $6 million 15 percent $17 million 10 percent 

Small establishments that do not 

perform a substantial number of the 

actions required by the final rule will 

bear relatively high costs for compliance 

with the provisions of this final rule. 

Although the final rule will raise 

product prices, the price increase 

(which would largely be determined by 

changes made by large establishments) 

may be much smaller than the increase 

in the average costs of very small 

producers. The average burden to very 

small establishments will be about 4 

percent of annual revenue. The average 

burden to small establishments will be 

1.5 to 3 percent of annual revenue. 

Establishments with above average 

costs, and even establishments with 

average costs, could be hard pressed to 

continue to operate. Some of these may 

decide it is too costly and either change 

product lines or go out of business. 

We use a model developed under 

contract by Eastern Research Group to 

estimate the effects of FDA regulations 

on small businesses (Ref. E27). The 

model is designed to assess the effects 

of a wide range of potential regulatory 

activities, ranging from HACCP to 

product labeling. CGMP regulations are 

included as a potential regulatory 

activity. The model allows us to predict 

the probability and frequency of small 

business failure as a result of our 

regulations. 

We ran the model for the final rule. 

The model predicts that, as a result of 

the final rule, 140 very small and 32 

small dietary supplement manufacturers 

will be at risk of going out of business. 

The model estimates the number of 

workers in those firms to be about 2,250. 

The regulatory costs of this final rule 

will also discourage new small 

businesses from entering the industry. 

The dietary supplement has been 

characterized by substantial entry of 

small businesses. Although we cannot 

quantify how much that will change, we 

expect that the rate of entry of very 

small and small businesses will 

decrease. 


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3. Regulatory Options 

a. Exemptions for small entities. The 

burden on small establishments would 

be reduced if they were exempt from 

some provisions of the final rule. Most 

entities (we estimate close to 90 percent) 

affected by this final rule, however, are 

small. Exempting small establishments 

from some or all of its provisions would 

substantially reduce benefits. 

b. Longer compliance periods. 

Lengthening the compliance period 

provides some regulatory relief for 

businesses with fewer than 500 

employees. The longer compliance 

period will allow additional time for 

setting up recordkeeping, making 

capital improvements to the physical 

plant, purchasing new or replacement 

equipment, and other one-time 

expenditures. It will also delay the 

impact of the annual costs of 

compliance. We have given businesses 

with fewer than 20 employees an 

additional 24 months and businesses 

with fewer than 500 but 20 or more 

employees an additional 12 months for 

compliance. The final rule, then, will be 

phased-in over 36 months, with firms 

with 500 or more employees complying 

after 12 months, firms with under 500 

but 20 or more employees after 24 

months, and firms with fewer than 20 

employees after 36 months. The cost 

savings of delay may well be larger than 

simply the present value of the delay 

because the firms with fewer than 500 

employees may also be able to reduce 

their compliance costs by taking 

advantage of increases in industry 

knowledge and experience in 

implementing these regulations. 

c. Reduced requirements in the final 

rule. The modification of requirements 

in this final rule, compared with the 

2003 CGMP Proposal, significantly 

reduce the costs borne by small 

businesses. We estimate the average 

setup costs under the 2003 CGMP 

Proposal to be $25,000 for very small 

establishments and $40,000 for small 

establishments. We estimate that the 

annual costs of the 2003 CGMP Proposal 

would be $90,000 for very small 

establishments and $300,000 for small 

establishments. The final rule therefore 

reduces annual costs for very small 

establishments to about half of the 

estimated costs of the proposed rule and 

reduces costs for very small 

establishments to about 60 percent of 

the estimated costs of the 2003 CGMP 

Proposal. Under the 2003 CGMP 

Proposal, 216 very small and 50 small 

businesses would be at risk of going out 

of business, over 50 percent more than 

under the final rule. 

4. Description of Recordkeeping and 

Reporting 

The Regulatory Flexibility Act 

requires a description of the 

recordkeeping and reporting required 

for compliance with this final rule. This 

final rule will require the preparation of 

records. As described in the 2003 CGMP 

Proposal, Preliminary Regulatory Impact 

Analysis, written records or electronic 

documents must be kept that 

demonstrate that specific actions 

occurred in the manufacturing process 

in compliance with the final rule. 

Records that will be required in this 

final rule will demonstrate that 

corrective actions were taken; that 

equipment, instruments, and controls 

used in laboratory operations and 

quality control were installed and 

calibrated properly; that maintenance 

programs were followed; and that the 

results of any testing show that 

components or dietary supplements 

meet the established specifications. 

The compliance cost of recordkeeping 

is the sum of both the initial design and 

printing of the recordkeeping 

documents and the recurring costs of 

maintaining the records. The cost of 

training personnel to use the new 

documents is a recurring cost depending 

on how frequently documents are 

modified, how often personnel turn 

over, and how complicated the tasks are 

that are being recorded. The recurring 

costs are measured by the workers’ wage 

rate multiplied by the expected labor 

hours necessary for a written or 

electronic record and the time necessary 

for management to review the records to 

see that actions are documented 

accurately. In addition, electronic 

records necessitate recurring time spent 

ensuring that the equipment is serviced 

and maintained properly. 

5. Summary 

The final rule will have a significant 

economic impact on a substantial 

number of small entities. 

(Comment 359) We received many 

comments on the 2003 CGMP Proposal 

Preliminary Regulatory Flexibility 

Analysis. Nearly all of the comments 

addressing small business state that the 

requirements of the 2003 CGMP 

Proposal, the testing requirements in 

particular, would be an enormous 

burden on small business. Other 

comments assert that, because of this 

burden, the rule is in violation of the 

Regulatory Flexibility Act. In addition, 

comments assert small business will be 

particularly burdened by the rule and 

that consumers will see little 

improvement in product safety as a 

result. 

Some small firms estimate annual 

testing costs for the 2003 CGMP 

Proposal as high as $600,000, as 

opposed to the $60,000 per year 

estimated by us. Another firm estimates 

setup costs in the range of 4 to 7 times 

our estimate and annual costs 8 to 30 

times our estimate. Comments also 

express concern that we have 

underestimated the number of 

businesses forced to close if this rule is 

made final as proposed; one comment 

states that the rule would cause 50 

percent of small businesses to shut 

down. Some comments assert that this 

rule is anti-competitive: That is, the 

comments claim that this rule will make 

dietary supplement manufacturing so 

expensive that only large companies 

will survive. In addition, a few 

comments note the loss of product 

choice, innovation, and domestic 

employment that accompany firm 

closures, in addition to the increase in 

prices of products made by remaining 

firms. In addition, another comment 

suggests that foreign manufacturers will 

be at an advantage because they will not 

have to comply with the rule’s 

requirements. 

Some comments reiterate the points 

made earlier that the use of statistical 

sampling and supplier certificates of 

analysis could help reduce the burden 

on small business. 

One comment states that it would be 

extremely costly for small firms to come 

into compliance with the 2003 CGMP 

Proposal, especially because, as several 

firms pointed out, small firms often 

produce batches that are small in size. 

A few comments, however, say that 

small firms should be made to comply 

with the new rule at the same time as 

large firms. 

We received many comments on the 

compliance period of this rule. Some of 

these comments favor the extended 

compliance periods granted to small 

and very small firms. Other comments 

do not support the compliance periods, 

stating that they are not long enough for 

firms to set up recordkeeping systems, 

make capital improvements, and so on. 

Other comments do not favor granting 

small firms more time to comply. Three 

comments state that granting small firms 

a longer compliance period defeats the 

purpose of the rule, by making it 

difficult for consumers to determine 

which dietary supplements comply with 

the CGMPs and which do not yet 

comply. Another comment suggests that 

products made by firms not in 

compliance 1 year after the rule’s 

effective date be labeled to say, ‘‘This 

product may not conform to government 

standards for purity and potency.’’


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Other comments propose a single 

compliance period for all firms. 

(Response) We disagree with 

comments that the burden of this final 

rule violates the Regulatory Flexibility 

Act. The act requires agencies to 

consider the burden of their regulatory 

proposals on small entities, analyze and 

consider effective alternatives that 

reduce the burden on small entities, and 

make their analyses available for public 

comment. We have considered the 

burden of this final rule on all covered 

firms, including small businesses, and 

as a result have modified certain 

requirements to reduce the costs of the 

final rule as compared with the 2003 

CGMP Proposal. In addition, small 

businesses are allowed more time to 

comply with the rule. The burden on 

small businesses remains large, but the 

Regulatory Flexibility Act does not 

require agencies to adopt regulations 

that impose the least burden on small 

entities. In addition, the Data Quality 

Act has been fulfilled by using the most 

objective data available. In this analysis, 

we used data from surveys and from 

other Federal agencies. Although more 

data are desirable, we consider the 

quality of the data used in this analysis 

and in the references to be the best 

available and sufficient to fulfill the 

requirements of the Regulatory 

Flexibility and Data Quality Acts. 

We have reduced the amount of 

testing required in this final rule in 

response to comments on the burden of 

testing costs on the 2003 CGMP 

Proposal. As explained in Section 

XXIV.B.7 of this document, we 

underestimated costs in the proposed 

rule because of an error in a contractor’s 

report. We have corrected the cost 

calculations, including estimated testing 

costs, for this final regulatory flexibility 

analysis. 

We note that foreign firms that sell 

dietary supplements in the United 

States are required to be in compliance 

with the final rule. 

In response to comments on the 

number of firms likely to go out of 

business, we have used our small 

business model to estimate that 172 

small and very small firms will be at 

risk of going out of business. Many other 

small firms—some of them already 

experiencing financial difficulties–may 

see their financial condition worsen as 

a result of this final rule. 

We disagree with the comments that 

oppose longer compliance periods for 

small businesses. The additional time 

will only slightly delay the full 

implementation (and full benefits) of 

this final rule, and may provide the 

margin of survival for some small 

businesses. 

D. Unfunded Mandates 

The Unfunded Mandates Reform Act 

of 1995 (Public Law 104–4) requires 

cost-benefit and other analyses for rules 

that would cost more than $100 million 

in a single year. The current (2005) 

inflation-adjusted statutory threshold is 

$122 million. This final rule qualifies as 

a significant rule under the statute. Most 

of the requirements of the Unfunded 

Mandates are fulfilled in the Executive 

Order 12866 analysis. The requirements 

under the Unfunded Mandates Reform 

Act of 1995 include assessing the rule’s 

effects on future costs; productivity; 

particular regions, communities, or 

industrial sectors; economic growth; full 

employment; job creation; and exports. 

The future costs from the rule are the 

recurring costs, which reach their longterm value in the third year after the 

effective date of this rule. These costs 

would be incurred, directly or 

indirectly, by the establishments that 

manufacture, process, pack, label, 

transport, distribute, receive, hold, or 

import dietary supplements or 

ingredients. Recurring costs from the 

regulatory requirements will be incurred 

in each future year. Table 29 of this 

document summarizes the annual future 

recurring costs. 

The costs, direct and indirect, of the 

rule will be shared among 

manufacturers, processors, packagers, 

transporters, receivers, holders, and 

importers of dietary supplements or 

ingredients, as well as domestic 

consumers. Much of the higher costs 

incurred by domestic suppliers of 

dietary supplement products as a result 

of these regulations will be passed on to 

consumers as higher prices. The higher 

prices will be offset by the benefits from 

these regulations. 

Although this final regulation is 

significant, we do not expect it to 

substantially affect national 

productivity, growth, jobs, or full 

employment. The dietary supplement 

industry is too small a part of the 

domestic economy to influence overall 

economic activity. 

This final rule will require additional 

controls throughout the production and 

distribution chain for the manufacture 

of dietary supplements. The additional 

costs will increase the total costs of 

production and distribution for all of 

the regulated products, including 

products sold within the United States 

and across national borders. These 

increased costs will be partly passed on 

to consumers in the form of higher 

prices, which will tend to reduce the 

quantity demanded of the regulated 

products. The increased prices of U.S. 

exports could reduce the quantity of 

U.S. exports demanded, particularly in 

comparison with exports from countries 

that do not implement similar 

regulations. We expect this effect to be 

insignificant, because under the final 

rule the increases in the price of U.S. 

exports (and resulting decreases in 

quantity demanded) will be quite small. 

XXV. Analysis of Environmental 

Impact 

We have carefully considered the 

potential environmental effects of this 

action. We have concluded under 21 

CFR 25.30(h) that this action is of a type 

that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

XXVI. Federalism 

We have analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. We have 

determined that the final rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Furthermore, we 

did not receive any comments from 

States or their representative 

organizations regarding to our analysis 

of the proposed rule regarding the 

principles set forth in Executive Order 

13132. Accordingly, we conclude that 

the final rule does not contain policies 

that have federalism implications as 

defined in the Executive order and, 

consequently, a federalism summary 

impact statement is not required. 

XXVII. References 

The following references have been 

placed on display in the Division of 

Dockets Management (HFA–305), Food 

and Drug Administration, 5630 Fishers 

Lane, rm. 1061, Rockville, MD 20857, 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday. (FDA has verified the 

Web site addresses, but FDA is not 

responsible for any subsequent changes 

to the Web sites after this document 

publishes in the Federal Register.) 

1. U.S. Food and Drug Administration, 

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to General Nutrition Products, Inc., 

Greenville, SC. Memorandum dated October 

25, 1999 by Roslyn F. Powers, Ph.D., Center 

for Food Safety and Applied Nutrition. 

2. U.S. Food and Drug Administration, 

Memorandum of Site Visit, August 11, 1999, 

to Perrigo Company of South Carolina, Inc., 

Greenville, SC. Memorandum dated October 


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25, 1999 by Roslyn F. Powers, Ph.D., Center 

for Food Safety and Applied Nutrition. 

3. U.S. Food and Drug Administration, 

Memorandum of Site Visit, August 17, 1999, 

to Takeda Vitamin and Food, Inc., 

Wilmington, NC. Memorandum dated 

October 25, 1999 by Roslyn F. Powers, Ph.D., 

Center for Food Safety and Applied 

Nutrition. 

4. U.S. Food and Drug Administration, 

Memorandum of Site Visit, September 21, 

1999, to Pharmavite Corporation, San 

Fernando, CA. Memorandum dated October 

25, 1999 by Roslyn F. Powers, Ph.D., Center 

for Food Safety and Applied Nutrition. 

5. U.S. Food and Drug Administration, 

Memorandum of Site Visit, September 21, 

1999, to Shaklee Manufacturing Center, 

Norman, OK. Memorandum dated October 

25, 1999 by Roslyn F. Powers, Ph.D., Center 

for Food Safety and Applied Nutrition. 

6. U.S. Food and Drug Administration, 

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1999, to Botanicals International, Long 

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1999 by Roslyn F. Powers, Ph.D., Center for 

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JM, Love LA. Contamination of Botanical 

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‘‘Aloe Commodities International, Inc., 

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to Excess Vitamin D.’’ March 26, 2004. 

Information accessed on June 22, 2006. 

Available at http://www.fda.gov/bbs/topics/ 

news/2004/NEW01043.html. 

9. Juran’s Quality Control Handbook (J.M. 

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associate editor, 4th ed., 1988). 

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NH. An outbreak of shigellosis at an outdoor 

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Administration, November 3, 2003. Available 

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industry/default.htm or available at http:// 

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species. In, Infections of the gastrointestinal 

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Microbial Contamination Levels in Wet 

Granulation and Direct Compression 

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26. U.S Food and Drug Administration, 

FDA Talk Paper, Solgar Vitamin and Herb 

Company Recalls Solgar’s Digestive Aid 100’s 

Dietary Supplements Because of Possible 

Salmonella Contamination, April 26, 2001; 

Karuna Corporation, Karuna Corporation 

Recalls HCl Nutritional Product Because of 

Possible Health Risk, May 17, 2001; Licata 

Enterprises, Licata Enterprises Recalls 

Digestive Aid Products Because of Possible 

Health Risk, May 18, 2001; Natural Organics, 

Inc., Natural Organics, Inc. Cooperates in the 

Recall of Digestive Aid Dietary Supplements 

Because of Possible Salmonella 

Contaminated Raw Material Supplied by 

American Laboratories, Inc., May 22, 2001. 

(Press releases available at http:// 

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archive_2001.html). 

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cleaned food-contact surfaces), DIS/TSS–4 

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Environmental Protection Agency, Jan 30, 

1979. Available on the Internet at http:// 

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28. ‘‘Guide to Minimize Microbial Food 

Safety Hazards for Fresh Fruits and 

Vegetables,’’ U.S. Food and Drug 

Administration, October 26, 1998. Available 

on the Internet at http://www.cfsan.fda.gov/ 

~dms/prodguid.html. 

29. Human Drug CGMP Notes, Volume 5, 

Number 4, Division of Manufacturing and 

Product Quality, Office of Compliance, 

Center for Drug Evaluation and Research, U. 

S. Food and Drug Administration, December 

1997. Available on the Internet at http:// 

www.fda.gov/cder/hdn/cnotesd7.pdf. 

30. ‘‘Action Levels For Poisonous Or 

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Administration, August 2000. Available on 

the Internet at http://www.cfsan.fda.gov/ 

~lrd/fdaact.html. 

31. ‘‘Hazard Analysis and Critical Control 

Point Principles and Application 

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on Microbiological Criteria for Foods, August 

14, 1997. 

32. ‘‘Draft Report of the Food Advisory 

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Group on Ingredient Identity Testing and 

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Group, Center for Food Safety and Applied 

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33. ‘‘Guidance for Industry Part 11, 

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Elements,’’ U.S. Department of Health and 

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Dietary Supplement Industry. Contract No. 

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Revised, March 2004. 

E3. ‘‘Herbal Rx: The Promises and Pitfalls.’’

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E6. Saper, Robert B., Stefanos N. Kales, 

Janet Parquin, Michael J. Burns, David M. 

Eisenberg, Roger B. Davis, and Russell S. 

Phillips. ‘‘Heavy Metal Content of Ayurvedic 

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(December 15, 2004): 2868–2873. 

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Nutrition, Report of Adverse Health 

Outcomes Associated With the Consumption 

of Dietary Supplements Which Were 

Prepared Using Poor Manufacturing 

Practices, June 11, 2001. 

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Klein-Schwartz, G. C. Rodgers, Jr., J. Youniss, 

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Journal of Emergency Medicine 22 

(September 2004): 335–392. 

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Regarding Dietary Supplements, May 30, 

2000. 

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FOODS—CLASS I. Enforcement Report,’’

November 24, 2004. Information accessed on 

June 22, 2006. Available at http:// 

www.fda.gov/bbs/topics/enforce/2004/ 

ENF00875.html; Slifman NR, Obermeyer WR, 

Aloi BK, Musser SM, Correll WA, Cichowicz 

SM, Betz JM, Love LA. Contamination of 

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Lanata. The New England Journal of 

Medicine. 1996;339:806–11; U.S. Food and 

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Mortality Weekly Report (MMWR) 2004; 

53:847–850. 

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Muin J. Khoury, and J. David Erickson, 

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of Medicine 341 (November 11, 1999): 1509–

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Kelley S. Scanlon, Charles G. Helmick, and 

Joseph Mulinare, ‘‘Cost-Effectiveness of 

Strategies to Prevent Neural Tube Defects.’’

In Cost-Effectiveness in Health and Medicine, 

edited by Marthe R. Gold, Joanna A. Siegel, 

Louise B. Russell, and Milton C. Weinstein. 

(New York: Oxford University Press, 1996), 

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with industry expert regarding inventory 

practices, April 4, 2000. 

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the Good Manufacturing Practices Regulation 

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8100: Task Order 1, pp. 4–23 to 4–25, 

November, 1993. 

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Food Safety and Applied Nutrition, Costs of 

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List of Subjects in 21 CFR Part 111 

Dietary foods, Drugs, Foods, 

Packaging and containers. 

■ Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, FDA is amending 21 

CFR chapter I by adding part 111 to read 

as follows: 

PART 111—CURRENT GOOD 

MANUFACTURING PRACTICE IN 

MANUFACTURING, PACKAGING, 

LABELING, OR HOLDING 

OPERATIONS FOR DIETARY 

SUPPLEMENTS 

Subpart A—General Provisions 

Sec. 

111.1 Who is subject to this part? 

111.3 What definitions apply to this part? 

111.5 Do other statutory provisions and 

regulations apply? 

Subpart B—Personnel 

111.8 What are the requirements under this 

subpart B for written procedures? 

111.10 What requirements apply for 

preventing microbial contamination from 

sick or infected personnel and for 

hygienic practices? 

111.12 What personnel qualification 

requirements apply? 

111.13 What supervisor requirements 

apply? 

111.14 Under this subpart B, what records 

must you make and keep? 

Subpart C—Physical Plant and Grounds 

111.15 What sanitation requirements apply 

to your physical plant and grounds? 

111.16 What are the requirements under 

this subpart C for written procedures? 

111.20 What design and construction 

requirements apply to your physical 

plant? 

111.23 Under this subpart C, what records 

must you make and keep? 

Subpart D—Equipment and Utensils 

111.25 What are the requirements under 

this subpart D for written procedures? 

111.27 What requirements apply to the 

equipment and utensils that you use? 

111.30 What requirements apply to 

automated, mechanical, or electronic 

equipment? 

111.35 Under this subpart D, what records 

must you make and keep? 

Subpart E—Requirement to Establish a 

Production and Process Control System 

111.55 What are the requirements to 

implement a production and process 

control system? 

111.60 What are the design requirements 

for the production and process control 

system? 

111.65 What are the requirements for 

quality control operations? 

111.70 What specifications must you 

establish? 

111.73 What is your responsibility for 

determining whether established 

specifications are met? 

111.75 What must you do to determine 

whether specifications are met? 

111.77 What must you do if established 

specifications are not met? 

111.80 What representative samples must 

you collect? 

111.83 What are the requirements for 

reserve samples? 

111.87 Who conducts a material review and 

makes a disposition decision? 


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111.90 What requirements apply to 

treatments, in-process adjustments, and 

reprocessing when there is a deviation or 

unanticipated occurrence or when a 

specification established in accordance 

with § 111.70 is not met? 

111.95 Under this subpart E, what records 

must you make and keep? 

Subpart F—Production and Process Control 

System: Requirements for Quality Control 

111.103 What are the requirements under 

this subpart F for written procedures? 

111.105 What must quality control 

personnel do? 

111.110 What quality control operations are 

required for laboratory operations 

associated with the production and 

process control system? 

111.113 What quality control operations are 

required for a material review and 

disposition decision? 

111.117 What quality control operations are 

required for equipment, instruments, and 

controls? 

111.120 What quality control operations are 

required for components, packaging, and 

labels before use in the manufacture of 

a dietary supplement? 

111.123 What quality control operations are 

required for the master manufacturing 

record, the batch production record, and 

manufacturing operations? 

111.127 What quality control operations are 

required for packaging and labeling 

operations? 

111.130 What quality control operations are 

required for returned dietary 

supplements? 

111.135 What quality control operations are 

required for product complaints? 

111.140 Under this subpart F, what records 

must you make and keep? 

Subpart G—Production and Process 

Control System: Requirements for 

Components, Packaging, and Labels and 

for Product That You Receive for Packaging 

or Labeling as a Dietary Supplement 

111.153 What are the requirements under 

this subpart G for written procedures? 

111.155 What requirements apply to 

components of dietary supplements? 

111.160 What requirements apply to 

packaging and labels received? 

111.165 What requirements apply to a 

product received for packaging or 

labeling as a dietary supplement (and for 

distribution rather than for return to the 

supplier)? 

111.170 What requirements apply to 

rejected components, packaging, and 

labels, and to rejected products that are 

received for packaging or labeling as a 

dietary supplement? 

111.180 Under this subpart G, what records 

must you make and keep? 

Subpart H—Production and Process 

Control System: Requirements for the 

Master Manufacturing Record 

111.205 What is the requirement to 

establish a master manufacturing record? 

111.210 What must the master 

manufacturing record include? 

Subpart I—Production and Process Control 

System: Requirements for the Batch 

Production Record 

111.255 What is the requirement to 

establish a batch production record? 

111.260 What must the batch record 

include? 

Subpart J—Production and Process Control 

System: Requirements for Laboratory 

Operations 

111.303 What are the requirements under 

this subpart J for written procedures? 

111.310 What are the requirements for the 

laboratory facilities that you use? 

111.315 What are the requirements for 

laboratory control processes? 

111.320 What requirements apply to 

laboratory methods for testing and 

examination? 

111.325 Under this subpart J, what records 

must you make and keep? 

Subpart K—Production and Process 

Control System: Requirements for 

Manufacturing Operations 

111.353 What are the requirements under 

this subpart K for written procedures? 

111.355 What are the design requirements 

for manufacturing operations? 

111.360 What are the requirements for 

sanitation? 

111.365 What precautions must you take to 

prevent contamination? 

111.370 What requirements apply to 

rejected dietary supplements? 

111.375 Under this subpart K, what records 

must you make and keep? 

Subpart L—Production and Process Control 

System: Requirements for Packaging and 

Labeling Operations 

111.403 What are the requirements under 

this subpart L for written procedures? 

111.410 What requirements apply to 

packaging and labels? 

111.415 What requirements apply to filling, 

assembling, packaging, labeling, and 

related operations? 

111.420 What requirements apply to 

repackaging and relabeling? 

111.425 What requirements apply to a 

packaged and labeled dietary 

supplement that is rejected for 

distribution? 

111.430 Under this subpart L, what records 

must you make and keep? 

Subpart M—Holding and Distributing 

111.453 What are the requirements under 

this subpart M for written procedures? 

111.455 What requirements apply to 

holding components, dietary 

supplements, packaging, and labels? 

111.460 What requirements apply to 

holding in-process material? 

111.465 What requirements apply to 

holding reserve samples of dietary 

supplements? 

111.470 What requirements apply to 

distributing dietary supplements? 

111.475 Under this subpart M, what records 

must you make and keep? 

Subpart N—Returned Dietary Supplements 

111.503 What are the requirements under 

this subpart N for written procedures? 

111.510 What requirements apply when a 

returned dietary supplement is received? 

111.515 When must a returned dietary 

supplement be destroyed, or otherwise 

suitably disposed of? 

111.520 When may a returned dietary 

supplement be salvaged? 

111.525 What requirements apply to a 

returned dietary supplement that quality 

control personnel approve for 

reprocessing? 

111.530 When must an investigation be 

conducted of your manufacturing 

processes and other batches? 

111.535 Under this subpart N, what records 

must you make and keep? 

Subpart O—Product Complaints 

111.553 What are the requirements under 

this subpart O for written procedures? 

111.560 What requirements apply to the 

review and investigation of a product 

complaint? 

111.570 Under this subpart O, what records 

must you make and keep? 

Subpart P—Records and Recordkeeping 

111.605 What requirements apply to the 

records that you make and keep? 

111.610 What records must be made 

available to FDA? 

Authority: 21 U.S.C. 321, 342, 343, 371, 

374, 381, 393; 42 U.S.C. 264. 

Subpart A—General Provisions 

§ 111.1 Who is subject to this part? 

(a) Except as provided by paragraph 

(b) of this section, you are subject to this 

part if you manufacture, package, label, 

or hold a dietary supplement, including: 

(1) A dietary supplement you 

manufacture but that is packaged or 

labeled by another person; and 

(2) A dietary supplement imported or 

offered for import in any State or 

territory of the United States, the 

District of Columbia, or the 

Commonwealth of Puerto Rico. 

(b) The requirements pertaining to 

holding dietary supplements do not 

apply to you if you are holding those 

dietary supplements at a retail 

establishment for the sole purpose of 

direct retail sale to individual 

consumers. A retail establishment does 

not include a warehouse or other storage 

facility for a retailer or a warehouse or 

other storage facility that sells directly 

to individual consumers. 

§ 111.3 What definitions apply to this part? 

The definitions and interpretations of 

terms in section 201 of the Federal 

Food, Drug, and Cosmetic Act (the act) 

apply to such terms when used in this 

part. For the purpose of this part, the 

following definitions also apply: 

Actual yield means the quantity that 

is actually produced at any appropriate 

step of manufacture or packaging of a 

particular dietary supplement. 


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Batch means a specific quantity of a 

dietary supplement that is uniform, that 

is intended to meet specifications for 

identity, purity, strength, and 

composition, and that is produced 

during a specified time period according 

to a single manufacturing record during 

the same cycle of manufacture. 

Batch number, lot number, or control 

number means any distinctive group of 

letters, numbers, or symbols, or any 

combination of them, from which the 

complete history of the manufacturing, 

packaging, labeling, and/or holding of a 

batch or lot of dietary supplements can 

be determined. 

Component means any substance 

intended for use in the manufacture of 

a dietary supplement, including those 

that may not appear in the finished 

batch of the dietary supplement. 

Component includes dietary ingredients 

(as described in section 201(ff) of the 

act) and other ingredients. 

Contact surface means any surface 

that contacts a component or dietary 

supplement, and those surfaces from 

which drainage onto the component or 

dietary supplement, or onto surfaces 

that contact the component or dietary 

supplement, occurs during the normal 

course of operations. Examples of 

contact surfaces include containers, 

utensils, tables, contact surfaces of 

equipment, and packaging. 

Ingredient means any substance that 

is used in the manufacture of a dietary 

supplement and that is intended to be 

present in the finished batch of the 

dietary supplement. An ingredient 

includes, but is not necessarily limited 

to, a dietary ingredient as defined in 

section 201(ff) of the act. 

In-process material means any 

material that is fabricated, compounded, 

blended, ground, extracted, sifted, 

sterilized, derived by chemical reaction, 

or processed in any other way for use 

in the manufacture of a dietary 

supplement. 

Lot means a batch, or a specific 

identified portion of a batch, that is 

uniform and that is intended to meet 

specifications for identity, purity, 

strength, and composition; or, in the 

case of a dietary supplement produced 

by continuous process, a specific 

identified amount produced in a 

specified unit of time or quantity in a 

manner that is uniform and that is 

intended to meet specifications for 

identity, purity, strength, and 

composition. 

Microorganisms means yeasts, molds, 

bacteria, viruses, and other similar 

microscopic organisms having public 

health or sanitary concern. This 

definition includes species that: 

(1) May have public health 

significance; 

(2) May cause a component or dietary 

supplement to decompose; 

(3) Indicate that the component or 

dietary supplement is contaminated 

with filth; or 

(4) Otherwise may cause the 

component or dietary supplement to be 

adulterated. 

Must is used to state a requirement. 

Pest means any objectionable insect or 

other animal including birds, rodents, 

flies, mites, and larvae. 

Physical plant means all or any part 

of a building or facility used for or in 

connection with manufacturing, 

packaging, labeling, or holding a dietary 

supplement. 

Product complaint means any 

communication that contains any 

allegation, written, electronic, or oral, 

expressing concern, for any reason, with 

the quality of a dietary supplement, that 

could be related to current good 

manufacturing practice. Examples of 

product complaints are: Foul odor, off 

taste, illness or injury, disintegration 

time, color variation, tablet size or size 

variation, under-filled container, foreign 

material in a dietary supplement 

container, improper packaging, 

mislabeling, or dietary supplements that 

are superpotent, subpotent, or contain 

the wrong ingredient, or contain a drug 

or other contaminant (e.g., bacteria, 

pesticide, mycotoxin, glass, lead). 

Quality means that the dietary 

supplement consistently meets the 

established specifications for identity, 

purity, strength, and composition, and 

limits on contaminants, and has been 

manufactured, packaged, labeled, and 

held under conditions to prevent 

adulteration under section 402(a)(1), 

(a)(2), (a)(3), and (a)(4) of the act. 

Quality control means a planned and 

systematic operation or procedure for 

ensuring the quality of a dietary 

supplement. 

Quality control personnel means any 

person, persons, or group, within or 

outside of your organization, who you 

designate to be responsible for your 

quality control operations. 

Representative sample means a 

sample that consists of an adequate 

number of units that are drawn based on 

rational criteria, such as random 

sampling, and that are intended to 

ensure that the sample accurately 

portrays the material being sampled. 

Reprocessing means using, in the 

manufacture of a dietary supplement, 

clean, uncontaminated components or 

dietary supplements that have been 

previously removed from manufacturing 

and that have been made suitable for 

use in the manufacture of a dietary 

supplement. 

Reserve sample means a 

representative sample of product that is 

held for a designated period of time. 

Sanitize means to adequately treat 

cleaned equipment, containers, utensils, 

or any other cleaned contact surface by 

a process that is effective in destroying 

vegetative cells of microorganisms of 

public health significance, and in 

substantially reducing numbers of other 

microorganisms, but without adversely 

affecting the product or its safety for the 

consumer. 

Theoretical yield means the quantity 

that would be produced at any 

appropriate step of manufacture or 

packaging of a particular dietary 

supplement, based upon the quantity of 

components or packaging to be used, in 

the absence of any loss or error in actual 

production. 

Water activity (aw) is a measure of the 

free moisture in a component or dietary 

supplement and is the quotient of the 

water vapor pressure of the substance 

divided by the vapor pressure of pure 

water at the same temperature. 

We means the U.S. Food and Drug 

Administration (FDA). 

You means a person who 

manufactures, packages, labels, or holds 

dietary supplements. 

§ 111.5 Do other statutory provisions and 

regulations apply? 

In addition to this part, you must 

comply with other applicable statutory 

provisions and regulations under the act 

related to dietary supplements. 

Subpart B—Personnel 

§ 111.8 What are the requirements under 

this subpart B for written procedures? 

You must establish and follow written 

procedures for fulfilling the 

requirements of this subpart. 

§ 111.10 What requirements apply for 

preventing microbial contamination from 

sick or infected personnel and for hygienic 

practices? 

(a) Preventing microbial 

contamination. You must take measures 

to exclude from any operations any 

person who might be a source of 

microbial contamination, due to a 

health condition, where such 

contamination may occur, of any 

material, including components, dietary 

supplements, and contact surfaces used 

in the manufacture, packaging, labeling, 

or holding of a dietary supplement. 

Such measures include the following: 

(1) Excluding from working in any 

operations that may result in 

contamination any person who, by 

medical examination, the person’s 


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acknowledgement, or supervisory 

observation, is shown to have, or 

appears to have, an illness, infection, 

open lesion, or any other abnormal 

source of microbial contamination, that 

could result in microbial contamination 

of components, dietary supplements, or 

contact surfaces, until the health 

condition no longer exists; and 

(2) Instructing your employees to 

notify their supervisor(s) if they have or 

if there is a reasonable possibility that 

they have a health condition described 

in paragraph (a)(1) of this section that 

could result in microbial contamination 

of any components, dietary 

supplements, or any contact surface. 

(b) Hygienic practices. If you work in 

an operation during which adulteration 

of the component, dietary supplement, 

or contact surface could occur, you must 

use hygienic practices to the extent 

necessary to protect against such 

contamination of components, dietary 

supplements, or contact surfaces. These 

hygienic practices include the 

following: 

(1) Wearing outer garments in a 

manner that protects against the 

contamination of components, dietary 

supplements, or any contact surface; 

(2) Maintaining adequate personal 

cleanliness; 

(3) Washing hands thoroughly (and 

sanitizing if necessary to protect against 

contamination with microorganisms) in 

an adequate hand-washing facility: 

(i) Before starting work; and 

(ii) At any time when the hands may 

have become soiled or contaminated; 

(4) Removing all unsecured jewelry 

and other objects that might fall into 

components, dietary supplements, 

equipment, or packaging, and removing 

hand jewelry that cannot be adequately 

sanitized during periods in which 

components or dietary supplements are 

manipulated by hand. If hand jewelry 

cannot be removed, it must be covered 

by material that is maintained in an 

intact, clean, and sanitary condition and 

that effectively protects against 

contamination of components, dietary 

supplements, or contact surfaces; 

(5) Maintaining gloves used in 

handling components or dietary 

supplements in an intact, clean, and 

sanitary condition. The gloves must be 

of an impermeable material; 

(6) Wearing, where appropriate, in an 

effective manner, hair nets, caps, beard 

covers, or other effective hair restraints; 

(7) Not storing clothing or other 

personal belongings in areas where 

components, dietary supplements, or 

any contact surfaces are exposed or 

where contact surfaces are washed; 

(8) Not eating food, chewing gum, 

drinking beverages, or using tobacco 

products in areas where components, 

dietary supplements, or any contact 

surfaces are exposed, or where contact 

surfaces are washed; and 

(9) Taking any other precautions 

necessary to protect against the 

contamination of components, dietary 

supplements, or contact surfaces with 

microorganisms, filth, or any other 

extraneous materials, including 

perspiration, hair, cosmetics, tobacco, 

chemicals, and medicines applied to the 

skin. 

§ 111.12 What personnel qualification 

requirements apply? 

(a) You must have qualified 

employees who manufacture, package, 

label, or hold dietary supplements. 

(b) You must identify who is 

responsible for your quality control 

operations. Each person who is 

identified to perform quality control 

operations must be qualified to do so 

and have distinct and separate 

responsibilities related to performing 

such operations from those 

responsibilities that the person 

otherwise has when not performing 

such operations. 

(c) Each person engaged in 

manufacturing, packaging, labeling, or 

holding, or in performing any quality 

control operations, must have the 

education, training, or experience to 

perform the person’s assigned functions. 

§ 111.13 What supervisor requirements 

apply? 

(a) You must assign qualified 

personnel to supervise the 

manufacturing, packaging, labeling, or 

holding of dietary supplements. 

(b) Each supervisor whom you use 

must be qualified by education, training, 

or experience to supervise. 

§ 111.14 Under this subpart B, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart B in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for fulfilling 

the requirements of this subpart B; and 

(2) Documentation of training, 

including the date of the training, the 

type of training, and the person(s) 

trained. 

Subpart C—Physical Plant and 

Grounds 

§ 111.15 What sanitation requirements 

apply to your physical plant and grounds? 

(a) Grounds. You must keep the 

grounds of your physical plant in a 

condition that protects against the 

contamination of components, dietary 

supplements, or contact surfaces. The 

methods for adequate ground 

maintenance include: 

(1) Properly storing equipment, 

removing litter and waste, and cutting 

weeds or grass within the immediate 

vicinity of the physical plant so that it 

does not attract pests, harbor pests, or 

provide pests a place for breeding; 

(2) Maintaining roads, yards, and 

parking lots so that they do not 

constitute a source of contamination in 

areas where components, dietary 

supplements, or contact surfaces are 

exposed; 

(3) Adequately draining areas that 

may contribute to the contamination of 

components, dietary supplements, or 

contact surfaces by seepage, filth or any 

other extraneous materials, or by 

providing a breeding place for pests; 

(4) Adequately operating systems for 

waste treatment and disposal so that 

they do not constitute a source of 

contamination in areas where 

components, dietary supplements, or 

contact surfaces are exposed; and 

(5) If your plant grounds are bordered 

by grounds not under your control, and 

if those other grounds are not 

maintained in the manner described in 

this section, you must exercise care in 

the plant by inspection, extermination, 

or other means to exclude pests, dirt, 

and filth or any other extraneous 

materials that may be a source of 

contamination. 

(b) Physical plant facilities. (1) You 

must maintain your physical plant in a 

clean and sanitary condition; and 

(2) You must maintain your physical 

plant in repair sufficient to prevent 

components, dietary supplements, or 

contact surfaces from becoming 

contaminated. 

(c) Cleaning compounds, sanitizing 

agents, pesticides, and other toxic 

materials. (1) You must use cleaning 

compounds and sanitizing agents that 

are free from microorganisms of public 

health significance and that are safe and 

adequate under the conditions of use. 

(2) You must not use or hold toxic 

materials in a physical plant in which 

components, dietary supplements, or 

contact surfaces are manufactured or 

exposed, unless those materials are 

necessary as follows: 

(i) To maintain clean and sanitary 

conditions; 

(ii) For use in laboratory testing 

procedures; 

(iii) For maintaining or operating the 

physical plant or equipment; or 

(iv) For use in the plant’s operations. 

(3) You must identify and hold 

cleaning compounds, sanitizing agents, 

pesticides, pesticide chemicals, and 

other toxic materials in a manner that 


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protects against contamination of 

components, dietary supplements, or 

contact surfaces. 

(d) Pest control. (1) You must not 

allow animals or pests in any area of 

your physical plant. Guard or guide 

dogs are allowed in some areas of your 

physical plant if the presence of the 

dogs will not result in contamination of 

components, dietary supplements, or 

contact surfaces; 

(2) You must take effective measures 

to exclude pests from the physical plant 

and to protect against contamination of 

components, dietary supplements, and 

contact surfaces on the premises by 

pests; and 

(3) You must not use insecticides, 

fumigants, fungicides, or rodenticides, 

unless you take precautions to protect 

against the contamination of 

components, dietary supplements, or 

contact surfaces. 

(e) Water supply. (1) You must 

provide water that is safe and sanitary, 

at suitable temperatures, and under 

pressure as needed, for all uses where 

water does not become a component of 

the dietary supplement. 

(2) Water that is used in a manner 

such that the water may become a 

component of the dietary supplement, 

e.g., when such water contacts 

components, dietary supplements, or 

any contact surface, must, at a 

minimum, comply with applicable 

Federal, State, and local requirements 

and not contaminate the dietary 

supplement. 

(f) Plumbing. The plumbing in your 

physical plant must be of an adequate 

size and design and be adequately 

installed and maintained to: 

(1) Carry sufficient amounts of water 

to required locations throughout the 

physical plant; 

(2) Properly convey sewage and liquid 

disposable waste from your physical 

plant; 

(3) Avoid being a source of 

contamination to components, dietary 

supplements, water supplies, or any 

contact surface, or creating an 

unsanitary condition; 

(4) Provide adequate floor drainage in 

all areas where floors are subject to 

flooding-type cleaning or where normal 

operations release or discharge water or 

other liquid waste on the floor; and 

(5) Not allow backflow from, or cross 

connection between, piping systems 

that discharge waste water or sewage 

and piping systems that carry water 

used for manufacturing dietary 

supplements, for cleaning contact 

surfaces, or for use in bathrooms or 

hand-washing facilities. 

(g) Sewage disposal. You must 

dispose of sewage into an adequate 

sewage system or through other 

adequate means. 

(h) Bathrooms. You must provide 

your employees with adequate, readily 

accessible bathrooms. The bathrooms 

must be kept clean and must not be a 

potential source of contamination to 

components, dietary supplements, or 

contact surfaces. 

(i) Hand-washing facilities. You must 

provide hand-washing facilities that are 

designed to ensure that an employee’s 

hands are not a source of contamination 

of components, dietary supplements, or 

any contact surface, by providing 

facilities that are adequate, convenient, 

and furnish running water at a suitable 

temperature. 

(j) Trash disposal. You must convey, 

store, and dispose of trash to: 

(1) Minimize the development of 

odors; 

(2) Minimize the potential for the 

trash to attract, harbor, or become a 

breeding place for pests; 

(3) Protect against contamination of 

components, dietary supplements, any 

contact surface, water supplies, and 

grounds surrounding your physical 

plant; and 

(4) Control hazardous waste to 

prevent contamination of components, 

dietary supplements, and contact 

surfaces. 

(k) Sanitation supervisors. You must 

assign one or more employees to 

supervise overall sanitation. Each of 

these supervisors must be qualified by 

education, training, or experience to 

develop and supervise sanitation 

procedures. 

§ 111.16 What are the requirements under 

this subpart C for written procedures? 

You must establish and follow written 

procedures for cleaning the physical 

plant and for pest control. 

§ 111.20 What design and construction 

requirements apply to your physical plant? 

Any physical plant you use in the 

manufacture, packaging, labeling, or 

holding of dietary supplements must: 

(a) Be suitable in size, construction, 

and design to facilitate maintenance, 

cleaning, and sanitizing operations; 

(b) Have adequate space for the 

orderly placement of equipment and 

holding of materials as is necessary for 

maintenance, cleaning, and sanitizing 

operations and to prevent 

contamination and mixups of 

components and dietary supplements 

during manufacturing, packaging, 

labeling, or holding; 

(c) Permit the use of proper 

precautions to reduce the potential for 

mixups or contamination of 

components, dietary supplements, or 

contact surfaces, with microorganisms, 

chemicals, filth, or other extraneous 

material. Your physical plant must 

have, and you must use, separate or 

defined areas of adequate size or other 

control systems, such as computerized 

inventory controls or automated systems 

of separation, to prevent contamination 

and mixups of components and dietary 

supplements during the following 

operations: 

(1) Receiving, identifying, holding, 

and withholding from use, components, 

dietary supplements, packaging, and 

labels that will be used in or during the 

manufacturing, packaging, labeling, or 

holding of dietary supplements; 

(2) Separating, as necessary, 

components, dietary supplements, 

packaging, and labels that are to be used 

in manufacturing from components, 

dietary supplements, packaging, or 

labels that are awaiting material review 

and disposition decision, reprocessing, 

or are awaiting disposal after rejection; 

(3) Separating the manufacturing, 

packaging, labeling, and holding of 

different product types including 

different types of dietary supplements 

and other foods, cosmetics, and 

pharmaceutical products; 

(4) Performing laboratory analyses 

and holding laboratory supplies and 

samples; 

(5) Cleaning and sanitizing contact 

surfaces; 

(6) Packaging and label operations; 

and 

(7) Holding components or dietary 

supplements. 

(d) Be designed and constructed in a 

manner that prevents contamination of 

components, dietary supplements, or 

contact surfaces. 

(1) The design and construction must 

include: 

(i) Floors, walls, and ceilings that can 

be adequately cleaned and kept clean 

and in good repair; 

(ii) Fixtures, ducts, and pipes that do 

not contaminate components, dietary 

supplements, or contact surfaces by 

dripping or other leakage, or 

condensate; 

(iii) Adequate ventilation or 

environmental control equipment such 

as airflow systems, including filters, 

fans, and other air-blowing equipment, 

that minimize odors and vapors 

(including steam and noxious fumes) in 

areas where they may contaminate 

components, dietary supplements, or 

contact surfaces; 

(iv) Equipment that controls 

temperature and humidity, when such 

equipment is necessary to ensure the 

quality of the dietary supplement; and 

(v) Aisles or working spaces between 

equipment and walls that are adequately 


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unobstructed and of adequate width to 

permit all persons to perform their 

duties and to protect against 

contamination of components, dietary 

supplements, or contact surfaces with 

clothing or personal contact. 

(2) When fans and other air-blowing 

equipment are used, such fans and 

equipment must be located and 

operated in a manner that minimizes the 

potential for microorganisms and 

particulate matter to contaminate 

components, dietary supplements, or 

contact surfaces; 

(e) Provide adequate light in: 

(1) All areas where components or 

dietary supplements are examined, 

processed, or held; 

(2) All areas where contact surfaces 

are cleaned; and 

(3) Hand-washing areas, dressing and 

locker rooms, and bathrooms. 

(f) Use safety-type light bulbs, 

fixtures, skylights, or other glass or 

glass-like materials when the light 

bulbs, fixtures, skylights or other glass 

or glass-like materials are suspended 

over exposed components or dietary 

supplements in any step of preparation, 

unless your physical plant is otherwise 

constructed in a manner that will 

protect against contamination of 

components or dietary supplements in 

case of breakage of glass or glass-like 

materials. 

(g) Provide effective protection against 

contamination of components and 

dietary supplements in bulk 

fermentation vessels, by, for example: 

(1) Use of protective coverings; 

(2) Placement in areas where you can 

eliminate harborages for pests over and 

around the vessels; 

(3) Placement in areas where you can 

check regularly for pests, pest 

infestation, filth or any other extraneous 

materials; and 

(4) Use of skimming equipment. 

(h) Use adequate screening or other 

protection against pests, where 

necessary. 

§ 111.23 Under this subpart C, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart C in 

accordance with subpart P of this part. 

(b) You must make and keep records 

of the written procedures for cleaning 

the physical plant and for pest control. 

(c) You must make and keep records 

that show that water, when used in a 

manner such that the water may become 

a component of the dietary supplement, 

meets the requirements of § 111.15(e)(2). 

Subpart D—Equipment and Utensils 

§ 111.25 What are the requirements under 

this subpart D for written procedures? 

You must establish and follow written 

procedures for fulfilling the 

requirements of this subpart D, 

including written procedures for: 

(a) Calibrating instruments and 

controls that you use in manufacturing 

or testing a component or dietary 

supplement; 

(b) Calibrating, inspecting, and 

checking automated, mechanical, and 

electronic equipment; and 

(c) Maintaining, cleaning, and 

sanitizing, as necessary, all equipment, 

utensils, and any other contact surfaces 

that are used to manufacture, package, 

label, or hold components or dietary 

supplements. 

§ 111.27 What requirements apply to the 

equipment and utensils that you use? 

(a) You must use equipment and 

utensils that are of appropriate design, 

construction, and workmanship to 

enable them to be suitable for their 

intended use and to be adequately 

cleaned and properly maintained. 

(1) Equipment and utensils include 

the following: 

(i) Equipment used to hold or convey; 

(ii) Equipment used to measure; 

(iii) Equipment using compressed air 

or gas; 

(iv) Equipment used to carry out 

processes in closed pipes and vessels; 

and 

(v) Equipment used in automated, 

mechanical, or electronic systems. 

(2) You must use equipment and 

utensils of appropriate design and 

construction so that use will not result 

in the contamination of components or 

dietary supplements with: 

(i) Lubricants; 

(ii) Fuel; 

(iii) Coolants; 

(iv) Metal or glass fragments; 

(v) Filth or any other extraneous 

material; 

(vi) Contaminated water; or 

(vii) Any other contaminants. 

(3) All equipment and utensils you 

use must be: 

(i) Installed and maintained to 

facilitate cleaning the equipment, 

utensils, and all adjacent spaces; 

(ii) Corrosion-resistant if the 

equipment or utensils contact 

components or dietary supplements; 

(iii) Made of nontoxic materials; 

(iv) Designed and constructed to 

withstand the environment in which 

they are used, the action of components 

or dietary supplements, and, if 

applicable, cleaning compounds and 

sanitizing agents; and 

(v) Maintained to protect components 

and dietary supplements from being 

contaminated by any source. 

(4) Equipment and utensils you use 

must have seams that are smoothly 

bonded or maintained to minimize 

accumulation of dirt, filth, organic 

material, particles of components or 

dietary supplements, or any other 

extraneous materials or contaminants. 

(5) Each freezer, refrigerator, and 

other cold storage compartment you use 

to hold components or dietary 

supplements: 

(i) Must be fitted with an indicating 

thermometer, temperature-measuring 

device, or temperature-recording device 

that indicates and records, or allows for 

recording by hand, the temperature 

accurately within the compartment; and 

(ii) Must have an automated device 

for regulating temperature or an 

automated alarm system to indicate a 

significant temperature change in a 

manual operation. 

(6) Instruments or controls used in the 

manufacturing, packaging, labeling, or 

holding of a dietary supplement, and 

instruments or controls that you use to 

measure, regulate, or record 

temperatures, hydrogen-ion 

concentration (pH), water activity, or 

other conditions, to control or prevent 

the growth of microorganisms or other 

contamination must be: 

(i) Accurate and precise; 

(ii) Adequately maintained; and 

(iii) Adequate in number for their 

designated uses. 

(7) Compressed air or other gases you 

introduce mechanically into or onto a 

component, dietary supplement, or 

contact surface or that you use to clean 

any contact surface must be treated in 

such a way that the component, dietary 

supplement, or contact surface is not 

contaminated. 

(b) You must calibrate instruments 

and controls you use in manufacturing 

or testing a component or dietary 

supplement. You must calibrate: 

(1) Before first use; 

(2) At the frequency specified in 

writing by the manufacturer of the 

instrument and control; or 

(3) At routine intervals or as 

otherwise necessary to ensure the 

accuracy and precision of the 

instrument and control. 

(c) You must repair or replace 

instruments or controls that cannot be 

adjusted to agree with the reference 

standard. 

(d) You must maintain, clean, and 

sanitize, as necessary, all equipment, 

utensils, and any other contact surfaces 

used to manufacture, package, label, or 

hold components or dietary 

supplements. 


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(1) Equipment and utensils must be 

taken apart as necessary for thorough 

maintenance, cleaning, and sanitizing. 

(2) You must ensure that all contact 

surfaces, used for manufacturing or 

holding low-moisture components or 

dietary supplements, are in a dry and 

sanitary condition when in use. When 

the surfaces are wet-cleaned, they must 

be sanitized, when necessary, and 

thoroughly dried before subsequent use. 

(3) If you use wet processing during 

manufacturing, you must clean and 

sanitize all contact surfaces, as 

necessary, to protect against the 

introduction of microorganisms into 

components or dietary supplements. 

When cleaning and sanitizing is 

necessary, you must clean and sanitize 

all contact surfaces before use and after 

any interruption during which the 

contact surface may have become 

contaminated. If you use contact 

surfaces in a continuous production 

operation or in consecutive operations 

involving different batches of the same 

dietary supplement, you must 

adequately clean and sanitize the 

contact surfaces, as necessary. 

(4) You must clean surfaces that do 

not come into direct contact with 

components or dietary supplements as 

frequently as necessary to protect 

against contaminating components or 

dietary supplements. 

(5) Single-service articles (such as 

utensils intended for one-time use, 

paper cups, and paper towels) must be: 

(i) Stored in appropriate containers; 

and 

(ii) Handled, dispensed, used, and 

disposed of in a manner that protects 

against contamination of components, 

dietary supplements, or any contact 

surface. 

(6) Cleaning compounds and 

sanitizing agents must be adequate for 

their intended use and safe under their 

conditions of use; 

(7) You must store cleaned and 

sanitized portable equipment and 

utensils that have contact surfaces in a 

location and manner that protects them 

from contamination. 

§ 111.30 What requirements apply to 

automated, mechanical, or electronic 

equipment? 

For any automated, mechanical, or 

electronic equipment that you use to 

manufacture, package, label, or hold a 

dietary supplement, you must: 

(a) Design or select equipment to 

ensure that dietary supplement 

specifications are consistently met; 

(b) Determine the suitability of the 

equipment by ensuring that your 

equipment is capable of operating 

satisfactorily within the operating limits 

required by the process; 

(c) Routinely calibrate, inspect, or 

check the equipment to ensure proper 

performance. Your quality control 

personnel must periodically review 

these calibrations, inspections, or 

checks; 

(d) Establish and use appropriate 

controls for automated, mechanical, and 

electronic equipment (including 

software for a computer controlled 

process) to ensure that any changes to 

the manufacturing, packaging, labeling, 

holding, or other operations are 

approved by quality control personnel 

and instituted only by authorized 

personnel; and 

(e) Establish and use appropriate 

controls to ensure that the equipment 

functions in accordance with its 

intended use. These controls must be 

approved by quality control personnel. 

§ 111.35 Under this subpart D, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart D in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for fulfilling 

the requirements of this subpart, 

including written procedures for: 

(i) Calibrating instruments and 

controls that you use in manufacturing 

or testing a component or dietary 

supplement; 

(ii) Calibrating, inspecting, and 

checking automated, mechanical, and 

electronic equipment; and 

(iii) Maintaining, cleaning, and 

sanitizing, as necessary, all equipment, 

utensils, and any other contact surfaces 

that are used to manufacture, package, 

label, or hold components or dietary 

supplements; 

(2) Documentation, in individual 

equipment logs, of the date of the use, 

maintenance, cleaning, and sanitizing of 

equipment, unless such documentation 

is kept with the batch record; 

(3) Documentation of any calibration, 

each time the calibration is performed, 

for instruments and controls that you 

use in manufacturing or testing a 

component or dietary supplement. In 

your documentation, you must: 

(i) Identify the instrument or control 

calibrated; 

(ii) Provide the date of calibration; 

(iii) Identify the reference standard 

used including the certification of 

accuracy of the known reference 

standard and a history of recertification 

of accuracy; 

(iv) Identify the calibration method 

used, including appropriate limits for 

accuracy and precision of instruments 

and controls when calibrating; 

(v) Provide the calibration reading or 

readings found; 

(vi) Identify the recalibration method 

used, and reading or readings found, if 

accuracy or precision or both accuracy 

and precision limits for instruments and 

controls were not met; and 

(vii) Include the initials of the person 

who performed the calibration and any 

recalibration. 

(4) Written records of calibrations, 

inspections, and checks of automated, 

mechanical, and electronic equipment; 

(5) Backup file(s) of current software 

programs (and of outdated software that 

is necessary to retrieve records that you 

are required to keep in accordance with 

subpart P of this part, when current 

software is not able to retrieve such 

records) and of data entered into 

computer systems that you use to 

manufacture, package, label, or hold 

dietary supplements. 

(i) Your backup file (e.g., a hard copy 

of data you have entered, diskettes, 

tapes, microfilm, or compact disks) 

must be an exact and complete record 

of the data you entered. 

(ii) You must keep your backup 

software programs and data secure from 

alterations, inadvertent erasures, or loss; 

and 

(6) Documentation of the controls that 

you use to ensure that equipment 

functions in accordance with its 

intended use. 

Subpart E—Requirement to Establish a 

Production and Process Control 

System 

§ 111.55 What are the requirements to 

implement a production and process 

control system? 

You must implement a system of 

production and process controls that 

covers all stages of manufacturing, 

packaging, labeling, and holding of the 

dietary supplement to ensure the quality 

of the dietary supplement and that the 

dietary supplement is packaged and 

labeled as specified in the master 

manufacturing record. 

§ 111.60 What are the design requirements 

for the production and process control 

system? 

(a) Your production and in-process 

control system must be designed to 

ensure that the dietary supplement is 

manufactured, packaged, labeled, and 

held in a manner that will ensure the 

quality of the dietary supplement and 

that the dietary supplement is packaged 

and labeled as specified in the master 

manufacturing record; and 

(b) The production and in-process 

control system must include all 

requirements of subparts E through L of 

this part and must be reviewed and 

approved by quality control personnel. 


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§ 111.65 What are the requirements for 

quality control operations? 

You must implement quality control 

operations in your manufacturing, 

packaging, labeling, and holding 

operations for producing the dietary 

supplement to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. 

§ 111.70 What specifications must you 

establish? 

(a) You must establish a specification 

for any point, step, or stage in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. 

(b) For each component that you use 

in the manufacture of a dietary 

supplement, you must establish 

component specifications as follows: 

(1) You must establish an identity 

specification; 

(2) You must establish component 

specifications that are necessary to 

ensure that specifications for the purity, 

strength and composition of dietary 

supplements manufactured using the 

components are met; and 

(3) You must establish limits on those 

types of contamination that may 

adulterate or may lead to adulteration of 

the finished batch of the dietary 

supplement to ensure the quality of the 

dietary supplement. 

(c) For the in-process production: 

(1) You must establish in-process 

specifications for any point, step, or 

stage in the master manufacturing 

record where control is necessary to 

help ensure that specifications are met 

for the identity, purity, strength, and 

composition of the dietary supplements 

and, as necessary, for limits on those 

types of contamination that may 

adulterate or may lead to adulteration of 

the finished batch of the dietary 

supplement; 

(2) You must provide adequate 

documentation of your basis for why 

meeting the in-process specifications, in 

combination with meeting component 

specifications, will help ensure that the 

specifications are met for the identity, 

purity, strength, and composition of the 

dietary supplements and for limits on 

those types of contamination that may 

adulterate or may lead to adulteration of 

the finished batch of the dietary 

supplement; and 

(3) Quality control personnel must 

review and approve the documentation 

that you provide under paragraph (c)(2) 

of this section. 

(d) You must establish specifications 

for dietary supplement labels (label 

specifications) and for packaging that 

may come in contact with dietary 

supplements (packaging specifications). 

Packaging that may come into contact 

with dietary supplements must be safe 

and suitable for its intended use and 

must not be reactive or absorptive or 

otherwise affect the safety or quality of 

the dietary supplement. 

(e) For each dietary supplement that 

you manufacture you must establish 

product specifications for the identity, 

purity, strength, and composition of the 

finished batch of the dietary 

supplement, and for limits on those 

types of contamination that may 

adulterate, or that may lead to 

adulteration of, the finished batch of the 

dietary supplement to ensure the quality 

of the dietary supplement. 

(f) If you receive a product from a 

supplier for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier), 

you must establish specifications to 

provide sufficient assurance that the 

product you receive is adequately 

identified and is consistent with your 

purchase order. 

(g) You must establish specifications 

for the packaging and labeling of the 

finished packaged and labeled dietary 

supplements, including specifications 

that ensure that you used the specified 

packaging and that you applied the 

specified label. 

§ 111.73 What is your responsibility for 

determining whether established 

specifications are met? 

You must determine whether the 

specifications you establish under 

§ 111.70 are met. 

§ 111.75 What must you do to determine 

whether specifications are met? 

(a) Before you use a component, you 

must: 

(1) Conduct at least one appropriate 

test or examination to verify the identity 

of any component that is a dietary 

ingredient; and 

(2) Confirm the identity of other 

components and determine whether 

other applicable component 

specifications established in accordance 

with § 111.70(b) are met. To do so, you 

must either: 

(i) Conduct appropriate tests or 

examinations; or 

(ii) Rely on a certificate of analysis 

from the supplier of the component that 

you receive, provided that: 

(A) You first qualify the supplier by 

establishing the reliability of the 

supplier’s certificate of analysis through 

confirmation of the results of the 

supplier’s tests or examinations; 

(B) The certificate of analysis includes 

a description of the test or examination 

method(s) used, limits of the test or 

examinations, and actual results of the 

tests or examinations; 

(C) You maintain documentation of 

how you qualified the supplier; 

(D) You periodically re-confirm the 

supplier’s certificate of analysis; and 

(E) Your quality control personnel 

review and approve the documentation 

setting forth the basis for qualification 

(and re-qualification) of any supplier. 

(b) You must monitor the in-process 

points, steps, or stages where control is 

necessary to ensure the quality of the 

finished batch of dietary supplement to: 

(1) Determine whether the in-process 

specifications are met; and 

(2) Detect any deviation or 

unanticipated occurrence that may 

result in a failure to meet specifications. 

(c) For a subset of finished dietary 

supplement batches that you identify 

through a sound statistical sampling 

plan (or for every finished batch), you 

must verify that your finished batch of 

the dietary supplement meets product 

specifications for identity, purity, 

strength, composition, and for limits on 

those types of contamination that may 

adulterate or that may lead to 

adulteration of the finished batch of the 

dietary supplement. To do so: 

(1) You must select one or more 

established specifications for identity, 

purity, strength, composition, and the 

limits on those types of contamination 

that may adulterate or that may lead to 

adulteration of the dietary supplement 

that, if tested or examined on the 

finished batches of the dietary 

supplement, would verify that the 

production and process control system 

is producing a dietary supplement that 

meets all product specifications (or only 

those product specifications not 

otherwise exempted from this provision 

by quality control personnel under 

paragraph (d) of this section); 

(2) You must conduct appropriate 

tests or examinations to determine 

compliance with the specifications 

selected in paragraph (c)(1) of this 

section; 

(3) You must provide adequate 

documentation of your basis for 

determining compliance with the 

specification(s) selected under 

paragraph (c)(1) of this section, through 

the use of appropriate tests or 

examinations conducted under 

paragraph (c)(2) of this section, will 

ensure that your finished batch of the 

dietary supplement meets all product 

specifications for identity, purity, 

strength, and composition, and the 

limits on those types of contamination 

that may adulterate, or that may lead to 


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the adulteration of, the dietary 

supplement; and 

(4) Your quality control personnel 

must review and approve the 

documentation that you provide under 

paragraph (c)(3) of this section. 

(d)(1) You may exempt one or more 

product specifications from verification 

requirements in paragraph (c)(1) of this 

section if you determine and document 

that the specifications you select under 

paragraph (c)(1) of this section for 

determination of compliance with 

specifications are not able to verify that 

the production and process control 

system is producing a dietary 

supplement that meets the exempted 

product specification and there is no 

scientifically valid method for testing or 

examining such exempted product 

specification at the finished batch stage. 

In such a case, you must document why, 

for example, any component and inprocess testing, examination, or 

monitoring, and any other information, 

will ensure that such exempted product 

specification is met without verification 

through periodic testing of the finished 

batch; and 

(2) Your quality control personnel 

must review and approve the 

documentation that you provide under 

paragraph (d)(1) of this section. 

(e) Before you package or label a 

product that you receive for packaging 

or labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier), you must visually 

examine the product and have 

documentation to determine whether 

the specifications that you established 

under § 111.70 (f) are met. 

(f)(1) Before you use packaging, you 

must, at a minimum, conduct a visual 

identification of the containers and 

closures and review the supplier’s 

invoice, guarantee, or certification to 

determine whether the packaging 

specifications are met; and 

(2) Before you use labels, you must, at 

a minimum, conduct a visual 

examination of the label and review the 

supplier’s invoice, guarantee, or 

certification to determine whether label 

specifications are met. 

(g) You must, at a minimum, conduct 

a visual examination of the packaging 

and labeling of the finished packaged 

and labeled dietary supplements to 

determine whether you used the 

specified packaging and applied the 

specified label. 

(h)(1) You must ensure that the tests 

and examinations that you use to 

determine whether the specifications 

are met are appropriate, scientifically 

valid methods. 

(2) The tests and examinations that 

you use must include at least one of the 

following: 

(i) Gross organoleptic analysis; 

(ii) Macroscopic analysis; 

(iii) Microscopic analysis; 

(iv) Chemical analysis; or 

(v) Other scientifically valid methods. 

(i) You must establish corrective 

action plans for use when an established 

specification is not met. 

§ 111.77 What must you do if established 

specifications are not met? 

(a) For specifications established 

under § 111.70(a), (b)(2), (b)(3), (c), (d), 

(e), and (g) that you do not meet, quality 

control personnel, in accordance with 

the requirements in subpart F of this 

part, must reject the component, dietary 

supplement, package or label unless 

such personnel approve a treatment, an 

in-process adjustment, or reprocessing 

that will ensure the quality of the 

finished dietary supplement and that 

the dietary supplement is packaged and 

labeled as specified in the master 

manufacturing record. No finished batch 

of dietary supplements may be released 

for distribution unless it complies with 

§ 111.123(b). 

(b) For specifications established 

under § 111.70(b)(1) that you do not 

meet, quality control personnel must 

reject the component and the 

component must not be used in 

manufacturing the dietary supplement. 

(c) For specifications established 

under § 111.70(f) that you do not meet, 

quality control personnel must reject the 

product and the product may not be 

packaged or labeled for distribution as 

a dietary supplement. 

§ 111.80 What representative samples 

must you collect? 

The representative samples that you 

must collect include: 

(a) Representative samples of each 

unique lot of components, packaging, 

and labels that you use to determine 

whether the components, packaging, 

and labels meet specifications 

established in accordance with 

§ 111.70(b) and (d), and as applicable, 

§ 111.70(a) (and, when you receive 

components, packaging, or labels from a 

supplier, representative samples of each 

unique shipment, and of each unique lot 

within each unique shipment); 

(b) Representative samples of inprocess materials for each manufactured 

batch at points, steps, or stages, in the 

manufacturing process as specified in 

the master manufacturing record where 

control is necessary to ensure the 

identity, purity, strength, and 

composition of dietary supplements to 

determine whether the in-process 

materials meet specifications 

established in accordance with 

§ 111.70(c), and as applicable, 

§ 111.70(a); 

(c) Representative samples of a subset 

of finished batches of each dietary 

supplement that you manufacture, 

which you identify through a sound 

statistical sampling plan (or otherwise 

every finished batch), before releasing 

for distribution to verify that the 

finished batch of dietary supplement 

meets product specifications established 

in accordance with § 111.70(e), and as 

applicable, § 111.70(a); 

(d) Representative samples of each 

unique shipment, and of each unique lot 

within each unique shipment, of 

product that you receive for packaging 

or labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier) to determine whether the 

received product meets specifications 

established in accordance with 

§ 111.70(f), and as applicable, 

§ 111.70(a); and 

(e) Representative samples of each lot 

of packaged and labeled dietary 

supplements to determine whether the 

packaging and labeling of the finished 

packaged and labeled dietary 

supplements meet specifications 

established in accordance with 

§ 111.70(g), and as applicable, 

§ 111.70(a). 

§ 111.83 What are the requirements for 

reserve samples? 

(a) You must collect and hold reserve 

samples of each lot of packaged and 

labeled dietary supplements that you 

distribute. 

(b) The reserve samples must: 

(1) Be held using the same containerclosure system in which the packaged 

and labeled dietary supplement is 

distributed, or if distributing dietary 

supplements to be packaged and 

labeled, using a container-closure 

system that provides essentially the 

same characteristics to protect against 

contamination or deterioration as the 

one in which it is distributed for 

packaging and labeling elsewhere; 

(2) Be identified with the batch, lot, 

or control number; 

(3) Be retained for 1 year past the 

shelf life date (if shelf life dating is 

used), or for 2 years from the date of 

distribution of the last batch of dietary 

supplements associated with the reserve 

sample, for use in appropriate 

investigations; and 

(4) Consist of at least twice the 

quantity necessary for all tests or 

examinations to determine whether or 

not the dietary supplement meets 

product specifications. 


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§ 111.87 Who conducts a material review 

and makes a disposition decision? 

Quality control personnel must 

conduct all required material reviews 

and make all required disposition 

decisions. 

§ 111.90 What requirements apply to 

treatments, in-process adjustments, and 

reprocessing when there is a deviation or 

unanticipated occurrence or when a 

specification established in accordance 

with § 111.70 is not met? 

(a) You must not reprocess a rejected 

dietary supplement or treat or provide 

an in-process adjustment to a 

component, packaging, or label to make 

it suitable for use in the manufacture of 

a dietary supplement unless: 

(1) Quality control personnel conduct 

a material review and make a 

disposition decision to approve the 

reprocessing, treatment, or in-process 

adjustment; and 

(2) The reprocessing, treatment, or inprocess adjustment is permitted by 

§ 111.77; 

(b) You must not reprocess any 

dietary supplement or treat or provide 

an in-process adjustment to a 

component to make it suitable for use in 

the manufacture of a dietary 

supplement, unless: 

(1) Quality control personnel conduct 

a material review and make a 

disposition decision that is based on a 

scientifically valid reason and approves 

the reprocessing, treatment, or inprocess adjustment; and 

(2) The reprocessing, treatment or inprocess adjustment is permitted by 

§ 111.77; 

(c) Any batch of dietary supplement 

that is reprocessed, that contains 

components that you have treated, or to 

which you have made in-process 

adjustments to make them suitable for 

use in the manufacture of the dietary 

supplement must be approved by 

quality control personnel and comply 

with § 111.123(b) before releasing for 

distribution. 

§ 111.95 Under this subpart E, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart E in 

accordance with subpart P of this part. 

(b) Under this subpart E, you must 

make and keep the following records: 

(1) The specifications established; 

(2) Documentation of your 

qualification of a supplier for the 

purpose of relying on the supplier’s 

certificate of analysis; 

(3) Documentation for why meeting 

in-process specifications, in 

combination with meeting component 

specifications, helps ensure that the 

dietary supplement meets the 

specifications for identity, purity, 

strength, and composition; and for 

limits on those types of contamination 

that may adulterate or may lead to 

adulteration of the finished batch of the 

dietary supplement; and 

(4) Documentation for why the results 

of appropriate tests or examinations for 

the product specifications selected 

under § 111.75(c)(1) ensure that the 

dietary supplement meets all product 

specifications; 

(5) Documentation for why any 

component and in-process testing, 

examination, or monitoring, and any 

other information, will ensure that a 

product specification that is exempted 

under § 111.75(d) is met without 

verification through periodic testing of 

the finished batch, including 

documentation that the selected 

specifications tested or examined under 

§ 111.75 (c)(1) are not able to verify that 

the production and process control 

system is producing a dietary 

supplement that meets the exempted 

product specification and there is no 

scientifically valid method for testing or 

examining such exempted product 

specification at the finished batch stage. 

Subpart F—Production and Process 

Control System: Requirements for 

Quality Control 

§ 111.103 What are the requirements under 

this subpart F for written procedures? 

You must establish and follow written 

procedures for the responsibilities of the 

quality control operations, including 

written procedures for conducting a 

material review and making a 

disposition decision, and for approving 

or rejecting any reprocessing. 

§ 111.105 What must quality control 

personnel do? 

Quality control personnel must 

ensure that your manufacturing, 

packaging, labeling, and holding 

operations ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record. To do so, quality control 

personnel must perform operations that 

include: 

(a) Approving or rejecting all 

processes, specifications, written 

procedures, controls, tests, and 

examinations, and deviations from or 

modifications to them, that may affect 

the identity, purity, strength, or 

composition of a dietary supplement; 

(b) Reviewing and approving the 

documentation setting forth the basis for 

qualification of any supplier; 

(c) Reviewing and approving the 

documentation setting forth the basis for 

why meeting in-process specifications, 

in combination with meeting 

component specifications, will help 

ensure that the identity, purity, strength, 

and composition of the dietary 

supplement are met; 

(d) Reviewing and approving the 

documentation setting forth the basis for 

why the results of appropriate tests or 

examinations for each product 

specification selected under 

§ 111.75(c)(1) will ensure that the 

finished batch of the dietary supplement 

meets product specifications; 

(e) Reviewing and approving the basis 

and the documentation for why any 

product specification is exempted from 

the verification requirements in 

§ 111.75(c)(1), and for why any 

component and in-process testing, 

examination, or monitoring, or other 

methods will ensure that such exempted 

product specification is met without 

verification through periodic testing of 

the finished batch; 

(f) Ensuring that required 

representative samples are collected; 

(g) Ensuring that required reserve 

samples are collected and held; 

(h) Determining whether all 

specifications established under 

§ 111.70(a) are met; and 

(i) Performing other operations 

required under this subpart. 

§ 111.110 What quality control operations 

are required for laboratory operations 

associated with the production and process 

control system? 

Quality control operations for 

laboratory operations associated with 

the production and process control 

system must include: 

(a) Reviewing and approving all 

laboratory control processes associated 

with the production and process control 

system; 

(b) Ensuring that all tests and 

examinations required under § 111.75 

are conducted; and 

(c) Reviewing and approving the 

results of all tests and examinations 

required under § 111.75. 

§ 111.113 What quality control operations 

are required for a material review and 

disposition decision? 

(a) Quality control personnel must 

conduct a material review and make a 

disposition decision if: 

(1) A specification established in 

accordance with § 111.70 is not met; 

(2) A batch deviates from the master 

manufacturing record, including when 

any step established in the master 

manufacturing record is not completed 

and including any deviation from 

specifications; 

(3) There is any unanticipated 

occurrence during the manufacturing 


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operations that adulterates or may lead 

to adulteration of the component, 

dietary supplement, or packaging, or 

could lead to the use of a label not 

specified in the master manufacturing 

record; 

(4) Calibration of an instrument or 

control suggests a problem that may 

have resulted in a failure to ensure the 

quality of a batch or batches of a dietary 

supplement; or 

(5) A dietary supplement is returned. 

(b)(1) When there is a deviation or 

unanticipated occurrence during the 

production and in-process control 

system that results in or could lead to 

adulteration of a component, dietary 

supplement, or packaging, or could lead 

to the use of a label not specified in the 

master manufacturing record, quality 

control personnel must reject the 

component, dietary supplement, 

packaging, or label unless it approves a 

treatment, an in-process adjustment, or 

reprocessing to correct the applicable 

deviation or occurrence. 

(2) When a specification established 

in accordance with § 111.70 is not met, 

quality control personnel must reject the 

component, dietary supplement, 

package or label, unless quality control 

personnel approve a treatment, an inprocess adjustment, or reprocessing, as 

permitted in § 111.77. 

(c) The person who conducts a 

material review and makes the 

disposition decision must, at the time of 

performance, document that material 

review and disposition decision. 

§ 111.117 What quality control operations 

are required for equipment, instruments, 

and controls? 

Quality control operations for 

equipment, instruments, and controls 

must include: 

(a) Reviewing and approving all 

processes for calibrating instruments 

and controls; 

(b) Periodically reviewing all records 

for calibration of instruments and 

controls; 

(c) Periodically reviewing all records 

for calibrations, inspections, and checks 

of automated, mechanical, or electronic 

equipment; and 

(d) Reviewing and approving controls 

to ensure that automated, mechanical, 

or electronic equipment functions in 

accordance with its intended use. 

§ 111.120 What quality control operations 

are required for components, packaging, 

and labels before use in the manufacture of 

a dietary supplement? 

Quality control operations for 

components, packaging, and labels 

before use in the manufacture of a 

dietary supplement must include: 

(a) Reviewing all receiving records for 

components, packaging, and labels; 

(b) Determining whether all 

components, packaging, and labels 

conform to specifications established 

under § 111.70 (b) and (d); 

(c) Conducting any required material 

review and making any required 

disposition decision; 

(d) Approving or rejecting any 

treatment and in-process adjustments of 

components, packaging, or labels to 

make them suitable for use in the 

manufacture of a dietary supplement; 

and 

(e) Approving, and releasing from 

quarantine, all components, packaging, 

and labels before they are used. 

§ 111.123 What quality control operations 

are required for the master manufacturing 

record, the batch production record, and 

manufacturing operations? 

(a) Quality control operations for the 

master manufacturing record, the batch 

production record, and manufacturing 

operations must include: 

(1) Reviewing and approving all 

master manufacturing records and all 

modifications to the master 

manufacturing records; 

(2) Reviewing and approving all batch 

production-related records; 

(3) Reviewing all monitoring required 

under subpart E; 

(4) Conducting any required material 

review and making any required 

disposition decision; 

(5) Approving or rejecting any 

reprocessing; 

(6) Determining whether all inprocess specifications established in 

accordance with § 111.70(c) are met; 

(7) Determining whether each 

finished batch conforms to product 

specifications established in accordance 

with § 111.70(e); and 

(8) Approving and releasing, or 

rejecting, each finished batch for 

distribution, including any reprocessed 

finished batch. 

(b) Quality control personnel must not 

approve and release for distribution: 

(1) Any batch of dietary supplement 

for which any component in the batch 

does not meet its identity specification; 

(2) Any batch of dietary supplement, 

including any reprocessed batch, that 

does not meet all product specifications 

established in accordance with 

§ 111.70(e); 

(3) Any batch of dietary supplement, 

including any reprocessed batch, that 

has not been manufactured, packaged, 

labeled, and held under conditions to 

prevent adulteration under section 

402(a)(1), (a)(2), (a)(3), and (a)(4) of the 

act; and 

(4) Any product received from a 

supplier for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier) for 

which sufficient assurance is not 

provided to adequately identify the 

product and to determine that the 

product is consistent with your 

purchase order. 

§ 111.127 What quality control operations 

are required for packaging and labeling 

operations? 

Quality control operations for 

packaging and labeling operations must 

include: 

(a) Reviewing the results of any visual 

examination and documentation to 

ensure that specifications established 

under § 111.70(f) are met for all 

products that you receive for packaging 

and labeling as a dietary supplement 

(and for distribution rather than for 

return to the supplier); 

(b) Approving, and releasing from 

quarantine, all products that you receive 

for packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier) before 

they are used for packaging or labeling; 

(c) Reviewing and approving all 

records for packaging and label 

operations; 

(d) Determining whether the finished 

packaged and labeled dietary 

supplement conforms to specifications 

established in accordance with 

§ 111.70(g); 

(e) Conducting any required material 

review and making any required 

disposition decision; 

(f) Approving or rejecting any 

repackaging of a packaged dietary 

supplement; 

(g) Approving or rejecting any 

relabeling of a packaged and labeled 

dietary supplement; and 

(h) Approving for release, or rejecting, 

any packaged and labeled dietary 

supplement (including a repackaged or 

relabeled dietary supplement) for 

distribution. 

§ 111.130 What quality control operations 

are required for returned dietary 

supplements? 

Quality control operations for 

returned dietary supplements must 

include: 

(a) Conducting any required material 

review and making any required 

disposition decision; including: 

(1) Determining whether tests or 

examination are necessary to determine 

compliance with product specifications 

established in accordance with 

§ 111.70(e); and 

(2) Reviewing the results of any tests 

or examinations that are conducted to 

determine compliance with product 

specifications established in accordance 

with § 111.70(e); 


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(b) Approving or rejecting any salvage 

and redistribution of any returned 

dietary supplement; 

(c) Approving or rejecting any 

reprocessing of any returned dietary 

supplement; and 

(d) Determining whether the 

reprocessed dietary supplement meets 

product specifications and either 

approving for release, or rejecting, any 

returned dietary supplement that is 

reprocessed. 

§ 111.135 What quality control operations 

are required for product complaints? 

Quality control operations for product 

complaints must include reviewing and 

approving decisions about whether to 

investigate a product complaint and 

reviewing and approving the findings 

and followup action of any investigation 

performed. 

§ 111.140 Under this subpart F, what 

records must you make and keep? 

(a) You must make and keep the 

records required under this subpart F in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for the 

responsibilities of the quality control 

operations, including written 

procedures for conducting a material 

review and making a disposition 

decision and written procedures for 

approving or rejecting any reprocessing; 

(2) Written documentation, at the time 

of performance, that quality control 

personnel performed the review, 

approval, or rejection requirements by 

recording the following: 

(i) Date that the review, approval, or 

rejection was performed; and 

(ii) Signature of the person performing 

the review, approval, or rejection; and 

(3) Documentation of any material 

review and disposition decision and 

followup. Such documentation must be 

included in the appropriate batch 

production record and must include: 

(i) Identification of the specific 

deviation or the unanticipated 

occurrence; 

(ii) Description of your investigation 

into the cause of the deviation from the 

specification or the unanticipated 

occurrence; 

(iii) Evaluation of whether or not the 

deviation or unanticipated occurrence 

has resulted in or could lead to a failure 

to ensure the quality of the dietary 

supplement or a failure to package and 

label the dietary supplement as 

specified in the master manufacturing 

record; 

(iv) Identification of the action(s) 

taken to correct, and prevent a 

recurrence of, the deviation or the 

unanticipated occurrence; 

(v) Explanation of what you did with 

the component, dietary supplement, 

packaging, or label; 

(vi) A scientifically valid reason for 

any reprocessing of a dietary 

supplement that is rejected or any 

treatment or in-process adjustment of a 

component that is rejected; and 

(vii) The signature of the individual(s) 

designated to perform the quality 

control operation, who conducted the 

material review and made the 

disposition decision, and of each 

qualified individual who provides 

information relevant to that material 

review and disposition decision. 

Subpart G—Production and Process 

Control System: Requirements for 

Components, Packaging, and Labels 

and for Product That You Receive for 

Packaging or Labeling as a Dietary 

Supplement 

§ 111.153 What are the requirements under 

this subpart G for written procedures? 

You must establish and follow written 

procedures for fulfilling the 

requirements of this subpart G. 

§ 111.155 What requirements apply to 

components of dietary supplements? 

(a) You must visually examine each 

immediate container or grouping of 

immediate containers in a shipment that 

you receive for appropriate content 

label, container damage, or broken seals 

to determine whether the container 

condition may have resulted in 

contamination or deterioration of the 

components; 

(b) You must visually examine the 

supplier’s invoice, guarantee, or 

certification in a shipment you receive 

to ensure the components are consistent 

with your purchase order; 

(c) You must quarantine components 

before you use them in the manufacture 

of a dietary supplement until: 

(1) You collect representative samples 

of each unique lot of components (and, 

for components that you receive, of each 

unique shipment, and of each unique lot 

within each unique shipment); 

(2) Quality control personnel review 

and approve the results of any tests or 

examinations conducted on 

components; and 

(3) Quality control personnel approve 

the components for use in the 

manufacture of a dietary supplement, 

including approval of any treatment 

(including in-process adjustments) of 

components to make them suitable for 

use in the manufacture of a dietary 

supplement, and releases them from 

quarantine. 

(d)(1) You must identify each unique 

lot within each unique shipment of 

components that you receive and any lot 

of components that you produce in a 

manner that allows you to trace the lot 

to the supplier, the date received, the 

name of the component, the status of the 

component (e.g., quarantined, approved, 

or rejected); and to the dietary 

supplement that you manufactured and 

distributed. 

(2) You must use this unique 

identifier whenever you record the 

disposition of each unique lot within 

each unique shipment of components 

that you receive and any lot of 

components that you produce. 

(e) You must hold components under 

conditions that will protect against 

contamination and deterioration, and 

avoid mixups. 

§ 111.160 What requirements apply to 

packaging and labels received? 

(a) You must visually examine each 

immediate container or grouping of 

immediate containers in a shipment for 

appropriate content label, container 

damage, or broken seals to determine 

whether the container condition may 

have resulted in contamination or 

deterioration of the packaging and 

labels. 

(b) You must visually examine the 

supplier’s invoice, guarantee, or 

certification in a shipment to ensure 

that the packaging or labels are 

consistent with your purchase order. 

(c) You must quarantine packaging 

and labels before you use them in the 

manufacture of a dietary supplement 

until: 

(1) You collect representative samples 

of each unique shipment, and of each 

unique lot within each unique 

shipment, of packaging and labels and, 

at a minimum, conduct a visual 

identification of the immediate 

containers and closures; 

(2) Quality control personnel review 

and approve the results of any tests or 

examinations conducted on the 

packaging and labels; and 

(3) Quality control personnel approve 

the packaging and labels for use in the 

manufacture of a dietary supplement 

and release them from quarantine. 

(d)(1) You must identify each unique 

lot within each unique shipment of 

packaging and labels in a manner that 

allows you to trace the lot to the 

supplier, the date received, the name of 

the packaging and label, the status of the 

packaging and label (e.g., quarantined, 

approved, or rejected); and to the 

dietary supplement that you distributed; 

and 

(2) You must use this unique 

identifier whenever you record the 

disposition of each unique lot within 


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each unique shipment of packaging and 

labels. 

(e) You must hold packaging and 

labels under conditions that will protect 

against contamination and deterioration, 

and avoid mixups. 

§ 111.165 What requirements apply to a 

product received for packaging or labeling 

as a dietary supplement (and for 

distribution rather than for return to the 

supplier)? 

(a) You must visually examine each 

immediate container or grouping of 

immediate containers in a shipment of 

product that you receive for packaging 

or labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier) for appropriate content 

label, container damage, or broken seals 

to determine whether the container 

condition may have resulted in 

contamination or deterioration of the 

received product. 

(b) You must visually examine the 

supplier’s invoice, guarantee, or 

certification in a shipment of the 

received product to ensure that the 

received product is consistent with your 

purchase order. 

(c) You must quarantine the received 

product until: 

(1) You collect representative samples 

of each unique shipment, and of each 

unique lot within each unique 

shipment, of received product; 

(2) Quality control personnel review 

and approve the documentation to 

determine whether the received product 

meets the specifications that you 

established under § 111.70(f); and 

(3) Quality control personnel approve 

the received product for packaging or 

labeling as a dietary supplement and 

release the received product from 

quarantine. 

(d)(1) You must identify each unique 

lot within each unique shipment of 

received product in a manner that 

allows you to trace the lot to the 

supplier, the date received, the name of 

the received product, the status of the 

received product (e.g., quarantined, 

approved, or rejected), and to the 

product that you packaged or labeled 

and distributed as a dietary supplement. 

(2) You must use this unique 

identifier whenever you record the 

disposition of each unique lot within 

each unique shipment of the received 

product. 

(e) You must hold the received 

product under conditions that will 

protect against contamination and 

deterioration, and avoid mixups. 

§ 111.170 What requirements apply to 

rejected components, packaging, and 

labels, and to rejected products that are 

received for packaging or labeling as a 

dietary supplement? 

You must clearly identify, hold, and 

control under a quarantine system for 

appropriate disposition any component, 

packaging, and label, and any product 

that you receive for packaging or 

labeling as a dietary supplement (and 

for distribution rather than for return to 

the supplier), that is rejected and 

unsuitable for use in manufacturing, 

packaging, or labeling operations. 

§ 111.180 Under this subpart G, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart G in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for fulfilling 

the requirements of this subpart. 

(2) Receiving records (including 

records such as certificates of analysis, 

suppliers’ invoices, and suppliers’

guarantees) for components, packaging, 

and labels and for products that you 

receive for packaging or labeling as a 

dietary supplement (and for distribution 

rather than for return to the supplier); 

and 

(3) Documentation that the 

requirements of this subpart were met. 

(i) The person who performs the 

required operation must document, at 

the time of performance, that the 

required operation was performed. 

(ii) The documentation must include: 

(A) The date that the components, 

packaging, labels, or products that you 

receive for packaging or labeling as a 

dietary supplement were received; 

(B) The initials of the person 

performing the required operation; 

(C) The results of any tests or 

examinations conducted on 

components, packaging, or labels, and of 

any visual examination of product that 

you receive for packaging or labeling as 

a dietary supplement; and 

(D) Any material review and 

disposition decision conducted on 

components, packaging, labels, or 

products that you receive for packaging 

or labeling as a dietary supplement. 

Subpart H—Production and Process 

Control System: Requirements for the 

Master Manufacturing Record 

§ 111.205 What is the requirement to 

establish a master manufacturing record? 

(a) You must prepare and follow a 

written master manufacturing record for 

each unique formulation of dietary 

supplement that you manufacture, and 

for each batch size, to ensure uniformity 

in the finished batch from batch to 

batch. 

(b) The master manufacturing record 

must: 

(1) Identify specifications for the 

points, steps, or stages in the 

manufacturing process where control is 

necessary to ensure the quality of the 

dietary supplement and that the dietary 

supplement is packaged and labeled as 

specified in the master manufacturing 

record; and 

(2) Establish controls and procedures 

to ensure that each batch of dietary 

supplement that you manufacture meets 

the specifications identified in 

accordance with paragraph (b)(1) of this 

section. 

(c) You must make and keep master 

manufacturing records in accordance 

with subpart P of this part. 

§ 111.210 What must the master 

manufacturing record include? 

The master manufacturing record 

must include: 

(a) The name of the dietary 

supplement to be manufactured and the 

strength, concentration, weight, or 

measure of each dietary ingredient for 

each batch size; 

(b) A complete list of components to 

be used; 

(c) An accurate statement of the 

weight or measure of each component to 

be used; 

(d) The identity and weight or 

measure of each dietary ingredient that 

will be declared on the Supplement 

Facts label and the identity of each 

ingredient that will be declared on the 

ingredients list of the dietary 

supplement; 

(e) A statement of any intentional 

overage amount of a dietary ingredient; 

(f) A statement of theoretical yield of 

a manufactured dietary supplement 

expected at each point, step, or stage of 

the manufacturing process where 

control is needed to ensure the quality 

of the dietary supplement, and the 

expected yield when you finish 

manufacturing the dietary supplement, 

including the maximum and minimum 

percentages of theoretical yield beyond 

which a deviation investigation of a 

batch is necessary and material review 

is conducted and disposition decision is 

made; 

(g) A description of packaging and a 

representative label, or a cross-reference 

to the physical location of the actual or 

representative label; 

(h) Written instructions, including the 

following: 

(1) Specifications for each point, step, 

or stage in the manufacturing process 

where control is necessary to ensure the 

quality of the dietary supplement and 


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that the dietary supplement is packaged 

and labeled as specified in the master 

manufacturing record; 

(2) Procedures for sampling and a 

cross-reference to procedures for tests or 

examinations; 

(3) Specific actions necessary to 

perform and verify points, steps, or 

stages in the manufacturing process 

where control is necessary to ensure the 

quality of the dietary supplement and 

that the dietary supplement is packaged 

and labeled as specified in the master 

manufacturing record. 

(i) Such specific actions must include 

verifying the weight or measure of any 

component and verifying the addition of 

any component; and 

(ii) For manual operations, such 

specific actions must include: 

(A) One person weighing or 

measuring a component and another 

person verifying the weight or measure; 

and 

(B) One person adding the component 

and another person verifying the 

addition. 

(4) Special notations and precautions 

to be followed; and 

(5) Corrective action plans for use 

when a specification is not met. 

Subpart I—Production and Process 

Control System: Requirements for the 

Batch Production Record 

§ 111.255 What is the requirement to 

establish a batch production record? 

(a) You must prepare a batch 

production record every time you 

manufacture a batch of a dietary 

supplement; 

(b) Your batch production record 

must include complete information 

relating to the production and control of 

each batch; 

(c) Your batch production record must 

accurately follow the appropriate master 

manufacturing record and you must 

perform each step in the production of 

the batch; and 

(d) You must make and keep batch 

production records in accordance with 

subpart P of this part. 

§ 111.260 What must the batch record 

include? 

The batch production record must 

include the following: 

(a) The batch, lot, or control number: 

(1) Of the finished batch of dietary 

supplement; and 

(2) That you assign in accordance 

with § 111.415(f) for the following: 

(i) Each lot of packaged and labeled 

dietary supplement from the finished 

batch of dietary supplement; 

(ii) Each lot of dietary supplement, 

from the finished batch of dietary 

supplement, that you distribute to 

another person for packaging or 

labeling; 

(b) The identity of equipment and 

processing lines used in producing the 

batch; 

(c) The date and time of the 

maintenance, cleaning, and sanitizing of 

the equipment and processing lines 

used in producing the batch, or a crossreference to records, such as individual 

equipment logs, where this information 

is retained; 

(d) The unique identifier that you 

assigned to each component (or, when 

applicable, to a product that you receive 

from a supplier for packaging or labeling 

as a dietary supplement), packaging, 

and label used; 

(e) The identity and weight or 

measure of each component used; 

(f) A statement of the actual yield and 

a statement of the percentage of 

theoretical yield at appropriate phases 

of processing; 

(g) The actual results obtained during 

any monitoring operation; 

(h) The results of any testing or 

examination performed during the batch 

production, or a cross-reference to such 

results; 

(i) Documentation that the finished 

dietary supplement meets specifications 

established in accordance with 

§ 111.70(e) and (g); 

(j) Documentation, at the time of 

performance, of the manufacture of the 

batch, including: 

(1) The date on which each step of the 

master manufacturing record was 

performed; and 

(2) The initials of the persons 

performing each step, including: 

(i) The initials of the person 

responsible for weighing or measuring 

each component used in the batch; 

(ii) The initials of the person 

responsible for verifying the weight or 

measure of each component used in the 

batch; 

(iii) The initials of the person 

responsible for adding the component to 

the batch; and 

(iv) The initials of the person 

responsible for verifying the addition of 

components to the batch; 

(k) Documentation, at the time of 

performance, of packaging and labeling 

operations, including: 

(1) The unique identifier that you 

assigned to packaging and labels used, 

the quantity of the packaging and labels 

used, and, when label reconciliation is 

required, reconciliation of any 

discrepancies between issuance and use 

of labels; 

(2) An actual or representative label, 

or a cross-reference to the physical 

location of the actual or representative 

label specified in the master 

manufacturing record; and 

(3) The results of any tests or 

examinations conducted on packaged 

and labeled dietary supplements 

(including repackaged or relabeled 

dietary supplements), or a crossreference to the physical location of 

such results; 

(l) Documentation at the time of 

performance that quality control 

personnel: 

(1) Reviewed the batch production 

record, including: 

(i) Review of any monitoring 

operation required under subpart E of 

this part; and 

(ii) Review of the results of any tests 

and examinations, including tests and 

examinations conducted on 

components, in-process materials, 

finished batches of dietary supplements, 

and packaged and labeled dietary 

supplements; 

(2) Approved or rejected any 

reprocessing or repackaging; and 

(3) Approved and released, or 

rejected, the batch for distribution, 

including any reprocessed batch; and 

(4) Approved and released, or 

rejected, the packaged and labeled 

dietary supplement, including any 

repackaged or relabeled dietary 

supplement. 

(m) Documentation at the time of 

performance of any required material 

review and disposition decision. 

(n) Documentation at the time of 

performance of any reprocessing. 

Subpart J—Production and Process 

Control System: Requirements for 

Laboratory Operations 

§ 111.303 What are the requirements under 

this subpart J for written procedures? 

You must establish and follow written 

procedures for laboratory operations, 

including written procedures for the 

tests and examinations that you conduct 

to determine whether specifications are 

met. 

§ 111.310 What are the requirements for 

the laboratory facilities that you use? 

You must use adequate laboratory 

facilities to perform whatever testing 

and examinations are necessary to 

determine whether: 

(a) Components that you use meet 

specifications; 

(b) In-process specifications are met 

as specified in the master manufacturing 

record; and 

(c) Dietary supplements that you 

manufacture meet specifications. 

§ 111.315 What are the requirements for 

laboratory control processes? 

You must establish and follow 

laboratory control processes that are 


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reviewed and approved by quality 

control personnel, including the 

following: 

(a) Use of criteria for establishing 

appropriate specifications; 

(b) Use of sampling plans for 

obtaining representative samples, in 

accordance with subpart E of this part, 

of: 

(1) Components, packaging, and 

labels; 

(2) In-process materials; 

(3) Finished batches of dietary 

supplements; 

(4) Product that you receive for 

packaging or labeling as a dietary 

supplement (and for distribution rather 

than for return to the supplier); and 

(5) Packaged and labeled dietary 

supplements. 

(c) Use of criteria for selecting 

appropriate examination and testing 

methods; 

(d) Use of criteria for selecting 

standard reference materials used in 

performing tests and examinations; and 

(e) Use of test methods and 

examinations in accordance with 

established criteria. 

§ 111.320 What requirements apply to 

laboratory methods for testing and 

examination? 

(a) You must verify that the laboratory 

examination and testing methodologies 

are appropriate for their intended use. 

(b) You must identify and use an 

appropriate scientifically valid method 

for each established specification for 

which testing or examination is required 

to determine whether the specification 

is met. 

§ 111.325 Under this subpart J, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart J in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for laboratory 

operations, including written 

procedures for the tests and 

examinations that you conduct to 

determine whether specifications are 

met; 

(2) Documentation that laboratory 

methodology established in accordance 

with this subpart J is followed. 

(i) The person who conducts the 

testing and examination must 

document, at the time of performance, 

that laboratory methodology established 

in accordance with this subpart J is 

followed. 

(ii) The documentation for laboratory 

tests and examinations must include the 

results of the testing and examination. 

Subpart K—Production and Process 

Control System: Requirements for 

Manufacturing Operations 

§ 111.353 What are the requirements under 

this subpart K for written procedures? 

You must establish and follow written 

procedures for manufacturing 

operations. 

§ 111.355 What are the design 

requirements for manufacturing 

operations? 

You must design or select 

manufacturing processes to ensure that 

product specifications are consistently 

met. 

§ 111.360 What are the requirements for 

sanitation? 

You must conduct all manufacturing 

operations in accordance with adequate 

sanitation principles. 

§ 111.365 What precautions must you take 

to prevent contamination? 

You must take all the necessary 

precautions during the manufacture of a 

dietary supplement to prevent 

contamination of components or dietary 

supplements. These precautions 

include: 

(a) Performing manufacturing 

operations under conditions and 

controls that protect against the 

potential for growth of microorganisms 

and the potential for contamination; 

(b) Washing or cleaning components 

that contain soil or other contaminants; 

(c) Using water that, at a minimum, 

complies with the applicable Federal, 

State, and local requirements and does 

not contaminate the dietary supplement 

when the water may become a 

component of the finished batch of 

dietary supplement; 

(d) Performing chemical, 

microbiological, or other testing, as 

necessary to prevent the use of 

contaminated components; 

(e) Sterilizing, pasteurizing, freezing, 

refrigerating, controlling hydrogen-ion 

concentration (pH), controlling 

humidity, controlling water activity 

(aw), or using any other effective means 

to remove, destroy, or prevent the 

growth of microorganisms and prevent 

decomposition; 

(f) Holding components and dietary 

supplements that can support the rapid 

growth of microorganisms of public 

health significance in a manner that 

prevents the components and dietary 

supplements from becoming 

adulterated; 

(g) Identifying and holding any 

components or dietary supplements, for 

which a material review and disposition 

decision is required, in a manner that 

protects components or dietary 

supplements that are not under a 

material review against contamination 

and mixups with those that are under a 

material review; 

(h) Performing mechanical 

manufacturing steps (such as cutting, 

sorting, inspecting, shredding, drying, 

grinding, blending, and sifting) by any 

effective means to protect the dietary 

supplements against contamination, by, 

for example: 

(1) Cleaning and sanitizing contact 

surfaces; 

(2) Using temperature controls; and 

(3) Using time controls. 

(i) Using effective measures to protect 

against the inclusion of metal or other 

foreign material in components or 

dietary supplements, by, for example: 

(1) Filters or strainers, 

(2) Traps, 

(3) Magnets, or 

(4) Electronic metal detectors. 

(j) Segregating and identifying all 

containers for a specific batch of dietary 

supplements to identify their contents 

and, when necessary, the phase of 

manufacturing; and 

(k) Identifying all processing lines and 

major equipment used during 

manufacturing to indicate their 

contents, including the name of the 

dietary supplement and the specific 

batch or lot number and, when 

necessary, the phase of manufacturing. 

§ 111.370 What requirements apply to 

rejected dietary supplements? 

You must clearly identify, hold, and 

control under a quarantine system for 

appropriate disposition any dietary 

supplement that is rejected and 

unsuitable for use in manufacturing, 

packaging, or labeling operations. 

§ 111.375 Under this subpart K, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart K in 

accordance with subpart P of this part. 

(b) You must make and keep records 

of the written procedures for 

manufacturing operations. 

Subpart L—Production and Process 

Control System: Requirements for 

Packaging and Labeling Operations 

§ 111.403 What are the requirements under 

this subpart L for written procedures? 

You must establish and follow written 

procedures for packaging and labeling 

operations. 

§ 111.410 What requirements apply to 

packaging and labels? 

(a) You must take necessary actions to 

determine whether packaging for dietary 

supplements meets specifications so 

that the condition of the packaging will 


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Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 34957 

ensure the quality of your dietary 

supplements; 

(b) You must control the issuance and 

use of packaging and labels and 

reconciliation of any issuance and use 

discrepancies. Label reconciliation is 

not required for cut or rolled labels if a 

100-percent examination for correct 

labels is performed by appropriate 

electronic or electromechanical 

equipment during or after completion of 

finishing operations; and 

(c) You must examine, before 

packaging and labeling operations, 

packaging and labels for each batch of 

dietary supplement to determine 

whether the packaging and labels 

conform to the master manufacturing 

record; and 

(d) You must be able to determine the 

complete manufacturing history and 

control of the packaged and labeled 

dietary supplement through 

distribution. 

§ 111.415 What requirements apply to 

filling, assembling, packaging, labeling, and 

related operations? 

You must fill, assemble, package, 

label, and perform other related 

operations in a way that ensures the 

quality of the dietary supplement and 

that the dietary supplement is packaged 

and labeled as specified in the master 

manufacturing record. You must do this 

using any effective means, including the 

following: 

(a) Cleaning and sanitizing all filling 

and packaging equipment, utensils, and 

dietary supplement packaging, as 

appropriate; 

(b) Protecting manufactured dietary 

supplements from contamination, 

particularly airborne contamination; 

(c) Using sanitary handling 

procedures; 

(d) Establishing physical or spatial 

separation of packaging and label 

operations from operations on other 

components and dietary supplements to 

prevent mixups; 

(e) Identifying, by any effective 

means, filled dietary supplement 

containers that are set aside and held in 

unlabeled condition for future label 

operations, to prevent mixups; 

(f) Assigning a batch, lot, or control 

number to: 

(1) Each lot of packaged and labeled 

dietary supplement from a finished 

batch of dietary supplement; and, 

(2) Each lot of dietary supplement, 

from a finished batch of dietary 

supplement, that you distribute to 

another person for packaging or 

labeling. 

(g) Examining a representative sample 

of each batch of the packaged and 

labeled dietary supplement to determine 

whether the dietary supplement meets 

specifications established in accordance 

with § 111.70(g); and 

(h) Suitably disposing of labels and 

packaging for dietary supplements that 

are obsolete or incorrect to ensure that 

they are not used in any future 

packaging and label operations. 

§ 111.420 What requirements apply to 

repackaging and relabeling? 

(a) You may repackage or relabel 

dietary supplements only after quality 

control personnel have approved such 

repackaging or relabeling. 

(b) You must examine a representative 

sample of each batch of repackaged or 

relabeled dietary supplements to 

determine whether the repackaged or 

relabeled dietary supplements meet all 

specifications established in accordance 

with § 111.70(g). 

(c) Quality control personnel must 

approve or reject each batch of 

repackaged or relabeled dietary 

supplement prior to its release for 

distribution. 

§ 111.425 What requirements apply to a 

packaged and labeled dietary supplement 

that is rejected for distribution? 

You must clearly identify, hold, and 

control under a quarantine system for 

appropriate disposition any packaged 

and labeled dietary supplement that is 

rejected for distribution. 

§ 111.430 Under this subpart L, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart L in 

accordance with subpart P of this part. 

(b) You must make and keep records 

of the written procedures for packaging 

and labeling operations. 

Subpart M—Holding and Distributing 

§ 111.453 What are the requirements under 

this subpart for M written procedures? 

You must establish and follow written 

procedures for holding and distributing 

operations. 

§ 111.455 What requirements apply to 

holding components, dietary supplements, 

packaging, and labels? 

(a) You must hold components and 

dietary supplements under appropriate 

conditions of temperature, humidity, 

and light so that the identity, purity, 

strength, and composition of the 

components and dietary supplements 

are not affected. 

(b) You must hold packaging and 

labels under appropriate conditions so 

that the packaging and labels are not 

adversely affected. 

(c) You must hold components, 

dietary supplements, packaging, and 

labels under conditions that do not lead 

to the mixup, contamination, or 

deterioration of components, dietary 

supplements, packaging, and labels. 

§ 111.460 What requirements apply to 

holding in-process material? 

(a) You must identify and hold inprocess material under conditions that 

protect against mixup, contamination, 

and deterioration. 

(b) You must hold in-process material 

under appropriate conditions of 

temperature, humidity, and light. 

§ 111.465 What requirements apply to 

holding reserve samples of dietary 

supplements? 

(a) You must hold reserve samples of 

dietary supplements in a manner that 

protects against contamination and 

deterioration. This includes: 

(1) Holding the reserve samples under 

conditions consistent with product 

labels or, if no storage conditions are 

recommended on the label, under 

ordinary storage conditions; and 

(2) Using the same container-closure 

system in which the packaged and 

labeled dietary supplement is 

distributed, or if distributing dietary 

supplements to be packaged and 

labeled, using a container-closure 

system that provides essentially the 

same characteristics to protect against 

contamination or deterioration as the 

one in which you distribute the dietary 

supplement for packaging and labeling 

elsewhere. 

(b) You must retain reserve samples 

for 1 year past the shelf life date (if shelf 

life dating is used), or for 2 years from 

the date of distribution of the last batch 

of dietary supplements associated with 

the reserve samples, for use in 

appropriate investigations. 

§ 111.470 What requirements apply to 

distributing dietary supplements? 

You must distribute dietary 

supplements under conditions that will 

protect the dietary supplements against 

contamination and deterioration. 

§ 111.475 Under this subpart M, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart M in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for holding 

and distributing operations; and 

(2) Records of product distribution. 


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34958 Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations 

Subpart N—Returned Dietary 

Supplements 

§ 111.503 What are the requirements under 

this subpart N for written procedures? 

You must establish and follow written 

procedures to fulfill the requirements of 

this subpart. 

§ 111.510 What requirements apply when a 

returned dietary supplement is received? 

You must identify and quarantine 

returned dietary supplements until 

quality control personnel conduct a 

material review and make a disposition 

decision. 

§ 111.515 When must a returned dietary 

supplement be destroyed, or otherwise 

suitably disposed of? 

You must destroy, or otherwise 

suitably dispose of, any returned dietary 

supplement unless the outcome of a 

material review and disposition 

decision is that quality control 

personnel do the following: 

(a) Approve the salvage of the 

returned dietary supplement for 

redistribution or 

(b) Approve the returned dietary 

supplement for reprocessing. 

§ 111.520 When may a returned dietary 

supplement be salvaged? 

You may salvage a returned dietary 

supplement only if quality control 

personnel conduct a material review 

and make a disposition decision to 

allow the salvage. 

§ 111.525 What requirements apply to a 

returned dietary supplement that quality 

control personnel approve for 

reprocessing? 

(a) You must ensure that any returned 

dietary supplements that are 

reprocessed meet all product 

specifications established in accordance 

with § 111.70(e); and 

(b) Quality control personnel must 

approve or reject the release for 

distribution of any returned dietary 

supplement that is reprocessed. 

§ 111.530 When must an investigation be 

conducted of your manufacturing 

processes and other batches? 

If the reason for a dietary supplement 

being returned implicates other batches, 

you must conduct an investigation of 

your manufacturing processes and each 

of those other batches to determine 

compliance with specifications. 

§ 111.535 Under this subpart N, what 

records must you make and keep? 

(a) You must make and keep records 

required under this subpart N in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for fulfilling 

the requirements of this subpart N. 

(2) Any material review and 

disposition decision on a returned 

dietary supplement; 

(3) The results of any testing or 

examination conducted to determine 

compliance with product specifications 

established under § 111.70(e); and, 

(4) Documentation of the reevaluation 

by quality control personnel of any 

dietary supplement that is reprocessed 

and the determination by quality control 

personnel of whether the reprocessed 

dietary supplement meets product 

specifications established in accordance 

with § 111.70(e). 

Subpart O—Product Complaints 

§ 111.553 What are the requirements under 

this subpart O for written procedures? 

You must establish and follow written 

procedures to fulfill the requirements of 

this subpart O. 

§ 111.560 What requirements apply to the 

review and investigation of a product 

complaint? 

(a) A qualified person must: 

(1) Review all product complaints to 

determine whether the product 

complaint involves a possible failure of 

a dietary supplement to meet any of its 

specifications, or any other 

requirements of this part 111, including 

those specifications and other 

requirements that, if not met, may result 

in a risk of illness or injury; and 

(2) Investigate any product complaint 

that involves a possible failure of a 

dietary supplement to meet any of its 

specifications, or any other 

requirements of this part, including 

those specifications and other 

requirements that, if not met, may result 

in a risk of illness or injury. 

(b) Quality control personnel must 

review and approve decisions about 

whether to investigate a product 

complaint and review and approve the 

findings and followup action of any 

investigation performed. 

(c) The review and investigation of 

the product complaint by a qualified 

person, and the review by quality 

control personnel about whether to 

investigate a product complaint, and the 

findings and followup action of any 

investigation performed, must extend to 

all relevant batches and records. 

§ 111.570 Under this subpart O, what 

records must you make and keep? 

(a) You must make and keep the 

records required under this subpart O in 

accordance with subpart P of this part. 

(b) You must make and keep the 

following records: 

(1) Written procedures for fulfilling 

the requirements of this subpart, 

(2) A written record of every product 

complaint that is related to good 

manufacturing practice, 

(i) The person who performs the 

requirements of this subpart must 

document, at the time of performance, 

that the requirement was performed. 

(ii) The written record of the product 

complaint must include the following: 

(A) The name and description of the 

dietary supplement; 

(B) The batch, lot, or control number 

of the dietary supplement, if available; 

(C) The date the complaint was 

received and the name, address, or 

telephone number of the complainant, if 

available; 

(D) The nature of the complaint 

including, if known, how the product 

was used; 

(E) The reply to the complainant, if 

any; and 

(F) Findings of the investigation and 

followup action taken when an 

investigation is performed. 

Subpart P—Records and 

Recordkeeping 

§ 111.605 What requirements apply to the 

records that you make and keep? 

(a) You must keep written records 

required by this part for 1 year past the 

shelf life date, if shelf life dating is used, 

or 2 years beyond the date of 

distribution of the last batch of dietary 

supplements associated with those 

records. 

(b) Records must be kept as original 

records, as true copies (such as 

photocopies, microfilm, microfiche, or 

other accurate reproductions of the 

original records), or as electronic 

records. 

(c) All electronic records must comply 

with part 11 of this chapter. 

§ 111.610 What records must be made 

available to FDA? 

(a) You must have all records required 

under this part, or copies of such 

records, readily available during the 

retention period for inspection and 

copying by FDA when requested. 

(b) If you use reduction techniques, 

such as microfilming, you must make 

suitable reader and photocopying 

equipment readily available to FDA. 

Dated: May 8, 2007. 

Andrew C. von Eschenbach, 

Commissioner of Food and Drugs. 

Dated: May 8, 2007. 

Michael O. Leavitt, 

Secretary of Health and Human Services. 

[FR Doc. 07–3039 Filed 6–22–07; 8:45 am] 

BILLING CODE 4160–01–S 


sroberts on PROD1PC70 with RULES