  SEQ CHAPTER \h \r 1 DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

[Docket No. 96N-0417]

RIN 0910-AB88

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

AGENCY:  	Food and Drug Administration, HHS.

ACTION: 	Final rule.

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

DATES: This rule is effective [insert date 60 days after date of
publication in the Federal Register].  

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

FOR FURTHER INFORMATION CONTACT:

     Vasiliosf Frankos 

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

     Food and Drug Administration,

     5100 Paint Branch Pkwy.,

     College Park, MD 20740,

     301-436-1850.

SUPPLEMENTARY INFORMATION:

Table of Contents

SUPPLEMENTARY INFORMATION:

Table of Contents

Background & Related Information -- What Led Us to Issue This Rule?

How is the Final Rule Organized? 

What Does the Final Rule Do?

Overview of CGMP

Highlights of the Final Rule

What General Comments Did We Receive?

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

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

What Comments Did We Receive on Written Procedures?

Overview

Written Procedures that Are Required by This Final Rule.

Written procedures for personnel (final subpart B).

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

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

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

	Written procedures for quality control operations, including written
procedures for conducting a material review and making a disposition
decision and written procedures for approving reprocessing (final
subpart F).  

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

Written procedures for laboratory operations (final subpart J).

Written procedures for manufacturing operations (final subpart K).

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

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

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

Written procedures for product complaints (final subpart O).

Written Procedures That are Not Required by This Final Rule

Written procedures for final subpart E (Requirement to Establish a
Production and Process Control System).

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

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

Written procedures for product recalls.  

Other Comments on Written Procedures

What Other General Comments Did We Receive?

What Legal Authority Comments Did We Receive?

Modeled After CGMP for Food	

Records Authority

Public Health Service Act Authority

The communicable disease risk posed by dietary supplements.

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

The interstate commerce nexus for the final rule.

The PHS Act.

The act.

Commerce Clause. 

Fifth Amendment.

Miscellaneous.

What Comments Did We Receive on the General Provisions? 

(Subpart A)

Organization of Final Subpart A

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

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

Actual Yield 

Batch

Batch Number, Lot Number, or Control Number	

Component

Contact Surface	

Ingredient

In process Material

Lot

Microorganisms

	10. Must

	11. Pest

	12. Physical Plant

	13. Product Complaint

	14. Quality 

	15. Quality Control

	16. Quality Control UnitPersonnel 

	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?

Identity.

Purity.

Strength.

Composition.

Other terms.

	26. What Definitions Did the Comments Want  

             Us to Delete?

D. Do Other Statutory Provisions and Regulations Apply? 

(Final § 111.5)	 

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

 	1.  “What Are These Regulations Intended to 

	Accomplish?”  

2. “Exclusions” (Proposed § 111.6)

	 		VII.  Comments on Personnel

(Final Subpart B)

Organization of Final Subpart B

Highlights of Changes to the Proposed Requirements for Personnel

Revisions

Changes After Considering Comments

General Comments on Proposed Subpart B  

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

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

Final § 111.10(a)  

Final § 111.10(b)	    

What Personnel Qualification Requirements Apply? (Final § 111.12)

What Supervisor Requirements Apply?(Final § 111.13)

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

  SEQ CHAPTER \h \r 1 VIII.  Comments on Physical Plant and Grounds 

(Final Subpart C)

Organization of Final Subpart C

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

Revisions

Changes After Considering Comments

General Comments on Proposed Subpart C

What Sanitation Requirements Apply to Your Physical Plant?  (Final §
111.15)

Final § 111.15(a) 

Final § 111.15(b)(1) 

Final § 111.15(c) (Proposed § 111.15(b)) 

Final § 111.15(d) 

Final § 111.15(e) 

Final § 111.15(f) 

Final § 111.15(g) 

Final § 111.15(h) 	

Final § 111.15(i) 

Final § 111.15(j) 

Final § 111.15(k) 

E. What Are the Requirements Under This Subpart for Written 

   Procedures?(Final § 111.16)

F. What Design and Construction Requirements Apply to Your  

   	   Physical Plant?(Final § 111.20)     

1.  Final § 111.20(a) and (b) 

2.  Final § 111.20(c) 

3.  Final § 111.20(d)

	 	4.  Final § 111.20(e) 

5.  Final § 111.20(f) 

6.  Final § 111.20(g)  

7.  Final § 111.20(h) 

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

  	(Final § 111.23)

IX.  Comments on Requirements Related to 

Equipment and Utensils

(Subpart D)

Organization of Final Subpart D

Highlights of Changes to the Proposed Requirements for Equipment and
Utensils

1. Revisions

2. Revisions Associated With the Reorganization.

3. Changes After Considering Comments

General Comments on Proposed Subpart D.

What Are the Requirements Under This Subpart for Written
Procedures?(Final § 111.25)

Final § 111.25

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

Final 111.27(a) 

Final § 111.27(a).

Final § 111.27(a)(2). 

Final § 111.27(a)(3). 

Final § 111.27(a)(4).

Final § 111.27(a)(5).

Final § 111.27(a)(6). 

Final § 111.27(a)(7). 

Final § 111.27(b) 

Final § 111.27(c) 

Final § 111.27(d) 

Final § 111.27(d)(1) 

Final § 111.27(d)(2) 

Final § 111.27(d)(3)

Final § 111.27(d)(4) 

Final § 111.27(d)(5)

Final § 111.27(d)(6)

Final § 111.27(d)(7) 

Reorganization of Certain Paragraphs in Proposed § 111.25.

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

Comments on the Organization and Framework of Proposed § 111.30

Comments Specific to Proposed § 111.30

Final § 111.30(a) and (b)

Final § 111.30(c)

Final § 111.30(d)

Final § 111.30(e) 

3. Reorganization of Certain Paragraphs in Proposed §          

   	111.30

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

    Keep? (Final § 111.35)

Final § 111.35(a) 

Final § 111.35(b)(1) and (b)(2) 

Final § 111.35(b)(3) 

Final § 111.35(b)(4) 

Final § 111.35(b)(5)

Final § 111.35(b)(6)

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

(Final Subpart E)

Reorganization of Proposed § 111.35 into Final Subpart E

General Comments on Proposed § 111.35

Final Subpart E and Highlights of Changes to the Proposed Regulations

Revisions

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

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

What Are the Requirements For to Use a Quality Control UnitOperations?
(Final § 111.65)

What Specifications Must You Establish? (Final § 111.70)

Final § 111.70(a)

Final § 111.70(b) 

Final § 111.70(c) 

Final § 111.70(d)      

Final § 111.70(e) 

Final § 111.70(f) 

Final § 111.70(g)	

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

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

Final § 111.75(a)  

Final § 111.75(b)

Final § 111.75(c) and (d)

Final § 111.75(e)

Final § 111.75(f)

Final § 111.75(g)

Final § 111.75(h)

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)

Final § 111.80(a)

Final § 111.80(b)

Final § 111.80(c)

Final § 111.80(d)

Final § 111.80(e) 

M. What Are the Requirements for Reserve Samples? 

   (Final § 111.83)

Final § 111.83(a)

Final § 111.83(b)(1)

Final § 111.83(b)(2)

Final § 111.83(b)(3)

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)

Final § 111.90

Final § 111.90(a)

Final § 111.90(b)

Final § 111.90(c)

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

     (Final § 111.95)

§ 111.95(a)

§ 111.95(b)

XI.  Comments on Requirements for Quality Control

(Final Subpart F)

Organization of Final Subpart F

Highlights of Changes to the Proposed Requirements for

        Quality Control Operations

Revisions

Changes associated With the Reorganization

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 the Quality Control Unit Personnel Do? (Final §
111.105)

Final § 111.105(a) 

Final § 111.105(b), (c), d), and (e) 

Final § 111.105(f)

Final § 111.105(g)

Final § 111.105(h)

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)

Final § 111.110(a)

Final § 111.110(b) 

Final § 111.110(c) 

	G. What Quality Control Operations Are Required for 

        a Material Review and Disposition Decision? 

       (Final § 111.113)

Final § 111.113(a)

Final § 111.113(b)

Final § 111.113(c)

What Quality Control Operations Are Required for    

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

Final § 111.117(a) through (c)

Final § 111.117(d)   

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(a) 

Final § 111.120(b)

Final § 111.120(c) 

Final § 111.120(d)

Final § 111.120(e) 

What Quality Control Operations Are Required for the     

        Master Manufacturing Record, the Batch Production     

        Record, and Manufacturing Operations? (Final § 111.123)

Final § 111.123(a)(1) 

Final § 111.123(a)(2) 

Final § 111.123(a)(3) 

Final § 111.123(a)(4) 

Final § 111.123(a)(5) 

Final § 111.123(a)(6) 

Final § 111.123(a)(7) 

Final § 111.123(a)(8)

Final § 111.123(b) 

	K. What Quality Control Operations Are Required for 

        Packaging and Labeling Operations? (Final § 111.127)

Final § 111.127(a) and (b)

Final § 111.127(a) 

Final § 111.127(b) 

Final § 111.127(c) 

Final § 111.127(d)

Final § 111.127(e) 

Final § 111.127(f) and (g)

Final § 111.127(h) 

L. What Quality Control Operations Are Required for     

   Returned Dietary Supplements? (Final § 111.130)    

Final § 111.130(a) 

Final § 111.130(a)(1) and (2)

Final § 111.130(b)

Final § 111.130(c)

Final § 111.130(d)

	M. What Quality Control Operations Are Required for 

        Product Complaints? (Final § 111.135)

N. What Records Must the Quality     

   Control Unit Personnel Make and Keep? (Final § 111.140)

Final § 111.140(a)

Final § 111.140(b)(1)

Final § 111.140(b)(2)     

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)

Organization of Final Subpart G  

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

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.40 (Final Subpart G)

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

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

Proposed § 111.35(d)

Final § 111.155(a)

Final § 111.155(b)

Final § 111.155(c)

Final § 111.155(d)

Final § 111.155(e)

What Requirements Apply to Packaging and Labels  

   Received? (Final § 111.160)

Final § 111.160(a)

Final § 111.160(b)

Final § 111.160(c) 

Final § 111.160(d)

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)

Final § 111.165(a)

Final § 111.165(b)

Final § 111.165(c)

Final § 111.165(d)

Final § 111.165(e)     

H. What Requirements Apply to Rejected Components,    

   Packaging, Labels, and to Rejected Products That are   

   Received for Packaging or Labeling as a Dietary   

   Supplement? (Final § 111.170)

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

   (Final § 111.180)

Final § 111.180(a)

Final § 111.180(b)(1)

Final § 111.180(b)(2)

Final § 111.180(b)(3)

  SEQ CHAPTER \h \r 1 XIII.  Comments on the Production and Process
Control System: 

Requirements for the Master Manufacturing Record 

(Final Subpart H)

Organization of Final Subpart H

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

Revisions

Changes Associated With the Reorganization

Changes After Considering Comments

General Comments on Proposed § 111.45 (Final Subpart H)

Comments on Written Procedures

Comments That Support Proposed § 111.45

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

Final § 111.205(a)

Final § 111.205(b)(1)

Final § 111.205(b)(2)

Final § 111.205(c)

What Must the Master Manufacturing Record Include? (Final 

     § 111.210)

Final § 111.210(a)

Final § 111.210(b)

Final § 111.210(c)

Final § 111.210(d)

Final § 111.210(e)

Final § 111.210(f)

Final § 111.210(g)

Final § 111.210(h)(1)

Final § 111.210(h)(2)

Final § 111.210(h)(3)

Final § 111.210(h)(4)

Final § 111.210(h)(5)

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)

Organization of Final Subpart I

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

Revisions  

Changes Associated With the Reorganization

Changes After Considering Comments

What is the Requirement to Establish a Batch Production Record? (Final
§ 111.255) 

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

Final § 111.260(a) 

Final § 111.260(b)

Final § 111.260(c)

Final § 111.260(d)

Final § 111.260(e) and (f)

Final § 111.260(g)

Final § 111.260(h)

Final § 111.260(i) 

Final § 111.260(j)

Final § 111.260(j)(1)

Final § 111.260(j)(2)

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

     	10. Final § 111.260(k)

General comments on proposed § 111.70(g)

Final § 111.260(k)(1)

Final § 111.260(k)(2)

Final § 111.260(k)(3)

     	11. Final § 111.260(l)

Final § 111.260(l)(1)

Final § 111.260(l)(1)(i)

Final § 111.260(l)(1)(ii)

Final § 111.260(l)(2)

Final § 111.260(l)(3)

Final § 111.260(l)(4)

12. Final § 111.260(m)

    		13. Final § 111.260(n)

 	E. Review of Batch Production Record Deviations (Proposed 

        § 111.50(d)(1),(e)(2), (e)(3), and (e)(4))

XV.  Comments on Production and Process Control System: Requirements for
Laboratory Operations

(Final Subpart J)

Organization of Final Subpart J

Highlights of the Changes to the Proposed Requirements for Laboratory
Operations

  		1. Revisions

  		2. Changes Associated With the Reorganization

  		3. Changes After Considering Comments

   	C. What Are the Requirements Under This Subpart for Written    

        Procedures? (Final § 111.303)

   	D. What Are the Requirements for the Laboratory Facilities?    

        (Final § 111.310)

   	E. What Are the Requirements for Laboratory Control 

        Processes? (Final § 111.315)

1. Final § 111.315(a)

2. Final § 111.315(b)

3. Final § 111.315(c)

4. Final § 111.315(d) 

5. Final § 111.315(e)

F. What Requirements Apply to Laboratory Methods for  

   Testing and Examination? (Final § 111.320)

   		1. Final § 111.320(a)

   		2. Final § 111.320(b)

G. Appropriate Test Method Validation 

   (Proposed § 111.60(b)(1)(v)) 

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

        (Final § 111.325)

  		1. Final § 111.325(a)

  		2. Final § 111.325(b)(1)  

  		3. Final § 111.325(b)(2)

XVI.  Comments on the Production and Process Control System: 

Requirements for Manufacturing Operations 

(Final Subpart K)

Organization of Final Subpart K  

Highlights of Changes to the Proposed Requirements for Manufacturing
Operations

Revisions

Changes Made After Considering Comments

Revisions Associated With the Reorganization

General Comments on Manufacturing Operations

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

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

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

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

     	1. Final § 111.365(a)

2. Final § 111.365(b)

3. Final § 111.365(c)

4. Final § 111.365(d)

5. Final § 111.365(e)

6. Final § 111.365(f)

7. Final § 111.365(g)

8. Final § 111.365(h)

9.  Final § 111.365(i)

10. Final § 111.365(j)

11. Final § 111.365(k)

H. What Requirements Apply to Rejected Dietary Supplements?   

        (Final § 111.370) 

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

        (Final § 111.375)

 XVII. Comments on Requirements for 

Packaging and Labeling Operations

(Final Subpart L)

Organization of Final Subpart L

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

Revisions

Changes Associated With the Reorganization 

Changes After Considering Comments  

General Comments on Proposed Requirements for Packaging and Labeling
Operations

General Comments on Requirements for What Must Be on the 

     Product Label Rather than for Labeling Operations 

What are the Requirements under this Subpart for Written            

     Procedures? (Final § 111.403) 

What Requirements Apply to Packaging and Labels? 

  (Final § 111.410)

Final § 111.410(a) 

Final § 111.410(b) 

Final § 111.410(c)

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)

Under this Subpart L, What Records Must You Make and        

   Keep? (Final § 111.430)

1. Final § 111.430(a)

2. Final § 111.430(b)

     

XVIII.  Comments on Holding and Distributing

(Final Subpart M)

Organization of Final Subpart M

Highlights of Changes to the Proposed Requirements for Holding and
Distributing

Revisions

Changes Associated With the Reorganization 

Changes After Considering Comments

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

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

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)

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

1. Final § 111.460(a)

2. Final § 111.460(b)

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

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

1. Final § 111.465(a)

     	2. Final § 111.465(b)

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

Under this Subpart, What Records Must You Make and Keep? (Final
§ 111.475)

XIX.  Comments on Returned Dietary Supplements

  (Final Subpart N)

Organization of Final Subpart N

Highlights of Changes to the Proposed Requirements for Returned Dietary
Supplements

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.85

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

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

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

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

What Requirements Apply to a Returned Dietary Supplement That the
Quality Control Unit Personnel Approves for Reprocessing?  (Final
§ 111.525)

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

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

Final § 111.535(a)

Final § 111.535(b)(1)

Final § 111.535(b)(2)

Final § 111.535(b)(3)

Final § 111.535(b)(4)

     

XX.  Comments on Product Complaints (Final Subpart O)

Organization of Final Subpart O

Highlights of Changes to the Proposed Requirements for Product
Complaints

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.95(Final Subpart O)

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

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

Final § 111.560(a)(1)

Final § 111.560(a)(2), (b), and (c)

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

Final § 111.570(a)

Final § 111.570(b)(1)

Final § 111.570(b)(2)

Final § 111.570(b)(2)(i)

Final § 111.570(b)(2)(ii)

  SEQ CHAPTER \h \r 1 XXI.  Comments on Records and Recordkeeping

(Final Subpart P)

Organization of Final Subpart P

Highlights of Changes to the Proposed Requirements for Records and
Recordkeeping 

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.125     

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

Final § 111.605(a)

Final § 111.605(b)     

Final § 111.605(c)     

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

Comments on Guidance Documents To Be Used with the Final Rule 

Comments on Consideration for Other CGMP Programs

Comments on Public Involvement

Public Involvement    

Comments on Implementation and Enforcement

E. Removal of References to Part 112

XX  SEQ CHAPTER \h \r 1 III. Paperwork Reduction Act of 1995

XXI  SEQ CHAPTER \h \r 1 V. Analysis of Impacts

Introduction

1. Summary of the Economic Analysis

     	2. Summary of Comments on the Economic Analysis

  	B. Final Regulatory Impact Analysis

1. The Need for the Final Current Good Manufacturing  

   Practice Rule 

2. Regulatory Options

3. Coverage of the Final Rule

4. Baseline Practices

     		a. Consumption

b. Manufacturing

		5. Baseline Risk 

 		6. Benefits

a. Reduced health costs associated with a reduced  

   number of acute illnesses

   		b. Fewer products recalled 

   		c. Reduced health costs associated with a reduced  

             number of chronic illnesses and conditions  

   		d. Benefits from known nutritional effects 

   		e. Benefits form uncertain nutritional effects

   		f. Total benefits

7. Costs

   		a. Description of the costs  

	   		b. Summary of general comments on costs

     	8. Summary of Benefits and Costs

     	9. Uncertainties in the Analysis 

C. Initial Final Regulatory Flexibility Analysis

1. Introduction 

2. Economic Effects on Small Entities

        		a. Number of small entities affected 

        		b. Costs to small entities 	 

3. Regulatory Options

        		a. Exemptions for small entities

	   		b. Longer compliance periods

4. Description of Recordkeeping and Reporting

5. Summary

D. Unfunded Mandates 

XXV. 	Analysis of Environmental Impact

XXVI. 	Federalism

XXVII.  	References

	I.  Background & Related Information– What Led Us to Issue This Rule?

     On October 25, 1994, the Dietary Supplement Health and Education
Act (DSHEA, Public Law 103-417) was signed into law.  DSHEA, among other
things, amended the Federal Food, Drug, and Cosmetic Act (the act) by
adding section 402(g) of the act (21 U.S.C. 342(g)).  Section 402(g)(2)
of the act provides, in part, that the Secretary of Health and Human
Services (the Secretary) may, by regulation, prescribe good
manufacturing practices for dietary supplements.  Section 402(g) of the
act also stipulates that such regulations shall be modeled after CGMP
regulations for food and may not impose standards for which there are no
current and generally available analytical methodology.

     In response to DSHEA, we issued an Advance Notice of Proposed
Rulemaking (the 1997 ANPRM) in the FEDERAL REGISTER of February 6, 1997
(62 FR 5700).  The 1997 ANPRM contained a CGMP outline submitted to us
on November 20, 1995 by representatives of the dietary supplement
industry.  The 1997 ANPRM also asked nine questions that addressed
issues that the industry outline did not.  For example, we asked if
there is a need to develop specific defect action levels (DALs) for
dietary ingredients.  We also asked whether a CGMP rule should require
manufacturers to establish procedures to document, on a continuing or
daily basis, that they followed pre-established procedures for making
dietary supplements.

     We received more than 100 comments in response to the 1997 ANPRM. 
We evaluated these comments before we drafted and ultimately issued a
proposed rule on CGMPs for dietary ingredients and dietary supplements
(which we discuss later in this part).       

Additionally, during 1999, we conducted a number of outreach activities
related to dietary supplements.  We held several public meetings to
develop our overall strategy for achieving effective regulation of
dietary supplements, which could include establishing CGMP regulations. 
We also held public meetings focused specifically on CGMPs and the
economic impact that any CGMP rule for dietary ingredients and dietary
supplements might have on small businesses.  Further, we toured several
dietary supplement manufacturing facilities to better understand the
manufacturing processes and practices that potentially would be subject
to CGMP requirements for dietary ingredients and dietary supplements.
(Refs. 1-6).  These activities contributed to our knowledge about the
industry.

     In the FEDERAL REGISTER of March 13, 2003 (68 FR 12157), we
published a proposed rule to establish CGMP requirements for dietary
ingredients and dietary supplements.  The preamble to the 2003 CGMP
Proposal addressed the comments we had received regarding the nine
questions in the 1997 ANPRM, discussed our legal authority to issue a
CGMP rule, and described the basis for each proposed requirement.  

     The 2003 CGMP Proposal specifically requested comment on a variety
of areas, including the need for written procedures, and recordkeeping
requirements.  Although the proposed rule’s comment period was
scheduled to end on June 11, 2003, in the FEDERAL REGISTER of May 19,
2003 (68 FR 27008), we extended the comment period to August 11, 2003.

     After we published the proposed rule, we conducted or participated
in outreach activities related to dietary supplements and dietary
ingredients.  We held public stakeholder meetings on April 29, 2003 in
College Park, MD, and on May 6, 2003 in Oakland, CA.  We also held a
public meeting, via satellite downlink, on May 9, 2003, with viewing
sites at our district and regional offices throughout the country. 
These public meetings gave an overview of the proposed rule, and
clarified specific points in the proposed rule.  Since the public
stakeholder meetings held as part of our outreach efforts, we also have
participated in several meetings with industry and 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 FEDERAL REGISTER we are also issuing an
interim final regulation that sets forth a procedure for requesting an
exception to a CGMP requirement in this final rule.  The interim final
rule allows for submission to, and review by, FDA of an alternative to
the required 100 percent identity testing of components that are dietary
ingredients (as discussed in section X, Subpart E), provided certain
conditions are met and also includes a requirement for retention of
records related to the FDA grant of an exception request. 

    

	II. How is the Final Rule Organized? 

     The 2003 CGMP Proposal was divided into eight subparts, with each
subpart devoted to a particular topic.  For example, proposed subpart A
was titled, “General Provisions” and contained sections describing
the rule’s scope, purpose, definitions, applicability of other
statutory and regulatory provisions, and exclusions.  As another
example, proposed subpart B was titled, “Personnel” and described
microbial contamination and hygiene requirements, personnel
qualification requirements, and supervisor requirements.  

In response to comments seeking a simpler, more “user-friendly”
final rule or seeking clarification of the rule’s applicability to
certain persons, items, or activities, and to reduce redundant
provisions or combine similar provisions, we have reorganized the final
rule into 16 subparts, with new subparts focusing on specific aspects of
the manufacturing process or addressing specific issues.  For example,
the proposed rule placed all production and process control requirements
for manufacturing, packaging, labeling, and laboratory operations in a
single subpart (proposed subpart E).  The final rule creates separate
subparts for the specific operations to make it easier to find the
relevant production and process control requirements for a particular
activity.  

The following table summarizes how we reorganized the rule.  We are
providing this information to help readers understand the structural
changes we made between the proposed and final rules.   

Table  1 - Reorganization and Revisions: 2003 CGMP Proposal and Final
Rule

Proposed 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))

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), (l)), § 111.37
(b)(11(iv), and

§ 111.40(a)(2)

111.77 (new)

111.80 (formerly proposed § 111.37(b)(11))

111.83 (formerly proposed §§ 111.37(b)(12), 111.50(h), and
111.83(b)(2))

111.87 (formerly proposed §§ 111.35(i), and (n), 111.37(b)(5) and
(b)(14), 111.40(a)(3), 111.50(d)(1), 111.85(a) and (c))

111.90 (formerly proposed §§ 111.35(i)(4), 111.50(d)(1), 111.50(f) and
(g), and 111.65(d))

111.95 (formerly proposed § 111.35 and (o))



F – 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), (c), 111.40(a)(3) and (b)(2),
111.50(d)(1), 111.65(d), and 111.70(c))

111.117 (formerly proposed §§ 111.30(b)(4), 111.37(b)(6) through
(b)(8))

111.120 (formerly proposed §§ 111.35(i)(4)(i) and (i)(4)(ii),
111.37(b)(2) and (b)(10), 111.40(a)(3) and (b)(2), and 111.50(e)(1))

111.123 (formerly proposed §§ 111.35(e)(2),(f), (i)(2), and (o)(2)
111.37(a), (b)(2), (b)(4), (b)(5), and (b)(11), 111.45(c), 111.50(d)(1),
(d)(2), and (g))

111.127 (formerly proposed §§ 111.37(b)(2), (b)(10), and (b)(11),
111.40(a)(2) and (a)(3), and 111.70(c), (d) and (e))

111.130 (formerly proposed §§ 111.37(b)(2) and (b)(15), and 111.85(a))

111.135 (new)

111.140 (formerly proposed §§ 111.35(j), 111.37(c) and (d), 



G – 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)-(5) and 111.40(a)(1)-(5))

111.160 (formerly proposed §§ 111.35(e)(4), and 111.40(a)(2) and
(b)(1)-(4))

111.165 (formerly proposed § 111.40(a)(1)-(5))

111.170 (formerly proposed § 111.74)

111.180 (formerly proposed §§ 111.35(d)(4), and 111.40(c)(1)(i)-(iv)
and (c)(2))



H – 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))



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),(5),(9) and 111.50(c)(1) through (c)(11), (c)(13), (c)(14),
(d)(2), and (e), (g) and 111.70 (b)(6) and (g))



J – 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)



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))



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

	

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

	III. What Does the Final Rule Do?

A.  Overview of CGMP

In considering the specific requirements necessary for dietary
supplement CGMPs, we considered information from a variety of sources. 
We considered information from our outreach activities, as described in
section I, comments to the 2003 CGMP Proposal, our own knowledge and
expertise about CGMP for foods, including dietary supplements, and
characteristics of CGMP that apply to manufacturing, labeling, packaging
and holding operations. 

The general food CGMPs in 21 CFR Part 110 largely address practices
designed to ensure that food is manufactured, processed, packed, and
held under sanitary conditions and that the food is safe, clean, and
wholesome.  Although the general food CGMPs in 21 CFR Part 110 apply to
a variety of food products, including dietary supplements, they do not
address the unique characteristics of certain specific types of food
products.  The agency has implemented separate, and more specific, CGMPs
for various types of food products to provide for process controls in
manufacturing that are not captured by the more general Part 110 food
CGMPs.  (See discussion in Section V – Legal Authority on product
specific CGMP requirements).  At the time DSHEA was enacted, there were
four such additional, specific food CGMP regulations; those for infant
formula (part 106), thermally processed low-acid canned food (part 113),
acidified food (part 114), and bottled water (part 129).  

Dietary supplements are a type of food product for which specific food
CGMPs also are needed.  Manufacturing process controls are needed to
ensure that a dietary supplement contains what the manufacturer intends.
 Unlike most foods, the majority of dietary supplements are packaged
into tablets, gelcaps, and capsules.  Some dietary supplements may
contain bioactive ingredients for which certain, controlled amounts are
intended to be in each tablet or capsule.  The process controls that
must be in place to ensure the tablet or capsule contains what it
purports to contain are different than those that must be in place to
ensure a food is manufactured, processed, packed, and held under
sanitary conditions.  Process controls for dietary supplement
manufacture include establishing and meeting specifications to ensure
the finished dietary supplement contains the correct ingredient, purity,
strength, and composition intended.

Vitamins can present a concentrated source of biologically active
components.  A vitamin, for example, that contains too high a
concentration, such as vitamin D at levels that are many times greater
than intended, can lead to illness and hospitalization. (Refs. 7-8).  A
manufacturer must establish a process for manufacturing a dietary
supplement product in order to produce the product consistently and
reliably each time.  In order to achieve consistency and reliability,
there must be process controls in place to ensure, for example, that
appropriate tests and examinations are conducted, a master manufacturing
record is prepared, each batch production follows the master
manufacturing record, and the finished tablet or capsule is placed in
the intended package with the intended label. 

These same types of controls are needed for herbal and botanical dietary
supplements.  Botanicals are often complex mixtures that can vary in
composition depending on factors such as the part of the plant used, the
location of harvesting and growing conditions that can vary from year to
year even in the same location.  It can be difficult to distinguish
between closely related species of botanicals, and the biological
activity of components of an incorrectly identified species can lead to
adverse consequences.  In addition, different species may be present in
different ratios or blends in a particular product.  Various products
might contain different parts of the plant--flower, leaf, root, stem,
extract--and the test methods for each can vary in the nature,
sensitivity, and specificity of the test. 

Well-established principles of CGMP require process controls at each
step of the manufacturing process as early in the production process as
possible.  Quality cannot be tested into the product only at the end. 
(Ref. 9).  Instead, the quality of the dietary supplement must be built
into the product throughout the manufacturing process; quality begins
with the starting material and continues with the product being
manufactured in a reproducible manner according to established
specifications.  It is not sufficient nor effective to rely solely on
end product testing to assure the quality of the individual dietary
supplement product sold to the consumer.  

CGMPs are intended to establish a comprehensive system of process
controls, including documentation of each stage of the manufacturing
process, that can minimize the likelihood of, or detect, problems and
variances in manufacturing as they occur and before the product is in
its finished form.  These process controls that are a part of CGMPs are
essential to ensure that the dietary supplement is manufactured,
packaged, held, and labeled, in a consistent and reproducible manner.  

Manufacturing according to CGMP means that the manufacturing process
incorporates a set of controls in the design and production processes to
assure a quality finished product.  CGMPs specific to dietary
supplements are necessary to help ensure that these products have the
identity, purity, strength, and composition that meets 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.  In fact, several comments asked us to define
“quality” and suggested various definitions, each of which related
to a dietary supplement having the identity, purity, strength and
composition intended (see comment 49 in section VI).  Some comments
distinguished the concept of quality from that of preventing
adulteration.  These comments objected to our statement that dietary
supplement CGMP requirements are needed to prevent adulteration and
stated that CGMP is focused on assuring that finished products are
manufactured using quality procedures, but are not related to preventing
adulteration.  Other comments asked us to define “adulteration.”  

	We agree that a critical aspect of CGMP is achieving control over
manufacturing processes.  Controls are necessary to ensure that you
manufacture what you intend so that the characteristics and/or
attributes desired in a final product will be consistently and reliably
achieved.  We disagree with the comments to the extent that they were
suggesting that quality is not related to preventing contamination in
the manufacturing process that may adulterate the finished product. 
However, we have reconsidered, as discussed in this section, what types
of adulteration and misbranding are necessary to control for in the
dietary supplement CGMP rule.  

To clarify what dietary supplement CGMP requirements are intended to
achieve, we have added a definition of quality in the final rule.  As
defined, quality means “that the dietary supplement consistently meets
the established specifications for identity, purity, strength, and
composition and has been manufactured, packaged, labeled, and held under
conditions to prevent adulteration under sections 402(a)(1), (a)(2),
(a)(3), and (a)(4) of the Federal Food, Drug, and Cosmetic Act.” 
Ensuring the quality of the dietary supplement means that you
consistently and reliably manufacture what you intend and that you
establish manufacturing controls to prevent the dietary supplement from
being adulterated under section 402(a)(1) of the act due to the presence
of contaminants, under section 402(a)(2) of the act, for example, if it
bears or contains any unintentionally added poisonous or deleterious
substance, under section 402(a)(3) of the act if the dietary supplement
consists in whole or in part of any filthy, putrid, or decomposed
substance, or if it is otherwise unfit for food, or under section
402(a)(4) of the act if the dietary supplement has been prepared,
packed, or held under insanitary conditions whereby it may have become
contaminated with filth, or whereby it may have been rendered injurious
to health.  The definition of quality limits to sections 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act the types of adulteration that you
must control for in this CGMP final rule. The definition applies to the
controls that are designed to prevent contamination of the product that
you intend to manufacture.   

In the 2003 CGMP Proposal, we said that our purpose was to present a
broad enough scope to the proposed rule so that we could receive the
depth and breadth of comment needed to develop a final rule that would
provide the proper balance of regulation (68 FR 12157 at 12161).  We
asked for comment on whether each of the provisions proposed was
necessary to ensure the safety and quality of the dietary supplement and
was adequate to protect the public health (id).  We stated that the
proposed rule “would establish the minimum CGMPs necessary to ensure
that, if you engage in activities related to manufacturing, packaging,
or holding dietary ingredients or dietary supplements, you do so in a
manner that will not adulterate and misbrand such dietary ingredients or
dietary supplements” (68 FR 12157 at 12158).  For example, we stated
that the proposed rule would require the manufacturer to test for toxic
compounds in botanicals that may likely be present to ensure that no
such compounds are present that may adulterate the dietary supplement
(68 12157 FR at 12162).  Further, we included a requirement that the
ingredients, other than dietary ingredients under section 201(ff) of the
act, be lawful under the applicable food additive regulations or be
generally recognized as safe (proposed § 111.35(d)(21 CFR 111.35(d)).

The approach that we set forth in the 2003 CGMP Proposal was designed to
prevent a manufacturer, under CGMP regulations, from using an
ingredient, whether a dietary ingredient or another component, in the
manufacture of a dietary supplement that would adulterate the product
under relevant provisions of the act, such as sections 402(a)(1) or
402(a)(2)(C).  The manufacturer would have been required to establish
specifications at any point, step, or stage in the manufacturing process
where control is necessary to prevent adulteration (proposed
§ 111.35(e)).  Thus, the manufacturer would not have been able to
establish a specification, consistent with proposed § 111.35(e), for
the use of an unlawful ingredient because such use would not prevent
adulteration.  In addition, the manufacturer would have to establish
specifications for contaminants that may adulterate or that could lead
to adulteration of the dietary supplement.  The manufacturer would have
to take necessary precautions to prevent the presence or level of
contaminants, that would otherwise adulterate the dietary supplement
under another provision of the act, from being present in the dietary
supplement.  The specifications were intended to ensure that adulterated
and misbranded dietary supplements would not reach the marketplace (68
FR 12157 at 12197). 

In addition to the general specifications established under proposed
§ 111.35(e), the proposed rule would have required the manufacturer to
establish specifications for the identity, purity, quality, strength,
and composition of the components received (proposed § 111.35(e)(1))
and for the finished batch of dietary supplement (proposed
§ 111.35(e)(3)).  Although we stated that the proposed rule did not
address questions related to the safety of dietary ingredients used (68
FR 12157 at 12172), if a dietary ingredient was deemed to be unsafe
under the act--under section 402(a()1) or another provision-- a
specification could not have been established for that dietary
ingredient, consistent with proposed § 111.35(e).  Thus, a
manufacturer would not be able to use, under dietary supplement CGMP, a
dietary ingredient, or other component, that would otherwise adulterate
the product under another provision of the act. 

Further, the proposed rule was designed to ensure that the correct label
was applied during manufacture (proposed §§  111.45(b)((7);
111.50(c)(12); 111.70(b)(7)) so that the dietary supplement label would
accurately identify the dietary supplement.  The proposed rule also
would have required the master manufacturing record to contain the
identity of each ingredient that is required to be declared on the
ingredient list in section 403 of the act (proposed § 111.45(b)(4)).  

Several comments seemed to question why the dietary supplement CGMP rule
would require that a manufacturer use lawful ingredients when other
provisions of the act would require such use.  In fact, some comments
objected to the proposed requirement in the rule that required that a
component, other than a dietary ingredient, be approved for use as a
food additive or be generally recognized as safe (GRAS).  The comments
stressed that such a provision was not necessary because the statute
already requires that such an ingredient be approved as a food additive
or be GRAS.  In light of these comments, we reconsidered our
interpretation of the scope of “prevent adulteration” in the
codified to the proposed rule and whether that interpretation should be
narrowed.  We also considered whether to require, as part of a CGMP
requirement, that the label that accurately reflects the ingredients in
the product be applied or whether such a requirement was not necessary,
given our existing authority in section 403 of the act.    

We determined that ensuring quality in dietary supplement CGMP, in part,
means that you produce what you intend to produce.  As stated in section
V, manufacturers must plan what they intend to produce, institute
adequate controls to achieve the desired outcome, and ensure that the
controls work so that the desired outcome is consistently achieved. 
Thus, for example, the manufacturer decides on the identity, purity,
strength, and composition of the dietary supplement it manufactures. 
The focus of CGMP is on process controls to ensure that the desired
outcome is consistently achieved, and not on the inherent safety of the
ingredients used (which is addressed by other statutory prohibitions). 

We agree with the comments that the safety of a particular ingredient is
governed by other provisions of the act.  If you manufacture a dietary
supplement, you have a responsibility as a manufacturer to evaluate the
safety of the ingredients under, for example, section 402(f) of the act.
 Dietary supplement CGMP would require you to establish the identity,
purity, strength, and composition specifications for the product and
ensure that such specifications are met in the finished batch of dietary
supplement.  Nothing in the dietary supplement CGMPs relieves
manufacturers from complying with any other substantive provisions of
the act relating to the safety of ingredients and other components.

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

Quality, as the term is used for the purposes of this final rule,
relates both to producing what is intended (i.e., establishing and
ensuring that specifications for the identity, purity, strength, and
composition are met) and to ensuring that the dietary supplement that
you intend to produce has been manufactured, packaged, labeled, and held
under conditions to prevent adulteration, within the meaning of sections
402(a)(1), (a)(2),(a)(3), and (a)(4) of the act.  Thus, this final rule
is not designed to specifically prevent all types of adulteration that
may occur under the act.  Rather, this final rule is designed to prevent
adulteration from those types of contamination that are commonly
controlled in other food CGMP regulations.  We do expect, however, that
compliance with CGMP requirements in the final rule will help to avoid
other types of adulteration.  Also, nothing in this rule exempts a
manufacturer from compliance with other relevant adulteration provisions
of the act.  

We are replacing the phrase “prevent adulteration” in the codified
with words that relate to ensuring the quality of the dietary
supplement.  Thus, for example, we have modified proposed § 111.35(e)
(now final § 111.70(a)) to read, “You must establish a specification
for any point, step, or stage in the manufacturing process where control
is necessary to ensure the quality of the finished dietary supplement
and that the dietary supplement is packaged and labeled as specified in
the master manufacturing record ” instead of “. . . necessary to
prevent adulteration.”  This phrase is replaced in several codified
provisions and an explanation of this change is not provided in the
preamble each time it is made.

Moreover, you have a responsibility under CGMP to ensure that the label
you specify in the master manufacturing record is applied to the
product.  Under section 403 of the act, you are required to ensure that
your label accurately reflects the ingredients in the product.  Because
section 403 of the act  provides that food, including dietary
supplements, is misbranded if a label that does not contain accurate
statements is applied, we do not need to impose the same requirement in
this final rule.  Thus, if the representative label in the master
manufacturing record for the product does not identify the correct
dietary ingredients and the label that lists an inaccurate information
is applied, that dietary supplement would be misbranded under section
403 of the act.  Such labeling would not be a violation of dietary
supplement CGMP unless there is a mix-up in your process control and you
do not put the representative label specified in the master
manufacturing record on the product.  Such a mix-up would be a violation
of dietary supplement CGMP requirements (see e.g., final
§§ 111.127(d), 111.160(e), 111.410(c), 111.415). 

Thus, in addition to stating “ensure the quality of the dietary
supplement,” in the codified instead of “prevent adulteration,” we
are adding the language “and that the dietary supplement is packaged
and labeled as specified in the master manufacturing record.”  Such
change is intended to clarify that the use of the packaging and labeling
that is stated in the master manufacturing record is what is required in
this final rule.   

A failure to follow the requirements in this final rule, including a
failure to establish required specifications, could result in an
enforcement action by the agency under section 402(g) of the act because
the dietary supplement is adulterated in that it was prepared, packed,
labeled, or held under conditions that do not meet current good
manufacturing practice regulations for dietary supplements.  The act
establishes certain prohibited acts and enforcement mechanisms to remove
adulterated product from the market and prevent manufacturers from
continuing to manufacture adulterated product.  Enforcement mechanisms
currently available to us under the act are not affected by this final
rule.

Finally, we have included, in this final rule the existing requirements
in part 110 that we believe are common to dietary supplement
manufacturing.  For example, the requirements in Subpart C, Physical
Plant and Grounds, are similar to those in § 110.20.  We recognize that
there may be operations related to the manufacturing of dietary
supplements for which certain provisions in part 110 apply, but that we
did not determine to be common to most dietary supplement manufacturing
operations.  For example, there may be some dietary supplements that are
dehydrated and rely on the control of moisture consistent with §
110.80(b)(14).  A manufacturer would be expected to comply with the
regulations in part 110 in addition to the regulations in part 111,
unless the regulations conflict.  To the extent that the regulations
conflict, the dietary supplement manufacturer must comply with the
regulation in part 111.

B.  Highlights of the Final Rule

The final rule:

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

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

●	Requires the establishment and use of written procedures for certain
operations, including those related to equipment, physical plant
sanitation, certain manufacturing operations, quality control,
laboratory testing, packaging and labeling, and product complaints;

●	Requires the establishment of specifications in the production and
process control system that will ensure dietary supplements meet the
identity, purity, strength, and composition established in
specifications and are properly packaged and labeled as specified in the
master manufacturing record;

●	Provides for the option to use a certificate of analysis (for
specifications other than the identity of a dietary ingredient) from a
component supplier instead of having manufacturers conduct tests or
examinations on the components they receive;

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

●	Requires use implementation of a quality control unit 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 the quality control unit personnel conducts a material
review and makes a disposition decision;

●	Requires the quality control unit 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 the quality control
unitquality 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 3 2 years beyond the date of
distribution of the last batch of dietary supplements associated with
those records.

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.

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 re-write the rule to be more user friendly. 

     Yet another comment says that any final rule we issue must clearly
set forth CGMP requirements.  This comment seems to suggest the
requirements need to be more detailed in describing what is required. 
The comment asserts that ambiguities in interpretation could result in
economic disadvantage for small businesses because they typically do not
have in-house legal counsel and, thus, must be more conservative in
interpreting ambiguous regulatory provisions.

     (Response) In response to these comments, as well as comments on
specific subparts and provisions, we have reorganized the final rule and
have re-phrased or introduced concepts in a “user-friendly” or plain
language format.  We also have eliminated certain redundant regulatory
requirements and combined similar requirements.  For example, rather
than put all production and process control system requirements in a
single subpart, we have reorganized the final rule to create a series of
subparts that first describe the requirements for the overall design and
implementation of the production and process control system and then
describe the requirements of the individual operations associated with
that system.  We also present each requirement as a question rather than
as a paragraph within a section.  This question format will help readers
focus on the subparts or sections that apply to specific operations. 

	As another example, we reduced the redundancy associated with the
inter-related nature of the proposed rule by combining most similar
requirements.  Both proposed §§ 111.35(m) and 111.60(b)(2) would
require you to keep testing and examination results.  The final rule
places this requirement in a single section (§ 111.325(b)(2)(ii)).

     The final rule also shortens the construction “includes, but is
not limited to” to “includes.”  We did this because the use of the
word “includes” indicates that the specified list that follows is
not exclusive.  The phrase “but is not limited to” is unnecessary. 

     Finally, some changes we have made to one specific section have an
impact on other sections.  For example, after considering the comments,
we revised subpart B to require you to establish and follow written
procedures to fulfill the requirements of subpart B.  Those written
procedures are records you must make and keep in accordance with the
recordkeeping requirements of subpart P, thus we made changes to include
that requirement of making and keeping records. 

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

	(Comment 2) Some comments state that dietary supplement CGMP
requirements will protect consumers from supplements that contain
inherently unsafe dietary ingredients.  Other comments request that we
take additional action to ensure the safety of dietary ingredients.	

	(Response) This final rule focuses on the manufacturing practices of
dietary supplements and not on whether certain dietary ingredients are
or are not safe.  Therefore, comments related to whether certain dietary
ingredients are inherently unsafe and any request to take actions
related to the inherent safety of dietary ingredients are outside the
scope of this rule.  

 	(Comment 3) Some comments support the rule, explaining that it will
address current problems with superpotent and subpotent dietary
supplements, undeclared ingredients, and varying levels of ingredients. 
Others indicate the rule will better protect consumers and increase
consumer confidence.  One comment states that CGMP requirements for
dietary supplements are not needed for responsible manufacturers because
they already manufacture safe dietary supplements.  Some comments state
that dietary supplement CGMP requirements are not needed because the
dietary supplements have a track record of safety.  Other comments say
there were more adverse events reported from drug use than from dietary
supplement use and that a large number of Americans take dietary
supplements, and on that basis suggested that dietary supplements are
safer than foods or drugs.

	(Response) We agree the final rule will better protect consumers and
help address the types of manufacturing problems identified in the
preamble to the 2003 CGMP proposal (see 68 FR 12157 at 12162 through
12163) through consistent use of established production processes and
controls.  	

	However, we disagree with the comments asserting dietary supplements
have a track record of safety such that dietary supplement CGMP
requirements are unnecessary.  Section 402(g) of the act does not
require us to establish a “bad” track record of safety in the
manufacture of dietary supplements before we may issue a dietary
supplement CGMP rule.  Furthermore, we disagree with the comments
comparing dietary supplement safety to drug safety; there are different
statutory requirements, different regulatory requirements, and different
safety evaluations for dietary supplements and drugs.  

	We also disagree that the final rule should apply only to manufacturers
who cannot manufacture dietary supplements responsibly.  Establishing
who is or is not a responsible manufacturer is not a threshold
requirement in section 402(g) of the act, and it would be impractical to
regulate dietary supplement CGMP in such a manner, because parties may
differ as to whether a particular manufacturer acted “responsibly”
in a particular situation.  All dietary supplement manufacturers are
subject to this final rule, just as all dietary supplement manufacturers
are subject to section 402(g) of the act.  We therefore are not
persuaded that dietary supplement CGMP requirements are not needed, or
should only be applied to manufacturers who have not acted
“responsibly.” 

	(Comment 4) Some comments state that our authority under the current
food CGMP regulation in part 110 and our authority to take actions
against adulterated and misbranded products generally are sufficient. 
Other comments state that DSHEA gives us the necessary legal authority
to protect the public health and that additional regulatory requirements
are unnecessary.  Several comments object to our statement that dietary
supplement CGMP requirements are needed to prevent adulteration.  These
comments suggest dietary supplement CGMP is focused on ensuring finished
products are manufactured using quality procedures, but are not related
to preventing adulteration.  Other comments state we should enforce
current food CGMP regulations rather than adopt new regulations. 

	(Response) We disagree that dietary supplement CGMP requirements are
not related to preventing adulteration.  In fact, under the statutory
scheme a dietary supplement is deemed to be adulterated under section
402(g)(1) of the act if it fails to meet CGMP requirements we promulgate
by regulation.  As we discussed in section III, dietary supplement CGMP
requirements are necessary to ensure the quality of the dietary
supplement; ensuring quality includes ensuring that the dietary
supplement has been manufactured, packaged, labeled, and held under
conditions to prevent adulteration under sections 402(a)(1), (a)(2),
(a)(3), and (a)(4) of the act.  

	We also disagree with those comments stating that the requirements in
part 110 are adequate and that no additional requirements are necessary.
 The comments do not explain why the specific requirements set forth in
the proposed rule that are not also in part 110 are unnecessary.  As
discussed in greater detail in response to comments on our legal
authority in section V, the particular characteristics and hazards of
dietary supplements call for CGMP requirements tailored to dietary
supplements.  Congress specifically provided independent authority under
section 402(g) of the act for us to promulgate CGMP requirements for
dietary supplements.  That authority would have been unnecessary if
Congress had concluded that part 110 was adequate.      

	We also disagree that enforcement of part 110 would eliminate a need
for dietary supplement CGMP requirements.  The dietary supplement CGMP
requirements include practices specifically tailored to the
characteristics and hazards of dietary supplements and their
manufacturers.  The comments asserting that current food CGMP
requirements in part 110 are sufficient provided no persuasive or
compelling reasons for that assertion, or for why we should not
implement dietary supplement CGMP requirements under section 402(g) of
the act.  For these reasons, we are not persuaded by the comments that
these dietary supplement CGMP requirements are not needed. 

	(Comment 5) Some comments object to the examples of manufacturing
problems that we used to support the need for CGMP requirements. 
Specifically, some comments object to the Prevention magazine citation
and also object to the nine examples we presented in the preamble to the
2003 CGMP Proposal (see 68 FR at 12161 through 12163).  We cited the
Prevention magazine survey on consumer use of dietary supplements to
show that only 41 percent of surveyed consumers who use vitamins and
minerals think those products are very safe, and only 50 percent think
the products are somewhat safe; among those using herbal products, only
24 percent thought the products were very safe, and only 53 percent
thought the products were somewhat safe.  We noted that 74 percent
supported increased government regulation of dietary supplements (see,
id.).  As one example of adulterated dietary supplements caused by
manufacturing practices, the preamble to the 2003 CGMP Proposal
mentioned an instance where a young woman suffered a life-threatening
abnormal heart function that was traced to a mislabeled or contaminated
dietary ingredient (68 FR 12157 at 12162).  Another example involved
recalls of super- and subpotent dietary supplements (id.).  

	Comments objecting to the Prevention survey said it provided no
rationale for why CGMP requirements are needed.  Other comments said the
nine examples we provided represent a failure to conform to an existing
regulation and do not demonstrate a need for a new CGMP regulation for
dietary supplements.  One comment disagrees that the CGMP requirements
would prevent adverse reactions, as one example suggested in the
preamble to the 2003 CGMP Proposal (see 68 FR 12157 at 12162) because,
the comment claims, most adverse reactions are not the result of
manufacturing problems.  Another comment states the example involving
plantain (68 FR 12157 at 12162), where a raw material was labeled as
“plantain” when it was, in fact, Digitalis lanata (a plant that can
cause life-threatening heart reactions), shows that, had there been a
system in place to test finished product for purity and identity or to
perform identity testing upon receipt, the manufacturer could have
prevented that adulterated product from entering the market place.  The
comment states identity testing is necessary in the final rule.  

	Another comment objects to the example of “non-food grade
chemicals” (id.) because the reference supporting the example involved
Gamma-Butyrolactone, a substance we have stated is an unapproved new
drug and not a dietary supplement.  Some comments say the risks cited in
the justification for these regulations are hypothetical or theoretical
and current statutory or regulatory authority is adequate. 

	(Response)  We disagree, in most part, with the comments.  We cited the
Prevention survey to illustrate consumer perception and support for
increased government involvement in dietary supplement regulation.  We
did not describe the survey as illustrating CGMP problems associated
with dietary supplements. 

	We also disagree that the risks cited in the preamble to the 2003 CGMP
Proposal are merely hypothetical or theoretical.  We provided actual
examples of failures in the manufacturing of products marketed as
dietary supplements.  The comments may have misunderstood what the CGMP
requirements for dietary supplements are intended to accomplish.  A
principal goal of the CGMP requirements is to have those who
manufacture, package, label, or hold dietary supplements do so in a
manner that ensures the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record.  It is the manufacturer who needs to establish
procedures for its manufacturing operations to ensure, for example, the
final product is produced according to its specifications in the master
manufacturing record, meets limits on contaminants, and is a quality
dietary supplement.  If a product does not meet its specifications, a
manufacturer who observes the CGMP requirements should know that and be
able to take corrective action before the dietary supplement enters the
marketplace.  The onus is on the manufacturer, and not simply on us, to
take action to prevent the adulterated product from entering the market
or, if the product has already been released, to remove the product from
the market.  The umbrella food CGMP requirements in part 110 do not
contain specific provisions establishing specifications, requiring
identity testing, or requiring in-process and/or finished product
testing.  Through this final rule, we are establishing a new CFR part
regarding CGMP requirements specifically for dietary supplements. 

	The examples we used in the preamble to the 2003 CGMP Proposal included
adverse event reports associated with contamination with Digitalis
lanata, the possible contamination of botanical ingredients with toxic
compounds, the use of nonfood-grade chemicals, the manufacture of super-
and subpotent dietary supplements, the presence of undeclared
ingredients, and the variability of ingredients from what is declared on
the label.  (Refs. 7, 8, 10; see, also, 68 FR 12157, at 12162-63, March
13, 2003)  These were all examples where products were manufactured,
labeled, and sold to the consumer as dietary supplements.  We disagree
with the comments’ assertions that all these problems can be
adequately dealt with by the food CGMP requirements in part 110, but
agree with the comment that, had there been a system in place “to
perform identity testing upon receipt, the manufacturer could have
prevented that adulterated product from entering the market place.” 
Most of these examples present situations in which the manufacturer
could have identified these problems through the dietary supplement CGMP
requirements for specifications and testing or examination, such as
identity verification, and could have prevented such products from
entering the market or at least provided a greater assurance that such
products would not make it into the marketplace.  The dietary supplement
CGMP requirements ensure adequate controls are in place to identify many
of these types of manufacturing errors before the product is in the
marketplace and not through post marketing adverse event reports or
consumers’ illnesses. 

	The dietary supplement industry is diverse, as are the number and types
of products marketed as dietary supplements.  As we stated in the
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12163), given the
wide range of public health concerns presented by the manufacturing
practices for dietary supplements, a comprehensive system of controls is
necessary.  This final rule will set the standards for CGMP for dietary
supplements that, if followed, will help ensure the quality of the
dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record.  The
establishment of production and process controls and adherence to these
and other CGMP requirements of this final rule will help to prevent the
types of events (and others) we described in the nine examples presented
in the preamble to the 2003 CGMP Proposal.  

	(Comment 6)  Several comments suggest that dietary supplements are no
different in safety or physiologic effect and require no different
requirements than conventional food with respect to CGMP.  One comment
disagrees with us that dietary supplements require different
requirements than conventional food because dietary supplements are
ground up or in powder form and may not be easily recognized or
differentiated; the comment says the same is true of many food
ingredients as well. 

	(Response)  We disagree with the suggestions by these comments that
dietary supplement CGMP requirements need not differ from those for
conventional foods.  By definition, a dietary supplement is in a
category of food separate and distinct from the category of conventional
food.  The definition of dietary supplement in section 201(ff) of the
act, in part, essentially describes a dietary supplement as a type of
food that differs from conventional food.  The definition refers to
sections 411(c)(1)(B)(i) and (c)(1)(B)(ii) of the act, which describe
the forms that dietary supplements intended to be ingested may take,
i.e., tablet, capsule, powder, softgel, gelcap, or liquid form, and if
not in such a form, limitations on how dietary supplements can be
represented, i.e., not as conventional food or as a sole item of a meal
or the diet.  

	Congress included separate additional provisions under section 402 of
the act (see sections 402(f) and 402(g) of the act) for when a dietary
supplement may be adulterated.  Congress considered that dietary
supplements may warrant CGMP requirements that are different than those
for conventional food.  Although dietary supplements may include
substances that are used as ingredients in conventional foods, the
amounts consumed as a dietary supplement and as a conventional food
product may not be the same and, in fact, may be more concentrated, and
in higher amounts, when taken as a dietary supplement.  The forms in
which dietary supplements are consumed differ (e.g., capsule, tablet),
as may the frequency, when compared to conventional foods.  The uses of
dietary supplements also differ from use as conventional food. 
Consequently certain manufacturing practices considered to be a part of
CGMP for dietary supplement manufacturing may not be necessary for all
types of food. 

C.  What Comments Did We Receive on Written Procedures?

1.  Overview

   In the CGMP proposal (68 FR 12157 at 12165), we stated that written
procedures were included in the dietary supplement CGMP outline
submitted to us by industry, namely, the National Nutritional Foods
Association standards (NNFA), the NSF International draft standards, and
the United States Pharmacopoeia (USP) draft Manufacturing Practices.  We
also stated that, to limit the burden to manufacturers, we were not
proposing to require written procedures for all the requirements.  We
invited comment on whether we should require written procedures for a
variety of operations; specifically, for complying with the CGMP
requirements, under proposed § 111.10 for personnel hygiene and for
preventing microbial contamination due to personnel (68 FR 12157 at
12182); maintenance, cleaning, and sanitation for the physical plant
under proposed § 111.15 (68 FR 12157 at 12187); calibrating instruments
and controls under proposed § 111.25(b), (c), and (d) (68 FR 12157 at
12191); maintaining, cleaning, and sanitizing equipment and utensils
under proposed § 111.25(e) (68 FR 12157 at 12192); calibrating,
inspecting, and checking automatic equipment under proposed § 111.30
(68 FR 12157 at 12193); the duties of the quality control unit under
proposed § 111.37 (68 FR 12157 at 12201); implementing the proposed
requirements for receipt of components, dietary supplements, packaging,
and labels under proposed § 111.40(a) and (b) (68 12157 at FR 12203);
preparing the master manufacturing record under proposed § 111.45 (68
FR 12157 at 12205); laboratory operations under proposed § 111.60 (68
FR 12157 at 12209); manufacturing operations under proposed § 111.65
(68 FR 12157 at 12211); packaging and labeling operations under proposed
§ 111.70 (68 FR 12157 at 12213); holding components, dietary
supplements, packaging, labels, and in-process materials under proposed
§§ 111.80 and 111.82 (68 FR 12157 at 12214); identifying,
quarantining, and salvaging returned dietary supplements under proposed
§ 111.85 (68 FR 12157 at 12216); and receiving, reviewing, and
investigating consumer complaints under proposed § 111.95 (68 FR 12157
at 12217).  

We stated that if comments assert that written procedures are necessary,
comments should include an explanation of why the requirement is
necessary to prevent adulteration including how such a requirement would
ensure the identity, purity, quality, strength, and composition of the
dietary supplement.  Conversely if comments assert that written
procedures are not necessary, we asked for an explanation of why and
how, in the absence of the requirement, one can prevent adulteration and
ensure the identity, purity, quality, strength, and composition of the
dietary supplement.

	(Comment 7)  Many comments stress the most critical aspect of a
successful CGMP system is effective process control, which requires
conducting key operations using written procedures.  Several comments
assert that written procedures are an important part of manufacturing
operations to ensure uniform practices in production operations, from
receiving through final operations.  Several comments assert written
procedures provide a sound basis for employee training and supervision. 
Several comments state that without a written training program, it is
very likely that some employees may not receive sufficient training, or
in some cases, any CGMP training at all.  One comment specifically
suggests that companies develop written procedures for the minimum CGMP
training common to all departments.  

     One comment points out that all well-recognized quality systems
require establishment of written procedures to ensure consistent process
control, and cites examples such as the International Organization for
Standardization (IOS), the American National Standards Institute (ANSI),
and the Malcolm Baldridge National Quality Award criteria.  Other
comments state that written procedures are necessary for the definition,
operation and documentation of a process control system, and that
without such procedures it would be virtually impossible for any
company, regardless of size, to consistently manufacture products that
meet established requirements for identity, purity, quality, strength,
and composition.  The comments note that written procedures contain the
necessary instructions for all employees to successfully execute their
respective functions.  Another comment supports a requirement for
conducting key operations using written procedures and states that
records document that operations were performed, but that written
procedures show how the task is to be performed and at what frequency it
should be performed.  One comment states effective communication is
essential to build quality into a process, and written procedures
provide that throughout all levels of an organization.  Another comment
states it is difficult to imagine how the quality control unit could
carry out its obligations under proposed § 111.37(b)(l) to “approve
or reject all processes, specifications, controls, tests, and
examinations, and deviations from or modifications to them ...” if
these are not subject to written procedures.

     Many comments which present one or more of these general reasons
for requiring written procedures also list operations that they believe
should be conducted using written procedures.  The operations that one
or more comments list as key operations are:

•     Employee training;

•     Cleaning the physical plant, including pest control;

•     Maintenance, cleaning and sanitizing of equipment and utensils; 

•     Calibration of equipment used in manufacturing or testing; 

•     All aspects of the production process, including a general
procedure to document the minimum investigation, review and approval
requirements for failures in manufacturing or packaging operations;

•     All quality control operations;

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

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

•     Laboratory operations, including the establishment of
specifications and descriptions of laboratory test methods used to
ensure that components, in-process materials, and finished product meet
established specifications;

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

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

•     Return and salvage operations; 

•     Handling of consumer complaints; and

•     Procedures for product recall.

     Many comments assert an effective process control system that
includes extensive written procedures would justify a decreased testing
burden with respect to the finished product.  One comment suggests we
exempt manufacturers from the requirement to test each finished batch of
product if they have a qualified manufacturing process that meets
certain basic criteria, including a requirement for written procedures
for each stage of the process.  One comment notes it would be clearer to
all parties if specific written procedures were listed as required and
stresses the importance of having all companies know exactly what is
procedurally expected of them.

     In addition to these general reasons for requiring that key
operations be conducted using written procedures, several comments
provide specific reasons for requiring that specific operations be
conducted using written procedures.  In response to our request for
comment on whether written procedures should be required for complying
with proposed § 111.10, (personnel hygiene and for preventing microbial
contamination due to personnel) one comment states that written
procedures help to ensure compliance with the proposed hygiene
requirements by clearly listing the requirements and requiring the
employees to follow them on a consistent basis.

     In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for maintenance, cleaning, and sanitation for the physical
plant under proposed § 111.15, one comment states that having written
procedures in place to clean the physical plant will ensure that there
is no cross-contamination.  Another comment states utility areas such as
effluent treatment, boilers, cooling towers, and water treatment plants
also should have documented procedures for cleaning in order to create a
general awareness of cleanliness throughout the plant.  Other comments
state that such written procedures should not be required because they
would not directly prevent contamination or ensure the identity, purity,
quality, strength, and composition of the dietary supplement if, as the
“bottom line,” a manufacturer maintains the physical plant in a
clean and sanitary condition.

     Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
calibrating instruments and controls under proposed § 111.25(b), (c)
and (d), several comments assert we should require manufacturers to
establish and follow written procedures for calibrating equipment and
controls.  According to these comments, such procedures would provide us
with a written record that is sufficient to evaluate the adequacy of the
company’s calibration procedures and would provide the necessary
controls to meet the underlying intent of the rule.  These comments
assert that written procedures will lessen the risk that adulterated
products will be produced. 

	In response to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
maintaining, cleaning, and sanitizing equipment and utensils under
proposed § 111.25(e), several comments assert such written procedures
are crucial.  These comments claim that written procedures promote
consistency, clearly lay out expectations for employees, facilitate
training, and provide a reference for individuals in performing their
job functions.  One comment states that written procedures for
maintaining, cleaning, and sanitizing equipment are an industry
standard.

      In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for preparing the master manufacturing record under
proposed § 111.45, one comment states that written procedures for
in-process control and quality checks should ensure the addition of the
proper ingredients in the proper amount, and proper blending and control
of other critical points.  Another comment states written procedures are
a critical element for ensuring consistent implementation of proper
corrective action.  Other comments state they do not support a
requirement for written procedures for preparing the master
manufacturing record; and one comment suggests such a written procedure
is not necessary because the proposed regulations for preparing the
master manufacturing record already delineate the requirements for what
information must be included in the master manufacturing record.  

     In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for laboratory operations under proposed § 111.60, some
comments specifically note the need for written procedures for the
laboratory test methods used to ensure that components, in process
materials, and finished product meet established specifications.  Some
comments emphasize written procedures would create a standard for
testing of products or groups of products and establishing parameters
for passing or failing products.

     In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for manufacturing operations under proposed § 111.65, one
comment asserts this is an effective way to train personnel and a means
to hold operators accountable to a quality standard.  Another comment
states written procedures can improve quality and consistency in a
manufacturing operation.

     In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for packaging and labeling operations under proposed §
111.70, one comment asserts this is an effective way to train personnel
and a means to hold operators accountable to a quality standard.

     Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
holding components, dietary supplements, packaging, labels, and
in-process materials under proposed §§ 111.80 and 111.82, one comment
asserts this is an effective way to train personnel and a means to hold
operators accountable to a quality standard.  Another comment states a
company cannot be considered to be a CGMP operation without having
written procedures for every product manufacturing activity, including
holding and distributing.  This comment states mix-ups and adulterations
will be more likely to occur if there are no written procedures for
control of storage locations, manner of storage, and container and
storage location identification codes.

     In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for returned dietary supplements, one comment states
written procedures should govern all return and salvage operations to
create a standard for quarantine and salvage and to establish parameters
for proper salvage conditions.

     Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
handling consumer complaints, some comments state written procedures
will encourage companies to handle consumer complaints in a uniform
manner.  One comment asserts written procedures should be required for
handling consumer complaints because some complaints could relate to
serious illness or injury.  The comment states that written procedures
would set out exactly what steps need to be taken when complaints are
reviewed and are the best way to ensure the essential information is
captured.

     (Response) We agree with the comments that effective process
control, using written procedures, is an important aspect of a
successful CGMP program.  We also agree requiring written procedures
will help to ensure consistent practices in operations – i.e., help to
ensure the operation is conducted in the same manner regardless of who
conducts the operation or when the operation is conducted.  We also
agree that written procedures provide a sound basis for employee
training and supervision, are an effective communication tool, and
enable the quality control unit personnel to carry out its the
responsibility to approve or reject all processes, specifications,
controls, tests, and examinations, and deviations from or modifications
to them.  In addition, written procedures establish expectations for
each covered operation so the operation does not proceed in an ad-hoc
manner.  Written procedures provide specific guidance if there is an
unanticipated occurrence and, thus, can play a key role in ensuring a
quality product, because actions to correct the unanticipated occurrence
can take place swiftly and with confidence in the outcome. 

     This final rule establishes the minimum CGMPs necessary for
activities related to manufacturing, packaging, labeling, and holding
dietary supplements to ensure a quality product.  The operations
required by this final rule must be conducted in a consistent manner,
regardless of who is conducting an operation or when the operation is
conducted.  As discussed in this section immediately below, with a few
exceptions we are requiring that you establish and follow written
procedures to fulfill the requirements for the operations covered by
this final rule.  The exceptions include final subpart A, which
addresses the scope of the rule rather than operations covered by the
rule; final subparts E, H and I, in which we conclude that a requirement
for written procedures would be redundant with other requirements; and
final subpart P, which establishes requirements for making and keeping
records rather than for conducting operations.

     We believe requiring you to establish and follow written procedures
to fulfill the requirements of subparts B through D, F, G, and J through
O, when combined with other requirements of this final rule, justifies
reduced requirements for testing finished batches of product compared to
the proposed requirements for such testing as found in proposed §
111.35.  By establishing and following written procedures, you will
focus your production and process control system on ensuring the quality
of the finished product at each stage in the production process rather
than relying entirely on testing at the end of the process. 

2.  Written Procedures that Are Required by This Final Rule

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

     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. 117). 

	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 cross-contamination and
that such written procedures must include written procedures for pest
control.  Cleaning operations and pest control must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted.  Failure to conduct cleaning operations and pest control
in a consistent manner could lead to failure in ensuring product
quality.  For example, application of a chemical such as a fumigating
agent or rodenticide in a production area must be performed correctly to
avoid contaminating dietary supplements.  Therefore, we disagree that
written procedures would not directly prevent contamination or ensure
the identity, purity, strength, and composition of the dietary
supplement even if a manufacturer maintains the physical plant in a
clean and sanitary condition.  

	We include in final subpart C a requirement that you establish and
follow written procedures for cleaning the physical plant and for pest
control (final § 111.16). 

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

     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 for dietary
supplements.  For example, equipment used for labeling operations has a
greater potential to contaminate a dietary supplement when labeling
operations are carried out in concert with packaging operations, because
the dietary supplement could be exposed to one or more contact surfaces
during the packaging operations.

	Final § 111.25(c) requires you to establish and follow written
procedures for maintaining, cleaning, and sanitizing, as necessary, all
equipment, utensils, and any other contact surfaces used to manufacture,
package, label, or hold components or dietary supplements.  Final §
111.25(c) relates to proposed § 111.25(e)(1) which would, in relevant
part, require you to maintain, clean, and sanitize as necessary, all
equipment, utensils, and contact surfaces used to manufacture, package,
label, or hold components, dietary ingredients, or dietary supplements. 


      (Comment 8) Some comments suggest that written procedures for
maintaining, cleaning, and sanitizing equipment require visual
inspection of equipment when more than one product is manufactured using
the same equipment, and that the presence of residual components from
one product in a different product could be harmful.  The comments also
suggest the written procedures include residual limits of components
from different product lines to guarantee the safety of the dietary
supplement.

     (Response) The final rule gives you flexibility to develop written
procedures appropriate to your products and equipment.  Consequently,
final § 111.25(c) neither requires nor prohibits any specific
procedure, such as the visual inspection suggested by the comment.

     As for the residual limits, the comment provides no data or other
information that would provide a basis for setting residual limits for
any particular components.  However, as we discuss more fully in the
discussion of final § 111.70(e) in section X, the final rule requires
you to establish and meet specifications for the identity, purity,
strength, and composition of dietary supplements and for limits on
contamination for dietary supplements that you manufacture   When
considering the specifications you must establish to ensure the quality
of the dietary supplements, you must take into account the need to
ensure that components or dietary supplements are not contaminated as a
result of using the same equipment.  Such equipment could be a source of
contamination if more than one product is manufactured using the
equipment and it is not properly cleaned and/or sanitized. 

	e.  Written procedures for quality control operations, including
written procedures for conducting a material review and making a
disposition decision and written procedures for approving or rejecting
reprocessing (final subpart F).

     Quality control operations must be conducted in a consistent
manner.  Failure by the quality control unit to carry out its quality
control operations in a consistent and appropriate way could lead to
failure to ensure product quality and to ensure the dietary supplement
is packaged and labeled as specified in the master manufacturing record.
 For example, you could use a component that should not have been
released for use in manufacturing, or you could distribute a packaged
and labeled dietary supplement that should not have been released for
distribution.

	We include in final subpart F a requirement that you establish and
follow written procedures for quality control operations (final §
111.103).  We agree with the comments that there should be written
procedures for investigating failures in manufacturing operations.  In
the CGMP proposal, we referred to the process of investigating such
failures as a “material review” and proposed a series of
requirements related to a material review and the disposition decision
that follows a material review.  The review must be conducted in a
consistent manner, and the criteria for making a disposition decision
must be consistent, regardless of who is conducting the material review
or when it is conducted, and regardless of who makes the disposition
decision and when the decision is made.  For example, if you do not have
written criteria for determining whether a deviation from specifications
has resulted in, or could lead to, adulteration, different individuals
who conduct a material review could reach different decisions regarding
the appropriate disposition of the affected dietary supplement,
including decisions that incorrectly result in the release of an
adulterated product.  As discussed more fully below in section X and XI,
the final rule requires that the quality control unit 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 the quality control
unit thatpersonnel 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, the
quality control unit 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 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 mix-ups, and suitably disposing of obsolete packaging and
labels.  These packaging and labeling operations must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted.  Failure to perform these operations in a consistent way
could lead to a failure to ensure the quality of the dietary supplement
and that the dietary supplement is labeled and packaged as specified in
the master manufacturing record.  For example, if you do not have
procedures for identifying filled, but unlabeled, containers of dietary
supplements, mix-ups could occur before the labels are applied.  The
final product could contain ingredients other than those identified on
the label specified in the master manufacturing record.  Therefore, we
include in final subpart L a requirement that you establish and follow
written procedures for packaging and labeling operations (final §
111.403).  

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

	We agree with the comments that written procedures for holding and
distributing operations are an effective means to hold operators
accountable to a CGMP standards, and that mix-ups and other problems
that affect the final product will be more likely to occur if there are
no written procedures for operations such as control of storage
locations, manner of storage, and container and storage location
identification codes.  The final provisions for holding and distributing
operations require, among other things, that you hold components and
dietary supplements under appropriate conditions of temperature,
humidity, and light so that the identity, purity, strength, and
composition of the components and dietary supplements are not affected;
that you hold components, dietary supplements, and in-process materials
under conditions that do not lead to the mix-up, contamination, or
deterioration of components or dietary supplements; and that you
distribute dietary supplements under conditions that will protect them
against contamination and deterioration.  

	These holding and distributing operations must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted.  Failure to follow these requirements for holding and
distributing in a consistent manner could lead to a failure to ensure
the quality of the dietary supplement product.  For example, if
employees do not know how to store an in-process batch of a botanical
dietary supplement to control humidity, the growth of mold could be
promoted.  Furthermore, if a distributor does not refrigerate a dietary
supplement that requires refrigeration to ensure its strength, the
dietary supplement may not meet its specification for strength. 
Therefore, we include in final subpart M a requirement that you
establish and follow written procedures for holding and distributing
operations (final § 111.453).  

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

	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 the quality control unit personnel conducts a material
review and makes a disposition decision.  You must destroy, or otherwise
suitably dispose of, any returned dietary supplement that the quality
control unit personnel does 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 the quality control unit personnel conducted its a
material review, the dietary supplement could be inadvertently co-mixed
with other containers of that same lot of product and then inadvertently
redistributed.  Therefore, we are including in final subpart N a
requirement that you establish and follow written procedures to fulfill
the requirements of subpart N (final § 111.503). 

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

	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); use aimplement
quality control unit operations in your 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 the
quality control unit personnel conduct all required material reviews and
makes all required disposition decisions (final § 111.87); and adhere
to certain requirements for treatment, in-process adjustments, and for
reprocessing (final § 111.90).  

	In considering whether we should require that you establish and follow
written procedures to fulfill the requirements of final subpart E, we
evaluated whether requirements in other subparts that address specific
operations for the production and process control system substitute for
the requirement of written procedures in final subpart E.

	Final subparts F through M establish specific requirements for
manufacturing, packaging, labeling, and holding dietary supplements,
including requirements for quality control operations (final subpart F);
components, packaging, labels, and product that is received for
packaging and labeling as a dietary supplement (final subpart G);
establishing a written master manufacturing record and batch record
(final subparts H and I); laboratory operations (final subpart J);
manufacturing operations (final subpart K); packaging and labeling
operations (final subpart L); and holding operations (final subpart M). 
We require you to establish and follow written procedures to fulfill the
requirements of final subparts F, G, J, K, L, and M.  Given these
requirements, we conclude it would be redundant to require you to
establish and follow written procedures to fulfill the requirements of
final §§ 111.55, 111.60, and 111.65 in subpart E.

	Final subpart J requires you to establish and follow laboratory control
processes that include the use of criteria for establishing appropriate
specifications (final § 111.315(a); use of sampling plans for obtaining
representative samples (final § 111.315(b)); use of criteria for
selecting appropriate examination and testing methods (final §
111.315(c)); use of criteria for selecting standard reference materials
used in performing tests and examinations (final § 111.315(d)); and use
of test methods and examinations in accordance with established criteria
(final § 111.315(e)).  In addition, under final § 111.303 you must
establish and follow written procedures for laboratory operations. 
Given the requirements of final subpart J, we conclude it would be
redundant to require you to establish and follow written procedures to
fulfill the requirements of final §§ 111.70, 111.75, and 111.80 in
subpart E.

	Final subpart M establishes requirements for holding reserve samples. 
Under final § 111.453 you must establish and follow written procedures
for holding operations.  Given the requirements of final subpart M, we
conclude that it would be redundant to require you to establish and
follow written procedures to fulfill the requirements of final § 111.83
in subpart E for reserve samples.

	Final subpart F establishes requirements for the quality control unit
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 with 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. 128) (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 actually save time and other resources because they
greatly facilitate employee training and ensure that activities are
performed consistently and correctly.  Some comments assert most
companies already have written procedures in place, so start-up costs
associated with such requirements would be minimal.  One comment notes
written procedures would be among the least costly of all the procedural
requirements proposed by FDA.

	(Response) We agree that requiring that operations be conducted using
written procedures can save time and other resources by facilitating
employee training and ensuring operations are performed consistently and
correctly.  Because following written procedures can help ensure
uniformity in the process and ensure the quality of the dietary
supplement at every step, periodic end product testing can be sufficient
to determine whether your manufacturing process is controlled.   CGMP is
premised upon quality assurance at every step of the process.  It is
less costly to establish and follow written procedures than it would be
to test each finished batch for conformance with specifications.  As
suggested by these comments, our analysis (section XXIV) shows that the
overall costs are reduced, in part, because requiring that certain
operations be conducted using written procedures enables us to reduce
requirements for testing at the finished batch stage.

	(Comment 12) One comment states training employees on the required
hygienic practices prior to their first day of handling product is
critical to ensuring product safety.

	(Response) The requirement to establish and follow written procedures
to fulfill the requirements of subpart B does not establish any fixed
requirement for when an employee must receive such training relative to
when the employee handles product.  However, final § 111.12(c) requires
that any person engaged in manufacturing, packaging, labeling or
holding, or in performing any quality control operations, must have the
education, training, or experience to perform the person's assigned
functions.  We therefore assume that employees will have the necessary
education, training, or experience for each operation that they perform
before they perform it. 

	(Comment 13) Some comments make recommendations for what written
procedures should contain, including general parameters that should be
included in all written procedures and specific parameters that should
be included in specific written procedures.  The general parameters
include identification of the company; title that reflects the
activities to be performed; identification or control number with a
revision level code; effective date; the number of pages in the
procedure (e.g., by a procedure such as listing page numbers using a
convention such as “page 1 of 4”); approval date and signature(s);
references to linked or related procedures or forms; definitions of
technical terms and acronyms; list of equipment, materials, and supplies
needed in performing the task; who has the responsibility for performing
each task; when and where a task is to be performed; concise step by
step instructions for performing the task; the expected results from
performing the task; what data to collect; and how to analyze, file, or
report the collected data.  In the specific case of written procedures
for cleaning equipment and utensils, some comments suggest the written
procedures include descriptions of appropriate cleaning agents, methods
of cleaning, and the intervals and schedules for cleaning equipment.

	(Response) We agree the suggestions provided by these comments are
useful to include in any written procedures.  However, to provide the
flexibility necessary to address diverse dietary supplement
manufacturing processes, we are leaving details such as these to the
judgment of the company rather than prescribing them within the final
rule.     

	(Comment 14) Some comments request the final rule include requirements
for managing changes to written procedures. One comment states changes
to written procedures should be reviewed, justified, documented,
approved, and implemented in a defined manner.  The comments explain
that “Change control procedures” define what is and what is not
covered by the written procedure and how proposed changes will be
identified or recommended, processed, reviewed and approved.

	(Response) As discussed in final Subpart F, the final rule requires
that the quality control unit 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.  We address SBREFA’s
regulatory flexibility issues by staggering compliance dates so that
certain businesses would have 24 and 36 months, respectively, to comply
with the final rule.  As for the assertion that food CGMPs do not
require written procedures, we discuss the requirements of food CGMPS in
relation to the requirements of these dietary supplement CGMPs in
section V.  The comment’s assertion that the 1997 ANPRM did not
contain written
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●	Cleaning and maintaining equipment and utensils used in the
manufacture of products; 

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

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

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

●	The control procedures employed for the receipt, storage, handling,
sampling, examination, and/or testing that may be necessary to assure
the identity of labeling and the appropriate identity, cleanliness and
quality characteristics of packaging materials for dietary products; 

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

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

(62 FR 5699 at pages 5704 through 5706).  

	(Comment 17) In the analysis of impacts in the 2003 CGMP Proposal (68
FR 12157 at 12222), we stated that we had considered imposing fewer CGMP
requirements for the manufacture of vitamins and minerals.  Although
this issue arose as a discussion of regulatory options that we had
considered and rejected, we received several comments on this subject. 
Some comments state we should not create different CGMP standards based
upon the type of dietary ingredient.  These comments state that one set
of appropriately flexible standards would be more efficient and less
confusing to industry than separate standards for each portion of the
industry.  Some comments say that different requirements for vitamins
and minerals would cause problems because most people who use these
products take a multivitamin/mineral preparation as their primary and
sole dietary supplement, so the risk of adverse events arising from
adulteration, misidentification, or misformulation of products would be
much higher if vitamins and minerals were subject to fewer requirements
compared to other dietary supplements.  Other comments supported the
concept of differing standards.  Some comments assert, in order for the
CGMP regulations to set minimum quality standards for all dietary
supplements, we would have to regulate each facet of the manufacture,
packaging, and storage of a dietary supplement independently of product
type.  These comments state reducing the requirements for vitamin and
mineral manufacturers would not allow the development of minimum quality
standards across the entire dietary supplement industry.

	(Response) The concept of fewer requirements for vitamins and minerals
was simply one regulatory option we considered as part of the 2003 CGMP
Proposal’s analysis of impacts (see 68 FR 12157 at 12220 through
12223).  We rejected it (id).  We disagree with the comments that there
should be fewer CGMP requirements for vitamins and minerals.  Neither
the 2003 CGMP Proposal, nor this final rule, imposes fewer requirements
on vitamin or mineral firms compared to firms that make other types of
dietary supplements.  

V. What Legal Authority Comments Did We Receive?

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

1.	Modeled After CGMP for Food

	(Comment 18)  Some comments support our approach of proposing
requirements that are more comprehensive than the CGMP requirements for
food.  One comment states that the current requirements for food CGMP
are less comprehensive than the CGMP requirements in current use by both
the food and dietary supplement industries and the current “best
practices” should be incorporated into the dietary supplement CGMP
rule.  Several comments state that the requirements for dietary
supplement CGMP do not need to be identical to the requirements in
existing food CGMP regulations; that appropriate manufacturing controls
are needed for dietary ingredients contained in dietary supplements to
protect the public health; that some borrowing of drug CGMP concepts may
be necessary; and that we should balance effective control with
necessary flexibility in the dietary supplement CGMP rule.  In addition,
one comment states that the USP manufacturing guidelines, which contain
wording from the drug CGMP requirements, are a model for dietary
supplement CGMP for many in industry.  

	Several comments express concern about not deviating too drastically
from the requirements in existing food CGMP regulations.  Although
several comments recognize that additional CGMP provisions for dietary
supplements, such as those related to identity, purity, strength,
quality, and composition, are needed, the comments say that we should
not regulate dietary supplement manufacturing in the same manner as drug
manufacturing because it would entail overly burdensome methods for
production and process controls.  Some comments contend that some of the
proposed rule requirements exceed the drug CGMP requirements.

	Most of the comments assert that the proposed dietary supplement CGMP
requirements are not modeled after the current good manufacturing
practice regulations for food.  The reasons for this assertion vary. 
Some assert that certain provisions in the proposed rule were not found
in, or differ from, the provisions in part 110.  Examples of proposed
requirements that comments indicate exceeded food CGMP included batch
testing, packaging and labeling, recordkeeping, consumer complaints, and
the use of validated methods.  Other comments state that the proposed
requirements exceeded those for food because the proposed rule provided
for finished testing of certain substances when used as dietary
supplements, such as garlic and ginger, whereas no such testing is
required under existing food CGMP regulations when those same substances
are used as conventional food.  One comment says the rule was modeled
after juice hazard analysis critical control point (HACCP) and therefore
goes beyond existing food CGMP regulations.  

	Some comments assert that the proposed requirements exceed the existing
food CGMP regulations because certain proposed provisions contained a
level of detail that is not in the food or the drug CGMP regulations, or
because elements of a provision in the proposed rule were similar to a
provision in part 210 (drug CGMP regulation).  Other comments disagree
with our rationale that the proposed rule was designed on the same
principles as the existing food CGMP regulations to address the
characteristics and hazards specific to dietary supplements, or to
prevent adulteration in preparing, packaging, or holding dietary
supplements.  The comments also disagree that we may include provisions
in the dietary supplement CGMP final rule that were not found in the
food CGMP regulations at the time DSHEA was enacted. 

	Several comments state that we exceed our legal authority for the
proposed rule because it used too broad a definition of “modeled
after.”  Some comments offer their own definitions of “model”;
others object to the use of the noun form “model” and provide
dictionary definitions of the verb form “modeled.”  A few comments
assert that the meaning of “model” is clear, despite different
dictionary meanings, and that the statute is not ambiguous under Chevron
U.S.A. Inc. v. Natural Resources Defense Council, 467 U.S. 837
(1984)(“Chevron”).  One comment states that, even if the language is
ambiguous and our interpretation merits deference, our interpretation is
too expansive and not based on a permissible construction of the
statute.  Another comment states that we did not explain why our
interpretation was consistent with our Congressional mandate.  

	(Response)  We agree with the comments stating that the dietary
supplement CGMP requirements in this final rule need not be identical to
the existing food CGMP regulations and that a system of manufacturing
controls specific to dietary supplements is needed.  We do not agree
that we exceeded the scope of our authority under section 402(g) of the
act in issuing the proposed requirements for dietary supplement CGMP or
these final requirements.  Our interpretation of the language in section
402(g) of the act, including the “modeled after” language, as to
what requirements of the act we have authority to issue, is based on a
permissible construction of the statute.

	The comments present the following general questions:  (1) Whether the
statute gives us authority to promulgate CGMP requirements for dietary
supplements that are not identical to the requirements in existing
current good manufacturing practice regulations for food; and 2) if so,
whether the requirements in this final rule that differ from those in
existing CGMP regulations for food are fairly encompassed within
Congress’s direction that the dietary supplement regulations shall be
“modeled after” food regulations and, therefore, are based on a
permissible construction of the statute.

	Under section 402(g)(1) of the act, a dietary supplement is deemed to
be adulterated if it has “been prepared, packed, or held under
conditions that do not meet current good manufacturing practice
regulations, including regulations requiring, when necessary, expiration
date labeling, issued by the Secretary under subparagraph (2).” 
Section 402(g)(2) of the act authorizes the Secretary, by regulation, to
“prescribe good manufacturing practices for dietary supplements.” 
Congress further provided that such regulations “shall be modeled
after current good manufacturing practice regulations for food” and
“may not impose standards for which there is no current and generally
available analytical methodology.”  

	In construing the meaning of section 402(g) of the act, and, in
particular, the language in that section stating that such regulations
shall be “modeled after current good manufacturing practice
regulations for food,” we are confronted with two questions.  First,
has Congress directly and unambiguously spoken to the precise question
at issue? (“Chevron step one”) (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 201(ff) of the act (21 U.S.C. 321(ff)).  Instead,
the statute calls for us to issue regulations that are “modeled
after” CGMP regulations for food.  The plain meaning of a “model”
or “modeled after,” as discussed in the 2003 CGMP Proposal (68 FR at
12165) and in the comments, relates to a pattern, plan, representation,
or simulation.  The use of the term “modeled after” makes it clear
that the regulations need not be identical to the original, but instead
are contemplated to differ from the original.   

	Thus, the additional, independent authority to promulgate current good
manufacturing practice regulations for dietary supplements that Congress
provided in section 402(g) of the act, without delineating what
requirements such a regulation could or could not include, left us with
considerable authority to fill in the gaps in ways that recognize the
differences between dietary supplements and other foods that warrant
different manufacturing controls.  A contrary interpretation, as some
comments suggested, that the “modeled after” language means the
requirements for dietary supplement CGMP must be precisely found in
current part 110, or other food CGMP regulations, would so narrowly
circumscribe our discretion as to make it impossible to tailor the
regulation to fit the products it is designed to address.  Such an
interpretation would lead to a rule that would “frustrate the success
of the regulation undertaken by Congress” because it would not take
into consideration the characteristics, hazards, and manufacturing
practices specific to dietary supplements (American Trucking Ass’ns v.
U.S., 344 U.S. 298, 311 (1953)). 

	Congress has also spoken to the precise question of which requirements
constitute current good manufacturing practice “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 consistent with our statutory authority for us to
look to all of our food CGMP regulations--including infant formula,
low-acid canned foods, acidified foods, and bottled water, as well as
our general food CGMP regulations--after which to model our dietary
supplement CGMP regulations.

	Congress has not spoken to the precise question of what specific
requirements for dietary supplements may be imposed under the “shall
be modeled after” language.  Given this ambiguity, therefore, under
Chevron step two, we may determine what requirements to include in this
final rule for dietary supplement CGMP, provided that our interpretation
is not arbitrary, capricious, or manifestly contrary to the statute
(Chevron, 467 U.S. at 844).  

	Accordingly, we considered the types of requirements in the existing
food CGMP regulations and used those as models for the dietary
supplement CGMP requirements.  We considered both the objectives and the
means of achieving the objectives in the existing food CGMP regulations.
 These CGMP food regulations include those for infant formula (part
106), general food (“umbrella” regulations) (part 110), thermally
processed low-acid canned food (part 113), acidified food (part 114),
and bottled water (part 129).  Each of these food CGMP regulations
provides objectives and means upon which we modeled the dietary
supplement CGMP regulations.  Just as the precise requirements of the
other food CGMP regulations are tailored to the particular
characteristics and hazards of the foods and manufacturing processes
being addressed, the dietary supplement CGMP requirements are also so
tailored. 

	For example, the infant formula CGMP regulation is intended to ensure
that the “safety and nutritional potency” of a formula are “built
into the manufacturing process” in order to establish a quality
control system to make sure that infant formula products are properly
manufactured (47 FR 17016 and 17017 (April 20, 1982)).  The specific
criteria in the regulations apply in determining whether the infant
formula meets the safety, quality, and nutrient requirements of the act
(§ 106.1(a)).  The means to achieving the objectives in the infant
formula regulations include, for example, requirements for ingredient
control (through a supplier’s guarantee or certification or through
analysis of the ingredient) (§ 106.20); preparation of a master
manufacturing order and a system to assure and verify the addition of
each ingredient (§ 106.25); either in-process batch testing (§
106.25(b)) or sampling and testing of each batch to ensure nutrient
requirements are met (§ 106.30); and coding to enable ready
identification of lots during their sale and distribution (§ 106.90).  

	The infant formula CGMP regulation also includes numerous requirements
that manufacturers maintain records: e.g., records on certain
food-packaging materials; records on nutrient premix testing;
certificate and guarantees from premix suppliers for required nutrients;
records of results of testing conducted by suppliers; records of tests
to establish the purity of each nutrient, the weight, and amounts of
nutrients; records to ensure proper nutrient quality control; records to
ensure required nutrient control at the final product stage;
distribution records; records on microbiological quality and purity of
raw materials; and records of audits (§ 106.100).  The infant formula
CGMP regulation also requires manufacturers to maintain procedures
describing how complaints will be handled; to follow those procedures;
and to investigate when a complaint shows a possible health hazard (§
106.100(K)).  Quality control records must contain enough information to
permit a public health evaluation of any batch of infant formula (§
106.100(o)).  All required records must be available for authorized
inspection (§ 106.100(l)).

	Many provisions of the dietary supplement CGMP final rule are similar
in objective and means and are “modeled after” the provisions of the
infant formula CGMP regulation.  For example, like the infant formula
regulation, the dietary supplement CGMP regulation is designed to
establish a quality control system to make sure that dietary supplements
are properly manufactured.  The dietary supplement regulation uses
similar means to ensure this goal, such as requirements for ingredient
control (through supplier’s certificate of analysis or testing or
examination) (final § 111.75(a)); preparation of a master manufacturing
record (final § 111.205); in-process batch monitoring (final §
111.75(b)) or batch testing or examination (final § 111.75(c)); and
coding to provide a batch, lot, or control number (final § 111.260(a)).
 Like the infant formula CGMP regulations, the dietary supplement CGMP
final rule contains recordkeeping requirements related to packaging
materials; certificates of analysis from suppliers; results of tests
that you conduct, for example, on ingredients or the finished batch; and
results of chemical, microbiological, or other tests that you conduct as
necessary to prevent the use of contaminated components (final §§
111.180(b)(2), 111.95, 111.260(h), 111.325(b)(2), and 111.365(d)).  Also
similar to the infant formula CGMP regulation, the dietary supplement
CGMP final rule requires manufacturers to maintain procedures for
handling complaints (final §§ 111.553 and 111.570(b)(1)); to
investigate certain complaints (final § 111.560(a)(2)); and to keep
records of complaints (final § 111.570(b)(2)).  Required dietary
supplement records must also, as with infant formula records, be
available for inspection by FDA (final § 111.610(a)).

	The “umbrella” food CGMP regulation in part 110 details practices
to ensure “(1) that food is manufactured, processed, packed, and held
under conditions that are sanitary, and (2) that such food is safe,
clean, and wholesome” (44 FR 33239 (June 8, 1979)).  Promulgated
primarily under the adulteration provisions of sections 402(a)(3) and
402(a)(4) of the act, as well as section 361 of the Public Health
Service Act (PHS Act), the umbrella CGMP food regulation requires a
quality control operation whose main purpose is “to provide a
systematic procedure for taking all actions necessary to prevent food
from being adulterated within the meaning of the act” (51 FR 22461,
(June 19, 1986)), as well as to prevent the spread of food-borne
communicable diseases (44 FR 33239 (June 8, 1979))(See § 110.5(a)). 
Part 110 also “specifies requirements that must be met to produce safe
and wholesome food” (51 FR 22461 (June 19, 1986)).  These umbrella
food CGMP requirements not only pertain to food safety, but also are
“concerned with contamination by filth or decomposition which may or
may not raise safety concerns” (51 FR 22462 (June 19, 1986)).

	The detailed requirements of the umbrella food CGMP regulation
accomplish these objectives through a variety of means.  For example,
there are specific personnel provisions requiring employees who may be
sources of microbial contamination to be excluded from certain
operations (§ 110.10(a)); persons working in contact with food,
food-contact surfaces, and food-packaging materials to follow hygienic
practices (§ 110.10(b)); and that certain personnel have sufficient
education or experience to produce clean and safe food (§ 110.10(c)). 
The umbrella food CGMP regulation also includes detailed requirements
concerning the grounds surrounding a food plant and the design of
buildings and structures to protect against contamination or to maintain
sanitary operations and produce safe food (§ 110.20).  Detailed
provisions also require that physical facilities be maintained in
sanitary condition and in sufficient repair to prevent food from being
adulterated (§ 110.35).  Any water that contacts food or food-contact
surfaces must be “safe and of adequate sanitary quality” (§
110.37(a)); plumbing, sewage and other disposal, as well as toilet
facilities, must also protect against contamination (§ 110.37(b), (c),
and (d)).  Similarly, equipment and utensils must be designed and
maintained to preclude adulteration and food contact surfaces must be
maintained to protect food from being contaminated by any source,
including unlawful indirect food additives (§ 110.40(a)).  All
operations for receiving, inspecting, transporting, segregating,
preparing, manufacturing, packaging, and storing food must be conducted
using adequate sanitation principles (§ 110.80).  Appropriate quality
control operations must be used to ensure that food is suitable for
human consumption and that food-packaging materials are safe and
suitable (§ 110.80).  Foods must be stored and transported under
conditions to protect against physical, chemical, and microbial
contamination, as well as against deterioration of the food and the
container (§ 110.93).

	The provisions of the umbrella food CGMP regulation serve as the model
for many dietary supplement CGMP provisions.  For example, the dietary
supplement CGMP requirements concerning personnel and microbial
contamination (final § 111.10(a)); hygienic practices (final §
111.10(b)); and education, training, or experience (final § 111.12) are
very similar to provisions in part 110.  In addition, the dietary
supplement CGMP requirements concerning the grounds, physical plant
facilities, cleaning materials, pest control, water supply, plumbing,
sewage disposal, bathrooms, and trash disposal (final §§ 111.15 and
111.20) closely resemble the analogous part 110 requirements.

	Because of the particular hazards associated with low-acid canned foods
and with acidified foods, the CGMP regulations for these foods contain
detailed provisions to ensure safe manufacturing.  Specifically, the
CGMP regulations for these foods protect the public health against
microbial contamination from these foods.  Part 113 sets out safe
manufacturing, processing, and packaging procedures for low-acid foods
in hermetically sealed containers.  The CGMP criteria in this part apply
in determining whether the facilities, methods, practices, and controls
used by commercial processors of such foods are operated “in a manner
adequate to protect the public health” (§ 113.5).  Processors of
low-acid canned foods must have a “scheduled process” that is
established by a qualified person and is “adequate under the
conditions of manufacture for a given product to achieve commercial
sterility” (§§ 113.3 and 113.83).  “Commercial sterility” of
thermally processed food means a condition achieved by applying heat to
render the food free of certain microorganisms (§ 113.3).  Part 113
requires that supervisors satisfactorily complete training at a school
approved by FDA (§ 113.10).  

	Part 113 also contains extremely detailed requirements on equipment and
procedures.  For example, each vessel used for pressure processing in
steam must be equipped with a mercury thermometer that is tested for
accuracy at least once a year, or more frequently if necessary, to
ensure its accuracy (§ 113.40(a)(1)).  Critical factors (variation of
which may affect the attainment of commercial sterility) must be
specified in the scheduled process and must be measured and recorded on
processing records frequently enough to ensure that the factors are
within the specified limits (at least every 15 minutes) (§§
113.40(a)(13); 113.83).  Observations and measurements of certain
operating conditions must be made and recorded at intervals of
sufficient frequency to ensure that commercial sterility of the food
product is being achieved (at least every hour) (§
113.40(g)(2)(ii)(c)).  There must also be a system to stop packaging
operations (or to segregate products) when the packaging conditions fall
below scheduled processes (§ 113.40(g)(2)(ii)(b)).  Regular
observations of container closures are required to be made and recorded
(§ 113.60).  Each container must be coded “to enable ready
identification of lots during their sale and distribution” (§
113.60(c)).  

	Before using raw materials and ingredients susceptible to
micro-biological contamination, the low-acid food processor must ensure
that they are “suitable for use in processing low-acid food” (§
113.81(a)).  Complete records covering all aspects of the establishment
of the scheduled process and of certain confirmation tests must be
maintained permanently (§ 113.83).  Scheduled processes must be readily
available to any duly authorized FDA employee (§ 113.87(a)).  Whenever
any process is less than the scheduled process or when critical factors
are not in control, the low-acid food must be reprocessed or set aside
for further evaluation as to public health significance (§ 113.89). 
Unless the evaluation demonstrates that the product is free of
microorganisms of potential public health significance, the product
either must be reprocessed to render it commercially sterile or
destroyed (§ 113.89).  

	All process deviations involving a failure to satisfy the minimum
requirements of the scheduled process must be recorded and kept in a
separate file detailing the deviations and actions taken (§ 113.89). 
Detailed information on processing and production must be entered on
forms (§ 113.100(a)).  Not later than 1 working day after the actual
process, and before the food is shipped or released for distribution, a
qualified representative of management must review all processing and
production records for completeness and to ensure that the product was
subjected to the scheduled process (§ 113.100(b)).  Records to identify
the initial distribution of the finished product must be kept to
facilitate segregation of lots that may have become contaminated or
otherwise rendered unfit for their intended use (§ 113.100(d)). 
Records must be maintained at the processing plant for at least one year
after the date of manufacturing and at a reasonably accessible location
for another two years (§ 113.100(e)).

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

	Whenever any acidified food process operation deviates from the
scheduled process or the pH of the finished product exceeds 4.6, the
processor must reprocess it, process it under part 113 requirements, or
set it aside for evaluation as to any potential public health
significance (§ 114.89).  Unless the evaluation demonstrates that the
food has undergone a process that has rendered it safe, the food must be
fully reprocessed to render it safe or be destroyed (§ 114.89).  

	A record must be made of the procedures used in the public health
evaluation and the results of the evaluation (§ 114.89).  Records must
be kept of examinations of raw materials, packaging materials, and
finished products, and of suppliers’ guarantees or certifications that
verify compliance with our regulations (§ 114.100(a)).  Processing and
production records showing adherence to scheduled processes must be
maintained and must have sufficient additional information such as
product code, date, container size, and product, to permit a public
health hazard evaluation of the processes applied to each lot, batch, or
other portion (§ 114.100(b)).  Departures from scheduled processes
having a possible bearing on public health or the safety of the food
must be recorded and kept in a separate file or log, along with the
action taken to rectify the departure and the product disposition (§
114.100(c)).  Records must be kept identifying initial distribution of
the finished product to facilitate segregation of lots that may have
become contaminated or otherwise unfit for their intended use.  Copies
of certain required records must be kept at a reasonably accessible
location for 3 years from the date of manufacture (§ 114.100).  The
criteria in the part 114 regulation, as well as those in part 110, apply
in determining whether an article of acidified food is adulterated under
section 402(a)(3) of the act in that it has been manufactured under such
conditions that it is unfit for food or under section 402(a)(4) of the
act in that it has been prepared, packed, or held under insanitary
conditions whereby it may have become contaminated with filth, or
whereby it may have been rendered injurious to health (§ 114.5).

	Many provisions of parts 113 and 114 also serve as models for
provisions in the dietary supplement final rule.  In many instances, the
analogous provision in the dietary supplement final rule allows more
flexibility in the means to achieve the goal.  For example, under final
§ 111.13 qualified personnel must be assigned to supervise the
manufacturing, packaging, labeling, or holding of dietary supplements. 
Although the supervisor must be qualified by education, training, or
experience to supervise, the more restrictive requirement of parts 113
and 114 to attend an FDA-approved school is not included.  The
“scheduled process”  for low-acid and acidified food manufacturing,
processing, and packing, is analogous to the required “system of
production and process controls” that dietary supplement manufacturers
must design and implement (final §§ 111.55, 111.60(a)).  Similarly,
the “critical factors” required to be specified in the scheduled
process for low-acid and acidified foods are akin to the
“specifications” that dietary supplement manufacturers must
establish for certain points in the manufacturing process (final
§ 111.70).  Just as low-acid food processors must establish procedures
to ensure that ingredients are suitable for use, so too must dietary
supplement manufacturers establish component and finished product
specifications (final § 111.70(b)and (e)).  Just as containers for
acidified food must ensure suitable protection from contamination,
packaging that comes into contact with dietary supplements must be safe
and suitable for use (final § 111.70(d)).  Dietary supplement
in-process points, like the “critical factors” for low-acid and
acidified food, must be monitored to detect any deviation or
unanticipated occurrence that may result in adulteration (final §
111.75(b)(2)).  

Rejected dietary supplements must also be held under quarantine (final
§§ 111.370, 111.425); dietary supplements which have been reprocessed,
treated, or which have had in-process adjustments must meet all
established product specifications and be approved before release (final
§ 111.90(c)).  Similar to coding low-acid or acidified foods, dietary
supplements must have assigned batch, lot, or control numbers (final §
111.415(f)).  The design, calibrations, and cleaning of equipment and
utensils must also result in the equipment and utensils being suitable
for their intended uses and not result in contamination of components or
dietary supplements (final § 111.27).  Written procedures for the
various controls are required (see, e.g., final §§ 111.8, 111.25,
111.103), and required written records (see, e.g., final §§ 111.14,
111.23, 111.35, 111.95) must be kept for 1 year past the shelf life
date, if shelf-life dating is used, or 3 years after the date of
distribution of the last associated batch of dietary supplement (final
§ 111.605).  All required dietary supplement CGMP records must be
readily available for inspection and copying by FDA (final §
111.610(a)).

	Finally, the bottled water CGMP regulation was promulgated to ensure
the safety and sanitary quality of these products, which include all
water processed and bottled for human consumption (38 FR at 32563 and
32564 (November 26, 1973)).  The criteria in part 129, as well as in
part 110, apply in determining whether the facilities, methods,
practices, and controls used to process, bottle, hold, and ship bottled
drinking water conform with good manufacturing practice “to assure
that bottled drinking water is safe and that it has been processed,
bottled, held, and transported under sanitary conditions” (§ 129.1). 
Part 129 requires plant construction and design features, such as a
separate bottling room and an enclosed room for washing and sanitizing
containers, to protect against contamination (§ 129.20).  All plant
equipment and utensils must be suitable for their intended use (§
129.40(a)).  

	Both the product water supply and the operations water supply must be
of a “safe, sanitary quality” in conformance with “the applicable
laws and regulations of the government agency or agencies having
jurisdiction” (§ 129.35(a)).  Samples of source water must be
analyzed at least once a year for chemical contaminants and once every 4
years for radiological contaminants (§ 129.35(a)(3)).  Source water
from other than a public water system must be sampled and analyzed for
microbiological contaminants at least once a week (id.).  The product
water-contact surfaces of all containers and equipment must be clean and
adequately sanitized and protected from contamination (§ 129.37(a)
and(b)).  Filling, capping, closing, sealing, and packaging of
containers must be done so as to preclude contamination of the water (§
129.37(d)).  All product water contact surfaces must be nontoxic and in
compliance with section 409 of the act (concerning food additives) (§
129.40(a)(2)).  

	Numerous production processes and controls for bottled water are also
required.  For example, all treatment of product water must be effective
in accomplishing its intended purpose and in accordance with section 409
of the act (§ 129.80(a)).  The treatment processes must be performed
with equipment and substances that will not adulterate the product (§
129.80).  Product water samples must be taken before bottling and
analyzed as often as necessary to assure uniformity and effectiveness of
the processes performed by the plant (§ 129.80(a)).  Cleaning and
sanitizing solutions must be sampled and tested to assure adequate
performance (§ 129.80(c)).  

	Each unit package from a batch or segment of continuous production run
must be identified by a production code (§ 129.80(e)).  The plant must
maintain information on the kind of product, volume, date, lot code, and
distribution of finished product to wholesale and retail outlets (id.). 
During the process of filling, capping, or sealing the containers,
performance must be monitored and the filled containers inspected to
assure that they are sound, properly capped or sealed, and coded and
labeled (§ 129.80(f)).  All containers and closures must be sampled and
inspected to ascertain that they are free from contamination (id.).  

	To assure that the plant’s production of bottled water complies with
applicable standards, laws, and regulations, the plant must analyze
product samples at specified intervals (§ 129.80(g)).  The methods used
to analyze the samples must be approved by the government agency with
jurisdiction (§ 129.80(g)(3)).  Records of the date of sampling, type
of product sampled, production code, and results of analysis must be
maintained (§ 129.80(g)(3)).  All required records must be maintained
at the plant for at least 2 years (§ 129.80(h)) and be available for
official review by FDA at reasonable times (id.).

	Provisions of the bottled water CGMP regulation also serve as a model
for provisions of the dietary supplement CGMP regulation.  For example,
water that is used in a manner such that the water may become a
component of a dietary supplement must at a minimum comply with
applicable Federal, State, and local requirements and not contaminate
the dietary supplements (final §§ 111.15(e)(2), 111.365(c)). 
Precautions that must be taken to prevent contamination of components or
dietary supplements include performing chemical, microbiological, or
other testing (final § 111.365(d)).  Filling, assembling, packaging,
labeling, and related operations must be performed to protect the
dietary supplement against adulteration (final § 111.415).  Equipment
and utensils must be suitable for their intended use (final §
111.27(a)).  Safe and adequate cleaning compounds and sanitizing agents
must be used (final § 111.15(c)(1)).  Representative samples of each
batch must be examined to ensure that the product meets established
specifications (final § 111.415(g)).  Each lot of packaged and labeled
dietary supplement must be assigned a batch, lot, or control number
(final § 111.415(f)).

	Moreover, our interpretation of permissible requirements for the
dietary supplement CGMP regulation is also consistent with the use of
the terms “good manufacturing practice” and “current good
manufacturing practice” in section 402(g) of the act.  Although these
terms are not defined in the act, GMP is generally used to refer to
methods used in, and the facilities and controls used for, product
manufacturing and related activities.  The umbrella food CGMP
regulation, for example, defines the “plant” covered by the
requirements of that regulation as the facility used for, or in
connection with, “the manufacturing, packaging, labeling, or holding
of human food” (§ 110.3(k)).  As we have described in detail, the
objectives of the existing food CGMP regulations and the precise means
(or requirements) used to achieve the objectives vary depending on the
particular hazards and characteristics of the products and their
manufacturing.  For example, the umbrella food CGMP regulation is
specifically designed to ensure that food is manufactured, processed,
packed, and held under sanitary conditions and that the food is safe,
clean, and wholesome.  Low-acid and acidified food CGMP requirements
focus on facilities, methods, practices, and controls to protect the
public health against the particular risks of microbial contamination
from these foods.  The infant formula CGMP regulation is aimed at
ensuring both the safety and nutritional potency of these special foods.
 Infant formula is often the sole item in the diet.  An infant formula
that does not meet the requirements for nutritional potency may cause a
hazard to the health of the infant (see, 61 FR 36154).  The bottled
water CGMP regulation embodies requirements for facilities, methods,
practices, and controls used in processing, bottling, holding, and
shipping of bottled water to ensure its safety and sanitary quality.  

	Like the food CGMP regulations after which they are modeled, the
dietary supplement CGMP final rule contains criteria for facilities,
methods, practices, and controls used in manufacturing, packaging,
labeling, or holding dietary supplements to ensure the quality of the
dietary supplement.  Quality includes consistently meeting the
established specifications for identity, purity, strength, and
composition of the dietary supplement and limits on contaminants, in
addition to manufacturing the dietary supplement under conditions to
prevent adulteration.  As Congress recognized in DSHEA, identity,
purity, strength, and composition are essential characteristics for
dietary supplements (see, e.g., section 403(s)(2) of the act (a dietary
supplement is misbranded if its labeling fails to list the name and
quantity of each dietary ingredient and if it fails to have the identity
and strength or the quality, purity, or compositional specifications it
is represented to meet)).  Yet without information about the identity,
purity, strength, or composition, the manufacturer could not know the
final contents of the dietary supplements it manufactures or whether its
processes are reliably and consistently producing the correct
combination and amounts of ingredients in a dietary supplement. 
Accordingly, the final rule requires a manufacturer to establish
specifications for the identity, purity, strength, and composition and
for limits on contaminants of the dietary supplements it manufactures
and ensure that such specifications are consistently met in the finished
batch of dietary supplement (§  111.75(e)).  Dietary supplements, like
infant formula, are relied upon by consumers not only to be safe, but
also in many instances to provide specific and important claimed health
benefits (see, e.g., section 403(r) of the act).  In the preamble to the
2003 CGMP Proposal, we discussed a number of examples illustrating
adulteration and improper formulation of dietary supplements caused by
manufacturing, packaging, or holding practices (49 FR at 12162 and 12163
(March 13, 2003)).  These dietary supplement CGMP requirements will help
to protect consumers against similar types of adulteration and against
reliance on products that are not properly formulated.   

	Generally recognized principles underlying CGMP also support our
interpretation of section 402(g) of the act.  Our  interpretation of
permissible CGMP regulations is reasonable based on recognized
principles for controlling the quality of manufactured products in
general. (Ref. 9)  As many comments asserted, if the dietary supplement
CGMP requirements are to be meaningful, they must ensure quality in the
finished product (see, for example, the discussion of comments regarding
the production and process control system in section X).  Controls to
ensure quality include planning processes to determine desired product
features or characteristics, a system of controls to ensure that the
desired product will be consistently produced, and making necessary
improvements to the process (id., at 2.6).  Manufacturers must plan what
they intend to produce, institute adequate controls to achieve the
desired outcome, and ensure that the controls work so that the desired
outcome is consistently achieved.  If the outcome is not consistently
achieved, corrective actions need to be implemented in order to reach
the desired outcome.  

	This final rule, like the other food CGMP regulations, embodies the
basic concepts of controlling quality, i.e., planning, control, and
improvement.  As discussed earlier in the “Overview of CGMP,” we
have defined the term “quality” for this dietary supplement CGMP
regulation to mean “that the dietary supplement consistently meets the
established specifications for identity, purity, strength, and
composition and has been manufactured, packaged, labeled, and held under
conditions to prevent adulteration under sections
402(a)(1),(a)(2),(a)(3), and (a)(4) of the Federal Food, Drug, and
Cosmetic Act.”  Identifying the desired characteristics of identity,
purity, strength, and composition of a dietary supplement, as required
in this final rule, is an essential part of the planning process to
manufacture a dietary supplement.  Without identifying specifications
for each of these characteristics of a dietary supplement, it is not
possible to control for, and repeatedly and reliably produce, the
desired end product.  Similarly, requirements for batch testing ensure
that there is consistency from batch to batch.  Packaging and labeling
requirements ensure that suitable packaging is used and that the label
identified in the master manufacturing record for the product is placed
on the finished product.  In addition, requirements related to consumer
complaints help to ensure that manufacturers are made aware of problems
related to their manufacturing processes, including those that may
result in illness or injury, so that they can take corrective actions to
prevent any future problems from occurring.  The procedures for
production and process control in this final rule also include as key
elements measures to prevent contamination that could adulterate the
product.  Requirements to protect against contamination during the
manufacturing, packaging, labeling, and holding operations help ensure
that this aspect of “quality” is also achieved for dietary
supplements.  In sum, this final rule embodies principles for
controlling quality through requirements designed to ensure both that
the dietary supplement meets its established specifications for
identity, purity, strength, and composition and that it is not
adulterated.  

	The dietary supplement CGMP requirements are also reasonable because
they take into consideration the different product forms in which these
products will be manufactured.  Unlike conventional foods, such as
fruit, vegetables, cereals, and dairy products, dietary supplements will
be sold in tablet, capsule, powder, or softgel form.  They may also be
sold as a concentrate, metabolite, constituent, or extract of a vitamin,
mineral, herb, botanical, or dietary substance.  Because dietary
supplements are often sold in different forms than conventional foods,
different processes and controls are needed to manufacture dietary
supplements than to manufacture conventional foods.  For example,
equipment must be able to manufacture dietary supplements in tablet or
softgel form.  Therefore, the final rule requires that controls be
established to ensure that the equipment functions in accordance with
its intended use (final § 111.30(e)) and will consistently manufacture
a product in whatever form is desired.  Consistent with basic CGMP
principles, ensuring the quality of the dietary supplement product
requires that the manufacturer establish precisely what it will produce
(specifications for its product), how it will make the product
(processes), and which process controls and tests it will use to ensure
reliable, reproducible results.  These CGMP requirements will help to
achieve these results.

	The dietary supplement CGMP requirements are also reasonable when
viewed in the context of the act as a whole.  See Brown & Williamson,
529 U.S. at 133.  Our mission is, in part, to protect the public health
by ensuring that foods are safe, wholesome, sanitary, and properly
labeled (21 U.S.C. 393(b)(2)(A)).  Section 701(a) of the act (21 U.S.C
371(a)) gives us the authority to promulgate regulations for the
efficient enforcement of the act in order to “effectuate a
congressional objective expressed elsewhere in the Act” (Association
of American, Physicians and Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204
(D.D.C. 2002) (citing Pharm. Mfrs. Ass’n. v. FDA, 484 F. Supp. 1179,
1183 (D. Del. 1980)).  The final rule is designed to help ensure that
dietary supplements consistently are manufactured to produce the product
established by the manufacturer, to bear the label identified in the
master manufacturing record, and to prevent adulteration.  The
requirements are written to facilitate efficient and effective action to
enforce their terms when necessary.  

	Some provisions of the dietary supplement CGMP final rule may be
similar to the existing drug CGMP regulations.  However, we have not
modeled these regulations after the drug CGMP regulations.  Controls
that relate to certain product forms (e.g., tablets, capsules, powder,
softgel) are required in this final rule based on the specific
characteristics of dietary supplements and the hazards associated with
these forms, not, as some comments imply, based on a desire to emulate
drug CGMP requirements.  The act does not state that there may not be
similarities between the dietary supplement CGMP requirements and the
CGMP requirements for drugs or other non-food products.  Inasmuch as
food CGMP regulations and other CGMP regulations are all based on CGMP
principles, it is neither surprising nor impermissible that there are
similarities between the dietary supplement CGMP requirements and drug
or device CGMP requirements.  Although we do not agree that any of the
CGMP requirements exceed drug GCMP requirements, even if a particular
requirement did, it is not prohibited under the statute.  As long as the
CGMP final rule is “modeled after” the food CGMP regulations, we
have satisfied the statutory requirements.  As noted, our interpretation
of “modeled after” means that the dietary supplement CGMP final rule
provisions share similar objectives and/or use similar means as the
existing food CGMP regulations.  To the extent that there are
similarities to drug CGMP regulations, those similarities are
appropriate and not prohibited by section 402(g) of the act.

	Consistent with our role “to fill in, through interpretation, matters
of detail related to [the statute’s] administration,” Barnhart v.
Walton, 535 U.S. 212, 225 (2002), we applied our scientific expertise,
policy judgment, and experience to promulgate dietary supplement CGMP
requirements that will protect the public health and effectively
implement our statutory authority to prescribe dietary supplement CGMP.
See United States v. Mead, 533 U.S. 218, 227-228 (2001); Nationsbank of
North Carolina v. Variable Annuity Life Ins.  Co., 513 U.S. 251, 256-58
(1995); Chevron, 467 U.S. at 844; Forester v. Consumer Product Safety
Com., 559 F.2d 774, 783 (D.C. Cir.  1977).

2.	Records Authority

	(Comment 19)  Some comments state that requirements related to record
keeping and access to such records are necessary to allow our inspectors
to assess the adequacy of a dietary supplement manufacturer’s
practices.  Additional comments state that access to records is
necessary to ensure that CGMP requirements are followed and to protect
the public health.  Several comments identify specific types of records
we should require in a final rule, including written procedures, batch
and master manufacturing records, distribution records, and lot numbers.
 Another comment states that training records should be required because
the qualifications and training of employees affects product quality.  

	Other comments, however, state that the record retention and access
requirements seem to be modeled after drug CGMP and not food CGMP. 
Other comments state that, even though records may be necessary to
ensure that CGMP requirements are followed, we do not have authority to
require access to and copying of such records.  Some comments assert the
authority to establish regulations for dietary supplement CGMP does not
imply there is authority to inspect records.  Several comments state we
cannot rely on section 701 of the act because there is not another
section of the act that authorizes us access to company records for
dietary supplement CGMP and section 701(a) of the act does not itself
give us the authority we need to require records inspection.  Another
comment suggests that the absence of an express grant of records
inspection authority means that records inspection is not necessary for
the efficient enforcement of the act.  

	Some comments assert that we have no record inspection authority under
section 704(a) of the act (21 U.S.C 374(a)).  A few comments suggest
that, because records inspection authority was not expressly granted in
DSHEA’s statutory language, as it was for OTC drugs and medical
devices, Congress provided no authority for records inspection for
dietary supplement CGMP.  The comments state that we have a longstanding
interpretation that section 704 of the act does not give us access to a
food manufacturer’s records.  Several comments state that it was
sufficient to have voluntary records access, stating that many companies
are willing to provide access to records.     

	Other comments say that our record inspection authority for dietary
supplement CGMP is limited to that under section 306(a) of the Public
Health Security and Bioterrorism Preparedness and Response Act of 2002
(Bioterrorism Act) (21 U.S.C. 350(c)), i.e., when we have a
“reasonable belief that an article of food is adulterated and presents
a threat of serious adverse health consequences . . ..”  Another
comment suggests an alternative standard to that in section 306(a) of
the Bioterrorism Act of a “reasonable belief that there is a public
health hazard” for when we may access records.  

	One comment cites In the Matter of Establishment Inspection of
Medtronic, Inc., 500 F. Supp 536 (D. Minn. 1980), to support its
assertion that we exceeded our statutory inspection authority in the
dietary supplement CGMP record requirements.  One comment states that a
warrantless inspection of dietary supplement CGMP records and criminal
consequences that may be imposed under the act for failure to comply
with the act provide a “powerful argument against expanding the
Agency’s inspection authority any further” and raise “serious
constitutional concerns.”  Several comments ask us to clarify our
jurisdiction for records inspection requirements or delete proposed §
111.125(c).

	Still other comments seek confirmation that the confidential and trade
secret information obtained by us under the rule would be protected from
disclosure under applicable statutes.  Among other things, the comments
cite the Trade Secrets Act, 18 U.S.C. 1905, and the Freedom of
Information Act (FOIA), 5 U.S.C. 552(b)(4).  Some comments express
concern that records inspection would violate “rights to privacy of
corporate manpower” or would compromise trade secrets.  The comments
request the rule specifically reconfirm our obligations under these
laws.    

	(Response)  We disagree with the comments suggesting that we have no
authority to require dietary supplement manufacturers to maintain
records to comply with CGMP under section 402(g) of the act; that the
absence of an express grant of records authority means records are not
needed for the efficient enforcement of the act; and that Congress
meant, by its silence, that we have no authority to issue records
requirements.  Clearly, just as Congress is not expected to express
“every single evil sought to be corrected” in a grant delegation 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 record-keeping and FDA access to
records, as models for these regulations.  Congress has delegated
substantial and sufficiently specific authority to us to promulgate
recordkeeping and access regulations  (Cf. United States v. Storer
Broadcasting, 351 U.S. 192, 202-03 (1956) (upholding a rule that
established limitations on broadcast licensing that were “not
specifically authorized by statute”)).  As stated earlier in this
section, the “modeled after” language in section 402(g) of the act
is ambiguous with respect to what specific CGMP requirements we are to
include in this final rule.  At the time Congress enacted section 402(g)
of the act there were several food regulations that contained
recordkeeping and record access requirements.  We included records
requirements in the food CGMP regulations for infant formula (part 106),
low acid food (part 113), acidified food (part 114), and bottled water
(part 129).  Accordingly, the directive in section 402(g) of the act is
sufficient authority for our recordkeeping requirements in this final
rule.  In addition, our authority to establish records requirements has
been upheld under other provisions of the act, which lacked explicit
recordkeeping authority for FDA, where we have found records to be
necessary (National Confectioners Assoc. v. Califano, 569 F.2d 690,
693-94 (D.C. Cir. 1978) (upholding requirements for source coding and
distribution records based on the statutory scheme as a whole)).   

	Moreover, records are an indispensable component of CGMP.  The records
required by this final rule provide the foundation for the planning,
control, and improvement processes that constitute a quality control
system.  Implementation of these processes in a manufacturing operation
serves as the backbone to CGMP.  The records will show what is to be
manufactured; what was, in fact, manufactured; and whether the controls
that the manufacturer put in place to control the identity, purity,
strength, and composition and limits on contaminants and to prevent
adulteration were effective.  Further, records will show whether and
what deviations from control processes occurred, facilitate evaluation
and corrective action concerning these deviations (including, where
necessary, whether associated batches of product should be recalled from
the marketplace), and enable a manufacturer to assure that the
corrective action was effective.  Written procedures also will help
ensure that personnel follow hygienic practices; permit evaluation of
whether equipment, including software that may run the equipment,
performs as it is intended; and help ensure that the equipment is
properly maintained and adequately cleaned.  

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

	The authority granted us under sections 402(g) and 701(a) of the act
not only includes the authority to establish record requirements, but
also includes access to such records.  Without such authority, the
dietary supplement CGMP requirements are, practically speaking, not
enforceable.  Under section 402(g)(1) of the act, the failure to meet
any current good manufacturing practice requirements, including the
failure to have a record that is required by this final rule, renders a
dietary supplement so manufactured to be adulterated as a matter of law.
 The introduction or delivery for introduction into interstate commerce
of an adulterated dietary supplement is a prohibited act under section
301(a) of the act (21 U.S.C. 331(a)), and acts done to an ingredient in
a dietary supplement, or to a dietary supplement, while held for sale
after shipment in interstate commerce that result in the ingredient or
dietary supplement being adulterated violates section 301(k) of the act
(21 U.S.C. 331(k).  Thus, in order for us to determine whether the
dietary supplement product is adulterated and whether a manufacturer has
committed a prohibited act, we must have access to the manufacturer’s
records that we are requiring to be kept under section 402(g) of the
act.

	In light of the foregoing, without access to such records, we would not
know whether a manufacturer was complying with the procedures and
processes required in this final rule.  For example, our investigator
must have access to the test results for the identity of a dietary
ingredient to determine whether such ingredient meets the
manufacturer’s specification for identity.  The investigator needs to
understand, by reviewing a record, what the software that runs a
production operation is set up to do and whether it performs those
functions to achieve the desired product characteristics.  Observation
of these processes alone, by an investigator, would not allow that
investigator to evaluate compliance with this final rule.  Moreover,
records often cannot be thoroughly evaluated by the investigator on
site.  In such cases, records must be readily available to food experts
at the Center for Food Safety and Applied Nutrition (CFSAN) and agency
consultants.  We must have accurate, reliable, and objective data about
the manufacturing specifications to be able to achieve an enforceable
rule.  

	We also disagree with comments stating our records inspection authority
is limited to that provided by section 306(a) of the Bioterrorism Act. 
There is no basis to conclude that Congress intended to limit our
authority to inspect records, to enforce section 402(g) of the act, to
the records inspection authority under the Bioterrorism Act.  The
Bioterrorism Act, enacted almost 8 years after section 402(g), to
address credible threats of serious adverse health consequences or death
to humans and animals, required record keeping to identify the immediate
previous sources and the immediate subsequent recipients of food  (21
U.S.C. 350c).    

	There is nothing in the Bioterrorism Act that reflects any
Congressional intent to modify section 402(g) of the act.  In fact,
section 414(d)(1) of the act, added by section 306(a) of the
Bioterrorism Act, shows a contrary intent.  Section 414(d)(1) provides
that “This section shall not be construed -(1) to limit the authority
of the Secretary to inspect records or to require establishment and
maintenance of records under any other provision of this Act.” 
Moreover, Congress, in the legislative history to the Bioterrorism Act,
supported our general approach of requiring recordkeeping pursuant
tousing authority in section 701(a) of the act in combination with other
provisions.  We are not relying on section 704 of the act for its
underlying authority to require recordkeeping and records access in this
final rule.  Those comments asserting that we do not have such authority
and the underlying references, for example, to past hearings on records
inspection authority under section 704 of the act, are not controlling
with regard to the action we are taking under sections 402(g) and 701(a)
of the act.  When there are other bases for jurisdiction and tools to
protect the public interest, we may use what “will be the most
effective in advancing the Congressional objective” (U.S. v. Midwest
Video Corp., 406 U.S. 649, 656 (1972)).  

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

	The dietary supplement industry, as the food industry as a whole, is a
pervasively regulated industry that is subject to warrantless
inspections (see, e.g., United States v. Biswell, 406 U.S. 311, 315
(1972) (“In the context of a regulatory inspection system of business
premises . . . the legality of the search depends not on consent but on
the authority of a valid statute.”); United States v. New England
Grocers Supply Co., 488 F. Supp. 230, 238 (D. Mass. 1980) (holding that
a warrantless inspection under 21 U.S.C. § 374 is ‘fully consistent
with the Fourth Amendment”); United States v. Acri Wholesale Grocery
Co., 409 F. Supp. 529, 533 (S.D. Iowa 1976) (holding that a warrantless
inspection, which includes photographic activities, conducted under 21
U.S.C. § 374 does not violate the Fourth Amendment); United States v.
Business Builders, Inc., 354 F. Supp. 141, 143 (N.D. Okla. 1973) (“the
statute takes the place of a valid search warrant”); United States v.
Del Campo Baking Mfg. Co., 345 F. Supp. 1371 (D. Del 1972) (finding
warrantless inspection of food establishment lawful under 21 U.S.C.
§ 374)).  

	As explained earlier in this section, we have ample authority, under
sections 402(g) and 701(a) of the act, to require that certain records
be kept and accessible to us upon inspection.  Records access is
imperative to the efficient enforcement of the dietary supplement CGMP
final rule, and we are not prohibited from requiring access to these
records under sections 402(g) and 701(a) of the act (See Permian Basin
Area Rate Cases, 390 U.S. 747, 780 (1968) (“in the absence of
compelling evidence that such was Congress’ intention . . . [the court
should not] prohibit administrative action imperative for the
achievement of an agency’s ultimate purposes.”)).   

	We also disagree with the comment suggesting that  voluntary records
access is sufficient.  In our experience, many manufacturers are not
willing, as the comments suggest, to provide records voluntarily to us.
(Ref. 152).  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
(Ssee, e.g., 21 U.S.C. 331(j), 18 U.S.C. 1905).  Further, our FOIA
regulations set forth the specific procedures for assuring such
protection. 

	It was not clear from the comments what was meant by “rights to
privacy of corporate manpower.”  We note that §§ 20.63 and 20.64
contain provisions for the protection of personal privacy.

  

3.	Public Health Service Act Authority

	(Comment 20) One comment acknowledges that we have authority under the
PHS Act to regulate intrastate activities that may cause the spread of
communicable diseases.  The comment states that, in any situation in
which we need to exercise our authority over any disease-causing
substance within the state where a component or dietary supplement is
manufactured, packed or held, we can and should exercise our authority
under the PHS Act.  However, the comment asserts that nothing in the
preamble clearly states whether we believe that the final rule will be,
in its entirety, binding on manufacturers, packers, and holders of
dietary supplements who are engaged solely in intrastate commerce, and
that we have not requested comment on this specific issue.  The comment
requests that we clearly state that the final rule applies only to
interstate commerce, except for activities that may spread communicable
diseases.  

	(Response)  We address each of these issues in turn.  

	a.  The communicable disease risk posed by dietary supplements

	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. 163).  In a small portion of healthy people [1-4%],
infection spreads from the GI tract into the blood stream, which can be
life-threatening.  Persons with immune compromising conditions (such as
cancer, AIDS, autoimmune disorders) are at greater risk of blood stream
infection. (Ref. 163). 

	 Campylobacteriosis, often due to infection with Campylobacter jejuni,
is characterized by diarrhea, fever, and abdominal cramps, which can be
severe. (Ref. 174).  These symptoms frequently relapse, and the disease
may become chronic in immune compromised persons.  People with
campylobacteriosis are also at increased risk of developing certain
post-infectious complications, which will prolong their recovery.    

	E. coli O157:H7 may cause infections with a very low infectious dose
(as low as 2 to 45 organisms), and may result in non-bloody and bloody
diarrhea, hemolytic-uremic syndrome (a cause of red blood cell
destruction, damage of blood vessel walls, and, in severe cases, kidney
failure (especially in young children), thrombotic thrombocytopenic
purpura (i.e., a blood disorder characterized by low platelets, low red
blood cell count, abnormalities in kidney function, and neurological
abnormalities (especially in adults), and death) (Ref. 185).  

	Animal tissues (e.g., organs from livestock), as well as botanicals,
used as components in dietary supplements may contain EHEC, Salmonella,
and Campylobacter jejuni.  In addition, because the same microorganisms
are also present in the environment, they may contaminate components
during manufacturing activities.  Moreover, people who harbor those
pathogens could transmit them to components and dietary supplements
during processing.  Therefore, components and dietary supplements, as
potential sources of communicable diseases, may be regulated under the
PHS Act.

	For these microorganisms (e.g., EHEC, Salmonella, and Campylobacter
jejuni) humans carry and transmit infections through their feces or by
direct contact with other persons.   For other microorganisms, domestic
and wild animals serve as the reservoir, and humans become infected when
contaminated tissues of infected animals are used in dietary
supplements.  For both categories of microorganisms, dietary supplements
can also become contaminated indirectly by human and animal fecal
contamination of water or through the production or processing
environment.

	Dietary supplements may contain a variety of components derived from
domestic and wild animals, such as powders prepared from whole or
partial gecko, deer antler velvet, and organs, such as cow liver and
brain, pork stomach, or sheep spleen from common domestic livestock. 
Each of these tissues may be contaminated with microorganisms such as
Salmonella, Campylobacter jejuni, and EHEC.  Even clinically normal
animals obtained from safe sources may harbor these communicable
pathogens and result in contaminated products. (Ref. 196). (Information
on these animals and potential pathogens can be accessed at (  HYPERLINK
"http://www.fsis.usda.gov/Science/Microbiology/" 
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. 2017 through 230)).  V. parahaemolyticus most
often causes gastroenteritis characterized by diarrhea, abdominal
cramps, nausea, vomiting, and fever.  (Ref. 241).  

	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. 252).

	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. 263).

	Therefore, because of the communicable disease concerns associated with
dietary supplements, we are asserting legal authority under the PHS Act
in support of the final rule.  As discussed in this section immediately
below, our authority under the PHS Act is not limited to interstate
activities.  It also covers intrastate activities.

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

	There are many opportunities for components and dietary supplements to
become contaminated with microorganisms that spread communicable
diseases.  The final rule requires firms to take all the necessary
precautions during the manufacture of a dietary supplement to prevent
such contamination.

  	These precautions, for example, include: performing manufacturing
operations under conditions and controls that protect against potential
microorganism growth; washing or cleaning components that contain soil
or other contaminants; performing microbiological testing, as necessary,
to prevent the use of contaminated components; sterilization,
pasteurization, freezing, refrigeration, and controlling hydrogen-ion
concentration (pH), humidity, and water activity (aw), or using  other
effective means to remove, destroy, or prevent the growth of
microorganisms and decomposition; and holding components and dietary
supplements that can support the growth of infectious microorganisms of
public health significance in a manner that prevents them from becoming
adulterated.

	Failure to properly clean components, or take any other appropriate
steps, such as those listed in the previous paragraph, could lead to
pathogen growth and the spread of communicable diseases.  If, for
example, a dietary supplement manufacturer purchased an animal-derived
ingredient that harbored Salmonella enterica, but failed to take the
steps necessary to inactivate the pathogen, the consumption of the
dietary supplement could lead to the spread of salmonellosis.

	The final rule also requires firms to take measures to exclude from
certain operations any sick persons who might contaminate material,
including components, dietary supplements, and contact surfaces used to
manufacture, package, label, or hold a dietary supplement.  

	c.  The interstate commerce nexus for the final rule

		i.  The PHS Act

	 (Comment 21) Several comments assert that, although the PHS Act may
extend to some intrastate activities, its reach is very limited.  The
comments appear to conclude that the reach of the PHS Act and the act
extends only to situations in which the finished dietary supplement is
shipped in interstate commerce. 

	(Response) We do not agree that this view is correct. 	The  PHS Act
extends to intrastate commerce.  Under section 361 of the PHS Act, we
may “make and enforce such regulations as in [our] judgment are
necessary to prevent the introduction, transmission, or spread of
communicable diseases from foreign countries into the States or
possessions, or from one State or possession into any other State or
possession.” (42 U.S.C. 264).  	In Louisiana v. Mathews, 427 F. Supp.
174, 176 (E.D. La. 1977), the court upheld FDA’s regulation that
banned the sale of small turtles to prevent the spread of disease caused
by turtles harboring Salmonella and Arizona microorganisms.  The ban
covered both interstate and intrastate sales.  The court held that the
intrastate ban is not only authorized by the law, but, under modern
conditions of transportation and commerce “is clearly reasonable to
prevent the interstate spread of disease”  (Id.).

	We are authorized under the PHS Act to regulate conduct that occurs
within a state to the extent necessary to prevent the interstate spread
of communicable diseases.  Such is the present case with respect to the
provisions of the dietary supplements CGMP final rule for which PHS Act
§ 361 provides authority.

	ii.	The act	

	The act extends to the sale of a dietary supplement that was
manufactured and distributed entirely in one state, if the supplement
contains any ingredient or uses any component that came from outside of
that state.  Such a dietary supplement is subject to section 301(k)of
the act, which prohibits “[t]he alteration, mutilation, destruction,
obliteration, or removal of the whole or any part of the labeling of, or
the doing of any other act with respect to, a food, drug, device, or
cosmetic, if such act is done while such article is held for sale
(whether or not the first sale) after shipment in interstate commerce
and results in such article being adulterated or misbranded.”  21
U.S.C. 331(k) (emphasis added).  See also 21 U.S.C. 321(b)(3) (defining
food to include articles used as components of food).	

	The interstate commerce prerequisite under section 301(k) or section
304(a) of the act is established when one or more components used in the
manufacture of the product have crossed state lines.  This principle is
known as “component jurisdiction” (See, e.g., Baker v. United
States, 932 F.2d 813, 814-15 (9th Cir. 1991); United States v. Article
of Food . . . Coco Rico, Inc., 752 F.2d 11, 14 (1st Cir. 1985);  United
States v. Dianovin Pharmaceuticals, Inc., 475 F.2d 100, 103 (1st Cir.),
cert. denied, 414 U.S. 830 (1973)(“appellants’ use of components
shipped in interstate commerce to make vitamin K for injection brought
their activities within § 331(k)”); United States v. Cassaro, Inc.,
443 F.2d 153, 155-56 (1st Cir. 1971); United States v. Detroit Vital
Foods, Inc., 330 F.2d 78, 81-82 (6th Cir.), cert. denied, 379 U.S. 832
(1964); United States v. Allbrook Freezing & Cold Storage, Inc., 194
F.2d 937, 939 (5th Cir. 1952); United States v. Varela-Cruz, 66
F.Supp.2d 274, 277-281 (D. P.R. 1999)).

	  SEQ CHAPTER \h \r 1 Nor does it matter that the interstate product
component comprises only a minute part of the article,   SEQ CHAPTER \h
\r 1 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 (Ssee 21 U.S.C. 379a (“In any action to enforce
the requirements of this Act respecting a device, food, drug, or
cosmetic the connection with interstate commerce required for
jurisdiction in such action shall be presumed to exist.”)).  	  

	In conclusion, the final rule covers not only finished products that
have moved in interstate commerce but also products made from
ingredients or components that have moved in interstate commerce.  This
is true regardless of the amount of the ingredient or component in the
product and regardless of whether the finished dietary supplement has
itself moved in interstate commerce.  The final rule also covers
products, components, and ingredients that may contribute to the spread
of communicable disease, regardless of whether the component,
ingredient, or product has itself moved in interstate commerce.  

iii.	Commerce Clause 

	(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 entirely consistent with the Commerce Clause of the Constitution.

iv.	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’n. of Pharmaceutical Manufacturersfrs. v.
Department of Health & Human Services, 586 F.Supp. 704 (S.D.N.Y 1986),
addressed the very question of whether terms such as “adequate,”
“appropriate,” “proper,” “sufficient,” and “suitable,”
in the drug CGMP regulation were vague.  The court found that the drug
CGMP regulation containing such terms was “sufficiently definite to
give notice of the required conduct to one who would avoid [their]
penalties, and to guide the judge in [their] application . . .” (Id.
at 753).  The court so held, in part, in light of the fact that the drug
CGMP statute was upheld against a constitutional vagueness attack in
United States v. Bel-Mar Laboratories, Inc., 284 F. Supp. 875, 883
(E.D.N.Y. 1968) (“the phrase ‘current good manufacturing practice’
is not strange to those in the trade to whom the subject section is
directed.”).  Furthermore, the use of such “ordinary terms to
express ideas which find adequate interpretation in common usage and
understanding” are not the types of terms that have been held to be
unconstitutionally vague (Boyce Motor Lines v. United States, 342 U.S.
337, 342 (1952)).  Some of these very terms have been in use for over 30
years in food CGMP regulations. 

	No comments were submitted objecting to the use of such terms, when the
umbrella food CGMP rule was revised in 1986 (See 51 FR 22458 (June 19,
1986)).  Also, when we began work on the dietary supplement CGMP rule,
we received and published for comment an industry draft of a CGMP
regulation for dietary supplements.  The industry draft used many of the
same terms.  For example, it provides in part: “Plumbing shall be of
adequate size and design and adequately installed and maintained” (62
FR 5700 at 5703 (Feb. 6, 1997)).  Thus, there has been sufficient common
usage of these terms in the food industry and, in particular, the
dietary supplement industry to enable manufacturers, and those who
enforce the requirements, to comprehend and apply such terms “with a
reasonable degree of certainty” to their particular operations  (Boyce
Motor Lines v. United States, 342 U.S. at 340 (“[F]ew words possess
the precision of mathematical symbols, most statutes must deal with
untold and unforeseen variations in factual situations, and the
practical necessities of discharging the business of government
inevitably limit the specificity with which legislators can spell out
prohibitions [and therefore] no more than a reasonable degree of
certainty can be demanded.”) ).  The same reasoning applies here.  It
addresses “untold and unforeseen variations in factual situations”
and, as such, “no more than a reasonable degree of certainty can be
demanded.”

	Agencies are permitted to, and indeed must, use such qualifying terms
to address the variety of conditions that exist at different companies. 
We do not need to, nor could we, predict with mathematical precision how
many inches or feet, for example, would be “adequate space” to allow
for cleaning a particular piece of equipment that could be applied to
every size of facility and every operation (id.).  Moreover, defining
such terms too precisely would unduly restrict the application of the
regulation to a very narrow, limited set of circumstances and not
provide industry with the needed flexibility to address the number and
variety of types of manufacturing operations that Congress intended for
this rule to cover (Ssee Freeman United Coal Mining Company v. Federal
Mine Safety and Health Review Commission, 108 F.3d 358, 363 (D.C. Cir.
1997) (citations omitted)(upholding a regulation that required equipment
to be “maintained in good repair,” the court rejected the vagueness
challenge: “specific regulations cannot begin to cover all of the
infinite variety of [conditions at firms and that]  . . .  [b]y
requiring regulations to be too specific [courts] would be opening up
large loopholes allowing conduct which should be regulated to escape
regulation.”); United States v. Bel-Mar Laboratories, Inc., 284 F.
Supp. at 883 (rejecting a vagueness challenge to the CGMP requirements
for drugs, noting that “[a]s a matter of fact, there are responsible
segments of opinion within the industry itself which oppose a greater
degree of specificity in this area.”). 

	Finally, it is important to understand that rules are not
unconstitutionally vague simply because they require interpretation by
regulated persons.  For example, courts have held that the term
“insanitary conditions” in the act is not unconstitutionally vague
(See Golden Grain Macaroni Co. v. United States, 209 F.2d 166, 168 (9th
Cir. 1953) (citing Boyce Motor Lines, supra); Berger v. United States,
200 F.2d 818 (8th Cir. 1952)).  In Berger, the court rejected the claim
that the term “insanitary condition” is unconstitutionally vague on
the ground that it does not specify the “degree of insanitation”
required for a violation (Id. at 822).  A law may require a person to
make “estimates of the degree of dirtiness and lack of sanitation”
which may result in a violation (Id.  See also Boyce Motor Lines v.
United States, 342 U.S. at 340 (It is not “unfair to require that one
who deliberately goes close to an area of proscribed conduct shall take
the risk that he may cross the line”.)).  There are sufficient
protections under the act to overcome any concerns related to how it
will be criminally enforced.  We disagree that such terms will lead to
“unbridled discretion” on how the rule is enforced.

	In short, we find that the rule is not unconstitutionally vague, and
does not violate section 706(2)(B) of the APA.  

6.	Miscellaneous

	(Comment 24) One comment states that the proposed rule violates section
402(f)(1)(A)(i) and (ii) of the act (21 U.S.C. 342 (f)(1)(A)(i) and
(ii)), which deem a dietary supplement adulterated if it contains a
dietary ingredient that presents an unreasonable risk of illness or
injury under conditions of use in labeling or ordinary conditions of
use, if none are suggested or recommended in labeling.  Under section
402(f) of the act, the government bears the burden of proof to show that
a dietary supplement is adulterated.  The comment states that the
proposed rule reversed the presumption under section 402(f) of the act,
and would revise the rule to require us to first show a violation under
section 402(f) of the act before we could take any enforcement action
under section 402(g).  Another comment states that, because the rule was
intended to enable manufacturers to be able to detect and avoid
adulteration through CGMP, the proposed rule created a presumption that
dietary supplements are adulterated until proven otherwise.  

	(Response)  The final rule does not violate section 402(f) of the act. 
Sections 402(f) and (g) of the act provide two independent bases under
which we may take enforcement action against dietary supplements.  A
dietary supplement may be adulterated either because a manufacturer has
failed to follow a CGMP requirement, or because a dietary supplement
presents an unreasonable risk of illness or injury, or both.  There
would be no reason to assert a second basis for adulteration under
section 402(g) of the act if one always had to demonstrate adulteration
under section 402(f) of the act as a prerequisite.   

	We also disagree with the comment that the proposed rule creates a
presumption that the dietary supplement is adulterated simply because
the proposed requirements would enable a manufacturer to detect and
avoid adulteration.  The requirements for CGMP are prophylactic and are
designed in part to ensure that all aspects of manufacturing, from
receipt through distribution, provide the necessary controls and
monitoring to ensure the quality of the dietary supplement, including
that it is manufactured, packaged, labeled, and held in a manner to
prevent adulteration. 

	(Comment 25) One comment states that, if there is reduced competition
through the enforcement of the rule, there will be a secondary effect of
elimination of speech on dietary supplement innovative uses.

	(Response)  The comment seems to conclude that, if a dietary supplement
manufacturer is not able to stay in business due to adverse enforcement
actions against it by us, or elects to not go into business based on the
possibility of enforcement action by us, there will be reduced
competition due to fewer products, less labeling, and “elimination of
speech on innovative uses.”  To the extent that the comment is
suggesting that the dietary supplement CGMP requirements are
unconstitutionally overbroad, this argument is wholly without merit (Cf.
 Wisconsin v. Mitchell, 508 U.S. 476, 488-89 (1993) (finding no merit to
an overbreadth argument that the possibility of enhanced sentences based
on prior racially motivated speech or associations constitutes an
impermissible chill on free speech)).  Manufacturing a dietary
supplement in a manner that violates the CGMP requirements causes the
product to be adulterated, and therefore, unlawful.  The fact that a
manufacturer may not stay in business, or elects not to enter business,
due to: (1) our implementation of CGMP requirements; or (2) our
enforcement against a product that violates CGMP requirements, does not
mean that we are somehow prohibiting speech.  In any event, there is no
First Amendment protection for speech that concerns unlawful activity
under the first prong of the test set out in Central Hudson Gas &
Electric Corp. v. Public Service Commission, 447 U.S. 557 (1980). 
Therefore, the comment’s suggestion that there is elimination of
speech based on the rulemaking is not supportable.  The requirements in
the final rule do not infringe on a manufacturer’s right to lawfully
label and market a dietary supplement.

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

(Subpart A)

A. Organization of Final Subpart A

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

Table 2 - Derivation of Sections in Final Subpart A

Final Rule	2003 CGMP Proposal



§ 111.1 Who Is Subject to These Regulations?	

§ 111.1



§ 111.2 What Definitions Apply to This Part?	

§ 111.3



§ 111.5 Do Other Statutory Provisions and Regulations Apply?	

§ 111.5



B.  Who Is Subject to These Regulations? 

(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 immediately below.

	(Comment 26) Some comments interpret the proposal as not applying to
persons who perform labeling operations.  For example, one comment
claims that proposed § 111.35(e), which would require manufacturers,
packagers, and persons who hold dietary supplements to establish
specifications, did not apply to “labelers” because the proposed
definition of “you” did not expressly mention persons who label
dietary supplements.  

     (Response) We disagree with the comments.  Various provisions in
the proposal expressly mentioned or pertained to labels and labeling
operations (see, e.g., proposed §§ 111.20(c)(6) (which would require
your physical plant to have separate or defined areas for packaging and
label operations), 111.30(a) (which would impose certain requirements on
automatic, mechanical, or electronic equipment used to “manufacture,
package, label, and hold” a dietary supplement), 111.35(a) (which
would require you to implement a system of production and process
controls that cover, among other things, all stages of labeling dietary
supplements), 111.37(a) (which would require you to use a quality
control unit to ensure, among other things, your label operations are
performed in a manner that prevents adulteration and misbranding),
111.40(b) and (c) (which would impose certain requirements on packaging
and labels you receive and on persons who perform label requirements),
and 111.70 (which would impose various requirements on packaging and
label operations)).  Although the proposed definition of “you” and
proposed § 111.1 did not include the word “label” or
“labeling,” we considered label operations to be part of a broader
manufacturing process, and it would be illogical to interpret the
proposal’s specific references to label operations as somehow being
inapplicable to labelers simply because a proposed definition of
“you” or a general “scope” provision did not mention labels or
otherwise distinguish label operations from the broader context of
manufacturing.  	

	In any case, to correct such misinterpretation, we have revised §
111.1 to include the word “label.”  Thus, under final § 111.1(a),
you are subject to the dietary supplement CGMP requirements if you
“manufacture, package, label, or hold a dietary supplement.”  We
also have made corresponding changes to other sections in this final
rule; for example, we have revised the definition of “you” in final
§ 111.3 to state that “you” means “a person who manufactures,
packages, labels, or holds” a dietary supplement, and we also have
inserted the word “labeling” in the title to this final rule.  We
have not explained this change in the preamble each time it is made in
the codified provision.

	In addition, we refer to “label” and “labeling” in the context
of CGMP requirements related to operations for ensuring the correct
label is on the product.  To help clarify that we are referring to
labeling requirements in this final rule for labeling operations and
not, for example, to the labeling requirements in part 101, we inserted
the word “operations” in the title of part 111 to read “Current
Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary Supplements.”  

	(Comment 27) Several comments ask for clarification about the rule’s
applicability to different types of businesses and practices.  Some
comments ask for a clear listing of who is subject to the rule, stating
that it is difficult to apply the rule’s specific provisions. 
According to these comments, the rule’s level of detail and
inflexibility does not account for variations in manufacturing needs
within the entire industry.

Several comments on various proposed sections ask who would be
responsible for complying with CGMP requirements if more than one party
was involved in the manufacturing, packaging, labeling, or holding of
the dietary supplement.  For example, some comments ask whether
consultants are subject to a specific proposed section; others ask who
would be responsible if a firm employed another firm to handle packaging
or labeling operations.  

Other comments request clarification regarding the rule’s
applicability to distributors.  Some comments claim that a person who
holds and sells packaged products should not be subject to dietary
supplement CGMP requirements.  Other comments state that dietary
supplement CGMPs should apply to distributors as well as manufacturers. 
These comments assert many supplement distributors are merely marketers
who employ contract manufacturers.  The comments said that, because
marketers are the parties providing supplements to consumers, we should
hold marketers responsible for their products and require marketers to
ensure that their contract manufacturers adhere to CGMP requirements. 
These comments argue we should not permit marketers to transfer their
responsibilities in delivering safe supplements.  Other comments assert
questions about the rule’s applicability are underscored by typical
dietary supplement labeling practices where the contact information
listed on the product label pertains to the distributor/marketer instead
of the actual manufacturer.

Collectively, these comments raise a basic question as to which party or
parties are responsible for complying with the dietary supplement CGMP
requirements where more than one party is involved in the manufacture,
packaging, labeling, or holding of that dietary supplement.

	(Response) In the 2003 CGMP Proposal, we stated that it would apply to
a wide variety of activities associated with the manufacture, packaging,
and holding of a dietary supplement, including labeling, testing,
quality control, holding, and distribution (68 FR 12157 at 12175).  We
stated under proposed part 111 you would need to comply with those
regulations directly applicable to the operations that you perform and
provided examples (id.).  All activities may not be performed by the
same person.  For example, a manufacturer may contract with another firm
to package and label the dietary supplement in the containers used for
distribution to consumers.  Alternatively, a distributor may contract
with one firm to manufacture a dietary supplement, and another firm to
package and label the dietary supplement that the distributor ultimately
distributes under its own name.  

	Under this final rule, you must comply with the CGMP requirements that
apply to your operations related to the manufacture, packaging,
labeling, and holding of dietary supplements.  It is not practical to
list all possible contractual relationships that persons may enter into
in the manufacture of a dietary supplement, or to list all businesses or
practices that may be subject to the requirements of this final rule in
order for persons to know whether they are subject to requirements of
this final rule.  To provide additional clarity about how this rule may
apply to various persons, we provide some examples in the following
paragraphs.  

A manufacturer that manufactures a dietary supplement, and then packages
and labels and distributes the dietary supplement, is subject to all the
requirements in this final rule.  If that manufacturer contracts with
another person to package and label the dietary supplement, then the
packager/labeler is responsible for complying with the requirements for
packaging and labeling operations, in addition to other relevant
requirements.  The packager/labeler, in this example, would need to
comply, not only with the specific requirements related to packaging and
labeling operations in subpart L, but also with the general requirements
related to personnel, physical plant, quality control, and other
requirements that apply to that firm's operations.  However the
packager/labeler would not need to comply with requirements that do not
apply to it; for example, the packager/relabeler would not have to
conduct testing on the finished batch of dietary supplement since it
does not manufacture the finished batch of dietary supplement.  

     A manufacturer who contracts with a person to do packaging, and
labeling, but who later distributes the packaged and labeled product, is
ultimately responsible for the dietary supplement it releases for
distribution.  The manufacturer would be responsible for the CGMP
requirements for the operations that it performs, including those
related to the release of the product for distribution.  For example,
the manufacturer must determine whether the packaged and labeled dietary
supplement it receives from the packager/labeler conforms to applicable
specifications (final § 111.127(d)), and must approve the release of
the packaged and labeled dietary supplement for distribution (final
§ 111.127(h)).  Although the manufacturer is not performing the
specific activities related to the packaging and labeling operations
done by another person, the manufacturer has an obligation to know what
and how such activities are performed so that it can make decisions
related to whether the packaged and labeled product conforms to
applicable specifications and whether to approve and release the product
for distribution.    

Some manufacturers may sell their finished batch of dietary supplement
to a packager/labeler that the packager/labeler may package, label, and
then hold and distribute.  The manufacturer and packager/labeler would
each be responsible for complying with the applicable CGMP requirements
related to the operations that they perform.  The manufacturer would not
be responsible for the oversight of the packager/labeler, since the
packager/labeler is not under the control of the manufacturer and has
control over the release of the packaged and labeled dietary supplement.
 

A manufacturer may decide to hire a contractor or a consultant for
specific operations within the scope of the manufacturer’s
responsibilities under the final rule.  For example, a manufacturer may
hire a person to calibrate its equipment.  The manufacturer is
responsible for complying with the requirements related to its
responsibilities, e.g., calibration requirements in this example, even
though the manufacturer has hired another person to perform that job
task. 

In another example, a distributor who purchases a packaged and labeled
dietary supplement and who then holds the product in a warehouse for
distribution to another physical location is subject to the requirements
related to its operations.  The codified uses the word “hold” since
it is a broad term which encompasses the activities of a distributor. 
Thus, the distributor would be responsible for complying with
requirements in subpart M, Holding and Distributing, in addition to
other requirements related to its operations (e.g., Personnel, Physical
Plant). 

In cases where a distributor contracts with a manufacturer to
manufacture a dietary supplement that the distributor then distributes
under its own label, the distributor has an obligation to know what and
how manufacturing activities are performed so that the distributor can
make decisions related to whether the packaged and labeled product
conforms to its established specifications and whether to approve and
release the product for distribution. 

	(Comment 28) Some comments state that the proposed rule requirements
would require the manufacturer to report adverse events to us, but would
not require those who distribute the product and whose name is likely to
be on the product label, to report adverse events to us.  The comments
state that reports of adverse events submitted by consumers to those who
distribute, but do not make, dietary supplements could be hidden from
the public if such persons are not required to submit those reports to
us. 

	(Response)  The comments may have misinterpreted the proposed rule. 
The requirement to review and investigate a product complaint is
distinct from any report about the product complaint to us.  Reporting a
complaint to us is voluntary and is not covered by these CGMP
requirements and would be voluntary, unless the complaint is subject to
the statutorily mandated reporting requirements for “significant
adverse events” pursuant to the “Dietary Supplement and
Non-Prescription Drug Consumer Protection Act” (Pub. L. 109-462)
signed into law on December 22, 2006.  (See discussion in section XX).

	Under the procedures that are set forth in subpart O, Product
Complaints (see section XX), a distributor and a manufacturer are both
subject to the requirements related to the review and investigation of a
product complaint that they receive.  

	(Comment 29) Some comments argue against including minimum CGMPs
necessary for activities related to manufacturing, packaging, labeling,
or holding dietary ingredients in the final rule.  Several comments
argue the proposed rule is overly broad and inconsistent with
Congressional intent.  These comments question whether Congress intended
that CGMP apply to persons involved in the manufacture, packaging,
labeling, and holding of dietary ingredients.  The comments also argue
that, if the rule applies to dietary ingredient manufacturers, we would
be establishing precedent and that we lack legal authority to regulate
ingredients rather than the finished products themselves.  The comments
state that neither food CGMP nor drug CGMP offers precedent or guidance
on regulating ingredients.  The comments argue those who provide dietary
ingredients should be subject to the existing general food CGMP
requirements in part 110 rather than to the dietary supplement CGMP
requirements.

     Several comments argue that many dietary ingredients are used in
regular foods and in drugs as well as in dietary supplements.  The
comments argue, for some dietary ingredients, their use in dietary
supplements represents a very small percentage of the dietary
ingredient’s worldwide usage.  The comments say we should allow those
who deal only with dietary ingredients to operate under one set of
regulations, such as the general food CGMP requirements in part 110. 
According to these comments, we have not demonstrated either a failure
of the current system or a compelling need to create different
regulations for raw materials common to both the food and dietary
supplement industries.  The comments would revise the title of part 111
and proposed § 111.1 and make conforming revisions throughout the
proposed rule to limit the rule’s applicability to dietary
supplements.

	In contrast, other comments say the rule should apply to dietary
ingredient manufacturers as well as to dietary supplement manufacturers.
 The comments state that excluding those who provide or supply dietary
ingredients would mean those who have the greatest expertise in these
goods would not be subject to dietary supplement CGMP requirements and
thus fail to cover a crucial step in preventing the adulteration or
contamination of dietary supplements.  The comments argue that, for some
dietary ingredients (especially raw botanical and agricultural goods),
the most critical point in ensuring an ingredient’s quality and purity
is at time of harvest or creation, and that this is particularly true
with new or original ingredients.  

	The comments state problems with dietary supplements often arise from
substandard ingredients, and the difficulty in testing the properties of
some botanical and other dietary ingredients at the in-process or
finished product stage makes it necessary to include dietary ingredient
manufacturers in the final rule.  Furthermore, these comments assert a
flexible testing scheme that they recommend (which emphasizes
establishing specifications for components, relying on certificates of
analysis from qualified suppliers, qualifying component suppliers, and
establishing written procedures, with testing of finished batches
serving as a check on the overall manufacturing process) makes it
important to regulate dietary ingredient manufacturers.

	Other comments suggest we issue a separate or modified set of CGMP
requirements that would apply to persons who manufacture, package,
label, or hold dietary ingredients.  These comments say the proposed
rule does not work for all dietary ingredients, especially those
converted from non-food grade to food grade during the manufacturing
process.  These comments said the rule should be modified for dietary
ingredients.

	(Response) Two issues seem to be raised by these comments: (1) whether
dietary ingredients are within the scope of this final rule; and (2)
whether dietary ingredient manufacturers are subject to this final rule.
 Dietary ingredients are included within the scope of this final rule
but dietary ingredient manufacturers are not necessarily subject to this
rule.  The definition of “component” in this final rule includes
“any substance intended for use in the manufacture of a dietary
supplement including those that may not appear in the finished batch of
the dietary supplement.  Component includes dietary ingredients (as
described in section 201(ff) of the act) and other ingredients”(final
§ 111.3).  The proposed rule, § 111.3, recognized that “dietary
ingredients” are “components” (68 FR 12157 at 12176) (describing
how dietary ingredients would fall within the proposed definition of
“component”).  

	There are specific requirements in this final rule that relate to
components, and thus dietary ingredients, that are used in the
manufacture of a dietary supplement.  For example, final § 111.70(b)
requires you to establish certain component specifications.  Such
requirements would include specifications for dietary ingredients as
“components.”  It is important to control the components used in the
manufacture of dietary supplements to ensure consistency and to ensure
the quality of the dietary supplement.  Since dietary ingredients are
considered components, the various requirements apply to dietary
ingredients as part of the production and process control.   Therefore,
we disagree to the extent comments were suggesting that there should be
no CGMP requirements related to the dietary ingredients used by a
manufacturer in the manufacture of dietary supplements.

	Dietary ingredients are included within the meaning of “component.”
 In those requirements in the proposed rule where “component”
encompasses “dietary ingredient” we are, in the final rule, removing
“dietary ingredient” in those requirements and only refer to
“component.”  Given the scope of the final rule, it is redundant to
refer to both “component” and “dietary ingredient” where the
latter is subsumed in the former.  

     In response to comments that questioned the need to include
manufacturers of dietary ingredients within the scope of part 111, we
have made changes to the scope of the rule, as applied to dietary
ingredient manufacturers.   As we explain more fully in our discussion
of final §§ 111.70, 111.73, 111.75, and 111.77 (see section X), after
considering comments about the overall production and process control
system, we revised the final rule’s approach to ensuring product
quality.  This approach emphasizes that it is important to ensure the
quality of the dietary supplement throughout the production and process
control system.  This approach emphasizes establishing specifications
for components and ensuring those specifications are met.  You may rely
on a certificate of analysis for specifications (except for the identity
of the dietary ingredient) only if you satisfy certain criteria, which
include qualifying the supplier of the components.  With this approach,
the goal of ensuring the quality of dietary supplements can be achieved
without applying the rule specifically to persons who manufacture,
package, label, or hold dietary ingredients that will be further
processed as a dietary supplement by other persons.  

     Consequently, we revised § 111.1 by deleting “dietary
ingredient.”  Therefore, those who manufacture, package, label, or
hold dietary ingredients are not subject to the final rule.  To
illustrate, assume you manufacture a dietary ingredient and sell that
bulk dietary ingredient to Company X.  Company X then utilizes the bulk
dietary ingredient in a dietary supplement.  Under final § 111.1(a),
you would not be subject to these dietary supplement CGMP requirements
because you are not manufacturing a dietary supplement, rather you are
manufacturing a dietary ingredient for further incorporation into a
dietary supplement by Company X.  If, however, you sell herbs in bulk to
Company X, and Company X simply packages the herbs into smaller units
for sale as a dietary supplement, you would be subject to the dietary
supplement CGMP requirements because you are manufacturing a dietary
supplement that Company X is simply packaging and labeling, and not
further processing into a dietary supplement.  In other words, in the
latter example, you would have acted as a manufacturer whose finished
product is simply repackaged or relabeled.  

	Under final § 111.1(a) persons engaged solely in activities relating
to the harvesting, storage, or distribution of raw agricultural
commodities that will be incorporated into a dietary supplement by
others are not included within the scope of the rule as a dietary
supplement manufacturer.  This is because those persons simply
“supply” a component (i.e., the raw agricultural commodity) that
another person will process into a dietary supplement; thus you do not
manufacture, package, label, or hold a dietary supplement.  

	Note, too, that if you manufacture and supply a component directly to
consumers as a dietary supplement, you would be considered a dietary
supplement manufacturer within the scope of final § 111.1(a). 
Likewise, if you manufacture a component and sell part of the batch to
another person who, in turn, will further process the component as a
dietary supplement and sell the remainder of the batch to consumers as a
dietary supplement, you would be subject to the dietary supplement CGMP
requirements, as a manufacturer, for the product sold to consumers and
not subject to an exclusion under final § 111.1(b), discussed in this
section.  In other words, final § 111.1(a) refers to the nature of your
activity, and simply engaging in some activities that do not bring you
within the scope of the final rule does not necessarily mean that all
your activities are outside the scope of the final rule.

	We do not agree, as some comments suggested, that we need to issue a
separate or modified set of CGMP requirements for dietary ingredients. 
That is because there are adequate controls established in this final
rule for the use of dietary ingredients used by the manufacturer of a
dietary supplement. However, if you manufacture, package, label, or hold
dietary ingredients that will be further processed as a dietary
supplement by another person, you must comply with food CGMP
requirements in part 110.  A dietary ingredient is a food under section
201(f) of the act, as a food, or as a component of food.  Because the
final rule gives manufacturers an incentive to qualify suppliers of
dietary ingredients, persons who manufacture, package, label, or hold
dietary ingredients may wish to familiarize themselves with these
dietary supplement CGMP requirements and use them in manufacturing,
packing, labeling, or holding operations for dietary ingredients.  	

	(Comment 30) Some comments argue if the final rule ultimately covers
dietary ingredient suppliers then we should clarify what constitutes a
“consumer.”  According to these comments, dietary ingredient
suppliers do not typically supply their products directly to those
individuals who will ultimately consume or ingest them.  Thus,
“consumers” of dietary ingredients are other companies, not
individuals.  The comments express concern about the possible
application of proposed § 111.95 which would require procedures for
handling complaints.

     (Response) The final rule applies only to persons who manufacture,
package, label, or hold dietary supplements and are not subject to an
exclusion in final § 111.1.  However, as explained above in the
previous response to comment 29), if a dietary ingredient manufacturer
also supplies or sells a dietary ingredient as a dietary supplement,
such manufacturer would be subject to final § 111.1(a) and subject to
all relevant dietary supplement CGMP requirements.  

	Some comments expressed concern about dietary ingredient manufacturers
having to comply with proposed § 111.95 on product complaints.  If a
dietary ingredient manufacturer receives a product complaint, we
encourage the manufacturer to evaluate the complaint to determine if it
may involve a problem with the manufacture of the dietary ingredient. 
In addition, we encourage the dietary ingredient manufacturer to notify
the dietary supplement manufacturer so that it can review the complaint
and investigate, as needed. 

	(Comment 31) Several comments question the proposal’s applicability
to persons who sell packaged products or seek clarification as to
whether the rule applies to dietary supplement manufacturers that
operate from homes and those that distribute product to other
distributors.  

	(Response) To the extent that the comments question whether retailers
or individuals who sell dietary supplements directly to individual
consumers are subject to the dietary supplement CGMP requirements, we
have revised the final rule by creating a new § 111.1(b) which states
that:

The requirements pertaining to holding dietary supplements do not apply
to you if you are holding those dietary supplements at a retail
establishment for the sole purpose of direct retail sale to individual
consumers.  A retail establishment does not include a warehouse or other
storage facility for a retailer or a warehouse or other storage facility
that sells directly to individual consumers. 

This means, for example, if you operate a storefront retail
establishment where you stock dietary supplements on your shelves for
purchase by individual consumers, we do not consider you to be
“holding” those dietary supplements in a manner that would require
you to comply with the holding provisions in this final rule.  Sale to
individual consumers, where you are not storing bulk dietary supplements
as one would in a warehouse or storage facility, does not fall within
the manufacturing, packaging, labeling, or holding activities that would
subject you to dietary supplement CGMP requirements.   

	However, if you operate storefront retail establishments, and those
retail establishments obtain their stocks from your warehouse, we would
consider your warehouse operations to be “holding” dietary
supplements and expect your warehouse operations to comply with the
rule’s holding requirements.  Such distribution is no different than
other warehouse operations that are normally subject to CGMP
requirements.  Consequently, to distinguish between “holding”
dietary supplements for retail sale to consumers and “holding”
dietary supplements in a warehouse for further distribution, final §
111.1(b) limits the exclusion to persons holding dietary supplements
“at a retail establishment for the sole purpose of direct retail sale
to individual consumers.”  Final § 111.1(b) also makes it clear that
a retail establishment does not include a warehouse or other storage
facility that a retailer uses to hold the dietary supplements or an
operation that sells directly to consumers, but that itself distributes
the product to the consumer from a warehouse or storage facility and not
from a storefront retail establishment.

	(Comment 32)  Many comments question the rule’s applicability to
various practitioners such as herbalists, acupuncturists, naturopaths,
and other health care providers who prepare individualized herbal
formulas for specific individuals on a
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●	These practitioners do not broadly sell products;

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

●	The testing and storage requirements of each finished batch cannot
apply to a small dispensary where several different modified herbal
formulas are prepared each day;     

●	Based on the projected costs to implement CGMPs, it would be
virtually impossible for an individual practitioner or university clinic
to develop the necessary quality control unit, maintain reserve samples,
maintain the required paperwork, or retrofit clinics to comply with the
rule;

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

●	Some practitioners do not consider themselves to be manufacturers; 

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

●	Despite the growing number of such practitioners, there is no proof
that greater harm has occurred to the general public from the herbs
these practitioners sell.  

     (Response)  We stated in the 2003 CGMP Proposal (68 FR 12157 at
12175) that we declined to exempt herbalist practitioners from the
proposed rule.  We continue to believe that the risks of adulteration
are not eliminated just because the practitioner is an herbalist, and
therefore, such an exemption should not be included in this final rule. 
However, after further consideration, we have determined that it would
be appropriate for us to consider the exercise of our enforcement
discretion in deciding whether to apply the  requirements of this final
rule to certain health care practitioners, such as herbalists,
acupuncturists, naturopaths, and other related health care providers.  

	We find it noteworthy that the comments identified two potential
safeguards that could support the exercise of our enforcement discretion
on whether to apply the requirements of the final rule to certain
practitioners:  1) adequate training in the professional practice; and
2) an individual client and practitioner relationship.  For example,
comments claimed that the practitioners receive adequate training to
formulate dietary supplements and that they provide the dietary
supplements to individuals in the course of a one-on-one consultation on
the premises of the practitioner. One comment from a practitioner states
that she received her training from an accredited 4-year university and
it included didactic and clinical training in acupuncture and Chinese
herbs.  Another comment from an organization provides detailed training
guidelines for practitioners, including 1600 hours of training, 400
hours of which should include clinical work.  Moreover, many comments
also assert that the practitioners are different from dietary supplement
manufacturers because they formulate the dietary supplements in the
course of a one-on-one consultation at their premises.  That enables
them to ensure the formulations are made to meet the specific needs of
the individuals.  

	We believe that a one-on-one consultation by a practitioner who is
adequately trained in their profession may not necessitate the same
types of controls as we are establishing in this final rule for
manufacturing activities that are on a larger scale.  Such a
practitioner may make some formulations in advance of the consultation
and still make the formulations in very limited quantities for the
individual client.  We believe that it would be appropriate to consider
the exercise of our enforcement discretion, on a case-by-case basis, to
determine whether to apply the requirements of this final rule to such
persons.  

	We do not expect the number of those subject to the consideration of
our enforcement discretion to be very large.  Many products that are
manufactured by practitioners would not necessarily be considered to be
dietary supplements (e.g., certain products used by traditional Asian
medicine practitioners).  Further, we are not considering exercising our
enforcement discretion with respect to practitioners who prepare batches
of herbs and sell them to individual consumers without determining
whether the dietary supplement is appropriate for each consumer’s
needs in a one-on-one personal consultation, or those that prepare
batches of a dietary supplement for which there is a known or suspected
safety concern.  	 

	(Comment 33)  Several comments asked us to exempt academic institutions
that provide training for therapeutic disciplines that use, for example,
herbal formulas in their practice regardless of whether the dietary
supplements they produce enter into interstate commerce.  Specifically,
these comments would revise the final rule to state that it does not
apply “to academic institutions that provide training in dispensing of
nutritional or herbal products and formulas related to courses in
therapeutic disciplines that provide such products and formulas as a
part of their therapy, for example, naturopathy, herbalism, traditional
Chinese medicine, and acupuncture.”	(Response)  Similar to what we
stated in response to comment 32, we believe that it may be appropriate
to consider the exercise of our enforcement discretion in circumstances
where an academic institution’s actions are similar to those of a
practitioner who is adequately trained in their profession and who
provides dietary supplements within the context of an individual client
and practitioner relationship.  In general, it is not our policy to
inspect an academic institution that provides training for therapeutic
disciplines that use, for example, dietary supplements in their
practice.  We intend to consider the exercise of our enforcement
discretion in those situations where there is a one-on-one consultation
that includes a practitioner with adequate training.  We intend to issue
guidance to further clarify how the agency intends to exercise its
enforcement discretion on the application of this final rule to certain
academic institutions.   

	(Comment 34) Several comments discuss the position taken by certain
nations, notably Australia and Canada, that have developed CGMP
requirements and related guidance for botanicals.   According to these
comments, these nations recognize that there are various types of
practitioners who sell herbs and herbal preparations in a clinical
setting, and do not consider such persons to be manufacturers.  The
comments ask us to follow the example of these nations.

	(Response)  We intend to consider the positions taken by other nations
to inform us in our decision making in any future guidance on how we
intend to exercise our enforcement discretion on the application of this
final rule to certain practitioners. 

	(Comment 35) Many comments say we should define when a dietary
supplement will be said to have entered interstate commerce.  The
comments state herbal practitioners (and academic institutions) often
purchase source herbs from outside their state, even if they prepare
these herbs for their specific customers within the state.  These
comments request we clarify that the rule does not apply to herbs
purchased out of state if prepared for local use.  Other comments
request clarification regarding clients who have moved across state
lines, yet maintain a relationship with an herbalist practitioner.   

	(Response) In section V we explain the interstate and intrastate issue
related to the final rule.  

	(Comment 36) A few comments assert individual practitioners and
practitioner organizations often are unaware of the opportunity to
comment on CGMP or regulatory issues.  Therefore, the comments say these
practitioners and organizations often fail to provide comment or
otherwise participate in rulemaking and say we should give these
practitioners and practitioner organizations a chance to comment.

	(Response) We provided many opportunities for comment and, therefore,
we decline to adopt the comments’ suggestion.  As we discuss in
section I, we published an ANPRM concerning dietary supplement CGMPs on
February 6, 1997 (62 FR 5700); the 1997 ANPRM provided an opportunity
for public comment.  On March 7, 2003, we issued a Talk Paper, along
with other background documents, announcing the issuance of a proposed
dietary supplement CGMP rule.  We made the rule available when it went
on display and before it published in the FEDERAL REGISTER on March 13,
2003 (68 FR 12157), and, again, provided an opportunity for public
comment.  We also held public meetings on April 29, 2003 in College
Park, MD and on May 6, 2003 in Oakland, CA.  We also held a public
meeting (via satellite downlink) on May 9, 2003, with viewing sites at
our district and regional offices throughout the country.  Thus, we
provided numerous opportunities for interested persons to learn about
the rule and to submit comments or otherwise participate in the
rulemaking process.  Consequently, we decline to provide yet another
opportunity for comment.

	(Comment 37) The preamble to the 2003 CGMP Proposal noted that comments
submitted in response to our 1997 ANPRM state we should not distinguish
between dietary supplements made in the United States and those made in
a foreign country (68 FR 12157 at 12174).  Although we agreed with the
comments and made no distinction between foreign and domestic firms in
the proposed rule, we invited comment on how we might ensure dietary
ingredients and dietary supplements exported to the United States have
been manufactured, packaged, labeled, and held consistent with part 111
(68 FR 12157 at 12175). 

	 Several comments argue the rule should apply to foreign firms as well
as domestic manufacturers to ensure a “level playing field” and to
protect American consumers.  Some comments say we should work with
foreign countries to harmonize our requirements and thus avoid potential
trade disputes under international trade agreements such as the General
Agreement on Tariffs and Trade (GATT).  Other comments suggest
compliance by foreign firms could be achieved through the use of third
party certification programs, such as the dietary supplement
verification program administered by USP, or the adoption of importer
verification provisions similar to those used in our HACCP requirements
for seafood (see § 123.12).

	In contrast, another comment says we should inspect foreign firms to
ensure compliance, whereas other comments claim we lack jurisdiction
over foreign firms. 	

(Response) We are amending proposed § 111.1 to clarify the
regulation’s applicability to foreign firms.  We explain in this
section how we may enforce the rule against foreign firms.  We, however,
are not making any changes in response to the comments calling for the
harmonization of the rule with foreign rules because this request is
beyond the scope of the final rule.

	 In response to comments, and for clarification, we have revised final
§ 111.1(a) to clarify that the regulation applies to the extent that
you manufacture, package, label, or hold a dietary supplement, including
a dietary supplement imported or offered for import in any State or
Territory of the United States, the District of Columbia, or the
Commonwealth of Puerto Rico.  

	With respect to the comments requesting that we make clear our position
for enforcing the rule against foreign firms, we explain our position as
follows.  Section 801(a) of the act authorizes us to refuse admission of
an imported food if it appears from the examination of such samples or
otherwise that such article is, among other things, adulterated.  A
foreign firm’s refusal to allow us to obtain records via an inspection
for CGMP purposes, as required by final § 111.610 (for the dietary
supplements the foreign firm offers for import into the United States),
would create the appearance that such imported dietary supplements are
adulterated under section 402(g) of the act, and thus, could lead to a
refusal of admission under section 801(a) of the act.    

	Foreign firms who ship to the United States must operate under
conditions that satisfy our regulations, including the requirement that
records be made available during the course of an FDA inspection.  We
note that except in circumstances where there is a public health
emergency or we receive information that would indicate the appearance
of adulteration of products shipped to the United States, foreign
inspections are generally scheduled well, e.g., weeks, in advance. 
Thus, we believe that taking action under Section 801 of the act is
appropriate if companies do not accommodate our inspectional request.

C.  What Definitions Apply to This Part?

(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 with the use of
“component” and thus not necessary in the final rule.  Because a
“dietary ingredient” is subsumed within the definition of
“component,” as explained in our response to comment 29, we deleted
“dietary ingredient” in those definitions where “component” was
used to avoid redundancy.  

In other provisions, we deleted “dietary ingredient” from the
definition because the use of those words was no longer necessary given
the narrowing of the scope of the rule as it applies to dietary
ingredient manufacturers (explained in response to comment 29 and 30). 
For example, we deleted “dietary ingredient” from the proposed
definition of “ingredient” that referred to the “manufacture of a
dietary ingredient or dietary supplement” and the “finished batch of
the dietary ingredient or dietary supplement.”  We did not need to
state “manufacture of the dietary ingredient” or refer to
“finished batch of dietary ingredient” because dietary ingredient
manufacturers that only supply such ingredients to other persons for
processing into a dietary supplement are not subject to the final rule. 
 

	We discuss changes to the definitions, other than the changes we have
made globally such as the deletion of “dietary ingredients,” the
change from “include, but not limited to” to “includes” or
“include,” the addition of labels and labeling, and the deletion of
the word quality from the phrase “identity, purity, quality, strength,
and composition,” as well as comments asking us to define more terms
or to delete certain definitions, in more detail immediately below.  

Actual Yield 

	The final rule defines “actual yield” as “the quantity that is
actually produced at any appropriate step of manufacture or packaging of
a particular dietary supplement.”  

We received no substantive comments to the proposed

definition.  

2.  Batch

	The final rule defines “batch” as “a specific quantity of a
dietary supplement that is uniform, that is intended to meet
specifications for identity, purity, strength, and composition, and that
is produced during a specified time period according to a single
manufacturing record during the same cycle of manufacture.”

	This definition differs from the proposed definition of “batch” by
stating that a batch is a specific quantity of a dietary supplement that
is “uniform.”  

	We inserted the word, “uniform” in response to comments asking that
we define “lot” to be consistent with “batch.”  We explain our
reasons for harmonizing the definitions and for inserting “uniform”
into the definition of “batch” in the response to comment 42.  

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

	(Comment 38) Several comments ask us to clarify what the “same cycle
of manufacture” is in the definition of “batch.”  One comment asks
if it meant the same product made with the same lot(s) of raw materials
regardless of how many days it took to produce the batch, or if it meant
a quantity produced in one day.  The comment also asks whether batches
produced on consecutive days, using the same formula, can be considered
to be the same batch with respect to the proposed testing requirements
if the quality control unit determined that different lots of raw
materials are equivalent (e.g., by meeting all specifications).

	(Response) The “same cycle of manufacture” refers to a process
during which equipment remains dedicated to the manufacture of the
batch.  The terms do not limit you to any particular time period or
require you to operate equipment continuously until you have completed
the “same cycle of manufacture.”  The “same cycle of
manufacture” also does not limit the number of lots of components you
use.  

	You may consider, as one batch, a product produced using different lots
of raw materials where the production of the batch is a continuous
process on a dedicated line.  However, for each component that you use
in the manufacture of the batch of dietary supplement, you would need to
establish specifications under final § 111.70, determine whether these
specifications are met under final § 111.73, and ensure that these
component specifications are met using the criteria under final
§ 111.75.  Further, you may not consider different batches of product
produced on consecutive days using the same formula to be the same batch
for purposes of testing requirements.  The term “different batches”
suggests that the production is not a continuous process on a dedicated
line.

	3.	Batch Number, Lot Number, or Control Number

	The final rule defines these terms as “any distinctive group of
letters, numbers, or symbols, or any combination of them, from which the
complete history of the manufacturing, packaging, labeling, and/or
holding of a batch or lot of dietary supplements can be determined.”

	We received no substantive comments on the definition.    We added the
word “and” before “or” to emphasize that the history of each
activity must be able to be determined.    

	4.	Component

	The final rule defines “component” as “any substance intended for
use in the manufacture of a dietary supplement, including those that may
not appear in the finished batch of the dietary supplement.  Component
includes dietary ingredients (as defined in section 201(ff) of the act)
and other ingredients.”

	The definition of component now refers only to the manufacture of a
dietary supplement (whereas the proposal also referred to the
manufacture of dietary ingredients).  We also made a non-substantive,
editorial revision in the last sentence to put parentheses around the
reference to section 201(ff) of the act and to change the word order so
that “component” includes “dietary ingredients . . . and other
ingredients.”  (The proposed definition had “components” including
“ingredients and dietary ingredients.”)  

	(Comment 39) Some comments would distinguish among “raw material,”
“components,” and “starting material” because the comments said
that defining “component” to include all these materials is
confusing.  One comment adds that many starting materials are not food
grade or approved food ingredients until they have been processed.  One
comment states the term “raw material” is typically used to describe
the materials (such as dietary ingredients, fillers, and processing
aids) that will be used to make the final product.  The comment further
states “component” is typically used to describe the specific items
used to assemble the finished product for the end user.  The components
would include packaging components such as bottles, caps, and labels, as
well as the bulk dietary supplement.  This comment also suggests that we
use the term “starting material” to distinguish substances used in
the manufacture of dietary ingredients from substances used in the
manufacture of dietary supplements.

	(Response) We decline to revise the rule as suggested by the comments. 
There may be differences in how components are referred to by certain
manufacturers and how we refer to it in this final rule.  However, for
purposes of this final rule we refer to all substances used in the
manufacture of dietary supplements as “components,” whether or not
those substances appear in the finished product.  

	Please note that, although ingredients are “components” under our
definition, not all components are ingredients.  For example, a solvent
used to make an herbal extract is not an ingredient when it is removed
from the extract by a process such as drying, because the solvent was
not intended to be present in the finished dietary supplement.  However,
the solvent would be a “component” because it was used in the
manufacture of the dietary supplement.  

	As for materials that might not be food grade or approved food
ingredients until processing, see the discussion in response to comment
240 in section XII.

	(Comment 40) Several comments express concern that “component”
could be interpreted to mean any constituent present in a botanical
extract or other natural product.  The comments say a single botanical
can contain tens of thousands of constituents or metabolites and that
chemists have not identified all constituents of a single botanical. 
According to the comments, the cost of testing for all constituents
would exceed a product’s total annual revenues.

	(Response) In general, we would consider the botanical extract or the
other natural product to be the “component” as defined in this final
rule rather than consider that all the various chemical substances
contained in the botanical extract or other natural product are
components.  Thus, if you are manufacturing a dietary supplement that is
intended to provide a certain substance (i.e. vitamin C ) and you add a
natural product which is intended to supply the Vitamin C (i.e. vitamin
C in the form of rosehips), we would consider the natural product (e.g.
rosehips that contains a certain amount of vitamin C) to be a component
which must be listed in the master manufacturing record. The component
specifications for the rosehips must include a specification for the
strength of the substance (e.g., vitamin C) in whatever amount you
determine is necessary to meet the specification for the strength of the
vitamin C in the finished batch of dietary supplement.  Under final §
111.70, we expect you to establish specifications for the natural
product and ensure that the specifications are met.   As an example
relevant to an extract, if you are manufacturing a dietary supplement
that is intended to provide a certain amount of vitamin C that derives
from the natural product rosehips, and the substance that you purchase
from a supplier to add as a component is a purified extract of rosehips
(rather than rosehips themselves), we would consider the purified
extract to be a component (as an ingredient).  The component
specifications for the purified extract must include a specification for
the strength of the substance (i.e., vitamin C) in whatever amount you
determine is necessary to meet the specification for the strength of the
vitamin C in the finished batch of dietary supplement.  However, in this
example “rosehips” would not be considered a component, because
“rosehips” is not what you added.  

5.	Contact Surface

	The final rule defines “contact surface” as “any surface that
contacts a component or dietary supplement, and those surfaces from
which drainage onto the component or dietary supplement, or onto
surfaces that contact the component or dietary supplement, occurs during
the normal course of operations.”  The final rule lists containers,
utensils, tables, contact surfaces of equipment, and packaging as
examples of “contact surfaces.”

	We did not receive any substantive comments on the proposed definition.
 We deleted “ordinarily” from “ordinarily occurs during the normal
course of operations” because “ordinarily” is redundant with
“normal.”

6.	Ingredient

	The final rule defines “ingredient” as “any substance that is
used in the manufacture of a dietary supplement and that is intended to
be present in the finished batch of the dietary supplement.  An
ingredient includes, but is not necessarily limited to, a dietary
ingredient as defined in section 201(ff) of the act.”  We did not
receive any substantive comments on this definition.  We made a
non-substantive, editorial change to replace “finished dietary
supplement” with “finished batch of the dietary supplement.”  

	(Comment 41) One comment says we should define “ingredient” better
to ensure consistent interpretation of CGMP at all levels throughout the
dietary supplement industry.  

	(Response) We disagree with the comment.  We believe the definition is
adequate, including as it does both dietary ingredients as described in
section 201 (ff) of the act and other ingredients that do not fit that
description, such as an emulsifier used to establish a uniform
dispersion in a liquid dietary supplement or a color additive used to
color a capsule.  Moreover, the comment did not explain or specify which
aspects of the proposed definition should be revised or explain why the
proposed definition would lead to inconsistent interpretations of CGMP.

7.	In-Process Material

	The final rule defines “in-process material” as “any material
that is fabricated, compounded, blended, ground, extracted, sifted,
sterilized, derived by chemical reaction, or processed in any other way
for use in the manufacture of a dietary supplement.”  

	We did not receive any substantive comments on the proposed definition.
   	

   8.	Lot

	The final rule defines “lot” as “a batch, or a specific
identified portion of a batch, that is uniform and that is intended to
meet specifications for identity, purity, strength, and composition; or,
in the case of a dietary supplement produced by continuous process, a
specific identified amount produced in a specified unit of time or
quantity in a manner that is uniform and that is intended to meet
specifications for identity, purity, strength, and composition.”

	The final rule differs from the proposed definition in that the
proposed definition of “lot” would have the batch or specific
identified portion of a batch be intended to have “uniform identity,
purity, quality, strength, and composition.”  	(Comment 42) One
comment agrees with the proposed definition for “lot,” but several
other comments would revise the definition to be more consistent with
the proposed definition of “batch.”  Specifically, the comments note
the proposed definition of “batch” would refer to a quantity of
dietary supplement that is “intended to meet specifications for
identity, purity, quality, strength and composition,” whereas the
proposed definition of “lot” would refer to a batch or specific
identified portion of a batch that is “intended to have uniform
identity, purity, quality, strength, and composition.”  The comments
would revise the definition of “lot” by deleting the phrase
“intended to have uniform” and inserting the phrase “intended to
meet specifications for” in order to make the definitions of
“batch” and “lot” consistent. 

	(Response) We agree that the definitions for “batch” and “lot”
should be consistent, but we disagree with the comments’ suggestion to
delete the term “uniform” from the definition of “lot.”  The
attributes of a lot or batch should be uniform throughout the lot or
batch and meet established specifications for those attributes.  If
samples from a lot or batch were tested for appropriate specifications
of identity, purity, strength, and composition, the attributes should be
consistent throughout the sample and be uniform from sample to sample
regardless of whether the test samples are taken from the beginning,
middle, or end of the lot or batch.  Consequently, we revised the
definition of “lot” to state, in relevant part, that a “lot” is
a batch or specific identified portion of a batch that “is uniform and
that is intended to meet specifications for identity, purity, strength,
and composition” or, for dietary supplements produced by a continuous
process, a specific identified amount produced in a specified unit of
time or quantity in a manner that is uniform and that is intended to
meet specifications for identity, purity, strength, and composition.”

	Similarly, we revised the definition of “batch” so that it states,
in relevant part, that a “batch” is a specific quantity of a dietary
supplement “that is intended to meet specifications for identity,
purity, strength, and composition.”

	These revisions make the definitions of “batch” and “lot”
consistent.

9.	Microorganisms

	The final rule defines “microorganisms” as “yeasts, molds,
bacteria, viruses, and other similar microscopic organisms having public
health or sanitary concern.”  It adds that the definition includes
species that: (1) May have public health significance; (2) may cause a
component or dietary supplement to decompose; (3) indicate that the
component or dietary supplement is contaminated with filth; or (4)
otherwise may cause the component or dietary supplement to be
adulterated.

	(Comment 43) One comment would revise the definition to identify
specific microorganisms that have public health or sanitary concern
(i.e., Salmonella species, Escherichia coli, Pseudomonas aeruginosa, and
Staphylococcus aureus).  The comment says this would be consistent with
USP requirements.  

	(Response) We disagree with the comment.  A list of specific
microorganisms could easily become outdated as new pathogens emerge, and
constantly issuing new rules to revise the list would be both
inefficient and impractical.  

	(Comment 44) One comment expresses concern that the proposed definition
for microorganisms would include microorganisms that are a natural part
of the ecology of all natural products.  The comment says certain levels
of microorganisms are expected on botanical raw materials (i.e., those
naturally occurring or introduced through organic cultivation
techniques) and that many do not present a public health risk.  The
comment expresses concern that non-pathogenic microorganisms that are
not a public health risk would be a “sanitary” concern that would
render a product adulterated.  The comment argues there should be little
concern about the presence of microorganisms that present no public
health consequence, and so we should revise the definition accordingly. 
The comment further discusses the difficulties in “sterilizing”
botanicals to render them free of microorganisms associated with
insanitary conditions.  The comment notes that some international
organizations have established “upper limits” for these organisms
for botanical supplements, which, in the comment’s opinion, represent
more realistic standards than trying to attain a “sterile” botanical
supplement.

	(Response) We disagree with the comment.  We do not interpret the
definition of “microorganism” as making the presence of
nonpathogenic microorganisms that are not a public health risk a
“sanitary concern” that would render a product adulterated. 
Instead, we interpret the definition as saying that microorganisms of
public health significance and microorganisms presenting sanitary
concerns are “microorganisms” under this rule.  These are the types
of microorganisms that may cause a component or dietary supplement to
become adulterated.  

	As for upper limits on microbial contamination, the comment offered no
suggested limits, and we decline to establish such limits in this rule. 
The final rule requires manufacturers to establish limits for those
types of contamination that may adulterate or lead to adulteration of
components or dietary supplements.  Thus, for example, a manufacturer of
a botanical dietary supplement would have to determine what, if any,
microorganisms are likely or certain to be present and establish limits,
as appropriate to prevent adulteration of the finished batch of the
dietary supplement.

	We have modified the word “have” with the word “may” to
indicate that the determination or evaluation of whether there is a
“public health significance” is not made after the fact.  There does
not have to be a factually established determination of public health
significance for you to conclude that the microorganisms “may
adulterate” the dietary supplement.  The change from “could cause”
to “may cause” is to be consistent with the previous change to
“may have.”

10.	Must

	The final rule explains that the word “must” is “used to state a
requirement.”  

	(Comment 45) One comment would revise the definition to say that the
term “must” be used to state mandatory requirements “unless shown
to be inapplicable or replaced by an alternative demonstrated to provide
at least an equivalent level of quality assurance.”

	(Response) We decline to revise the rule as suggested by the comment. 
The comment’s revision would undermine the reasons for issuing a rule.
 Rules create enforceable requirements.  It is not clear, nor did the
comment discuss, how we could enforce the requirements in this final
rule if firms were able to avoid a particular requirement by declaring
them to be “inapplicable” or substituting alternatives which they
felt they had demonstrated were “at least an equivalent level of
quality assurance.”  There would be inconsistency in the general CGMP
practices used within the dietary supplement industry and uncertainty as
to whether the process and production controls ensure the quality of the
dietary supplement.  Consequently, we decline to revise the rule as
suggested by the comment.

	We have, however, made a non-substantive, editorial change to the
definition so that “must” is used to state “a requirement.”  The
proposed definition had referred to “mandatory requirements.”  Since
a requirement by its nature is mandatory the word “mandatory” is
unnecessary.  

11.	Pest

	The final rule defines “pest” as “any objectionable insect or
other animal, including birds, rodents, flies, mites, and larvae.”

	We did not receive any substantive comments on this definition. 
However, on our own initiative, we made non-substantive, editorial
changes to delete the words, “but not limited to” after
“including” and to place the word “animals” in the singular. 

12.	Physical Plant

	The final rule defines “physical plant” as “all or any part of a
building or facility used for or in connection with manufacturing,
packaging, labeling, or holding a dietary supplement.”

	We received no substantive comments on this definition.  The final rule
is substantially similar to the proposed rule’s definition of
“physical plant.”    We  added “any” and placed “part” in
the singular to clarify that individual parts of a building or facility
are subject to the CGMP requirements. 

13.	Product Complaint

	The final rule defines “product complaint” as “any communication
that contains any allegation, written, electronic, or oral, expressing
concern, for any reason, with the quality of a dietary supplement, that
could be related to current good manufacturing practice.  Examples of
product complaints are: foul odor, off taste, illness or injury,
disintegration time, color variation, tablet size or size variation,
under-filled container, foreign material in a dietary supplement
container, improper packaging, mislabeling, or dietary supplements that
are superpotent, subpotent, or contain the wrong ingredient, or contain
a drug or other contaminant (e.g., bacteria, pesticide, mycotoxin,
glass, lead).”

	This definition modifies the proposed rule’s definition of
“consumer complaint,” which would define such a complaint as any
“communication that contains any allegation, written or oral,
expressing dissatisfaction with the quality of a dietary supplement
related to good manufacturing practices.  Examples of product quality
related to good manufacturing practices are: Foul odor, off taste,
superpotent, subpotent, wrong ingredient, drug contaminant, other
contaminant (e.g., bacteria, pesticide, mycotoxin, glass, lead),
disintegration time, color variation, tablet size or size variation,
under-filled container, foreign material in a dietary supplement
container, improper packaging, or mislabeling.  For the purposes of this
regulation, a consumer complaint about product quality may or may not
include concerns about a possible hazard to health.  However, a consumer
complaint does not include an adverse event, illness, or injury related
to the safety of a particular dietary ingredient independent of whether
the product is produced under good manufacturing practices.”

	We explain the reasons for revising the proposed definition in our
response to the comments immediately below.

	(Comment 46)  Some comments would broaden the definition of consumer
complaint to include complaints from dietary ingredient suppliers.  One
comment would change “consumer complaint” to “customer
complaint.”

	(Response)  As discussed in section VI, the final rule does not apply
to those who only manufacture dietary ingredients.  However, we
encourage such firms that receive complaints about a dietary supplement
to share those complaints with those in the manufacturing chain
associated with that dietary supplement’s manufacture so others may
take corrective action as needed.  Those who engage in the manufacture
of a dietary supplement, including manufacturing, packaging, labeling,
and holding operations, are responsible for complying with this final
rule’s product complaint requirements.  

	Furthermore, we encourage packagers, labelers, and distributors who
receive a product complaint to notify those in a dietary supplement’s
manufacturing chain about product complaints they receive or they,
themselves, generate that may relate to operations outside the
packagers’, labelers’, or distributors’ control.  For example, a
distributor who purchases a dietary supplement in bulk for packaging and
labeling may complain about product quality to the dietary supplement
manufacturer.  The manufacturer who receives the complaint must then
take appropriate action to determine whether the complaint involves a
possible failure of a dietary supplement to meet any CGMP requirements. 
Thus, the final rule revises the term “consumer complaint” to
“product complaint” to emphasize that the complaint is about the
product regardless of the complaint’s source.

	(Comment 47)  One comment disagrees that “disintegration time” and
“tablet size” are appropriate examples of complaints about product
quality specifications.

	(Response)  We disagree with this comment.  Complaints about
disintegration time or tablet size could indicate a problem with the
production and process control system that may affect the quality of the
dietary supplement.  

	(Comment 48)  Some comments disagree with the proposed definition of
“consumer complaint” because it excluded an adverse event, illness,
or injury related to the safety of a particular dietary ingredient.  The
comments say there should be a consistent approach for handling all
complaints, including adverse events.  One comment states consumers will
not be able to determine whether a product quality issue related to CGMP
caused an adverse event.  This comment expresses concern that not
classifying adverse events as consumer complaints could lead
manufacturers to avoid investigating certain adverse events and,
therefore, prevent them from determining the appropriate cause and
implementing the associated corrective action.  The comments stress we
should not treat complaints related to CGMP issues differently from
other complaints and urged us to classify all adverse events as consumer
complaints, whether or not they might have been caused by a particular
dietary ingredient. 

	A few comments state the proposal, which did not specifically address
adverse event reporting, but did address the broader category of
consumer complaints and would require companies to investigate
“adverse event reports,” may simply create more confusion and may
contradict the overall objective of a comprehensive adverse event
reporting system.  The comments also state neither the food CGMP
regulations nor the 1997 ANPRM defined “consumer complaints.”  The
comments say we should delete this definition and deal with consumer
complaints separately as part of the new CFSAN Adverse Event Reporting
System (CAERS).

	One comment states we should define the term “serious adverse dietary
supplement experience.”  The comment would define a “serious adverse
dietary supplement experience” as:

any adverse dietary supplement experience occurring at any dose that
results in any of the following outcomes: death, a life-threatening
adverse dietary supplement experience, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect.  Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse dietary
supplement experience and, based upon appropriate medical judgment, they
may jeopardize the patient or subject and may require medical or
surgical intervention to prevent one of the outcomes listed in this
definition.   

	(Response)  We decline to include in the definition of “product
complaint” an adverse event related to the safety of a particular
dietary ingredient.  The final rule establishes CGMP requirements for
dietary supplements and does not focus on whether dietary ingredients
that manufacturers may use in their dietary supplements are inherently
safe.  Nevertheless, we encourage firms to investigate all complaints,
regardless of whether the complaints relate to CGMP.  Furthermore,
mandatory reporting to FDA of serious adverse events is now required as
a result of the enactment of the “Dietary Supplement and
Non-Prescription Drug Consumer Protection Act” (Pub. L. 109-462)
signed into law on December 22, 2006.  In any event, consistent with
these CGMP requirements, manufacturers must establish limits on
contamination, as needed, for all ingredients or any component they use
in manufacturing a dietary supplement.  

	We agree it may be unclear whether a particular product complaint is
related to CGMP.  Final § 111.560, relating to product complaints,
applies in situations where the product complaint involves a “possible
failure of a dietary supplement to meet any of its specifications or any
other requirements of this part.”  Thus, if a firm is unclear whether
a particular complaint it receives relates to a CGMP issue, we would
consider that complaint to be related to a “possible failure” to
meet CGMP.  Consequently, the firm must comply with the requirements in
subpart O, unless the firm affirmatively determines that the complaint
is not related to a “possible failure” to meet CGMP, and therefore,
is not a “product complaint.”  To make this clear, we revised the
definition so that it applies to any “communication. . . that could be
related to good manufacturing practice” rather than to be any
“communication. . . that is related to good manufacturing practice.”

	We disagree with comments that suggested that the requirements for
product complaints would somehow contradict the overall objective of the
CFSAN CAERS.  This final rule has no effect on the mandatory or
voluntary reporting of adverse events.  We agree some adverse events may
be related to a failure to ensure the quality of the dietary supplement
as required by the final rule.  To the extent that an adverse event is
associated with CGMP, it would be considered a “product complaint”
under the final rule.  The fact that it is considered a product
complaint does not mean that such complaint could not be voluntarily
reported as an adverse event through CAERS.  Such a complaint may be
required to be reported under the mandatory reporting requirements of
the “Dietary Supplement and Non-Prescription Drug Consumer Protection
Act” (Pub. L. 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 product complaint.

	We made several editorial or grammatical changes to the definition of
product complaint in this final rule for simplicity and revised the
order of the listed examples of product complaints.  For example, the
proposed definition of “consumer complaint” states the term “means
communication that contains any allegation * * * .”  The final rule
defines “product complaint” as meaning “any communication that
contains any allegation * * *.”  Another non-substantive change was to
insert the words “dietary supplements that are” before
“superpotent, subpotent” to give the reader a clear understanding as
to the article that is superpotent or subpotent.  

	Finally, we added “electronic” as an example of how a product
complaint could be communicated to ensure that all forms of
communication are included and added “current” to modify “good
manufacturing practice” for consistency. 

	We discuss in section V, our general response to the comment that
stated that neither the food CGMP regulations nor the 1997 ANPRM
contains a definition of “consumer complaint,” is in our discussion
of whether this final rule exceeds our authority or it has to be
identical to the food CGMP regulations.  More specifically, we
acknowledge that the industry draft that we published in the 1997 ANPRM
did not define “consumer complaint.”  The industry draft did contain
provisions that would be directed to “complaints files.”  The
provisions for complaint files would require the use of written
procedures to handle complaints; retention of records of complaints for
a certain time period; and the inclusion of specific information in the
record of a complaint.  

	14. Quality 

	For purposes solely of this final rule we have decided to define
“quality.”  Quality means that the dietary supplement consistently
meets the established specifications for identity, purity, strength, and
composition and limits on contaminants and has been manufactured,
packaged, labeled, and held under conditions to prevent adulteration
under sections 402(a)(1), (a)(2), (a)(3), and (a)(4) of the Federal
Food, Drug, and Cosmetic Act. 

	(Comment 49)  Some comments asked that we define “quality.”  Some
comments claimed the proposal described “quality” in terms of
“identity,” “purity,” and “composition.”  One comment would
define “quality” as “the total characteristics of a product that
bear on its ability to satisfy stated (i.e., labeled) or implied needs
of identity, purity, strength and composition.”  Another comment would
define “quality” as “having the appropriate identity, purity, and
strength for the intended purpose.”  Another comment would define
quality using all the other attributes of identity, purity, strength and
composition.

	(Response)  For purposes only of this final rule, we have added a
definition of quality.  This definition is not intended to apply to CGMP
requirements other than those that apply to dietary supplements.  In
section III, in the Overview discussion, we discuss the concept of
“quality” as it applies to these dietary supplement CGMP
requirements and the distinction between the use of the term in the
final rule and in the proposed rule. 

	Because we have defined “quality” as encompassing identity, purity,
strength, and composition, we have revised each section with
requirements for the “identity, purity, quality, strength, and
composition” to remove the word “quality.”  The affected sections
in this final rule are: § 111.3 (definition of batch); § 111.3
(definition of lot); § 111.65 (What are the requirements to have a
quality control unitoperations?); § 111.70 (What Specifications Must
You Establish?); § 111.75 (What must You Do to Determine Whether
specifications are met?); § 111.80 (What Rrepresentative Ssamples must
Yyou Ccollect?); § 111.95 (What Records Must You Make and Keep?); §
111.105 (What Must the Quality Control Unit Personnel Do?); § 111.455
(What Requirements Apply to Holding Components, Dietary Supplements,
Packaging, and Labels?); and § 111.515 (When must a Rreturned Ddietary
Ssupplement be Ddestroyed, or Ootherwise Ssuitably Ddisposed of?).

15.  Quality Control

	The final rule defines “quality control” as “a planned and
systematic operation or procedure for ensuring the quality of a dietary
supplement.”  The proposed rule defined “quality control” as “a
planned or systematic operation for preventing a dietary ingredient or
dietary supplement from being adulterated.”

	(Comment 50) One comment suggests revising the definition to use more
positive language.  Specifically, the commenter would define “quality
control” as “a planned and systematic operation or procedure for
ensuring the quality of dietary supplement products.”

	(Response) We agree that the comment’s suggested language conveys a
positive concept about quality control’s role and value and adopt the
language in part.  The final rule’s quality control requirements will
help ensure compliance with other CGMP requirements and, therefore, will
help ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record.  We have defined the term “quality” in this
final rule as including preventing a dietary supplement from being
adulterated.  Consequently, we revised the definition of “quality
control” to state that “quality control” means a planned and
systematic operation or procedure “for ensuring the quality of a
dietary supplement."  We deleted “for preventing a dietary ingredient
or dietary supplement from being adulterated” in the proposed
definition since the concept of quality includes preventing
adulteration.

	16.  Quality Control UnitPersonnel

	The final rule defines “quality control unitpersonnel” as “any
person, persons, or group, within or outside your organization, thatwho
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 unit
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
the quality control unit’s functionoperations, 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,” .” and We also added a new § 111.12(b) to require
you to identify who is responsible for your quality control operations. 
Under final § 111.12(b) each person who is identified to perform
quality control operations must be qualified to do so and have distinct
and separate responsibilities related to performing such operations from
those responsibilities that the person otherwise has when not performing
such operations.  Throughout the codified, we use the term “quality
control personnel” when referring to the performance of specific
quality control operations.  The term “quality control personnel”
refers to the person or persons designated to perform the particular
quality control operation.

	17.  Representative Sample

	The final rule defines “representative sample” as “a sample that
consists of an adequate number of units that are drawn based on rational
criteria, such as random sampling, and that are intended to ensure that
the sample accurately portrays the material being sampled.”  This
definition is similar to the proposed definition of “representative
sample.”  We have added “an adequate” before “number” to
emphasize that the sample must be sufficient for its purpose.  We also
made non-substantive grammatical changes to insert “that are”
between “and” and “intended.”

	(Comment 52) Some comments note the proposed rule would use the terms
“representative sample,” “reserve sample,” and “representative
reserve sample” but would only define “representative sample.” 
The comments ask us to clarify the distinction, if any, between these
terms.

	(Response) A “reserve sample” is a sample that is to be held or
kept for a designated time.  It differs from a “representative
sample” in the sense that a representative sample is not always kept;
for example, one might take a representative sample to test product
quality, but one would not necessarily keep every tested sample.  

	To clarify this distinction, the final rule now defines a “reserve
sample” as “a representative sample of product that is held for a
designated period of time.”  We also revised the rule to refer solely
to a “reserve sample” rather than use both  “reserve sample” and
“representative reserve sample.”

 	18. Reprocessing

	The final rule defines “reprocessing” as “using, in the
manufacture of a dietary supplement, clean, , uncontaminated components
or dietary supplements that have been previously removed from
manufacturing and that have been made suitable for use in the
manufacture of a dietary supplement.”  We modified the definition
that, in part, read “. . . dietary supplements that have been
previously removed from manufacturing 

for reasons other than insanitary conditions” by removing “for
reasons other than insanitary conditions” to expand the scope of what
may be reprocessed.  We explain the reason for the latter change in our
response to the comments immediately below in this section.  We also
changed “unadulterated” to “uncontaminated” to be consistent
with the revisions we have made in other sections including the
definition of quality. 

	(Comment 53) Some comments ask us to clarify whether components or
dietary supplements that have been successfully treated to reduce
microbial levels to acceptable levels can be reprocessed.  Some comments
object to the proposed definition of “reprocessing” because it did
not include components or dietary supplements removed for insanitary
conditions, and several comments object to the restrictions to
reprocessing described in proposed §§ 111.35(i)(4)(iii) and 111.50(f),
because, they argue, the definition and sections associated with
reprocessing would not permit the reprocessing of previously insanitary
ingredients even if there are processes available that are safe and
effective in removing foreign matter, microorganisms, or chemicals that
may have rendered the ingredient “insanitary.”  One comment would
revise the definition as follows: “Reprocessing means using, in the
manufacture of a dietary supplement, clean, unadulterated components * *
* or dietary supplements that have been previously removed from
manufacturing for reasons other than insanitary conditions or that have
been successfully reconditioned so that they are suitable for use.”

	(Response) We agree that materials can be treated, subjected to
in-process adjustments, or reprocessed when there are suitable processes
available, and we revised the definition of “reprocessing” to
reflect this.  However, there must be appropriate oversight of the
treatment, in-process adjustments, and reprocessing so the dietary
supplement will still meet required specifications.  Therefore, we added
a conforming requirement to final §§ 111.90(b) and 111.140(b)(3)(vi)
to require oversight by the quality control unit personnel for any
reprocessing, treatment, or in-process adjustment of a dietary
supplement that have been previously removed from manufacturing and that
have been made suitable for use in the manufacture of a dietary
supplement (see sections X and XI).  

	19.  Reserve Sample

	The final rule contains a new definition of “reserve sample.” 
“Reserve sample” is defined as “a representative sample of product
that is held for a designated period of time.” We explain our reasons
for creating this definition in this section under the definition of
“representative sample”.

	20. Sanitize

     The final rule defines “sanitize” as “to adequately treat
cleaned equipment, containers, utensils or any other cleaned contact
surface by a process that is effective in destroying vegetative cells of
microorganisms of public health significance, and in substantially
reducing numbers of other microorganisms, but without adversely
affecting the product or its safety for the consumer.” 

	The final rule’s definition of “sanitize” differs from the
proposal in that the proposed definition would have specified a
reduction of 5 logs or 99.999 percent reduction of “representative
disease microorganisms of public health significance” and “other
undesirable microorganisms” and would have specified the use of heat
or chemicals.  The preamble to the 2003 CGMP Proposal explained that we
based the proposed definition of “sanitize” on the definition of
“sanitization” in the “Food Code” (which is a model that gives
food control authorities a scientifically sound technical and legal
basis for regulating the retail and food service segment of the
industry) because dietary supplements are often consumed without further
processing, similar to foods consumed in retail outlets (68 FR at
12179).  The preamble to the 2003 CGMP Proposal also explained that, to
achieve the reduction levels in the proposed definition, one would need
to validate control measures to ensure they are both appropriate to
their operation and scientifically sound.  The preamble explained that
in many cases, manufacturers may rely on a written certification from
the equipment manufacturer or may obtain a written scientific evaluation
of a process, especially in cases where two or more control measures are
used to accomplish the 99.999 percent reduction in the target pathogen,
to ensure the process is adequate to destroy microorganisms of public
health significance or to prevent their growth. 

	(Comment 54) Many comments object to the proposed text concerning the
application of heat or chemicals to a food contact surface to yield a
reduction of 5 logs or 99.999 percent of representative disease
organisms of public health significance.  The comments state the aspect
of the proposed definition is overly prescriptive, beyond our legal
authority, and would not provide additional public health benefits. 
Many comments say it is inappropriate to use the definition of
sanitization from our Food Code because retail and manufacturing
operations are distinct.  A few comments assert the process of
manufacturing dietary supplements shares more in common with food or
drug manufacturing than with retail operations.  Most comments recommend
that we define “sanitize” in the manner that was presented in the
1997 ANPRM and consistent with the current food CGMP definition at §
110.3 so that “sanitize” means “to adequately treat dietary
product contact surfaces by a process that is effective in destroying
vegetative cells of microorganisms of public health significance, and in
substantially reducing numbers of other undesirable microorganisms, but
without adversely affecting the product or its safety for the
consumer.” 

	One comment states that consistently validating the effectiveness of
the sanitizing procedure is impractical and recommended we state instead
that equipment, utensils, etc., should be cleaned and sanitized in a
manner that keeps undesirable microorganisms and other adulterants from
contaminating all components, ingredients, in-process materials, and
finished product.  The comment claims that, by this approach, the
microbial and analytical test results of product produced on a
facility’s equipment, coupled with random testing of final rinse water
after cleaning and sanitizing equipment and utensils, would provide
sufficient and continuous evidence of a proper and effective cleaning
and sanitizing plan.  

	Two comments claim that the proposed definition for sanitize denotes
“validation methodology” found in drug CGMP, and that we must base
dietary supplement CGMP on food rather than on drug standards.  

	Other comments express concern about validating control measures to
ensure that they are scientifically sound and appropriate to operations
and the economic burden to do the testing.  A few comments state it
would be difficult to show a 100,000-fold reduction on an already
cleaned surface, particularly if the pre-sanitization level is at or
near the lower limit of the test method employed.  

	One comment states the definition required the manufacturer to
demonstrate a 100,000-fold reduction in microbial count every time a
food contact surface is sanitized. A few comments express concern that
processing lines would have to be closed down each time they are
sanitized in order to test them, creating a financial hardship
especially on smaller operations.  Other comments ask us to give
companies the flexibility necessary to monitor sanitation needs based on
individual products and manufacturing operations to be consistent with
existing industry practices and food and drug CGMPs. 

	One comment requests we clarify that a sanitizing agent for use on food
processing equipment must be approved in accordance with part 178
--Indirect Food Additives: Adjuvants, Production Aids and Sanitizers and
our expectations with respect to what documentation would be necessary
to prove the effectiveness of the sanitizer used.  Two comments say the
proposed definition of sanitize means that manufacturers must perform
validation studies to demonstrate that the sanitizers they are using
reduce the microbial load on equipment by 100,000-fold, a requirement
for a “sanitizer” under regulations issued by the Environmental
Protection Agency (EPA).  The comments say a sanitizer should not be
held to this standard for the purpose of reducing microbial loads on
food product contact surfaces, and that manufacturers of a solid dosage
form may not need to “sanitize” their equipment because the
processing environment is not suitable for microbial growth due to the
low water activity.  One comment recommended using the approach in the
Food Code, which specifies conditions under which chemical sanitizers
listed in § 178.1010 may be used, including the requirement that they
be used in accordance with the EPA-approved manufacturer’s label use
instructions, and be used for dietary supplements rather than imposing a
validation requirement on manufacturers.

	Some comments would divide the definition of “sanitize” by creating
separate definitions for “sanitize” and “sanitizing agent.”  The
comments would define “sanitize” as meaning “to adequately treat
equipment, containers, utensils, or any other dietary product contact
surface by applying a sanitizing agent on cleaned food contact
surfaces.”  One comment would define “sanitizing agent” as
“cumulative heat or chemicals that, when evaluated for efficacy, yield
a reduction of 5 logs, which is equal to 99.999 percent reduction, of
representative disease microorganisms of public health significance and
substantially reduce the numbers of other undesirable microorganisms,
but without adversely affecting the product or its safety for the
consumer.”  Another comment would define “sanitizing agent” in a
similar manner, except it would omit references to a 5-log reduction.

	(Response) The proposed definition of “sanitize” was intended to
give firms the flexibility to monitor sanitation needs based on their
products and operations.  We did not intend to suggest that
manufacturers had to demonstrate a 100,000 fold reduction in microbial
count every time they sanitized a contact surface, nor did we intend, as
some comments claimed, to have firms close down processing lines every
time they were sanitized to test them for microbial reduction.  Rather,
the language of the proposed rule was intended to make it clear that
processes used to sanitize contact surfaces should be effective. 
However, we recognize that the proposed definition caused confusion as
to our intent.  The proposed definition may have been interpreted as
proposing validation to ensure an area was sanitized; however our intent
was simply to require that effective sanitizers and sanitizing processes
be used, just as in food establishments.  Therefore, in order to clarify
the provision, we have revised the definition of “sanitize” to be
consistent with § 110.3(o).  The final rule defines “sanitize” as
adequately treating “cleaned equipment, containers, utensils, or any
other cleaned contact surface by a process that is effective in
destroying vegetative cells of microorganisms of public health
significance, and in substantially reducing numbers of other
microorganisms, but without adversely affecting the product or its
safety for the consumer.”  The final definition of sanitize does not
include any statements about mechanisms that you may use to achieve
compliance because including such non-binding information is
inconsistent with our current practices for establishing regulations.

     We note that EPA has regulatory authority over certain uses of
sanitizers as pesticide chemicals and we have regulatory authority over
certain uses of sanitizers as food additives.  Under section
201(q)(1)(B) of the act, as amended by the Food Quality Protection Act
(FQPA) (Public Law 104-170) and the Antimicrobial Regulation Technical
Corrections Act (ARTCA) (Public Law 105-324), certain substances used as
food contact surface sanitizing solutions are subject to the
Environmental Protection Agency’s (EPA) regulatory authority as
pesticide chemicals.  EPA recently codified tolerance exemptions under
section 408 of the act for those food contact surface sanitizing
solutions that were previously subject to our authority at § 178.1010
and transferred to EPA’s authority under FQPA and ARTCA (see 40 CFR
180.940 (69 FR 23113 (April 28, 2004)).  Such pesticide chemicals must
comply with the Pesticide Tolerance regulations in 40 CFR 180.940. 
Sanitizers used on food packaging must comply with our regulations at §
178.1010.  For an in depth discussion of appropriate sanitizers for food
contact surface use, see the EPA’s Pesticides; Tolerance Exemptions
for Active and Inert Ingredients for Use in Antimicrobial Formulations
(Food Contact Surface Sanitizing Solutions) (69 FR 23113 (April 28,
2004)) and DIS/TSS-4 Efficacy Data Requirements Sanitizing Rinses (for
previously cleaned food-contact surfaces) (Jan 30, 1979) (Ref. 274)
(available on the internet at

http://  HYPERLINK "http://www.epa.gov/oppad001/"  www.epa.gov/oppad001/
dis_tss_docs/dis-04.htm).  

	21. Theoretical Yield 

	The final rule defines “theoretical yield” as “the quantity that
would be produced at any appropriate step of manufacture or packaging of
a particular dietary supplement, based upon the quantity of components
or packaging to be used, in the absence of any loss or error in actual
production.”

	We received no substantive comments on the proposed definition.

	22. Water Activity

	The final rule defines “water activity” as “a measure of the free
moisture in a component or dietary supplement and is the quotient of the
water vapor pressure of the substance divided by the vapor pressure of
pure water at the same temperature.”

	We received no substantive comments on the proposed definition. 

	23. We

	The final rule explains that “we” means the United States Food and
Drug Administration.

	The final rule’s definition is identical to the proposed definition. 
We received no substantive comments on the proposed definition. and,
therefore, finalized it without change.

	24. You

	The final rule defines “you” as a “person who manufactures,
packages, labels, or holds dietary supplements.”

	25. What Other Terms Did the Comments Want Defined?

	(Comment 55) Some comments ask us to define “adulteration” (based
on the provisions of section 402 of the act), “dietary ingredient,”
and “dietary supplement” (based on the definition in section 201(ff)
of the act).

	(Response) We decline to revise the rule as suggested by the comments. 
The terms have meaning within the context of the act and case law. 
Further, under final § 111.3 the act’s definitions and
interpretations “apply to such terms when used in these
regulations.”  Thus, there is no need for us to define the terms as
requested by the comments. 

	(Comment 56) Proposed § 111.35(e)(2) would require a person to
establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration, and proposed § 111.35(f) would require monitoring of the
in-process control points, steps, or stages to ensure these established
specifications are met and to detect any unanticipated occurrence that
may result in adulteration.  Some comments ask us to define the term
“control point” as “any point, step or stage in the manufacturing
process where control is necessary to prevent adulteration.”

	(Response) We decline to add a definition of “control point” as
requested by the comments.  Instead, we revised final § 111.75(b)
(formerly proposed § 111.35(f)) to state that you must monitor the
in-process points, steps, or stages where control is necessary to ensure
the quality of the finished batch of dietary supplement; this revision
eliminates the need to define “control point.”

	(Comment 57) Several comments would have us define one or more of the
following terms: identity, purity, strength, and composition.  Some
comments suggest specific text for the definitions.  

	Similarly, some comments suggest codifying the preamble description
that we used for these terms – i.e., the phrase “identity, purity,
quality, strength, and composition” means that the production on a
batch-by-batch basis is consistent with the master manufacturing record
and is what it is represented on the label to be (identity); is without
impurities and is the desired product (purity); is the identity, purity,
and strength for its intended purpose (quality); is the concentration,
that is, the amount per unit of use intended (strength); and is the
intended mix of product and product-related substances (composition) (68
FR 12157 at 12176).  One comment says “identity” should mean “a
substance or product is what it is represented on the label to be.”  

	One comment says that it does not seem appropriate to define the term
“purity” to mean “without impurities.”  The comment states it
would be difficult to consider an herbal extract as being “pure”
because it is a mixture of naturally occurring compounds in a solvent. 
Another comment suggests the term “purity” be defined to mean
“free from objectionable and/or deleterious levels of impurities
including, but not limited to, heavy metals, pesticides, mycotoxins,
radioactivity, filth, extraneous material, molds, yeasts and bacteria. 
Another comment suggests defining the term “purity” as “having the
intended identity and composition and being without significant
impurities.”  However, the comment does not explain what is meant by
“without significant impurities.” 

	One comment suggests defining the term “strength” as “having the
intended concentration, that is, the amount of the dietary ingredient
per unit of use (tablet, capsule, soft gel, teaspoon, or other unit).”
 Another comment expresses concern about the use of the term
“strength” in relationship to non-standardized herbals because there
are no current industry standards for these products.  This comment
suggests we clarify the term “strength” so it refers to having the
correct amount of a stated ingredient.  One comment notes St. Johns wort
has a composition of approximately 40 different constituents in addition
to the essential oil that contains numerous constituents.  The comment
asks which constituent it should use to determine “strength.” 
Another comment would use the term “quantity” instead of
“strength.”

     One comment would define “composition” as “having the
intended mix of components or ingredients, including dietary
ingredients.”  Another comment would delete “composition” from the
rule because, the comment claimed, an FDA investigator might conclude
that “composition” refers to every constituent of every botanical. 
According to this comment, there are many tests that could be used to
identify the botanical constituents, but that it would be economically
exhausting considering the number of botanical constituents, and it
would not contribute to quality or safety.

	(Response) We decline to revise the rule to define identity, purity,
strength, or composition.  The exact way in which the dietary supplement
industry uses these terms may vary, and defining these terms could limit
the flexibility that is needed to accommodate such variations.  

	Nevertheless, to elaborate on our interpretation of identity, purity,
strength, and composition, and to respond to the particular concerns
raised by some comments, we provide the following information.

	a.  Identity

	The “identity” of a dietary supplement refers to the dietary
supplement’s consistency with the master manufacturing record and/or
that it is the same as described in the master manufacturing record. 

	b.  Purity

	The “purity” of a dietary supplement refers to that portion or
percentage of a dietary supplement that represents the intended product.
 For example, amino acids generally can exist in two forms (i.e., dextro
(D-, or right) and levo (L-, or left) forms) called enantiomers. 
Enantiomers have the same chemical formula and the same chemical
structure, but differ in their three-dimensional orientation.  If you
manufacture a dietary supplement to provide the amino acid L-arginine,
and you determine that 90 percent of the manufactured product is
L-arginine and 10 percent of the manufactured product is D-arginine, you
could describe your L-arginine product as “90 percent pure.”  As
another example, if you manufacture a mixture of triglycerides that
provides polyunsaturated fatty acids in the diet, the manufactured
triglycerides may contain small amounts of free fatty acids and sterols.
 The free fatty acids, and sterols could derive, for example, from the
source of the triglycerides or could be byproducts of the manufacturing
process.  If you determine that 95 percent of the manufactured product
is the mixture of the triglycerides that provides the polyunsaturated
fatty acids, and 5 percent of the product is free fatty acids and
sterols, you could describe the purity of your product as “95 percent
pure.” 

	Just as we use the term “purity” to refer to the identity and
amount of a dietary supplement that is the desired product, we use
“impurity” to refer to the identity and amount of a dietary
supplement that is not the desired product.  In the above examples, we
view the D-arginine that is present in the product that is intended to
be L-arginine as an “impurity,” and we view the free fatty acids and
sterols that are present in the product that is intended to be a mixture
of triglycerides that provide polyunsaturated fatty acids in the diet as
“impurities.”  For the purposes of these examples, we do not view
these “impurities” as “contaminants.”  

	If the comments were concerned that the dietary supplement CGMP
requirements regarding a dietary supplement’s “purity” mean that
we expect you to characterize each constituent of a natural product to
determine whether each constituent is present in a certain
pre-established quantity (i.e., purity specification) to determine
whether it contributes to the “purity” of the dietary supplement or
would be considered as an “impurity,” we do not consider such
constituents to be “components” of a dietary supplement (see
discussion of the definition of component in this section). For example,
if manufacture a dietary supplement containing fish oil, we would not
consider the triglycerides, which are constituents of the fish oil, to
be components.  Likewise, we would not consider particular fatty acids
(such as the polyunsaturated fatty acids docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA)), which are constituents of the
triglycerides, to be components of the dietary supplement.  In this
example, you would be required to establish a purity specification for
the amount of triglycerides in the fish oil.  (Note that if you are
manufacturing fish oil to provide the fatty acids DHA and EPA in the
dietary supplement, the component specifications for the fish oil must
include a strength specification for DHA and EPA in whatever amount you
determine is necessary to meet the specification for strength of DHA and
EPA in the dietary supplement.) We do, however, expect you to set
appropriate limits on contaminants – e.g., toxic substances – that
are known to be constituents of botanical extracts or other natural
products that are likely or certain to contain constituents that are
harmful.

	c.  Strength

The strength of a dietary supplement relates to its concentration.  By
concentration, we mean the quantitative amount per serving (for example,
weight/weight, weight/volume, or volume/volume).  Therefore, for
purposes of this final rule, strength does not refer simply to the
quantity of an ingredient, rather it refers to the amount of a stated
ingredient per a specified unit of measure.  

	If the comments were concerned that the “strength” of a dietary
supplement meant that you need to establish the quantitative amount per
unit of measure of each constituent in a dietary ingredient, such as a
botanical extract or natural product, we do not consider such
constituents to be “components” of a dietary supplement, unless you
add such constituents as components (as in an extract) (see discussion
of the definition of component in this section).  

	We do not consider the rule’s requirements on dietary supplement
strength as necessarily relating to the individual constituents of such
products.  Whether the requirements regarding dietary supplement
strength apply to one or more constituents of dietary ingredients in a
dietary supplement depends on what you are manufacturing.  For example,
if you are manufacturing vitamin C, and your source of vitamin C is
rosehips, you would  establish a strength specification for vitamin C 
in the finished batch of the dietary supplement (e.g., "x mg of vitamin
C per tablet"). You are required to ensure that the dietary supplement
does in fact contain "x mg of vitamin C per tablet."  Alternatively, if
you are manufacturing rosehips and not vitamin C from rosehips, the
strength specification that you establish for the finished batch of the
dietary supplement is the strength of the rosehips themselves (i.e., the
concentration of rosehips in the final product, such as “x mg of
rosehips per tablet”).  You are required to ensure that the product
does in fact contain “x mg of rosehips per tablet.”  

	We discuss the requirements to establish and meet specifications in our
discussion of subpart E (see section X). 

	d.  Composition

	A dietary supplement’s “composition” refers to the specified mix
of product and product-related substances in a dietary supplement.  For
example, a dietary supplement manufactured to provide vitamin C may
contain, in addition to vitamin C, a tablet coating agent and substances
used as binders.  The composition could be described as the percent of
the dietary supplement that is vitamin C, the tablet-coating agent, and
each binder.

	e. Other terms

	(Comment 58) Several comments would revise the rule to define
“manufacturer.”  Many comments ask whether the rule applies to
certain types of companies or professionals and said a definition of
“manufacturer” would clarify the rule’s applicability. 

	Some comments suggest specific text for a definition.  For example, one
comment would define “manufacturer” as “a person who formulates or
changes the composition or physical characteristics of a dietary
supplement or who packages or labels the product in a container for
distribution” to clarify that a company that does not manufacture a
specific dietary supplement, but purchases a dietary supplement in bulk
and then packages or labels the bulk dietary supplement for sale to
consumers, is still subject to dietary supplement CGMP requirements. 
The comment cites our proposed definition of “manufacturer” in our
infant formula CGMP proposal (see 61 FR 36153 at 36209 (July 9, 1996)
(proposing to define a “manufacturer” as “a person who prepares,
re-constitutes or otherwise changes the physical or chemical
characteristics of an infant formula or packages or labels the product
in a container for distribution”)). 

	Other comments would define “manufacturer” to exclude a health care
practitioner or herbalist and noted the Canadian Natural Health Product
regulations do not apply to health care practitioners.

	(Response) We decline to define “manufacturer” in the final rule. 
In section III, footnote 1, we explain that “manufacture” is a broad
term and is not limited to production, packaging, or labeling
activities.  Consequently, we prefer to explain our interpretation of
the final rule in this preamble and to have the codified provisions
state general principles rather than attempt to capture subtleties in a
definition of “manufacturer.”    

	(Comment 59) Proposed § 111.35(e)(1) through (e)(3) would require you
to establish specifications for identity, purity, quality, strength, and
composition at receipt, in-process, and finished batch stages, while
proposed § 111.35(g)(1) would require you to test each dietary
supplement at the finished batch stage before release for distribution
to confirm that specifications are met, provided that there are
scientifically valid analytical methods available to perform such
testing.  If your quality control unit determined that finished batch
testing could not be completed for any specification because a
scientifically valid analytical method was not available, proposed §
111.35(g)(2) and (g)(3) would require you to perform testing on
components and at the in-process stage to determine whether that
specification is met.  The preamble to the 2003 CGMP Proposal explained
that a scientifically valid analytical method is one that is based on
scientific data or results published in, for example, scientific
journals, references, text books, or proprietary research (68 FR 12157
at 12198).  

	Several comments agree that scientifically valid analytical methods are
those that are based on scientific data or results published in
scientific journals, references, textbooks, or proprietary research. 
However, several comments ask us to define or better explain the terms
“test” or “scientifically valid analytical method” as used in
the dietary supplement CGMP final rule.  One comment argues that,
because of the evolving nature of methodology for ingredients used in
dietary supplements, we should give the industry more guidance as to
what can be considered authoritative for the purpose of compliance with
CGMP.  Some comments state we should acknowledge methods from the
Institute for Nutraceutical Advancement (INA), American Herbal
Pharmacopoeia (AHP), European Pharmacopoeia, and the World Health
Organization (WHO) as scientifically valid analytical methods.  One
comment notes the USP establishes scientifically valid procedures in its
compendia and encouraged us to designate compendial procedures as
"scientifically valid" by defining "scientifically valid" to include
compendial procedures.  The comment further argues that failure to
acknowledge compendial procedures as scientifically valid would be
inconsistent with section 403(s)(2)(D) of the act, which acknowledges
the role of compendia, by considering a dietary supplement misbranded if
the supplement is covered by the specifications of an official
compendium, is represented as conforming to the specifications of an
official compendium, and fails to so conform. 

	Other comments would define “validation” and “verification” and
directed us to “ANSI Standard A8402-1994” (a description of
validation and verification standards).  

	(Response) We decline to define “test,” “scientifically valid
analytical method,” or “scientifically valid method” in this final
rule.  As the comments recognized, the analytical methods for components
are evolving.  A regulatory definition for “test,” “scientifically
valid analytical method” or “scientifically valid method” could
become obsolete if we based it on specific sources such as INA, AHP, or
USP that may or may not themselves stay current or that may be modified
in a manner that did not enjoy widespread support.  

	The preamble to the 2003 CGMP Proposal acknowledged that compendia can
have a role in establishing tests used to determine whether
specifications are met.  For example, we noted that compendial standards
may be appropriate reference materials for use in conducting tests or
examinations (68 FR 12157 at 12208).  However, we did not list specific
compendia that would be suitable sources or scientifically valid
analytical tests, and are not listing such compendia in this final rule.
 The compendia identified in the comments, i.e., INA, ANSI, 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 unit’s responsibilitypersonnel
to approve the use of those scientifically valid tests that will ensure
a product’s identity, purity, strength, and composition whether or not
such tests are contained in a particular compendium.  

	 We also decline to define “validation” and “verification”
because the final rule does not establish any requirements that use
these terms.

	(Comment 60) One comment asks us to define the terms “adequate,”
“sufficient,” and “qualified” and argues that, without these
definitions, an FDA investigator may assert that something or someone is
not adequate, sufficient, or qualified.

	(Response) We decline to define “adequate,” “sufficient,” or
“qualified” in this final rule.  Deciding what is “adequate” or
“sufficient,” or who is “qualified” must be done on a
case-by-case basis, depending on the operations and the particular
facts.  As explained in section V, we do not need to, nor could we,
predict with mathematical precision how many inches or feet, for
example, would be “adequate space” to allow for cleaning a
particular piece of equipment that could be applied to every size of
facility and every operation.  Furthermore, defining “adequate,” as
defined in part 110, as “that which is needed to accomplish the
intended purpose in keeping with good public health practice” would
still require context to determine whether, in a particular operation
and based on a particular set of facts the particular practice was
“adequate.”  Moreover, for terms such as “adequate,”
“sufficient,” and “qualified,” where there has been common usage
in the food industry to enable manufacturers and FDA investigators to
comprehend and apply such terms to a particular operation, we do not
believe a definition for these terms is necessary. 

	(Comment 61) Several comments would define the terms “certificate of
analysis,” “certificate of compliance/ conformance,” and
“continuing product guarantee.”   Most comments include these terms
in a list of terms that they want us to define to ensure consistent
interpretation of the rule throughout the industry.  One comment says a
standard for documentation, such as a certificate of analysis, would put
greater emphasis on the firm’s responsibility to comply with CGMP.  

	(Response) We decline to define these terms as suggested by the
comments.  We have included, in the codified, the use of a certificate
of analysis as an option to determine whether certain specifications
have been met.  The final § 111.75(a)(2)(ii)(B) requires that certain
information be provided in a “certificate of analysis.”  This
provision states that the certificate of analysis must include a
description of the test or examination method(s) used, limits of the
test or examinations, and actual results of the tests or examinations,
provided you satisfy certain other criteria.  

	As for the claim that a standard for documentation, such as a
certificate of analysis, would emphasize a firm’s responsibility to
comply with CGMP, we encourage firms who are excepted from the scope of
the rule in final § 111.1 and who supply dietary ingredients and other
components to follow dietary supplement CGMP requirements.

	We decline to define “certificate of compliance/ conformance” or
“continuing product guarantee” because the final rule does not
establish any requirements that use these terms. 

	26. What Definitions Did the Comments Want Us to Delete?

	(Comment 62) Some comments would delete certain definitions (e.g.,
“component” and “ingredient”) because these terms do not appear
in the food CGMP, the 1997 ANPRM, or both.

	(Response) We decline to delete any definition for the reasons stated
by the comments.  As discussed in section V, Congress did not require
dietary supplement CGMP requirements to be identical to the food CGMP
requirements, so the mere fact that a definition may not appear in a
food CGMP regulation does not mean we must delete that definition from
this final rule, especially when the comments offered no other
justification for deleting the definition.  Definitions provide clarity
and consistency in interpreting various terms in a rule.  

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

	Final § 111.5 states: “In addition to these regulations, you must
comply with other applicable statutory provisions and regulations under
the act related to dietary supplements.” Proposed § 111.5 stated
that, in addition to the dietary supplement CGMP requirements, “you
must comply with other applicable statutory provisions and regulations
under the act related to the manufacturing, packaging or holding of
dietary ingredients or dietary supplements.”  

Section 111.5 reminds you that other statutory or regulatory
requirements, not included in the dietary supplement CGMP requirements,
may apply to your particular products, operations or activities.  In our
further review of this provision, we determined that we do not need to
elaborate on the individual operations and have shortened the provision
to eliminate the references to particular operations.  You are required
to comply with other applicable statutory and regulatory requirements,
and we have retained this provision to ensure you understand that this
final rule does not relieve you of your responsibilities to comply with
other applicable statutory and regulatory requirements related to
dietary supplements.

 

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

	The final rule omits sections that were in the proposed rule.  Proposed
§ 111.2, “What Are These Regulations Intended to Accomplish,” would
have described the rule’s purpose as establishing the minimum CGMP you
must use to the extent that you manufacture, package, or hold a dietary
supplement.    Proposed § 111.6, “Exclusions,” would have excluded
“persons engaged solely in activities related to the harvesting,
storage, or distribution of raw agricultural commodities that will be
incorporated into a dietary supplement by other persons” from the
dietary supplement CGMP requirements. 

	1.  “What Are These Regulations Intended to Accomplish?”  (Proposed
§ 111.2)

	We elected to remove proposed § 111.2 from the final rule because we
realized that it created no enforceable obligations and provided little,
if any, helpful information.  The few comments that address proposed §
111.2 either disagreed with its general statement or sought to weaken
the provision; the comments’ arguments prompted us to reconsider
whether proposed § 111.2 was necessary at all, and, in the end, we
decided to delete the proposed section.  We describe the comments on
proposed § 111.2 immediately below.

	(Comment 63) Several comments argue the proposed rule went beyond the
“minimum standards” mentioned in proposed § 111.2.  These comments
also assert the proposed rule lacked flexibility. 

(Response) We disagree with the comments.  In several instances, the
proposed requirement is practically identical to requirements in the
umbrella food CGMP regulations.  For example, most of the proposed
requirements for personnel, physical plants, and equipment and utensils
correspond to long-established, similar requirements in the umbrella
food CGMP regulations in part 110.  In other instances, the proposed
rule would require a particular action or result (such as establishing
specifications for components, in-process controls, manufactured dietary
supplements, and packaged and labeled dietary supplements under proposed
§ 111.35(e)), but gave firms the flexibility and the responsibility to
decide what those specifications will be.  We have included flexibility
where it is appropriate to do so, and, after we revised parts of the
rule in response to the comments, the final rule provides more
flexibility than the proposal.  For example, final § 111.75 sets forth
criteria for relying on a certificate of analysis to ensure that certain
specifications for components are met and for when you can test a subset
of finished batches for a select number of specifications; this differs
considerably from the proposal which would have required testing all
batches for all specifications. 

(Comment 64) One comment would revise proposed § 111.2 to read as
follows: 

These regulations recommend general minimum current good manufacturing
practices that, when modified by manufacturer product specifications,
will extend to the manufacture, package, or holding of dietary
ingredients or dietary supplements for that manufacturer.

(Response) We decline to revise the rule as suggested by the comment. 
Section 402(g) of the act states that “The Secretary may by regulation
prescribe good manufacturing practices for dietary supplements.”  If a
dietary supplement has been prepared, packaged, labeled, or held under
conditions that do not meet the final rule’s requirements, the dietary
supplement is deemed to be adulterated under section 402(g)(1) of the
act.  Here, the comment’s suggestion that dietary supplement CGMP
requirements could be “modified by manufacturer product
specifications” would create uncertainty over whether manufacturers
could unilaterally “modify” their product specifications to fit a
batch that failed to meet specifications or claim that a violation was
“cured” by a manufacturer’s new product specification.  In any
event, given that we decided to omit proposed § 111.2 altogether, the
change sought by the comment is moot.  

2. “Exclusions” (Proposed § 111.6)

As we stated earlier in this section, proposed § 111.6 would exclude
from the dietary supplement CGMP requirements persons who engage solely
in activities related to the harvesting, storage, or distribution of raw
agricultural commodities that would be incorporated into a dietary
supplement by other persons.  However, as we explained in our response
to comment 27[x] in this section, we decided that the exclusion was not
necessary, given the changes that we made to final § 111.1(a).  

	Nevertheless, we received several comments on proposed § 111.6, and we
address those comments here.

	(Comment 65) One comment would revise the rule to exclude or use
different requirements for small businesses.  The comment suggested we
categorize small businesses by employment levels or dollar sales and
adopt a tiered enforcement strategy similar that used in other
government programs, such as those under the Occupational Safety and
Health Act, the Americans with Disabilities Act, and the Family Leave
Act.  Another comment would exempt small businesses from the specific
requirements for testing if those businesses produce annual batch runs
of 25,000 capsules and tablets.

	(Response) We decline to exclude small businesses from the final rule
or to have different criteria for such businesses.  As we stated in our
response to comments 1,3 and 16 x, there is no reason to assume that
Congress meant to apply different or lesser CGMP requirements, or no
CGMP requirements at all, to dietary supplements made by small
businesses.  Dietary supplement CGMP requirements help to ensure the
quality of the dietary supplement and, among other things, that a
dietary supplement meets its specifications, that it contains the
ingredients specified in its master manufacturing record, and that it is
not contaminated.  Consumers should be able to expect that the dietary
supplements they purchase meet CGMP requirements regardless of the
manufacturer’s size.  However, to help businesses comply with dietary
supplement CGMPs, we are giving businesses with fewer than 500 employees
but 20 or more employees a compliance date of 24 months after the date
of publication of this final rule, and we are giving businesses with
fewer than 20 employees a compliance date of 36 months after the date of
publication of this final rule. 

	We carefully considered the size of a business when developing these
regulations.  The most common SBA size standard applicable to
manufacturers covered by this final rule is 500 employees.  Based on
comments and our knowledge of the dietary supplement industry, we know
that there are a number of dietary supplement manufacturers who fall
significantly below the standard of 500 employees.  To accommodate these
manufacturers, we have established different compliance dates as noted. 


	(Comment 66)  One comment would exempt “consolidators” (whom it
described as individuals who purchase raw agricultural commodities for
sale to raw ingredient manufacturers) from the rule.  Some comments
suggest expanding the exclusion pertaining to harvesting, storage, and
distribution of raw agricultural commodities to include other common and
basic raw botanical processing activities, such as drying, chopping,
cutting, size reduction, sifting, grinding, and storage.  One comment
would delete the word  “solely” to make the rule more flexible and
make it possible to exclude producers, who do not manufacture a distinct
product, from the CGMP rule.  Another comment expresses concern about
potential safety issues that can arise from the early stages of
manufacturing, such as the use of improper handling of agricultural
commodities and the risk of adulteration; the comment says businesses
involved in producing or distributing raw agricultural commodities
should be subject to some requirements under the rule.  A few comments
ask us to draft guidance documents to address activities such as
wildcrafting, plant identification, good agricultural practices, and
good hygienic practices for wildcrafters (persons who harvest plants
grown in the wild), and growers and brokers and specific service
providers (millers, extractors).  Some comments would exempt individual
wildcrafters because wildcrafters deal in relatively small amounts of
material at a time and sell their material to larger brokers who combine
materials from different pickers together.

	(Response) As explained in our responses to comments 29 and 30, [x],
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.  

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rvesting, 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. 

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

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

 Mandatory reporting to FDA of serious adverse events is now required as
a result of the enactment of the “Dietary Supplement and
Non-Prescription Drug Consumer Protection Act” (Pub. L. 109-462)
signed into law on December 22, 2006. (See discussion in section XX).

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

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

  It is also worth noting that standard references used in many
industries establish clear expectations for documentation and record
keeping practices for assuring quality control in manufacturing
operations. (Ref. 130);(Ref. 9).

 In discussing section 306 of the Bioterrorism Act (Maintenance and
Inspection of Records for Foods), Congress stated, “The managers did
not adopt a Senate proposal to authorize the Secretary to require the
maintenance and retention of other records for inspection relating to
food safety, because the Secretary has authority under section 701(a) of
the [act] to issue regulations for the ‘efficient enforcement of this
Act’ and this authority, in combination with other provisions (such as
section 402 [of the act]), gives the Secretary the authority to require
appropriate record keeping in food safety regulations.” (H.R. Conf.
Rep. No. 107-481, at 135 (2002), (Ref. 141))

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