Food Compliance Program Guidance Manual 7321.008 - Dietary Supplements on Foreign and Domestic Inspections, Sampling, and Imports

FOOD AND DRUG ADMINISTRATION

COMPLIANCE PROGRAM PROGRAM 7321.008

Date of Issuance: 09/18/2024 Cover Page — Page 1

CHAPTER 21 – FOOD COMPOSITION, STANDARDS, LABELING, AND ECONOMICS

SUBJECT:

DIETARY SUPPLEMENTS – FOREIGN AND DOMESTIC

INSPECTIONS, SAMPLING, AND IMPORTS

IMPLEMENTATION

DATE:

9/30/2024

DATA REPORTING

PRODUCT CODES

All Human Food Dietary Supplements

Class Code: Select appropriate code

Industry Code: 54

Subclass Code: B, C, and Y only

PIC Code: Select appropriate code

USE APPROPRIATE PRODUCT CODES

PRODUCT/ASSIGNMENT

CODES (PAC)

21008

21008F

21008D

21008W

21008P

21R829

REPORT PROGRAM ACTIVITIES UNDER THE

FOLLOWING PAC CODES:

all sample collection and analysis

all full scope inspections of dietary supplement

manufacturers under 21 CFR part 111

all inspections of dietary supplement facilities

responsible for introducing their own brand of finished

products into commerce under 21 CFR part 111

all inspections of dietary supplement warehouse

facilities under 21 CFR part 111

all inspections of dietary supplement

packaging/labeling facilities under 21 CFR part 111

all activities involving nutritional health fraud

PROGRAM 7321.008

Date of Issuance: 09/18/2024 Cover Page — Page 2

FIELD REPORTING REQUIREMENTS:

The Office of Regulatory Affairs (ORA) field division completes the Establishment Inspection

Report (EIR), including an inspection classification consistent with Field Management Directive

(FMD) 86 and FDA policies including this compliance program, within ORA established timeframes.

The ORA division files the inspection documents electronically no later than 30 working days from

the close of the inspection using the appropriate module (eNSpect, or Compliance Management

System (CMS)) accessible to both ORA and Center for Food Safety and Applied Nutrition (CFSAN).

ORA divisions should, as soon as practical, report significant inspection findings into eNSpect, as per

the Investigations Operations Manual (IOM). For inspections initially classified as Official Action

Indicated (OAI) due to failure to comply with Dietary Supplement Current Good Manufacturing

Practice (CGMP) regulation in 21 CFR part 111, submit the written classification analysis and

electronic documents to CFSAN’s Office of Compliance (OC), Division of Enforcement (DE) for

evaluation through CMS in accordance with Regulatory Procedures Manual (RPM) timeframes.

During an inspection, if you obtain information pertaining to inadequate notification of mandatory

reporting requirements (e.g., reporting of serious adverse events

, FDA notification of New Dietary

Ingredients

, FDA notification of structure/function claims

) report under separate headings in the EIR.

Report all operations, foreign, domestic and import, under the PAC(s) in this compliance program,

see Table 1-1.

Time spent reviewing import labels that does not result in a sample collection must be reported as an

import label examination (LEX) for labeling (LBL) using the appropriate PAC(s) from above.

The ORA divisions should use this revised compliance program for all sample collections and CGMP

inspections satisfying the statutory obligation for inspections of dietary supplement manufacturers.

For further information see Part V Regulatory/Administrative Strategy

Federal Food, Drug and Cosmetic Act (FD&C Act), § 761

FD&C Act, § 413

FD&C Act, § 403(r)(6)

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Date of Issuance: 09/18/2024 Cover Page — Page 3

PART I – BACKGROUND ............................................................................................................... 4

PART II - IMPLEMENTATION ....................................................................................................... 5

Objectives .................................................................................................................................... 5

Program Management Instructions .............................................................................................. 5

PART III - INSPECTIONAL ........................................................................................................... 11

Operations .................................................................................................................................. 11

A. Inspections (Domestic and Foreign) ........................................................................................... 11

B. Investigations .............................................................................................................................. 18

C. Domestic Field or Label Exams ................................................................................................. 19

D. Sample Collections (Domestic) .................................................................................................. 21

E. Sample Collections and Label Examinations (Import) .............................................................. 24

F. Import Activities ......................................................................................................................... 25

G. Shipping ...................................................................................................................................... 26

Reporting.................................................................................................................................... 27

PART IV - ANALYTICAL ............................................................................................................. 28

Analyzing Laboratories .............................................................................................................. 28

Analyses to be Conducted .......................................................................................................... 28

Methodology .............................................................................................................................. 28

Reporting.................................................................................................................................... 31

PART V - REGULATORY/ADMINISTRATIVE STRATEGY .................................................... 31

Findings...................................................................................................................................... 31

Actions ....................................................................................................................................... 32

Regulatory Follow-Up ............................................................................................................... 38

PART VI - REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS ......................... 40

References .................................................................................................................................. 40

Attachments ............................................................................................................................... 41

Program Contacts ....................................................................................................................... 42

PART VII - CENTER RESPONSIBILITIES .................................................................................. 43

ATTACHMENT A – EXEMPTIONS FROM NUTRITION LABELING ("SUPPLEMENT

FACTS" LABEL) ............................................................................................................................. 44

ATTACHMENT B – STANDARD LANGUAGE FOR WARNING LETTERS IN AREAS OF

EMPHASIS ...................................................................................................................................... 45

ATTACHMENT C – GUIDANCE ON EVIDENCE DEVELOPMENT AND

DOCUMENTATION TO SUPPORT REGULATORY ACTION .................................................. 54

ATTACHMENT D – CGMP REQUIREMENTS APPLICABLE TO OPERATIONS

PERFORMED BY FIRM ................................................................................................................. 55

ATTACHMENT E – PAC USAGE DECISION TREE .................................................................. 58

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART II — Page 4

PART I – BACKGROUND

In 1994, Congress passed the Dietary Supplement Health and Education Act (DSHEA). The term

“dietary supplement” is defined in section 201(ff) of the Federal Food, Drug, and Cosmetic Act

(FD&C Act) as a product (other than tobacco) that is labeled as dietary supplement, intended for

ingestion, and is intended to supplement the diet, that bears or contains one or more of the following

dietary ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary

substance for use by man to supplement the diet by increasing the total dietary intake; or a

concentrate, metabolite, constituent, extract or combination of any ingredient described above.

The dietary supplement market in the United States has grown significantly since the enactment of

DSHEA and is worth more than $40 billion in 2019, up from $4 billion in 1994. The number of

dietary supplement products on the market has exponentially increased from approximately 4,000

products on the market in 1994 to estimates ranging from 50,000 to more than 80,000 different

products on the market in 2019. These products are produced through a global supply chain that

includes more than 10,000 facilities.

The Current Good Manufacturing Practice (CGMP) in Manufacturing, Packaging, Labeling, or

Holding Operations for Dietary Supplements final rule was published on June 25, 2007. A primary

objective of FDA’s dietary supplement inspection program is to ensure that dietary supplement

products meet federal standards for quality and accurate labeling. Dietary supplements are subject to

certain requirements of The FDA Food Safety Modernization Act (FSMA) and applicable sections of

the Federal Food, Drug, and Cosmetic Act (FD&C Act), including section 761 (Serious Adverse

Event Reporting for Dietary Supplements).

This compliance program provides for sampling and surveillance inspection coverage of dietary

supplement manufacturing establishments subject to the requirements of CGMP as per 402(g) of the

FD&C Act, FSMA and implementing regulations. The focus of surveillance inspections is

compliance with CGMP to ensure that products are not adulterated or misbranded – including those

products making drug claims or that contain other misleading claims, products that contain new

dietary ingredients or unsafe food additives, and other risks. Increased surveillance of dietary

supplements in the areas of concern is warranted. Current sampling initiatives include sampling of

raw botanical ingredients and finished dietary supplements containing botanical ingredients that are at

risk for contamination with elevated levels of toxic elements, dietary supplements spiked with drug

ingredients not declared on their labels, and dietary supplements labeled as containing other unlawful

ingredients.

FDA will use information gathered from sample collections and surveillance inspections to, among

other things, adjust FDA’s regulatory program activities to protect and promote the public’s health.

The inspectional guidance in this program is structured to provide for efficient use of resources

devoted to routine surveillance coverage, with consideration of program priorities. It also provides

guidance for conducting for-cause inspections as appropriate.

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Date of Issuance: 09/18/2024 PART II — Page 5

PART II - IMPLEMENTATION

Objectives

The goal of this compliance program is to ensure that establishments consistently manufacture

dietary supplements of acceptable quality and minimize consumer’s exposure to adulterated

and/or misbranded dietary supplements. The objectives of this program are:

• To conduct inspections of domestic and foreign dietary supplement manufacturers subject

to 21 CFR part 111 within mandated FSMA inspection frequencies and enforcement

follow-up timeframes.

• To collect and analyze domestic and import samples to determine if they comply with the

requirements of the FD&C Act.

• To enforce dietary supplement regulations for products that do not comply with the FD&C

Act and verify implementation of corrective actions in follow-up inspections or

investigations.

• To collect information to determine if dietary supplements are being labeled in accordance

with applicable requirements.

• To collect compliance information for FDA to modify or develop enforcement strategies.

Program Management Instructions

A. Inspection Priorities

There are four different inspectional approaches based on FDA resource, priorities, and

dietary supplement establishment operations:

• Full Scope Manufacturing Inspection – will cover compliance with all applicable CGMP

requirements for firms that manufacture dietary supplements.

• Distributor Inspection – will cover compliance with the applicable CGMP requirements

for firms that are ultimately responsible for introducing or causing introduction of the

firm’s brand of finished dietary supplements into interstate commerce. Distributors are

the responsible party listed on product labeling and must ensure that finished product on

the market is not misbranded or adulterated.

• Warehouse Inspection – will cover compliance with the applicable CGMP requirements

for firms that hold, and possibly distribute dietary supplements, but do not perform

manufacturing, packaging, or labeling operations.

• Packaging/Labeling Inspection – will cover compliance with the applicable CGMP

requirements for firms that solely perform packaging and/or labeling operations.

CFSAN will provide a list of dietary supplement firms due for inspection during a fiscal year

inspectional cycle under FD&C Act section 421 (FSMA 201) to ORA divisions. This list will

identify the likely scope of inspection under dietary supplement CGMP for each facility (e.g.,

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART II — Page 6

full scope manufacturer, distributor, warehouse, package/label), when possible. The division

should change the scope of inspection based on the type of operations performed by the firm.

The following factors should guide prioritization of firms for full scope dietary supplement

inspections:

• Firms that are responsible for a Class 1 or Class 2 recall since the previous inspection.

• The firm’s previous inspection was classified “Official Action Indicated” (OAI).

• The firm has no FDA inspectional history.

• The firm is known to manufacture high-risk dietary supplements. See description of

high-risk dietary supplement below.

• Firms that are implicated in an event that may impact public health. The FDA may

obtain this information from a variety of sources, including, but not limited to, federal,

state, local, or tribal partners; foreign competent authorities; from the Adverse Event

Reporting; from consumer complaints, or from other intelligence information available

to CFSAN.

When possible, firms manufacturing high-risk dietary supplements should be given priority.

Firms with high-risk dietary supplements include, but are not limited to:

• Firms manufacturing botanical supplements: the botanical ingredients may contain

contaminants, such as toxic elements or microbial pathogens. Additionally, botanical

extracts can present challenges for identity and strength testing.

• Firms manufacturing dietary supplements that contain bovine ingredients: certain cattle

materials are prohibited from use in human food (21 CFR 189.5); ingredients with

bovine origin should be adequately processed to remove the prohibited material.

Additionally, bovine ingredient should originate from countries with designation granted

by the Agency.

• Firms manufacturing dietary supplements that contain potential new dietary ingredients:

new dietary ingredients without the necessary safety assessment could pose a public

health risk. FD&C Act 413(a) states that a dietary supplement which contains a new

dietary ingredient shall be deemed adulterated under section 402(f) unless it meets the

requirements found under 413(a)(1) or 413(a)(2).

• Firms manufacturing multiple dosage forms: e.g., powder, liquid, gummy, or softgel

dosage forms.

Product Selection During Inspection

Products should be selected for review using a risk-based approach including quality

indicators (recalls, complaints, adverse events, out-of-specification (OOS), etc.), target

populations (pediatric, pregnant, geriatric), sales volume, and manufacturing complexity.

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Priority should be given to dosage forms (capsules, tablets, liquids, powders, gummies, etc.)

not previously covered during an FDA inspection. If more than one product is selected for

coverage during the inspection, coverage of different dosage forms should be considered. It is

important that the products chosen fit the definitional requirements of a dietary supplement, as

defined in section 201(ff)(1), (2) and (3): contains at least one dietary ingredient, intended to

be ingested, and labeled as a dietary supplement. Since this label determination can be fact-

dependent and other critical factors may not be readily apparent, investigators are encouraged

to consult with Center representatives early in an inspection, if not before, to ensure selection

of appropriate product(s).

Selection of components to cover during the product reviews should consider the ingredients

identified in Information on Select Dietary Supplement Ingredients and Other Substances. If

the product selected for review uses different component types (botanical, vitamin, mineral,

animal derived, etc.), the components selected for review should include components of

different types.

B. Planning Instructions

(1) Inspections

Dietary supplement FY workplan will assign all firms as PAC 21008F, Full Scope

Inspections. Depending on the dietary supplement operations being performed the

appropriate dietary supplement PAC should be utilized by the Investigator conducting the

inspection.

(2) Sampling

Samples may be collected during inspections covered by this compliance program for both

for-cause and surveillance, and under routine surveillance sampling programs such as the

Sample Collection Operation Planning Effort (SCOPE).

If a facility is involved in ongoing compliance activities or the current inspection may be

classified as OAI, the division should consult with their Compliance Branch to determine

whether collection of samples for the surveillance purpose is appropriate.

(3) Resources and Reporting

Divisions should try to coordinate resources so that inspections conducted under this

program also meet inspection obligation for other programs. For example, if the dietary

supplement firm also manufactures conventional food, a conventional food CGMP

inspection or PCHF inspection may be performed at the same time. Please see Table 1 for

additional resource and reporting information.

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Date of Issuance: 09/18/2024 PART II — Page 8

Table 1 –Reporting PACs

Reporting PAC

Description

21008

Dietary Supplement Sample Collection and Analysis

(all examinations and sample collections)

21008F

Dietary Supplement Full Scope Inspections at

Manufacturers under 21 CFR 111

21008D

Dietary Supplement Inspections of Distributors under

21 CFR 111

21008W

Dietary Supplement Inspections of Warehouse

Facilities under 21 CFR 111

21008P

Dietary Supplement Inspections of sole

Packaging/Labeling Facilities under 21 CFR 111

21R829

All Activities involving Nutritional Health Fraud

Table 2 – Planning PACs

Planning PAC

Description

21008

Dietary Supplement Sample Collection and

Analysis

21008F

Dietary Supplement Full Scope Inspections at

Manufacturers under 21 CFR 111

Table 3 – Operation Codes

Operation Type

Operation Code

Inspection

11 (foreign) / 12 (domestic)

Investigation

15 (foreign) / 13 (domestic)

Remote Regulatory Assessment

19 (foreign) / 16 (domestic)

Sample Collection

33 (import) / 31 (domestic)

Sample Analysis

43 (import) / 41 (domestic)

Label/Document Review

52 (import) / 51 (domestic)

Field Exam

C. Interactions between Compliance Programs

If a facility is inspected under this program and the covered food product is subject to

additional regulations, compliance programs, or assignments outside the scope of this

compliance program, then additional inspection and reporting requirements should be covered

per the respective interacting programs.

This compliance program may have some interactions with the following CPGMs. Use the

appropriate PAC when reporting sample collections under this compliance program:

• Domestic Acidified and Low-Acid Canned Foods, 7303.803A

• Domestic and Import Food Additives and Color Additives, 7309.006

• Foreign Supplier Verification Programs Inspections, 7303.878

• Juice HACCP Inspection Program, 7303.847

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• Medical Foods – Import and Domestic, 7321.002

• Mycotoxins in Domestic and Imported Foods, 7307.001

• Pesticides and Industrial Chemicals in Domestic and Imported Foods, 7304.004

• Preventive Controls and Sanitary Human Food Operations 7303.040

• Seafood Processor, Products, and Importer Inspection Program, 7303.842

• Toxic Elements in Food & Foodware and Radionuclides in Food – Import and

Domestic, 7304.019

• Sanitary Transportation Inspections (currently an assignment)

D. Food Defense Measures and Food Facility Registration

Field inspection staff should confirm that each facility inspected under this program has a

current food facility registration per the Public Health Security and Bioterrorism Preparedness

and Response Act of 2002 (the Bioterrorism Act) and Section 415 of the FD&C Act. If

registration information obtained during the inspection (foreign and domestic) is different

from the information in the Food Facility Registration Module (FFRM), send an email to

[email protected] in accordance with IOM subchapter 5.4.1.5.2

‘Food Facility Registration Resources’.

E. Interaction with Other Federal Agencies, State and Local Counterparts, and Foreign

Authorities

(1) Federal Agencies

Follow IOM subchapter 3.1.3.2 ‘Discussion with Federal Inspector’ when federal officials

from other agencies are present during FDA inspections or investigations. See IOM

subchapter 3.2 ‘Federal Agency Interaction’ for a list of Memorandums of Understanding

(MOU) between the FDA and other Federal agencies that may be applicable to inspections

conducted under this program 225-10-0010 and 225-19-032. A complete list of MOUs may

be found here.

(2) State and Local Counterparts

Divisions will collaborate with commissioned State agencies to make them aware of the

requirements of this program and deadlines for deliverables. Divisions will offer State

agencies opportunities to accompany FDA on inspections or assist as necessary and when

possible.

(3) Foreign Authorities

Follow ORA/DFHAFO procedures when foreign competent authorities are present during

FDA foreign inspections or investigations.

F. When to Contact Other Offices within the FDA

For technical assistance regarding dietary supplements, please contact

[email protected]. If the question(s) is related to an ongoing inspection or

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investigation, please include “ONGOING EI” as the prefix in the subject line in addition to

the firm name and FEI if possible. If the question(s) is related to a product covered by

additional commodity-specific regulations (e.g., acidified, seafood, juice) include appropriate

SMEs and ORA National Experts on the email to [email protected].

Dietary supplements are exempt from the preventive control requirements in Subparts C & G

of 21 CFR part 117, so most questions regarding dietary supplements would be directed to the

dietary supplement email address dsTAN[email protected]. You may also copy SMEs

on the rTAN list. However, there are circumstances when it is appropriate to send questions

that may be related to dietary supplements to the PCHF regulator technical assistance network

(rTAN), which can be reached at [email protected]. These circumstances

include:

• Field inspection staff are not sure if a product is a conventional food covered under 21

CFR 117 or a dietary supplement covered under 21 CFR 111.

• Field inspection staff are inspecting/preparing to inspect a dietary ingredient facility

which would be covered under 21 CFR 117.

• Field inspection staff are not sure if a product is a dietary ingredient manufacturer

covered under 21 CFR 117 or a dietary supplement manufacturer covered under 21

CFR 111.

If an inspection is in-progress and an answer is required as soon as possible, field inspection

staff should indicate that in the e-mail subject heading. While the rTAN e-mail inbox is the

preferred method of communication for ongoing inspections, FDA field inspection staff may

also contact the designated SMEs from the rTAN to request that they operate in a reasonable

“on call” capacity during an inspection window. This will ensure that SMEs are available to

answer questions or respond to concerns during an inspection. If field inspection staff want to

reach out to several SMEs, please send one email and include everyone on it to minimize

duplication of effort and to ensure consistency of guidance.

A list of rTAN commodity-specific SMEs, ORA National Expert SMEs, and lead program

contacts (rTAN list) can be found in the resource library or open-access DS SharePoint site.

G. Resource Instructions

• Resources for sample collections, analyses, import field/label exams, and emerging

issues for dietary supplements are provided in the ORA Field Workplan.

• Resources will be allocated through a prioritization process.

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART III — Page 11

PART III - INSPECTIONAL

Operations

Inspections conducted under this compliance program should evaluate the establishment’s

adherence to the Dietary Supplement CGMP, other applicable regulatory requirements, and the

FD&C Act generally.

Information on how to respond to the FDA 483 Inspectional Observations should be provided to

the facility’s management. For foreign inspections, firm’s responses to FDA 483 should be

sent to FDA483responsein[email protected]. Field inspection staff must inform the firm

that the adequacy of their response to the FDA 483 may impact FDA’s determination of the need

for follow-up action. FDA expects the firm to respond to the FDA 483 within 15 business days of

the end date of the inspection.

During inspections at U.S. facilities that are also importers, the Foreign Supplier Verification

Programs: What Do Manufacturers/Processors Covered by the PC Supply-Chain Program Need

to know about FSVP? document should be provided to firm management.

A. Inspections (Domestic and Foreign)

The appropriate PAC should be used based on the firm’s operations and the inspectional

approach(es) utilized during a dietary supplement inspection. The only dietary supplement

PAC that can be used in combination with other dietary supplement PACs during an

inspection is Distributor Inspection PAC 21008D. The ‘Required Elements’ should be

documented for each dietary supplement PAC that is utilized during an inspection. Please

reference Attachment E – PAC Usage Decision Tree for an infographic on determining which

PAC should be used during an inspection.

Manufacturing Inspections

Manufacturing inspections will be conducted at firms that conduct some or all of the

manufacturing steps for a dietary supplement, and will cover compliance with all CGMP

requirements, Full Scope Manufacturing Inspections.

Full Scope manufacturing inspection coverage includes all required elements listed below, see

Attachment D for additional details as to what the elements include, and any other CGMP

requirements applicable to the operations the firm performs. At least two finished dietary

supplement products must be covered during the product review. Cover additional products if

significant deficiencies are found during the product review. Collection of finished product

labels, in their original state (this does not include label proofs, or label specifications), should

be collected for every product covered during the inspection. If the original label is not

available at the manufacturer, reasonable measures should be taken to collect evidence of how

the finished product will be labeled in its final form.

PROGRAM 7321.008

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Determine if distributor operations are occurring at this site. If so, then the distributor PAC

21008D will be used in addition to PAC 21008F and document the Distributor inspection

required elements. Evidence for 483 items should include the pervasiveness of an issue if it

can be documented.

Required Elements

1. Online Labeling Review: Evaluate the firm’s website, social media, and any other online

presence for the use of disease claims which would make the products unapproved new drugs,

potential misbranded labeling, ingredients of concern identified in the Select Dietary

Supplement Ingredient Directory, Active Pharmaceutical Ingredients (APIs), and New Dietary

Ingredients (NDIs). Capture screenshots with the website and date/time clearly visible on the

image which will be included as attachments in the EIR.

Disease Claim References – 21 CFR 101.93(g)(2)(i) – (x)

Misbranding –21 CR 101.36(a) – (j), and 21 CFR 101.9

Allergen Cross Contamination/Declaration/Warning Statements: Sections 201(qq) and

403(w) of the FD&C Act; 21 CFR part 117 subpart B; Guidance for Industry; Compliance

Policy Guide 555.250

Iron Warning Statement: 101.17(e) – Solid Oral Dosage Form

Active Pharmaceutical Ingredients - Dietary Supplement Ingredient Directory, Orange

Book

New Dietary Ingredients - NDI Database

Adverse Event Reporting Requirements- Guidance for Industry

Structure Function Claims- 21 CFR 101.93(b) – (f), Structure/Function Claims

• Structure Function Claim Disclaimer – 21 CFR 101.93(b)

2. On-Site Label Review: Evaluate at least 3 product labels (this may or may not include

products that were reviewed as part of the online labeling review). This review will cover

nutrition labeling, adverse event reporting requirements, structure function and disease claims,

the inclusion of a structure function disclaimer, allergen labeling, and other applicable

labeling requirements. This information along with the online labeling review must be

captured and documented in the EIR, specifically in the Labeling Observation Table.

3. Requirements of Quality Control: Review written procedures for the responsibilities of

quality control and ensure quality control personnel conduct required activities. Such

activities may include, but are not limited to, review of written procedures, specifications,

testing, and processes; conducting material reviews and making disposition decisions as

necessary; review and approval of calibration; releasing components, packaging, and labeling

from quarantine; approving or rejecting any treatment or in-process adjustment; reviewing and

approving all master manufacturing records, and batch production records; reviewing and

approving any reprocessing, repackaging or relabeling; and reviewing and approving all

return and complaint operations.

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4. Quality Indicators: Review recall operations performed by the firm; complaint

investigations, including adverse events; laboratory out-of-specification (OOS) investigations;

deviation investigations initiated after an unanticipated occurrence, or a deviation from the

master manufacturing record; and returned product investigations.

5. Facility and Equipment: Conduct a walkthrough inspection of areas where components and

finished dietary supplements are exposed to the environment and evaluate the sanitation and

maintenance of the facility and equipment. Evaluate the potential for contamination, allergen

cross-contact, and pests. Determine the adequacy of employee hygiene. Review written

procedures for holding and distribution and related records.

6. Product Review

a. Master Manufacturing Record – Review the master manufacturing record and determine

whether it contains required information and identifies appropriate specifications for the

points, steps, or stages in the manufacturing process where control is necessary to ensure

the quality of the dietary supplement.

b. Batch Production Record – Review executed batch records and determine whether it

contains required information and documents specifications for the points, steps, or

stages in the manufacturing process where control is necessary to ensure the quality of

the dietary supplement are met.

c. Dietary Ingredients and Components – Review all dietary ingredient specifications and

testing/examination methods and results (dietary ingredients are raw materials listed

inside the dietary Supplement Facts label) for the finished products followed during the

inspection. If the finished product contains a large number of ingredients, such as in a

multivitamin, a minimum of seven ingredient specifications should be covered based on

the ingredient risk potential. When possible, vary ingredients selected to cover

mineral/vitamin, botanical/enzyme, and protein/(probiotic/prebiotic). Review at least

three component specifications and testing/examination methods and results (components

are materials listed in the “Other Ingredients” section of the label such as excipients) for

the finished products followed during the inspection. Ensure appropriate scientifically

valid specifications have been established and appropriate scientifically valid

testing/examination methods have been performed to ensure specifications are met.

Determine whether methods used to verify specifications are also appropriate and

scientifically valid.

d. Packaging and Labeling – Review at least two specifications for packaging components

and/or label specifications and associated testing/examination methods performed on

these materials.

e. Finished Dietary Supplement – Ensure appropriate finished dietary supplement

specifications have been established. Review testing/examination data or documentation

showing finished dietary supplement specifications are met. Determine whether methods

used to verify specifications are appropriate and scientifically valid.

Distributor Inspections

PROGRAM 7321.008

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Distributor inspections should be conducted at firms that contract out some, or all, of their

manufacturing, but are ultimately responsible for introducing or causing introduction of the

firm’s brand of finished dietary supplements into interstate commerce. This includes firms

that may choose to warehouse products or at firms that do not hold or physically distribute

products. Distributors are the responsible party listed on product labeling in accordance with

21 CFR 101.5(a)-(e) and must ensure that finished product on the market is not misbranded or

adulterated. If possible, at least three finished dietary supplement products should be included

in the product review; if three finished products are not available, review the number of

finished products available. Collection of finished product labels, in their original state (this

does not include label proofs, or label specifications), should be collected for every product

covered during the inspection. All required elements applicable to the distributor’s operations

should be covered.

If the distributor is warehousing and distributing products, then PAC 21008W will be used in

addition to PAC 21008D. If the distributor does not warehouse or physically distribute

products from a location such as an office, then PAC 21008D will be the only PAC used. If

the distributor is conducting manufacturing activities such as blending and encapsulating, then

PAC 21008F will be used in conjunction with PAC 21008D. If the distributor is conducting

packaging and/or labeling operations, then PAC 21008P will be used in addition to PAC

21008D. Refer to the required elements for each applicable inspection type pertinent to the

firm’s operations.

Required Elements

1. Online Labeling Review: Evaluate the firm’s website, social media, and any other online

presence for the use of disease claims which would make the products unapproved new drugs,

potential misbranded labeling, ingredients of concern identified in the Select Dietary

Supplement Ingredient Directory, Active Pharmaceutical Ingredients (APIs), and New Dietary

Ingredients (NDIs). Capture screenshots with the website and date/time clearly visible on the

image which will be included as attachments in the EIR.

Disease Claim References – 21 CFR 101.93(g)(2)(i) – (x)

Misbranding –21 CR 101.36(a) – (j), and 21 CFR 101.9

Allergen Declaration/Warning Statements: Sections 201(qq) and 403(w) of the FD&C Act;

Guidance for Industry

Iron Warning Statement: 101.17(e) – Solid Oral Dosage Form

Active Pharmaceutical Ingredients - Dietary Supplement Ingredient Directory, Orange

Book

New Dietary Ingredients - NDI Database

Adverse Event Reporting Requirements- Guidance for Industry

Structure Function Claims- 21 CFR 101.93(b) – (f), Structure/Function Claims

• Structure Function Claim Disclaimer – 21 CFR 101.93(b)

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART III — Page 15

2. On-Site Label Review: Evaluate at least 3 product labels (this may or may not include

products that were reviewed as part of the online labeling review). This review will cover

nutrition labeling, adverse event reporting requirements, structure function and disease claims,

the inclusion of a structure function disclaimer, allergen labeling, and other applicable

labeling requirements. This information along with the online labeling review must be

captured and documented in the EIR, specifically in the Labeling Observation Table.

3. Responsibility: Identify/confirm who is the most responsible individual at the firm, who

controls the website and label content, who created and controls the formulation(s), who are

the firm’s contract manufacturer(s) - including the name, address, FEI’s, and any related

quality agreements. This information must be collected for products associated with the online

labeling review and the on-site label review. Document who is responsible for holding reserve

samples.

4. Complaints and Returns: Determine how the firm reviews product complaints and review

any written procedures for handling complaints, adverse events, and product returns. Review

the investigations performed by quality control for complaints received along with any related

disposition decisions. Review the firm’s complaint log, along with complaints received by

FDA, to ensure that all requirements of Subpart O are being followed. Determine if serious

adverse events were reported to FDA. Document how the firm handles product returns,

including salvaging, reprocessing, or treating returned products, to ensure that all

requirements of Subpart N are being followed.

Warehouse Inspections

Warehouse inspections will be conducted at all firms that hold and/or fulfill dietary

supplements, but do not perform manufacturing, packaging, or labeling. These firms may

distribute their own brand of dietary supplement products, as well as dietary supplement

products owned by someone else. All required elements applicable to the operations must be

covered. If a distributor is also warehousing, then PAC 21008D will be used in addition to

PAC 21008W and document the Distributor inspection required elements.

Required Elements

1. Physical Plant and Grounds: Conduct a walkthrough inspection of areas where finished

dietary supplements are held. Evaluate the sanitation, maintenance, and pest control of the

facility. Verify written sanitation procedures were established.

2. Holding: Verify written procedures are established and followed to ensure dietary

supplements are held to prevent the mix-up, contamination, or deterioration of dietary

supplements, including holding under appropriate conditions of temperature, humidity, and

light.

3. Distribution: Ensure dietary supplements are distributed under conditions that will protect the

dietary supplements against contamination and deterioration. Verify distribution records are

kept.

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4. Returns: Ensure returned product is identified and quarantined until quality control personnel

conduct a material review and make a disposition decision according to established written

procedures.

Packaging and Labeling Inspections

Packaging and Labeling inspections will be conducted at firms that solely conduct packaging,

labeling, re-packaging, and/or relabeling operations. A Manufacturing inspection must be

conducted for firm’s that conduct any other manufacturing steps (such as blending, tableting,

encapsulating) for a dietary supplement and will utilize PAC 21008F. At least two finished

dietary supplement products must be covered during the product review. Cover additional

products if significant deficiencies are found during the product review. Collection of finished

product labels, in their original state (this does not include label proofs, or label

specifications), should be collected for every product covered during the inspection.

Determine if distributor operations occur at this site. If so, then the distributor PAC 21008D

will be used in addition to PAC 21008P and document the Distributor inspection required

elements. Evidence for 483 items should include the pervasiveness of an issue if it can be

documented.

Required Elements

1. Requirements of Quality Control: Review written procedures for the responsibilities of

quality control and ensure quality control personnel conduct required activities. Such

activities may include, review of written procedures, specifications, testing, and processes;

conducting material reviews and making disposition decisions as necessary; review and

approval of calibration; releasing bulk supplement products, packaging, and labeling from

quarantine; approving or rejecting any treatment or in-process adjustment; reviewing and

approving all master manufacturing records, and batch production records; reviewing and

approving any reprocessing, repackaging or relabeling; and reviewing and approving all

return and complaint operations.

2. Quality Indicators: Review recall operations performed by the firm; complaint

investigations, including adverse events; laboratory out-of-specification (OOS) investigations;

deviation investigations initiated after an unanticipated occurrence, or a deviation from the

master manufacturing record; and returned product investigations.

3. Facility and Equipment: Conduct a walkthrough inspection of areas where bulk materials

and finished dietary supplements are exposed to the environment and evaluate the sanitation

and maintenance of the facility and equipment. Evaluate the potential for contamination,

allergen cross-contact, and pests. Determine the adequacy of employee hygiene. Review

written procedures for holding and distribution and related records.

4. Product Review

a. Master Manufacturing Record – Review the master manufacturing record and

determine whether it contains required information and identifies appropriate

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specifications for the points, steps, or stages in the manufacturing process where

control is necessary to ensure the quality of the dietary supplement.

b. Batch Production Record – Review the executed batch record and determine whether

it contains required information and documents specifications for the points, steps, or

stages in the manufacturing process where control is necessary to ensure the quality of

the dietary supplement are met.

c. Bulk Dietary Supplements – Review bulk supplement specifications and

testing/examination methods and results which must provide sufficient assurance that

the product received is adequately identified and is consistent with the purchase order.

Ensure appropriate scientifically valid specifications have been established and

appropriate scientifically valid testing and/or examination methods have been

performed to ensure specifications are met.

d. Packaging and Labeling – Review at least two specifications for packaging

components and/or label specifications and associated testing/examination methods

performed on these materials.

Adverse Event Reporting

CFSAN Adverse Event Reporting System (CAERS) is a database that contains information on

adverse event reports submitted to FDA. Verify that the firm has a record keeping system in

place for maintaining records of adverse event reports. Determine if the firm has a process in

place to report serious adverse events, if the firm has submitted any reports to the FDA since

the last inspection, and if any serious adverse event reports exist but were not submitted.

Review the labels for up to five different dietary supplement products manufactured,

packed, or distributed by the firm being inspected, to assure that the labels bear a domestic

address or domestic phone number, (i.e. either a complete address within the US to include

firm name, street address (or P.O. Box), city, state and zip code or complete telephone

number to include the area code) through which the person responsible for submitting

reports of serious adverse events to the Agency can receive the reports. Labels lacking the

information described above are misbranded; divisions should follow procedures noted in

Part V.

Edible Ruminant Products from BSE Affected or At-Risk Countries

Bovine-derived ingredients cannot be used in dietary supplements if they adulterate the

product under any provision of Section 402 of the Act. If an investigator encounters any one

of the conditions below related to use of a bovine-derived ingredient, the following evidence

must be collected and forwarded to CFSAN for further regulatory consideration.

1) A bovine-derived ingredient is a prohibited cattle material under 21 CFR 189.5(a) if it

is a specified risk material that has not been inspected and passed for human

consumption by a competent authority or is otherwise a prohibited material under 21

CFR 189.5(a). Affirmative evidence of the use of prohibited cattle material must be

PROGRAM 7321.008

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collected.

2) If the firm is using bovine-derived ingredients, they must have records to show that the

food is not manufactured from, processed with, or does not otherwise contain

prohibited cattle materials (21 CFR 189.5(c)). Documentation of the lack of these

records must be collected.

Dietary Supplements Containing Ephedrine Alkaloids

1) If the product label states that it contains “ephedra” or other botanical ephedrine

alkaloid sources, attempt to determine from the firm whether they have evidence that

it does not contain ephedrine alkaloids. Determine whether the firm relies on

certificates of authenticity or other assurances from suppliers that the ephedra species

used does not contain naturally occurring ephedrine alkaloids or has laboratory

evidence that the product does not contain ephedrine alkaloids.

2) If a product claims to contain ephedrine alkaloids or contains “ephedra” and the firm

does not appear to have evidence that it does not contain ephedrine alkaloids, the

inspection should specifically cover the following items:

• Collection of interstate documentation of the products shipped from the

manufacturer or supplier to the firm (this information should be tied into an

affidavit).

• From whom does the firm obtain products?

• Where does the firm warehouse their products?

• What volume of product do they buy and sell?

• Do they sell to consumers only or also to other distributors?

• Is the product being offered for sale through sponsored websites?

• Collect all labeling, ads, and promotional material currently used.

3) If the firm does not manufacture the products, the division should attempt to get

information from the firm about their supplier. If the suppliers are not located in the

same division, the division should issue an assignment to the home division of the

supplier for follow-up.

4) If the investigator can document that the product is being offered for sale, proceed

with the collection of an official sample as instructed below under Part III(1)(D)(1),

Area of Emphasis #5 (Ephedrine Alkaloid Analysis).

B. Investigations

Domestic or foreign investigations (OP 13 or OP 15, respectively) may be performed at

facilities covered by this program. See IOM subchapter 8.1.9 General Investigation Reporting

for guidance covering how to conduct and report an investigation.

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If a domestic or foreign facility assigned for inspection is no longer operational, does not

manufacture products that fall under FDA jurisdiction, or cannot be inspected for any other

reason, an investigation may be created by utilizing the washout conversion function in

eNSpect. Administrative information should be updated in Firm Management Services (FMS)

as appropriate.

C. Domestic Field or Label Exams

Products shipped in bulk form, not distributed to consumers in such form, and used in the

manufacture of other dietary supplements or that are to be processed, labeled, or repacked

at a site other than where originally processed or packed are exempt from the

requirements for nutrition labeling ("Supplement Facts" label) (21 CFR 101.36(h)(3)).

However, they must contain other mandatory elements of the food label, specifically, the

products’ common or usual name, the name and place of business of the manufacturer or

other responsible firm, a list of ingredients, and the net contents.

Investigators must review the list of firms that have filed for a small business nutrition

labeling exemption prior to conducting inspections to determine whether the firm has been

issued an exemption from CFSAN. Investigators must verify the firm's status with firm

management after issuing the FDA 482, but prior to conducting any field exams. Do not

conduct field exams in firms that are exempt from compliance.

NOTE: In accordance with 21 CFR 101.9(j)(1)(i), a nutrient content claim, a health

claim, or any other statement about the nutrient content or benefits of the product

(other than ingredient statements) on a dietary supplement label negates the exempt

status of the product and triggers the requirement for nutrition labeling (“Supplement

Facts” label).

Specific questions about the exempt status of a domestic firm, importer, or broker should be

directed to CFSAN/ODSP ([email protected]), and industry web-based submission link:

https://www.cfsanappsexternal.fda.gov/scripts/NLE/client/login.cfm.

Review the label of 2-3 products focusing on the following Areas of Emphasis. Refer to the

references provided in Part VI of this program for additional information to assist

during reviewing labels under each Area of Emphasis.

Areas of Emphasis

1) Products or ingredients promoted in the products that claim to diagnose, mitigate,

treat, cure, or prevent disease. (Sections 301(d), 505(a) and 502(f)(1) of the FD&C

Act).

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Note: The Agency will, on a case-by-case basis, consider enforcement

actions against products that bear disease claims. Investigators should

review claims made for dietary supplements on labels or in labeling,

including the firm’s website and social media accounts. Products that bear

disease claims or that appear to bear unauthorized health claims (e.g., health

claims are authorized by regulation and are about reduction in risk of a

disease or health condition and involves a food or food component) that do

not meet the requirement should be referred to CFSAN for evaluation.

2) Products that contain a new dietary ingredient (NDI) without the required NDI

notification submission (Section 413 of the FD&C Act), and products that contain

ingredients listed on the Dietary Supplement Ingredient Directory.

3) Products that bear authorized health claims or nutrient content claims that do not

qualify for making the claims. For example, for the approved calcium and

osteoporosis, and calcium, vitamin D, and osteoporosis claims, phosphorus content

cannot exceed calcium content (refer to FDA Food Labeling Guide, Appendix C -

Health Claims).

4) Products suspected of containing prohibited cattle (bovine) materials, including failure

to maintain adequate records by firms that manufacture or process dietary supplement

containing cattle derived material to support the materials are free from bovine

spongiform encephalopathy (BSE).

5) Products that are labeled to contain or declare a source of ephedrine alkaloids.

6) Products that are marketed as dietary supplements but fail to bear a statement of

identity on the principal display panel (dietary supplement, herbal supplement, etc.), or

nutrition label, i.e., the absence of "Supplement Facts" on the label and the product is

not covered by an exemption. (see above list for exempt domestic firms and

importers).

7) Products that fail to disclose a major food allergen as required.

8) Products that declare “Siberian ginseng” (Section 403u of the FD&C Act).

The term "ginseng" may only be considered to be a common or usual name (or part

thereof) for any herb or herbal ingredient derived from a plant classified within the

genus Panax, and only labeling or advertising for herbs or herbal ingredients classified

within that genus may include the term "ginseng."

9) Products that fail to bear other mandatory label information (e.g., ingredient statement,

domestic address or phone number for serious adverse event reporting, name and place

of business of the manufacturer, packer, or distributor, net quantity of contents).

10) Products that fail to bear nutrition ("Supplement Facts" label) labeling or with

significant format deviations (21 CFR 101.36).

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11) Products in solid dosage form with added iron or iron salts that are claimed in the

supplement facts label but fail to bear the required warning statement (21 CFR

101.17(e)(1)).

D. Sample Collections (Domestic)

Compliance (for-cause) and surveillance samples may be collected during inspections covered

by this compliance program. These samples may be covered under interacting compliance

programs listed in Part II(2)(C) of this program, under routine surveillance sampling programs

such as the Sample Collection Operation Planning Effort (SCOPE), under CFSAN or ORA

active assignments, or as directed for compliance purposes.

When requesting CFSAN reviews for compliance cases of bulk ingredients to be used in the

manufacturing of a dietary supplement, the labels would need to include the finished product

information including serving size, frequency, direction of use, intake, etc… CFSAN/Office of

Analytics and Outreach (OAO) and Office of Food Safety (OFS) requires this information to

perform a reliable health hazard assessment and policy determination for contamination

exposure.

Documentary samples will generally consist of the label and any labeling that is available with

the product at time of purchase; this may include labeling and marking information available

on the product page for the website where the product is sold. No physical sample is required.

When the configuration of the container makes it difficult to determine the total amount of

label space available to bear labeling it will be necessary to collect the actual container along

with the label. If the firm operates a website for dietary supplement product(s), Divisions

should review the product website page for any labeling information available.

1) Compliance Samples

Areas of Emphasis Nos. 1, 2, 6-11

a) The sample will consist of an original label, or quality photograph (and one product

container, if warranted) for the product being sampled and associated labeling,

including the firm’s website where products are promoted with disease claims and

offered for sale. This is a documentary sample only; no physical sample is required.

Prepare a Collection Report (C/R) for each product label collected and mark as

"Documentary" in the Sample Type field.

b) For samples collected for undeclared allergens sample collection must include

documentation of allergenic raw material and evidence that the allergen is undeclared,

e.g., raw material label, formulation of final product, manufacturing and batching

records and final product label.

c) Indicate "Compliance" in the Basis field of the C/R. Under Reason for Collection

indicate "Label Review Only."

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d) Send the sample to your compliance branch for label review, sample classification,

and regulatory consideration.

Area of Emphasis No. 3 (Nutrient Analysis)

In order to make authorized health claims or nutrient content claims, products must meet

certain nutritional requirements. Refer to 21 CFR 101 Subparts C-F for specific

requirements for nutrient content claims and health claims.

Investigators should also refer to FDA’s website for both authorized health claims and

nutrient content claims (relative or comparative claims) to determine if the amount of the

nutrient listed on the nutrition label qualifies the product to make the claim. If analysis is

necessary to verify the level of the nutrient, a physical sample must be collected.

a) The sample will consist of 24 consumer size retail packages, 2 packages from each of

12 randomly selected shipping cases or 10% of the number of packages in the same

inspection lot (collected in duplicate), whichever is smaller. Do not commingle lots.

Note: This sample size includes the 702(b) portion. Number the

subsamples as 1a, 1b, 2a, 2b, etc., to separate the units for analysis from

units that comprise the 702(b) portion.

b) Prepare a Collection Report (C/R) for each sample collected and mark as "Official" in

the Sample Type field.

c) Indicate "Compliance" in the Basis field of the C/R. Under Reason for Collection

indicate "For <insert Nutrient(s) forming the basis for the claim> analysis."

Area of Emphasis No. 4

FDA regulations prohibit the use of certain cattle materials in food, including dietary

supplements (see 21 CFR 189.5 and Part I, Background of this program for further

information). FDA regulations at 21 CFR 189.5(c), include record keeping that

demonstrates that products are not made with prohibited cattle materials. Records must be

maintained for 2 years and FDA must be allowed to inspect and copy them.

a) The EIR and supporting documents will be reviewed by CFSAN/OC/DE, a

determination will be made on a case-by-case basis whether additional regulatory

follow-up is necessary.

Area of Emphasis No. 5 (Ephedrine Alkaloid Analysis)

Products suspected of containing ephedrine alkaloids must have a physical sample sent to

the lab for confirmation of the presence of ephedrine alkaloids, as an Official Sample.

a) For products that potentially contain a source of ephedrine alkaloids, each sample size

shall consist of three retail units of each product.

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b) Collect a maximum of 5 samples, each sample consisting of a unique lot number.

c) Include information on the size of each lot sampled on the collection report.

d) If the product is manufactured or warehoused at another location, this must be

indicated on the collection report.

2) Surveillance Samples

Sampling should be coordinated to be collected onsite during inspections. Retail

samples should only be collected when inspections do not generate sufficient samples to

meet division workplan obligations. See IOM chapter 4 – ‘Sampling’ for guidance

covering how to collect and report a sample.

Nutrient Analysis

For nutrient analysis, collect 3 units (each unit must contain a minimum of 12 servings) of

the product. For example, 3-2 lb. tins; 3-100 tablet bottles; 3-30 capsule packets; 3-12 bar

packages. Contact Nutrient Analysis Branch at The Atlanta Human and Animal Food

Laboratory (ATLHAF) if necessary and if there are any additional questions on sample

size.

Further, investigators should consider the following information for the collection of

samples for nutrient analysis:

a) Collect for nutrient analysis only those vitamin, mineral, and protein supplements or

combination vitamin/mineral supplements that have at least one nutrient declared on

the label at or above 25% of the Reference Daily Intake (RDI) or Daily Reference

Value (DRV).

Note: For each nutrient declared at or above 25% of RDI, include on the collection

report a statement for each nutrient whether the nutrient is naturally occurring or

added. This information is necessary to support the appropriate charge should

analysis indicate a nutrient deficiency.

b) If inspections do not generate sufficient samples to meet division workplan obligations

domestic and domestic-import surveillance samples may be collected at the retail

level. Attempt to sample products that have been manufactured within the

collecting division so that follow-up compliance sampling with interstate

documentation may be conducted, if necessary. However, if it isn’t possible to

generate samples in this manner, select any appropriate product in line with the

collection guidance below.

c) In selecting samples for collection, consider factors which might result in lower

nutrient quality, such as age of product (sample oldest lot), liquid products (moisture

and pH can degrade vitamins), and effect of light on some nutrients (sample product in

transparent packages when appropriate).

d) Do not sample products that are expired or are within six months of their expiration

dates. This will allow sufficient time for analysis and regulatory consideration if the

sample is found violative.

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e) Do not collect dietary supplements of herbals, botanicals, or animal extracts, etc. for

nutrient analysis unless the product also contains a protein, vitamin, or mineral with a

label declaration of at least 25% of the RDI or DRV. Refer to 21 CFR 101.9 for a list

of nutrients and their established RDI or DRV levels.

f) Each sample must represent a single manufacturing lot code. Do not commingle lots

within a sample.

Microbiological Analysis by USP methods

Collect a sample for microbiological analysis if the product is suspected of having

microbial contamination (such as Salmonella species, Escherichia coli, Staphylococcus

aureus, Clostridium species, or yeast and mold). The following methods could be used for

the microbiological analysis of the collected samples.

a) 〈2021〉 MICROBIAL ENUMERATION TESTS—NUTRITIONAL AND DIETARY

SUPPLEMENTS.

b) 〈2022〉 MICROBIOLOGICAL PROCEDURES FOR ABSENCE OF SPECIFIED

MICROORGANISMS—NUTRITIONAL AND DIETARY SUPPLEMENTS.

c) 〈2023〉 MICROBIOLOGICAL ATTRIBUTES OF NONSTERILE NUTRITIONAL

AND DIETARY SUPPLEMENTS.

d) Per sample, collect 11 subsamples containing approximately 150 grams/sub-sample.

Each sample must represent a single manufacturing lot code.

e) Analytical lab will be directed by ORS/OFFLO Program Manager.

E. Sample Collections and Label Examinations (Import)

For products in import status, a sample collection is normally not indicated and referral of the

information/documentation to the import field division Compliance Branch (CB) through a

labeling examination, including the product label, for articles which appear to be violative. A

product label or acceptable copy of a full product label including all sides of the product

packaging must be collected for CFSAN to complete a full evaluation of a dietary

supplement’s label.

When requesting CFSAN reviews for compliance cases of bulk ingredients to be used in the

manufacturing of a dietary supplement, the labels would need to include the finished product

information including serving size, frequency, direction of use, intake, etc… CFSAN/Office of

Analytics and Outreach (OAO) and Office of Food Safety (OFS) requires this information to

perform a reliable health hazard assessment and policy determination for contamination

exposure.

Label Examinations

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Shipments of dietary supplements being setup for a labeling examination, including the product

label, should be prioritized based on the Areas of Emphasis 1-11 above.

Sample Collections

A Compliance sample for Area of Emphasis #3 will consist of 12 retail packages, regardless of

size. Collect one retail package from each of 12 randomly selected shipping container or 10%

of the number of packages from a single lot, whichever is smaller. Do not commingle lots. In

those circumstances where there are not 12 boxes/cases/cartons of a product being offered for

import, then multiple 'retail packages' may be collected from the same shipping container.

Under Reason for Collection indicate "For <insert Nutrient(s) forming the basis for the

claim> analysis."

Sample collections for Microbial USP Analysis, Nutrient Analysis, and Ephedrine Alkaloid

Analysis, should follow the directions above in D. Sample Collections (Domestic).

F. Import Activities

Ephedrine Alkaloid-Containing Dietary Supplements (Area of Emphasis #5)

Dietary supplements containing ephedrine alkaloids are covered by Import Alert 54-13

"Detention Without Physical Examination of Dietary Supplements And Bulk Dietary

Ingredients Containing Ephedrine Alkaloids From All Countries." A label examination (LEX)

will be performed to support regulatory action.

Edible Ruminant Products from BSE Affected or At-Risk Countries

Import Alert 17-04 "Detention Without Physical Examination Bulk Shipments of High-Risk

Bovine Tissue from BSE-Countries--Bovine Spongiform Encephalopathy" addresses bovine-

derived materials intended for human consumption as either finished dietary supplement

products or for use as ingredients in dietary supplements.

Be alert for shipments subject to the APHIS prohibition for BSE,

https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/animal-disease-information/cattle-

disease-information/cattle-bse/cattle-bse. Refer such entries to the local USDA/APHIS Plant

Protection Quarantine (PPQ) Agriculture Quarantine Inspection Veterinary Medical Officer

(AQI VMO); the current list of contacts may be found at:

https://www.aphis.usda.gov/contact/trade.

Dietary Ingredients of Concern

CFSAN, in conjunction with ORA, will identify potential ingredients of concern through

import alerts, directed assignments, and/or guidance, which warrant additional follow-up.

Dietary ingredients of concern include NDIs, ingredients that are not dietary ingredients and

pre-DSHEA ingredients that raise safety or other concerns. Ingredients included in the Dietary

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Supplement Ingredient Directory should be documented by label examination (LEX) and

submitted for regulatory consideration in CMS. Divisions should contact Dietary Supplements

and Labeling Assessment Branch (DSLAB) directly for any questions regarding the status of

an NDI for use in dietary supplements or dietary supplements containing a dietary ingredient of

concern.

Dual Language Labels

Attention should be given to dietary supplement labels which contain the indicated information

in one or more languages other than English. Divisions should conduct a label examination to

verify the translation accuracy of ingredients and other labeling requirements, particularly

regarding declaration of major food allergens, edible ruminant ingredients, herbal/botanical

ingredients, color additives (FD&C Yellow Nos. 5 and 6), and sulfites. If the division does not

have a staff member who can translate, please notify the General Program contact person for

assistance.

Dietary Supplements Subject to Import Alerts

Numerous import alerts are in effect for dietary supplement products or ingredients, including

multiple import alerts under the 54 heading (54-##). Import alert 66-41, “Detention Without

Physical Examination of Unapproved New Drugs Promoted in the U.S.”, may be applicable to

dietary supplements and references multiple foreign manufacturers importing dietary

supplements found to contain drug ingredients bear disease claims in the labeling of products.

Import alert 23-15, "Detention Without Physical Examination of Food Products That Are, or

That Contain, Areca (Betel) Nuts, Including Finished Dietary Supplements and Bulk Dietary

Ingredients", may be applicable to dietary supplements. In addition, import alert 99-39,

“Detention Without Physical Examination of Imported Food Products appear To Be

Misbranded,” may be applicable to dietary supplements.

G. Shipping

Divisions are required to coordinate with their servicing lab prior to sample collection. Except

for the analyses noted below, please refer to the Laboratory Servicing Table (LST) to identify

an appropriate servicing laboratory. Follow IOM subchapter 4.7 ‘Sampling: Preparation,

Handling, Shipping.’

For samples collected for health claim or nutrient content claim analysis, i.e., Area of

Emphasis 3, indicate the suspect nutrient forming the basis for the health claim or nutrient

content claim in the Reason for Collection section of the collection report.

Microbial USP analysis laboratory should be determined by ORS/OFFLO Program Manager.

Samples for Ephedrine Alkaloid Analysis should be directed to Arkansas Human and Animal

Food Laboratory (ARLHAF) as the primary servicing laboratory, and Seattle Human and

Animal Food Laboratory (SEAHAF) as the back-up laboratory.

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Reporting

Establishment inspection reports must be completed in eNSpect per IOM subchapter 5.7.1

‘Establishment Inspection Report (EIR)’, for all dietary supplement inspections. Each of the

‘Required Elements’ would be covered under separate section headings in the EIR. See IOM

subchapter 8.1 ‘Investigations and Inspections’ for guidance covering how to conduct and report

an investigation.

All corrective actions taken by a firm in response to inspectional observations must be

documented in the Corrective Action Reporting (CAR) system, accessible via eNSpect and CMS.

Voluntary corrections should be encouraged for all observations and when possible verified prior

to the close of the inspection. Use eNSpect to report corrective actions observed during the

inspection and those received after the inspection but before the inspection report is finalized in

eNSpect. Use CMS to report and assess any corrective actions received after the report has been

finalized in eNSpect.

Report resources utilized for sample collection and label examination using the following

Program Assignment Codes (PAC) and Problem Area Flags (PAF):

PAC

PAF

PAF Description

21008

NIS

Nutrient Sample Reporting

21008

DIS

Dietary Supplements Analysis (Ephedrine Alkaloid)

21008

MIC

Microbiological Analysis

21008

LEX LBL

Label Examination

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Date of Issuance: 09/18/2024 PART IV — Page 28

PART IV - ANALYTICAL

Analyzing Laboratories

Divisions are required to coordinate with their servicing lab prior to sample collection. Please

refer to the Laboratory Servicing Table (LST) for additional guidance. For Ephedrine Alkaloid

analysis ARKL is the primary servicing laboratory and PNL is the back-up laboratory. Currently,

for Microbiological USP analysis the Analytical lab will be directed by ORS/OFFLO Program

Manager.

Analyses to be Conducted

Nutrient Analysis/Nutrition Sample Reporting (NIS)

Dietary Supplements Analysis (Ephedrine Alkaloid) (DIS)

Dietary Supplement Microbiological Analysis (DSMA)

Methodology

A. Nutrient Analysis

1. Label Review

The label of each sample will be reviewed for conformance with 21 CFR 101.9, 101.36

and other applicable labeling requirements.

2. Analyses

a) Do not perform nutrient analyses on samples containing more than one manufacturing

lot code. Notify the collecting division to re-sample if this occurs.

b) For compliance samples collected for nutrient analysis in support of an unqualified

health claim or nutrient content claim, analyze only for the suspect nutrient.

c) Otherwise:

• Select for analysis ONLY those nutrients that are declared as being present at

or above 25% of the RDI or DRV.

• With the above criteria in mind, select a maximum of four (4) nutrients per

product, giving first priority to the following nutrients: Vitamin A/Beta

Carotene, Selenium, Folic Acid, Pantothenic Acid, Calcium, Potassium,

Vitamin C or Vitamin D.

• For any remaining analysis, select those nutrients declared at the highest

percentages of the RDI or DRV at or above 25%. In the case of "ties",

randomly select from among the "ties" nutrients for the last selection.

d) Perform analyses for the selected ingredients as follows:

Compliance Samples

Prepare a composite by taking equal portions from each subsample. Use either the "a"

or the "b" subsamples. For tablets, capsules, or caplets take a minimum of 2 units per

subsample. For other dosage forms, use equal measured amounts from each

subsample. The composite should contain an amount of analyte sufficient to perform

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several determinations. A separate composite shall be prepared by the check analyst

for all check analyses. Retain the remaining sub-samples as the 702(b) portion.

Surveillance Samples

Sample portion for original analysis should be taken from a single subsample.

Composite a minimum of 12 servings for tablets, capsules, or bars (e.g., 12 tablets,

capsules, bars, etc.) provided that the serving size is 1 tablet, capsule, bar, etc. For

liquids or powders, take an appropriately sized (equal to 12 servings) analytical

portion from a well-mixed subsample. Another subsample unit will be used for the

check analysis if necessary. Additional subsample units will remain intact.

Analyze the composite by methods contained in the AOAC, USP, FDA Foods

Program Compendium of Analytical Laboratory Methods, or National Formulary, as

applicable and appropriate. Use of methods contained in one of these compendiums

must take precedence over use of other methods. If AOAC, USP, or National

Formulary methods are not available, then use of an appropriate validated method

from the scientific literature or from in-house work is appropriate. Compendial

methods must be considered before non-compendial methods are considered.

All methods used whether compendial or non-compendial, must be validated through

the use of recovery and reproducibility studies, use of positive and negative controls,

use of Standard Reference Material, when available, or in-house quality

assurance/quality control materials, etc.

Use of in-house quality assurance/quality control samples is suitable for QA/QC

purposes only when adequate documentation of the origin, age, handling (storage

procedures), composition, frequency of analysis and results of analysis, etc. is readily

available.

e) For nutrients labeled as USP, the appropriate USP analytical method shall be used for

analysis.

f) Randomly select vitamin or mineral supplements, labeled as meeting USP

requirements, for dissolution/disintegration testing using current USP methodology.

Priority should be given to calcium supplements then folate/folic acid supplements,

and then other appropriate supplements. This testing is not mandatory, and the

laboratory should use its discretion in determining when and how many samples to

select for dissolution/disintegration testing within the constraints of the available

resources.

g) Perform a check analysis on any sample meeting the conditions outlined in Part V D.

1. Nutrient Analysis—Conditions of Concern. The check analysis should be performed

by a second analyst using an official AOAC method, a USP method where designated,

or one approved by the Center.

CAUTION: Do not allow the sample to "age" as many nutrients deteriorate and

some minerals precipitate with time. Vitamins A and C break down when

PROGRAM 7321.008

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improperly handled. Begin original analysis and check analysis (if necessary) as soon

after compositing as possible.

h) When requested by the Center to support compliance actions, analyze samples labeled

with a dietary fiber content using an official AOAC method of appropriate scope (e.g.

985.29, 991.42, 991.43, 993.19, 2017.16).

B. Ephedrine Alkaloid Analysis

Servicing labs will use either of the following published methods for original analysis of each

sample. Additional methods are being developed, and once approved, they may also be used.

Each sample should be tested for the six ephedrine alkaloids (EA) included in the methods.

JAOAC Int. 2003 Jul-Aug: 86(4): 657-68; “Determination of Ephedrine Alkaloids in Dietary

Supplements and Botanicals by Liquid Chromatography/Tandem Mass Spectrometry:

Collaborative Study”. The method may be verified for use in the quantitative determination of

each sample and/or confirmation of identity. When possible, it is recommended to determine

the concentration of ephedrine alkaloids using liquid chromatography (LC) with tandem mass

spectrometry (MS/MS) selective detection as dietary supplements often contain ingredients

which interfere with quantification by LC with ultraviolet (UV) detection.

AOAC Official Method 2003.13 Ephedrine Alkaloids in Botanical and Dietary Supplements

published as JAOAC Int. 2004 Jan-Feb: 87(1): 1-14; “Determination of Ephedrine Alkaloids

in Botanicals and Dietary Supplements by HPLC-UV: Collaborative Study.”

No further evaluation is necessary for samples testing negative by either method. For a sample

testing positive, additional analyses are to be conducted, such that the end product is at least a

quantitative original analysis, a quantitative check analysis, and an MS confirmation of

identity. If an MS confirmation method is also quantitative, it may serve as both the original

and check analysis as long as the two analyses are performed by separate analysts.

Analysis of each sample is on a composite basis only, e.g., do not analyze individual tablets or

capsules.

Show the calculation and report the concentration (µg/g) for individual and total EAs for the

composite as directed in the methodology.

Determine the average weight for hard tablets and capsules and the average capsule content

weight for soft capsules.

C. Dietary Supplement Microbial Analysis

Laboratories will use the USP online for the current methodology. See chapters below for

specific analytical guidance.

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART IV — Page 31

a. 〈2021〉 MICROBIAL ENUMERATION TESTS—NUTRITIONAL AND DIETARY

SUPPLEMENTS

b. 〈2022〉 MICROBIOLOGICAL PROCEDURES FOR ABSENCE OF SPECIFIED

MICROORGANISMS—NUTRITIONAL AND DIETARY SUPPLEMENTS

c. 〈2023〉 MICROBIOLOGICAL ATTRIBUTES OF NONSTERILE NUTRITIONAL

AND DIETARY SUPPLEMENTS

Reporting

Nutrient Analysis

Use PAC 21008 PAF NIS to report all samples analyzed under this program.

Nutrient Analysis Branch (NAB) in SFFL will report all samples classified as Lab Class 3 based

on nutrient analyses to the compliance branch of the collecting division for appropriate regulatory

follow-up.

Ephedrine Alkaloids

Use PAC 21008 PAF DIS to report the daily dosage level of ephedrine alkaloids found in the

product.

Classify samples found to contain any ephedrine alkaloids as Lab Class 3.

Notify the collecting division and the CFSAN Program Contact of samples that are classified as

Lab Class 3 as soon as the original, check, and confirmation analysis are complete, and the

laboratory supervisor has cleared the worksheet. Promptly report positive and negative findings

into FACTS.

Microbial USP Analysis

Use PAC 21008 PAF MIC to report all samples analyzed under this program.

Classify samples based on the guidance in 〈2023〉 Microbiological Attributes of Nonsterile

Nutritional and Dietary Supplements.

Notify the collecting division, CFSAN Program Contact and ORS Program Contact of samples

that are classified as Lab Class 2/3 as soon as the analyses are completed in FACTS.

PART V - REGULATORY/ADMINISTRATIVE STRATEGY

Findings

The goal of this regulatory and administrative strategy is to obtain high rates of industry

compliance with the dietary supplement CGMP regulations under 21 CFR Part 111, and labeling

requirements under 21 CFR Part 101, and other applicable laws and regulations (including those

relating to new dietary ingredients and other ingredients) and to gain prompt voluntary correction

of violations and/or deficiencies. Regulatory recommendations such as Warning Letters or

Untitled Letters must be submitted to CFSAN using MARC-CMS via electronic copy (e.g., MS

PROGRAM 7321.008

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word, pdf files, other electronic documents, etc.) through proper supervisory channels when

significant GMP observations are found and documented, when potentially unlawful ingredients

are identified, and/or when significant labeling deviations exists, including health fraud with

inappropriate claims being made for products. However, as appropriate, swift enforcement action

will be taken when significant problems present a threat to public health. If a division determines

that there is a direct threat to public health during an inspection, such as a shipment of dietary

supplement found to be positive for pathogens or containing undeclared allergens, the division

should immediately contact CFSAN/OC and Office of Policy, Compliance, and

Enforcement/Division of Compliance and Enforcement (OPCE/DCE) to discuss enforcement

options. Refer to Attachment B for standard language on significant violations.

Actions

Please note that all reasonable steps should be taken to obtain voluntary compliance prior to

initiating regulatory action. If the facility’s response is inadequate to protect public health, all

available administrative and legal tools should be considered, such as a regulatory meeting,

untitled letter, warning letter, administrative detention, registration suspension, mandatory recall,

seizure, or injunction. If the division feels that administrative or legal action is warranted (with

the exception of regulatory meeting, untitled letter, or warning letter), management should initiate

a preliminary assessment call with CFSAN Office of Compliance Division of Enforcement (DE).

Refer to the Regulatory Procedures Manual (RPM) for more information; Chapter 4 - Advisory

Actions; Chapter 5- Administrative Actions; and Chapter 6- Judicial Actions.

A. Administrative and Legal Actions for Imminent Public Health Hazards

FDA-Requested Recall or Mandatory Recall Order

Although unusual in the absence of demonstrating specific product contamination, an FDA-

requested recall could be considered in urgent situations and based on a Class I health

hazard evaluation. Refer to RPM Chapter 7- Recall Procedures for more information. If a

determination is made that there is reasonable probability that an article of food is

adulterated under section 402 of the FD&C Act or misbranded under section 403(w) of the

FD&C Act and the use or exposure to such article will cause a serious adverse health

consequences or death to humans or animals (SAHCODHA) and the firm refuses to take

voluntary corrective actions, including recall, after FDA request, mandatory recall under

section 423 may be warranted.

Administrative Detention

If a determination is made that there is reason to believe that an article of food is adulterated

or misbranded, administrative detention under section 304 of the FD&C Act may be

considered to prevent the movement of such food while the FDA prepares for additional

action (e.g., seizure, injunction).

Seizure/ Injunction

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When the facility’s response to the Warning Letter does not adequately address direct or

indirect risks, if violations are sufficiently egregious and/or persistent, and/or if the facility

refuses to conduct a voluntary recall, a seizure and/or injunction should be considered.

Suspension of Food Facility Registration

If a facility registered under section 415(a) manufactures, processes, packs, receives, or

holds food that has a reasonable probability of causing SAHCODHA; and that facility

created, caused or was otherwise responsible for that reasonable probability of

SAHCODHA; or knew of, or had reason to know of, the reasonable probability of

SAHCODHA, and packed, received, or held such food, suspension of food facility

registration may be considered. If warranted, the state should be engaged to determine if

state enforcement actions such as embargo or permit revocation can be utilized to stop

production or the movement of product while FDA is considering enforcement actions.

B. Compliance Activities

The following should be used in recommending an appropriate regulatory action to

CFSAN/DE:

GMP Violations

Manufacturers of dietary supplements:

• Failure to establish and follow written quality control review procedures or significant

quality control procedures not implemented.

• Lack of written master manufacturing records or elements of the MMR not included.

• Failure to establish finished product specification release criteria. Failure to test all or

a subset of finished batches to ensure the batch meets finished product specification

release criteria.

• Failure to establish component specifications for dietary ingredients or failure to

conduct identity testing.

• Failure to use appropriate and scientifically valid methods to test components or

finished products.

• No written batch records or significant elements not included in batch records.

• Significant physical plant or equipment deficiencies.

Distributors of dietary supplements:

• Failure to establish and follow written procedures for quality control including

procedures for release of packaged and labeled dietary supplements.

• Failure to establish and ensure packaging and labeling specifications are met.

• Failure to establish and follow written procedures for holding and distributing

operations.

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• Failure to establish and follow written procedures for packaging and/or labeling

operations; and manufacturing and batching records pertaining to these operations.

• Failure to establish and follow written procedures for product complaints.

• Failure to establish and follow written procedures for returned dietary supplements.

Label Violations

Division compliance branches should refer to the references provided in Part VI when

evaluating labels under the Areas of Emphasis listed below. FDA’s website includes a

dietary supplement labeling guide that includes additional information for use in evaluating

labels. Refer to Attachment B for standard language to be included in Warning Letters.

DOMESTIC PRODUCTS

Areas of Emphasis Nos. 6, 10, and 11

OHAFO CB may consider issuing Warning Letters directly to firms whose product(s):

1) Fail to bear nutrition information under 21 CFR 101.36 and are not exempt; or

2) Are in solid oral dosage form and contain added iron or iron salts but do not bear the

mandatory warning statement.

This direct reference authority applies only to product labels that fall into statements (1)

and/or (2) above but conform to all the other areas of emphasis including providing

mandatory labeling information. Regulatory recommendations against product labels that

do not conform to one of the other areas of emphasis must be handled as indicated under

Regulatory/Administrative Strategy.

ODSP must be included on the distribution list for these letters. A copy of these direct

reference Warning Letters must be uploaded into the CMS case file.

Areas of Emphasis 1, 2, 3, 5, 6, 7, 8, 9 and 10

Divisions should prepare Warning Letter recommendations to firms whose product(s) are

intended to supplement the diet but:

• Fail to bear statement of identity on the principal display panel, i.e., use of the term

“dietary supplement” or “[*] supplement” with the blank [*] filled in with the name

of the dietary ingredient or a term appropriately descriptive of dietary ingredients in

the product.

• Bear (a) a health claim or a nutrient content claim that has not been authorized by

FDA; (b) a health claim that is not the subject of a letter granting enforcement

discretion in response to the court decision in Pearson vs. Shalala; (c) a nutrient

content claim that is not appropriately based on an authoritative statement as

provided for in section 403(r)(2)(6) of the Act; (d) or any health claim that appears

to be based on an authoritative statement under the Food and Drug Administration

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Modernization Act (FDAMA). At this time, the Act does not provide for the use of

health claims based on authoritative statements in the labeling of dietary

supplements.

• Bear egregious disease claims or structure/function claims that may be

unsubstantiated. Products that bear inappropriate disease claims or that appear to

bear egregiously false or misleading structure/function claims should be referred to

CFSAN for evaluation.

• Bear nutrition labeling (“Supplement Facts” label) with missing elements of 101.36

including significant format deviations under 21 CFR 101.36(e).

• Uses the term “ginseng” to describe the product or an ingredient and the product or

ingredient is not an herb or herbal ingredient derived from a plant classified within

the genus “Panax.”

• Fail to disclose a major food allergen as required.

• Fail to bear other mandatory nutrition labeling.

Nutrient Analysis

1. Conditions of Concern

• The analysis supports the fact that the product does not qualify to make the

health claim or nutrient content claim contained on the product label (Area of

Emphasis No. 3), or

• The sample does not comply with the requirement in 21 CFR 101.9(g)(4)

regarding nutrients that are not present in the declared amounts.

This same threshold applies when recommending regulatory action against products

labeled as meeting a USP monograph.

Generally, for products that do not qualify to make a certain health claim or nutrient

content claim, the recommendation would be accompanied by supporting analytical

results. However, there may be instances where a deviation in this area may be

supportable based solely on label review without related analytical results.

2. Applicable Charges for Regulatory Actions

The appropriate charge(s) for the above types of deviations would be:

• 403(a)(1) (false and misleading labeling) for products that do not qualify for a

health claim or nutrient content claim on the product label.

• 403(a)(1) (false and misleading labeling) and also 402(b)(1) (adulteration;

valuable constituent has been in whole or in part omitted...) for products that do

not comply with 21 CFR 101.9(g)(4). These are the charges to be included in

all regulatory actions involving nutrient deficiencies recommended under this

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program.

• 403(r)(1) (nutrient content claims) if the product includes a nutrient content or

health claims and the product does not meet the nutrient requirements to make

the claim, based on the analytical results.

Adverse Event Reporting Requirements

Section 761 of the Act applies to the requirements for adverse event reporting. Firms

are required by statute to submit to FDA all reports of serious adverse events associated

with dietary supplements that they receive. FDA expects responsible persons to perform

follow up investigations of those serious adverse events reported to them to obtain at

least the minimum five data elements needed to make a submission to FDA. FDA stated

in the Guidance for Industry that it does not intend to pursue enforcement action against

firms who make diligent efforts to follow-up but are unsuccessful in obtaining the

minimum information needed to make a submission. In addition, the statute requires

that firms make and keep records of all adverse events reported to them for 6 years,

regardless of whether the adverse event is reported to FDA.

If you find that a firm has failed to perform any or all of these requirements, the division

should submit a Warning Letter recommendation. If the firm has performed the

requirements but the documentation or actions appear to be inadequate, the division may

consider submitting an Untitled Letter recommendation.

Ephedrine Alkaloid Containing Dietary Supplements

The Center is prepared to move forward quickly against dietary supplement products

determined by analytical testing to contain ephedrine alkaloids. Voluntary actions by the

responsible firms (e.g., destruction of existing inventory and commitment to comply with the

law and regulations) are an acceptable and efficient alternative to enforcement action that still

achieves compliance and removes adulterated product from the market. Where possible,

voluntary action should be publicized in order to provide appropriate deterrence to other

firms.

In the absence of voluntary actions, compliance branches should discuss the findings with the

CFSAN Compliance/Enforcement contact. If appropriate, divisions should submit seizure

recommendations through CMS.

Refer to Section 6-1 of the RPM for additional guidance on submitting seizure

recommendations. The recommendation package should include the worksheet for the

positive findings, legible digital copies of product labels, and all supporting documentation.

Follow-up source/supplier for raw materials:

Division Compliance Branches must request trace back investigation of finished product and

suppliers for any product that tests positive for ephedrine alkaloids. If the product or raw

PROGRAM 7321.008

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material is of import origin, submit the relevant information on country, port of entry, shipper,

importer, etc. to ORA Division of Import Operations (DIO) ICB through CMS as an import

alert recommendation.

Products Containing Edible Ruminant Tissue or Tissue-Derived Ingredients from BSE

Affected or At-Risk Countries

Bovine-derived ingredients cannot be used in dietary supplements if they adulterate the

product under any provision of Section 402 of the Act.

If evidence of any one of the following situations is collected in a firm, the division must

forward the EIR and all documentation through CMS to CFSAN for further regulatory

consideration.

1. A bovine-derived ingredient is a prohibited cattle material under 21 CFR 189.5(a) if it is a

specified risk material that has not been inspected and passed for human consumption by a

competent authority or is otherwise a prohibited material under 21 CFR 189.5(a).

Affirmative evidence of the use of prohibited cattle material must be collected.

2. If the firm is using bovine-derived ingredients, they must have records to show that the

food is not manufactured from, processed with, or does not otherwise contain prohibited

cattle materials (21 CFR 189.5(c)). Documentation of the lack of these records must be

collected.

Products Containing Identified Ingredients of Concern

Regulatory action against dietary supplements that contain ingredients that may be unlawful for

any reason, including new dietary ingredients that have not complied with the requirements in

section 413 of the Act, ingredients that are not dietary ingredients, ingredients that are unsafe

food additives, and ingredients that raise safety concerns, are a priority for the Center. Please

consult with ODSP to determine whether action against an ingredient will be supported and

what the appropriate charge(s) should be.

C. Imports

When imported products identified as dietary supplements or as dietary supplement ingredients

appear to be non-compliant based on FDA statute/regulation, based on label examination,

sample collection and/or are subject to detention without physical examination (DWPE),

divisions should consider detaining the entry per the established process.

In addition, for those violative firms and products not already subject to DWPE for the

indicated violation, the Division should submit a recommendation for DWPE to ORA DIO’s

Import Compliance Branch (ICB), as appropriate, via CMS. Divisions should follow the

criteria outlined in the RPM Chapter 9 - Import Operations and Actions, Subchapter for

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Detention without Physical Examination when recommending firms and/or products for

addition DWPE under the appropriate Import Alert. An original or quality copy of the label

MUST be included in the package submitted to the ORA DIO ICB for review, along with other

relevant evidence to support the violation.

D. Additional Information

Voluntary correction by a firm is often the most effective and expedient means to obtain

compliance and to protect public health. Divisions should take steps to obtain voluntary

correction prior to initiating regulatory action. When voluntary correction is not forthcoming,

pursue routine regulatory procedures to address significant observations. Refer to FMD-86

Establishment Inspection Report Conclusions and Decisions for further guidance.

If a facility inspected under this program has a Class I recall and/or conditions are observed

that represent a significant public health concern, a conference call between the division

Compliance Branch, and CFSAN/OC and ORA/OHAFO program contacts identified in part

VI of this program should be scheduled before closing the inspection to discuss possible

enforcement strategies. If this information is known prior to beginning the inspection, a call

should be scheduled prior to the start of the inspection.

The division should submit any recommendation for enforcement follow-up through CMS. If

CFSAN feels an inspection classified as VAI should be classified as OAI, a request will be

made to the division to provide the full narrative EIR and exhibits through CMS for review. If

subsequently an OAI reclassification is suggested by CFSAN, a meeting will be scheduled

between the divisions and CFSAN/OC and OPCE/DCE.

Regulatory Follow-Up

To verify the implementation of corrective actions, divisions should conduct follow-up

inspections within 6 months of the compliance action being finalized for facilities with inspection

classifications of OAI and that were observed to have significant CGMP deficiencies, and/or

significant misbranding violations according to FMD-86 and RPM Chapter 4 - Advisory Actions.

If there are significant deficiencies or a risk to public health, then follow-up must be

conducted as soon as possible after the close of the inspection and completion of compliance

action. Follow-up inspections may include the collection of product samples at the request of

CFSAN OC or at the division’s discretion.

Prior to initiating the re-inspection, divisions should hold an enforcement strategy discussion with

CFSAN OC, ORA OHAFO program contacts, and state partners to discuss potential follow-up

actions if the firm continues to have significant violations. If the follow-up inspection reveals that

the firm continues to have conditions that are likely to lead to the adulteration and misbranding of

dietary supplements, the division should consider enforcement action based on these repeat

offenses. Divisions should initiate a call with CFSAN OC, CFSAN ODSP, and ORA OHAFO

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART V — Page 39

program contacts when an inspection revealed significant repeat observations. FDA Contacts for

Regulatory Partners.

Facilities with an inspection classification of NAI and VAI should be re-inspected at the

frequency designated in the Food Safety Modernization Act (FSMA) for high risk and non-high-

risk facilities.

Nutrient Analysis

Compliance Samples

If the domestic sample was collected as required in 21 CFR 101.36(f)(1) and a lot size suitable for

seizure is available, recommend a seizure. If the domestic sample does not fully comply with the

requirements of 21 CFR 101.36(f)(1) or if a lot size suitable for seizure is not available,

recommend issuance of a Warning Letter.

Surveillance Samples

Warning Letter recommendations should be prepared and forwarded for surveillance

samples meeting the criteria in V. B. Label Violations above.

Import Samples

For import samples that fail to bear nutrition labeling, submit an import alert recommendation

for addition of the responsible firm and product to DWPE to ORA’s DIO/ICB through CMS.

Each recommendation must include a copy of the available entry documents, the collection

report (if the recommendation is based on sample collection), an original product label (or

quality copy), all analyst worksheets (if the recommendation is based on sample collection),

and other pertinent information, such as documentation of method performance for all "Non-

Official" methods utilized.

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART VI — Page 40

PART VI - REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS

References

Major guidance and reference materials pertaining to this program are listed below. Additional

guidance may be found in the resource library.

A. Investigations Operations Manual (IOM)

B. Regulatory Procedures Manual (RPM)

C. FDA Food Labeling Guide

D. FDA Dietary Supplement Label Guide

E. United States Pharmacopeia (USP)

For Areas of Emphasis

No. 1 – Products that make disease and/or drug claims - Sections 301(d), 505(a) and 502(f)(1) of the

FD&C Act.

No. 2 – Products that contain new dietary ingredients without the required notification - Sections

402(f) and/or 413 of the FD&C Act, Dietary Supplement Ingredient Advisory List and

Attachment C.

No. 3 – Products that bear health claims or nutrient content claims--See 21 CFR 101.13 and 101.14,

section 403(r)(1)(A) and 403(r)(1)(B), FDA Food Labeling Guide, Qualified Nutrient Content

Claims, and Qualified Health Claims.

No. 4 – Failure to maintain records for cattle derived material--See 21 CFR 189.5.

No. 5 – Products that appear to contain a source of ephedrine alkaloids--See 21 CFR 119.1, section

402(f)(1)(A) of the Act, and Attachment C.

No. 6 – Products bearing significant “Supplement Facts” label deviations--See 21 CFR 101.36,

section 403(q)(5)(F) and Chapter IV of the Dietary Supplement Labeling Guide. Products that

fail to bear an appropriate statement of identity--See 21 CFR 101.3(g), section 403(s)(2)(B)

and Small Entity Compliance Guide: Statement of Identity, Nutrition Labeling and Ingredient

Labeling of Dietary Supplements.

No. 7 – Products that fail to declare a major food allergen--See Sections 201(qq) and 403(w) of the

Act

No. 8 – Products labeled with “Siberian ginseng”--See Section 403(u) of the Act and 21 CFR

101.4(h).

No. 9 – Products that fail to bear other mandatory labeling information--See Dietary Supplement

Labeling Guide.

No.10 – Products bearing significant “Supplement Facts” label deviations--See 21 CFR 101.36,

section 403(q)(5)(F) of the Act and Chapter IV of the Dietary Supplement Labeling Guide.

No.11 – See 21 CFR 101.17(e)(1), section 403(a)(1) of the Act and Small Entity Compliance Guide:

Label Warning Statements for Iron-Containing Supplements and Drugs

PROGRAM 7321.008

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Attachments

A. Exemptions from Nutrition Labeling (“Supplement Facts” Label)

B. Standard Language for Warning Letters

C. Guidance on Evidence Development and Documentation to Support Regulatory Action

D. CGMP Requirements Applicable to Operations Performed by Firm

E. PAC Usage Decision Tree

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART VI — Page 42

Program Contacts

CFSAN

Purpose

Name

Organization

Contact

General Program

Guidance

Joshua Adams

CFSAN/DFPG/PAMB

312-596-4166

Enforcement

Guidance

Quyen Tien

CFSAN/OC/DE

215-717-3705

Laboratory

Technical

Information

Guodong Zhang

CFSAN/ORS/DM/MMDB

240-402-2943

Technical

Information

Haijing Hu

CFSAN/ODSP

301-796-6555

Technical

Information

dsTAN

CFSAN/ODSP

See part II(2)(F)

ORA

Purpose

Name

Organization

Contact

Domestic/Foreign

Guidance

National Expert

Siobhan Taylor

ORA/OHAFO

303-236-3015

Domestic/Foreign

Guidance

National Expert

Gary Pecic

ORA/OHAFO

303-236-9601

Domestic/Foreign

Guidance

Program Expert

Rupa Pradhan

ORA/OHAFO/DDHAFO

781-281-4843

Import Operations

and Compliance

FDA Imports Inquiry

ORA/OIO/DIO and

DAPE

301-796-0356

Laboratory

Technical

Information

Zachary Miller (Micro)

Yanxuan (Tina) Cai

(Chemistry)

ORS/OFFLO

303-236-9694

240-402-1369

Technical

Information

dsTAN

ORA/OHAFO

See part II(2)(F)

PROGRAM 7321.008

Date of Issuance: 09/18/2024 PART VII — Page 43

PART VII - CENTER RESPONSIBILITIES

The Office of Dietary Supplement Programs will provide subject matter expertise in the maintenance

and evaluation of the Compliance Program and provide guidance to the Office of Compliance with

regard to program priorities, relevant evaluation questions, and recommended program changes. The

Office of Compliance will lead the effort and work in conjunction with the Office of Dietary

Supplement Programs to prepare routine compliance program evaluations. Evaluation will be

conducted on a periodic basis and outline the program office’s current objectives, general and specific

program evaluation questions, list recommendations for process improvement, and highlight data

patterns and trends for better targeting and resource allocation. The Office of Compliance will make

these evaluations available as well as FSMA Tracker reports that can be run annually or as frequently

as needed to track accomplishments.

Working in conjunction with the Program Office, the Program and Assignment Monitoring Branch

(PAMB) of the Division of Field Programs and Guidance (DFPG) will prepare a yearly summary

report for this compliance program. The summary will outline the Program Office’s current

objectives, highlight their accomplishment data for the year, and list recommendations for the

upcoming year. The report will be made available on the Inside.FDA intranet site under the

Programs and Initiatives page:

https://fda.sharepoint.com/sites/insideFDA-CFSAN-Office-of-

Compliance/SitePages/Compliance%20Programs%20Sub%20Pages/Compliance-Program-

Summaries.aspx

Change History

Item

Change

Date

Created 21008P PAC for Packaging and Labeling inspections

9/18/2024

Remove 21008L PAC for Limited Focus inspections

9/18/2024

Updated all PACs to ensure adequate coverage and proper evidence development

9/18/2024

Updated POCs and hyperlinks

9/18/2024

Create Attachment E - PAC Usage Decision Tree

9/18/2024

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT A — Page 44

ATTACHMENT A – EXEMPTIONS FROM NUTRITION LABELING ("SUPPLEMENT

FACTS" LABEL)

A dietary supplement is not required to have a "Supplement Facts" label if it is:

a. Offered for sale by a small business that has not more than $50,000 gross sales per year

from food sales or no more than $500,000 from total sales in accordance with 21 CFR

101.36(h)(1).

b. A low-volume product (i.e., less than 100,000 units sold annually) sold by a firm with less

than 100 full-time equivalent employees in accordance with 21 CFR 101.36(h)(2) and for

which a claim for exemption has been filed annually with CFSAN Office of Nutrition and

Food Labeling (ONFL).

c. Shipped in bulk form, not distributed to consumers in such form, and used in the

manufacture of other dietary supplements in accordance with 21 CFR 101.36(h)(3).

NOTE: The exemptions for small businesses and low-volume products are available only to products

whose labels bear no claims or other nutrition information.

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT E — Page 45

ATTACHMENT B – STANDARD LANGUAGE FOR WARNING LETTERS IN AREAS OF

EMPHASIS

Follow the format in Chapter 4 - Advisory Actions of the current edition of the Regulatory

Procedures Manual (RPM). This is not an all-inclusive list, as appropriate, specimen

charges for both domestic and import cases that may be applicable to this program

include:

Dietary Supplement Health Fraud (New and Misbranded drug violations under section 505(a)

and 502(f)(1)):

• Your product(s) is/are not generally recognized as safe and effective for the above-referenced

uses and, therefore, the product(s) is/are “new drugs” under section 201(p)(1) of the Act [21

U.S.C. 321(p)(1)]. New drugs may not be legally introduced or delivered for introduction into

interstate commerce without prior approval from FDA, as described in sections 301(d) and

505(a) of the Act [21 U.S.C. 331(d), 355(a)]. FDA approves a new drug on the basis of

scientific data submitted by a drug sponsor to demonstrate the drug is safe and effective.

• A drug is misbranded under section 502(f)(1) of the Act [21 U.S.C. 352(f)(1)] if the drug fails

to bear adequate directions for its intended use(s). “Adequate directions for use” means

directions under which a layperson can use a drug safely and for the purposes for which it is

intended (21 CFR 201.5). Prescription drugs, as defined in section 503(b)(1)(A) of the Act [21

U.S.C. 353(b)(1)(A)]), can only be used safely at the direction, and under the supervision, of a

licensed practitioner. Your product(s) is/are intended for treatment of one or more diseases

that are not amenable to self-diagnosis or treatment. Therefore, it is impossible to write

adequate directions for a layperson to use this product safely for its intended purposes.

Accordingly, your product(s) fail/fails to bear adequate directions for its intended use and,

therefore, the product(s) is/are misbranded under section 502(f)(1) of the Act [21 U.S.C. §

352(f)(1)]. The introduction or delivery for introduction into interstate commerce of this

misbranded drug violates section 301(a) of the Act [21 U.S.C. § 331(a)].

Adulterated Dietary Supplement:

• Your dietary supplement product(s) is/are adulterated within the meaning of section 402(g)(1)

of the Act [21 U.S.C. § 342(g)(1)] because the products have been prepared, packed, or held

under conditions that do not meet the Current Good Manufacturing Practice (CGMP)

regulation for dietary supplements (21 CFR Part 111).

• Your product(s) is/are adulterated within the meaning of section 402(f)(1)(A)(i) of the Federal

Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 342(f)(1)(A)(i)] because it is a dietary

supplement that presents a significant or unreasonable risk of illness or injury under the

conditions of use recommended or suggested in the labeling.

• Your product(s) is/are adulterated under sections 402(f)(1)(B) and 413(a) of the Act [21

U.S.C. §§ 342(f)(1)(B) and 350b(a)] because they contain a new dietary ingredient for which

there is inadequate information to provide reasonable assurance that such ingredient does not

present a significant or unreasonable risk of illness or injury.

• Your product(s) is/are adulterated under section 402(f)(1)(A) of the Act because it contains

ephedrine alkaloids that cause the product to present an unreasonable risk of illness or injury

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT B — Page 46

under conditions of use recommended or suggested in the labeling, or if no conditions of use

are recommended or suggested in the labeling, under ordinary conditions of use (21 CFR

119.1).

• The product is adulterated under section 402(a)(3) of the Act because it was manufactured

from, processed with, or otherwise contains material from cattle and the firm does not have

records sufficient to demonstrate that the food is not manufactured from, processed with, or

does not otherwise contain, prohibited cattle materials. 21 CFR 189.5(d).

• Your product(s) is/are adulterated under section 402(a)(1) [21 U.S.C. § 342(a)(1)] of the Act,

because they bear or contains a poisonous or deleterious substance which may render them

injurious to health. [pathogens or heavy metal contaminants identified from analytical results

and/or OOS reports].

• Your [insert product] is adulterated under section 402(a)(2)(C)(i) of the Act [21 U.S.C. §

342(a)(2)(C)(i)] because it contains [non-dietary ingredient], an unsafe food additive under

section 409(a) of the Act [21 U.S.C. § 348(a)]. If a substance added to food is not generally

recognized as safe (GRAS) by qualified experts for its intended use in food and does not

qualify for any of the other exemptions from the food additive definition, it is a food

additive.2 Food additives require premarket approval based on data demonstrating safety. Any

food additive that has not been approved for its intended use in food is deemed to be unsafe

and causes the food to be adulterated under section 402(a)(2)(C)(i) of the Act [21 U.S.C. §

342(a)(C)(i)].

o The definition of “food additive” in section 201(s) of the Act [21 U.S.C § 321(s)] does

not include dietary ingredients used in dietary supplements as defined in section

201(ff)(1) of the Act [21 U.S.C § 321(ff)(1)] or substances that are GRAS under the

conditions of intended use. [Name of ingredient] does not qualify as a dietary

ingredient under section 201(ff)(1) of the Act [21 U.S.C. § 321(ff)(1)] because it is not

a vitamin, mineral, amino acid, herb or other botanical, dietary substance for use by

man to supplement the diet by increasing the total dietary intake, or concentrate,

metabolite, constituent, extract, or combination of any of the preceding dietary

ingredient types. Neither is [name of ingredient] GRAS under its conditions of use in

your dietary supplement product. Because [name of ingredient] does not qualify as a

dietary ingredient and is not GRAS or otherwise exempt from the food additive

definition, your [name of the product] is adulterated under section 402(a)(2)(C)(i) of

the Act because they contain an unsafe food additive. The introduction or delivery for

introduction into interstate commerce of any food that is adulterated is a prohibited act

under section 301(a) of the Act [21 U.S.C. § 331(a)].

• The term “dietary supplement” is defined in section 201(ff) of the Federal Food, Drug, and

Cosmetic Act (the Act) [21 U.S.C. § 321(ff)]. Given that you have declared [Insert new

dietary ingredient (NDI) previously reviewed and cleared by CFSAN] as a dietary ingredient

in the labeling of your product, we assume you have a basis to conclude that [insert NDI] is a

“dietary ingredient” under section 201(ff)(1) of the Act [21 U.S.C. § 321(ff)(1)]. If you have a

basis to conclude that [insert NDI] is a “dietary ingredient,” it would also be a “new dietary

ingredient” (i.e., a dietary ingredient not marketed in the United States before October 15,

1994) under section 413(d) of the Act [21 U.S.C. § 350b(d)].

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT B — Page 47

Under section 413 of the Act [21 U.S.C. § 350b], a dietary supplement that contains a new

dietary ingredient shall be deemed adulterated under section 402(f) of the Act [21 U.S.C. §

342(f)] unless it meets one of two requirements:

a. The dietary supplement contains only dietary ingredients that have been present in

the food supply as an article used for food in a form in which the food has not been

chemically altered; or

b. There is a history of use or other evidence of safety establishing that the dietary

ingredient when used under the conditions recommended or suggested in the

labeling of the dietary supplement will reasonably be expected to be safe and, at

least 75 days before being introduced or delivered for introduction into interstate

commerce, the manufacturer or distributor of the dietary ingredient or dietary

supplement provides FDA with information, including any citation to published

articles, which is the basis on which the manufacturer or distributor has concluded

that a dietary supplement containing such dietary ingredient will reasonably be

expected to be safe.

To the best of FDA’s knowledge, there is no information demonstrating that [Insert NDI] was

lawfully marketed as a dietary ingredient in the United States before October 15, 1994, nor is

there information demonstrating that this ingredient has been present in the food supply as an

article used for human food in a form in which the food has not been chemically altered.

Assuming [Insert NDI] is a dietary ingredient, in the absence of such information, [Insert NDI]

would be subject to the notification requirement in section 413(a)(2) of the Act [21 U.S.C. §

350b(a)(2)] and 21 CFR 190.6. Products for which the manufacturer or distributor is required to

submit a new dietary ingredients notification under section 413(a)(2) and 21 CFR 190.6, but for

which the required notification has not been submitted, are adulterated under sections 402(f) and

413(a) of the Act [21 U.S.C. §§ 342(f) and 350b(a)].

• Even if a new dietary ingredient notification had been submitted under section 413(a)(2) and

21 CFR 190.6, we know of no evidence that would establish that [Insert NDI] could be

lawfully marketed as a new dietary ingredient in your [Name of Product] product. In the

absence of a history of use or other evidence of safety establishing that [Insert NDI], when

used under the conditions recommended or suggested in the labeling as a dietary ingredient,

will reasonably be expected to be safe, dietary supplements containing [Insert NDI] as a new

dietary ingredient are adulterated under sections 402(f) and 413(a) of the Act because there is

inadequate information to provide reasonable assurance that such ingredient does not present

a significant or unreasonable risk of illness or injury. Introduction of such products into

interstate commerce is prohibited under sections 301(a) and (v) of the Act [21 U.S.C. § 331(a)

and (v)]. To the best of FDA’s knowledge, there is no history of use or other evidence of

safety establishing that [Insert NDI] will reasonably be expected to be safe when used as a

dietary ingredient.

Misbranded Dietary Supplement:

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT B — Page 48

• Your product is misbranded within the meaning of section 403(q)(5)(F) of the Act in that the

label fails to bear nutrition labeling ("Supplement Facts" label), which is required under 21

CFR 101.36, and is not exempt from this requirement.

• Your product is misbranded within the meaning of sections 403(i)(1) and 403(s)(2)(B) of the

Act in that the label fails to identify the product using the term dietary supplement (21 CFR

101.3(g)).

• Your product is misbranded within the meaning of section 403(r)(1)(A)/(B) of the Act in that

the label bears the nutrient content claim/health claim "___," which has not been authorized

by FDA regulation or on the basis of an authoritative statement under section 403(r)(2)(G) or

403(r)(3)(C) of the Act, or has not been the subject of a letter granting enforcement discretion

in response to the Pearson vs. Shalala court decision.

• Your product is misbranded within the meaning of sections 403(a)(1) and 201(n) of the Act in

that the label, labeling, or display of the product with added iron, fails to bear the required

warning statement (21 CFR 101.17(e)).

• Your product is misbranded within the meaning of section 403(u) of the Act in that it purports

to be or is represented as ginseng, but it is not an herb or herbal ingredient derived from a

plant classified within the genus Panax.

• Your product is misbranded within the meaning of section 403(w) of the Act [21 U.S.C. 343

(w)] in that the label fails to declare all major food allergens present in those products, as

required by section 403(w)(1). Section 201(qq) of the Act [21 U.S.C. 321(qq)] defines a major

food allergen as milk, egg, fish, crustacean shellfish, tree nuts, wheat, peanuts, soybeans, and

sesame, as well as any food ingredient that contains protein derived from one of these foods,

with the exception of highly refined oils. A food is misbranded if it is not a raw agricultural

commodity and it is, or it contains an ingredient that bears or contains, a major food allergen,

unless either:

o The word "Contains," followed by the name of the food source from which the major

food allergen is derived, is printed immediately after or adjacent to the list of

ingredient, [section 403(w)(1)(A) of the Act, 21 U.S.C. 343(w)(1)(A)]; or

o The common or usual name of the major food allergen in the list of ingredients is

followed in parentheses by the name of the food source from which the major food

allergen is derived, except that the name of the food source is not required when either

the common or usual name of the food source appears elsewhere in the ingredient list

(unless the name of the food source that appears elsewhere in the ingredient list

appears as part of the name of an ingredient that is not a major food allergen) [section

403(w)(1)(B) of the Act, 21 U.S.C. 343(w)(1)(B)].

• For tree nuts, fish, or crustacean shellfish, the term "name of the food sources from which the

major food allergen is derived" means the name of the specific type of nut or species of fish or

Crustacean shellfish [section 403(w)(2), 21 U.S.C. 343(w)(2)].

• Your product is misbranded within the meaning of section 403(q)(1)(A) of the Act [21 U.S.C.

§ 343(q)(1)(A)] because the product label fails to include a serving size in accordance with 21

CFR 101.36(b). The terms "serving" or "serving size" for a dietary supplement are defined in

21 CFR 101.9(b) and 21 CFR 101.12(b) Table 2, as the maximum amount recommended on

the label for consumption per eating occasion.

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT B — Page 49

• Your product is misbranded within the meaning of section 403(y) of the Act [21 U.S.C. §

343(y)] in that the label fails to bear a domestic address or domestic phone number through

which the responsible person (as described in section 761) may receive a report of a serious

adverse event with such dietary supplements. Specifically, each product label does not include

a complete domestic address or domestic phone number.

• Your product is misbranded within the meaning of section 403(i)(2) of the Act [21 U.S.C. §

343(i)(2)] in that the product label fails to declare the common or usual names of each

ingredient used as required by 21 CFR 101.36 and 21 CFR 101.4.

• Your product is misbranded within the meaning of section 403(e)(2) of the Act [21 U.S.C. §

343(e)(2)] because the label fails to accurately declare the net quantity of contents on the

principal display panel as required by 21 CFR 101.7 and 15 U.S.C. § 1453(a)(2) of the Fair

Packaging and Labeling Act.

• Your product is misbranded under section 403(e)(1) [21 U.S.C. § 343(e)(1)] of the Act in that

the labels fail to declare the place of business, including the ZIP code, in accordance with 21

CFR 101.5.

• Your product is misbranded within the meaning of section 403(s)(2)(C) of the Act [21 U.S.C.

§ 343(s)(2)(C)] because the label fails to identify the part of the plant (e.g., root, leaves) from

which each botanical dietary ingredient in the product is derived, as required by 21 CFR

101.4(h)(1).

• Under section 201(ff)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. §

321(ff)(1)], a dietary ingredient is a vitamin; mineral; herb or other botanical; amino acid;

dietary substance for use by man to supplement the diet by increasing the total dietary intake;

or a concentrate, metabolite, constituent, extract, or combination of the preceding substances.

[Name of non-dietary ingredient] is not a vitamin, a mineral, an herb or other botanical, or an

amino acid. In addition, according to our research, [name of non-dietary ingredient] is not a

dietary substance for use by man to supplement the diet by increasing the total dietary intake.

Finally, [name of non-dietary ingredient] is not a concentrate, metabolite, constituent, extract,

or combination of a vitamin; mineral; herb or other botanical; amino acid; or dietary substance

for use by man to supplement the diet by increasing the total dietary intake.

Accordingly,[name of non-dietary ingredient] is not a dietary ingredient within the definition

set forth in section 201(ff)(1) of the Act. Declaring [non-dietary ingredient] in your product

labeling as a dietary ingredient causes your products marketed as dietary supplements to be

misbranded under section 403(a)(1) of the Act [21 U.S.C. § 343(a)(1)] in that the labeling is

false or misleading in any particular.

Area of Emphases

Area of Emphasis No. 1

Products that bear disease claims on the labels or labeling and offered for sale:

The product is not generally recognized as safe and effective for the above-referenced uses and,

therefore, it is a “new drug” under section 201(p)(1) of the Act [21 U.S.C. 321(p)(1)]. New drugs may

not be legally introduced or delivered for introduction into interstate commerce without prior approval

from FDA, as described in sections 301(d) and 505(a) of the Act [21 U.S.C. 331(d), 355(a)]. FDA

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT B — Page 50

approves a new drug on the basis of scientific data submitted by a drug sponsor to demonstrate the

drug is safe and effective.

A drug is misbranded under section 502(f)(1) of the Act [21 U.S.C. 352(f)(1)] if the drug fails to bear

adequate directions for its intended use(s). “Adequate directions for use” means directions under

which a layperson can use a drug safely and for the purposes for which it is intended (21 CFR 201.5).

Prescription drugs, as defined in section 503(b)(1)(A) of the Act [21 U.S.C. 353(b)(1)(A)]), can only

be used safely at the direction, and under the supervision, of a licensed practitioner. The product is

intended for treatment of one or more diseases that are not amenable to self-diagnosis or treatment.

Therefore, it is impossible to write adequate directions for a layperson to use this product safely for its

intended purposes. Accordingly, the product fails to bear adequate directions for its intended use and,

therefore, the product(s) is/are misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)].

The introduction or delivery for introduction into interstate commerce of this misbranded drug violates

section 301(a) of the Act [21 U.S.C. § 331(a)].

Area of Emphasis No. 2

The product is adulterated under sections 402(f)(1)(B) and 413(a) of the Act [21 U.S.C. §§

342(f)(1)(B) and 350b(a)] because they contain a new dietary ingredient for which there is inadequate

information to provide reasonable assurance that such ingredient does not present a significant or

unreasonable risk of illness or injury.

Area of Emphasis No. 3

The product is misbranded within the meaning of section 403(r)(1)(A)/(B) of the Act in that the label

bears the nutrient content claim/health claim “ ,” which has not been authorized by FDA regulation

or on the basis of an authoritative statement under section 403(r)(2)(G) or 403(r)(3)(C) of the Act, or

has not been the subject of a letter granting enforcement discretion in response to the Pearson vs.

Shalala court decision.

Area of Emphasis No. 4

The product is adulterated under section 402(a)(3) of the Act because it was manufactured from,

processed with, or otherwise contains material from cattle and the firm does not have records sufficient

to demonstrate that the food is not manufactured from, processed with, or does not otherwise contain,

prohibited cattle materials. 21 CFR 189.5(d).

Area of Emphasis No. 5

The product is adulterated under section 402(f)(1)(A) of the Act because it contains ephedrine

alkaloids that cause the product to present an unreasonable risk of illness or injury under conditions of

use recommended or suggested in the labeling, or if no conditions of use are recommended or

suggested in the labeling, under ordinary conditions of use (21 CFR 119.1).

Area of Emphasis No. 6

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT B — Page 51

The product is misbranded within the meaning of sections 403(i)(1) and 403(s)(2)(B) of the Act in that

the label fails to identify the product using the term dietary supplement (21 CFR 101.3(g)).

Failure to bear an appropriate statement of identity on the principal display panel, i.e., use of the term

"dietary supplement" or " supplement", with the blank filled in with the name of the dietary ingredient

or a term appropriately descriptive of dietary ingredients in the product:

The product is misbranded within the meaning of 403(s)(2)(B) of the Act [21 U.S.C. § 343 (s)(2)(B)]

because it does not include a statement of identity as a “dietary supplement” as required by 21 CFR

101.3(g).

Area of Emphasis No. 7

The product is misbranded within the meaning of section 403(w) of the Act [21 U.S.C. 343 (w)] in that

the label fails to declare all major food allergens present in those products, as required by section

403(w)(1). Section 201(qq) of the Act [21 U.S.C. 321(qq)] defines a major food allergen as milk, egg,

fish, crustacean shellfish, tree nuts, wheat, peanuts, soybeans, and sesame, as well as any food

ingredient that contains protein derived from one of these foods, with the exception of highly refined

oils. A food is misbranded if it is not a raw agricultural commodity and it is, or it contains an

ingredient that bears or contains, a major food allergen, unless either:

1.The word “Contains,” followed by the name of the food source from which the major food

allergen is derived, is printed immediately after or adjacent to the list of ingredient, [section

403(w)(1)(A) of the Act, 21 U.S.C. 343(w)(1)(A)]; or

2. The common or usual name of the major food allergen in the list of ingredients is followed in

parentheses by the name of the food source from which the major food allergen is derived,

except that the name of the food source is not required when either the common or usual name of

the food source appears elsewhere in the ingredient list (unless the name of the food source that

appears elsewhere in the ingredient list appears as part of the name of an ingredient that is not a

major food allergen) [section 403(w)(1)(B) of the Act, 21 U.S.C. 343(w)(1)(B)].

For tree nuts, fish, or crustacean shellfish, the term “name of the food sources from which the major

food allergen is derived” means the name of the specific type of nut or species of fish or Crustacean

shellfish [section 403(w)(2), 21 U.S.C. 343(w)(2)].

Guidance on the allergen labeling requirements in section 403(w) may be found on FDA’s website at

www.fda.gov.

Specifically, your product [name of product] is misbranded under section 403(w) in that the product

fails to declare the major food allergen [name of major allergen], which is a [dietary ingredient]

[subcomponent of the dietary ingredient x], as specified by the Act.

Area of Emphasis No. 8

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT B — Page 52

The product is misbranded within the meaning of section 403(u) of the Act in that it purports to be or

is represented as ginseng, but it is not an herb or herbal ingredient derived from a plant classified

within the genus Panax.

Area of Emphasis No. 9

The following are examples of the types of deviations that could fall under this area. It is not intended

to be a comprehensive list of labeling deviations in this Area of Emphasis.

Failure to bear net weight:

The product is misbranded under section 403(e)(2) of the Act because the label fails to bear the net

quantity of contents.

Failure to bear domestic address or domestic phone number on product:

The product is misbranded within the meaning of section 403(y) of the Act [21 U.S.C. § 343(y)]

because the label fails to include a domestic address or domestic phone number through which the

responsible person (as described in section 761) may receive a report of a serious adverse event

with such dietary supplements. “Domestic address or domestic phone number” means a complete

address or phone number.

Failure to bear name and place of business of manufacturer or packer:

The product is misbranded under section 403(e)(1) of the Act because the label does not bear the

name and place of business of the manufacturer, packer, or distributor.

Area of Emphasis No. 10

The product is misbranded within the meaning of section 403(q)(5)(F) of the Act in that the label fails

to bear nutrition labeling (“Supplement Facts” label), which is required under 21 CFR 101.36, and is

not exempt from this requirement.

Area of Emphasis No. 11

The product is misbranded within the meaning of sections 403(a)(1) and 201(n) of the Act in that the

label, labeling, or display of the product with added iron, fails to bear the required warning statement

(21 CFR 101.17(e)).

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT E — Page 53

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT E — Page 54

ATTACHMENT C – GUIDANCE ON EVIDENCE DEVELOPMENT AND

DOCUMENTATION TO SUPPORT REGULATORY ACTION

• CPG Sec 120.500 Health Fraud - Factors in Considering Regulatory Action (See link:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cpg-sec-120500-

health-fraud-factors-considering-regulatory-action)

• IOM (See link: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-

investigations/inspection-references/investigations-operations-manual (Chapter 2- see 2.5.11 –

Detention Powers and Criteria for Detention, 2.10.1 Human Food, 2.10.2 Human Drugs),

Chapter 5- See 5.10.7.5 Drug/Dietary Supplement Status

• CPG Sec 100.250 Food Facility Registration- Human and Animal Food (See link:

https://www.fda.gov/media/88691/download)

• Guidance for Industry and FDA Staff: Questions and Answers Regarding Mandatory Food

Recalls (See link: https://www.fda.gov/media/117429/download)

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT D — Page 55

ATTACHMENT D – CGMP REQUIREMENTS APPLICABLE TO OPERATIONS

PERFORMED BY FIRM

1. Labeling Review – Evaluate the product labels, printed promotional materials, and online

presence including websites and social media for the use of diseases claims that would make

the products unapproved new drugs. Verify labels comply with the nutrition labeling

(“Supplement Facts” label), adverse event reporting requirements, allergen labeling, and other

applicable labeling requirements.

2. Requirements of Quality Control – Review procedures for the responsibilities of quality

control and ensure quality control personnel conduct required activities. Verify that Quality

Control has complied with the following requirements:

a. Establish and follow written procedures for the responsibility of the quality control

operations.

b. Identify the personnel responsible for quality control operations and their qualifications.

c. Approval of procedures for manufacturing and the procedures are followed.

d. Approval of master manufacturing records and batch records for applicable operation at

the firm.

e. Approval of specifications the firm has for components, in process materials, labels,

packaging, and finished products.

f. Determine if QC personnel reviewed and approved all laboratory control processes

associated with the production and process control system, if applicable.

g. Review firm’s documentation to ensure appropriate tests or exams are used to for

components and finished products testing.

h. Assess the firm’s disposition decision for approval of components, packaging, labels, in-

process and finished product specifications.

i. Review the results of the firm’s qualification of the supplier of the components, and

review Certificates of Analysis for the incoming materials.

j. Review test result to make disposition determination on components, packaging, labels,

in-process and finished products.

k. Review adequacy of corrective actions.

3. Quality Indicators – Review recalls, quality complaint investigations, adverse events,

laboratory out-of-specification (OOS) investigations, and deviation investigations.

a. Evaluate testing and examination methods to ensure they are scientifically valid

b. Evaluate the reference standards and the characterization process of the reference

standards if firm develops in-house reference standards.

c. Review if laboratory record reflects the analytical results used to support disposition

decisions.

d. Evaluate the record keeping for laboratory operations.

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT D — Page 56

4. Facility and Equipment – Conduct a walkthrough inspection of areas where components or

finished dietary supplements are exposed to the environment and evaluate the sanitation and

maintenance of the facility and equipment. Evaluate the potential for contamination, allergen

cross-contact, and pests. Determine the adequacy of employee hygiene.

a. Assess the water quality when water is a component of the dietary supplement.

b. Assess calibration of equipment for manufacturing, including automated, mechanical or

electronic equipment used in manufacturing, packaging etc.

c. Access the firm’s controls established for equipment (including software on a computer

controlled process) and if changes are approved by QC personnel and instituted only by

authorized personnel.

d. Request and review firm’s written procedures for cleaning, sanitizing (if necessary), and

maintenance of all equipment and utensils and contact surfaces, and are they followed?

e. Request and review established written procedures and assess the firm’s control of the

holding and distributing space for components, finished product, reserved samples, etc.

5. Product Review –

a. Master Manufacturing Record – Review the master manufacturing record and determine

whether it contains required information and identifies appropriate specifications for the

points, steps, or stages in the manufacturing process where control is necessary to ensure

the quality of the dietary supplement.

b. Batch Production Record – Review the executed batch record and determine whether it

contains required information and documents specifications for the points, steps, or stages

in the manufacturing process where control is necessary to ensure the quality of the dietary

supplement are met. Review batch records and determine if they received adequate review

to make a decision to release or reject the batch for distribution. Evaluate if personnel

engaged in production activities are following written procedures for manufacturing

operations.

c. Components – Review at least three components used in the product to ensure appropriate

specifications have been established. Review testing data or documentation showing

component specifications are met. Determine whether methods used to verify

specifications are appropriate and scientifically valid. Evaluate that precautionary

measures are being used to prevent contamination of components of dietary supplements.

d. Finished Dietary Supplement – Ensure appropriate finished dietary supplement

specifications have been established. Review testing data or documentation showing

finished dietary supplement specifications are met. Determine whether methods used to

verify specifications are appropriate and scientifically valid. Evaluate that rejected dietary

supplements have been properly quarantined and dispositioned.

e. Manufacturing, Packaging, and Labeling Operations - Includes procedures, processes, and

control of the packaging and labeling operations for dietary supplement products. It

includes written procedures for packaging and labeling, packaging and labeling

process, visual inspection of package and labeling, control for the use of packages and

labeling, label specifications, label reconciliations.

PROGRAM 7321.008

Date of Issuance: 09/18/2024 ATTACHMENT D — Page 57

i. Review MMR and BPR and observe manufacturing, packaging and labeling

operations.

ii. Confirm that packaging and label used meet the established specifications.

iii. Evaluate that labels received have been properly reviewed and released by QC

personnel and that required lot traceability procedures are being used.

iv. Evaluate that rejected packaging and labels have been properly quarantined and

dispositioned.