USP Dietary Supplement Verification Program€¦ · Participation is voluntary and open to participants manufacturing dietary supplement products. The USP-DSVP covers dietary supplement

USP Dietary Supplement Verification Program

B U I L D I N G T R U S T , C L A R I T Y , a n d C o N f I D e N C e

Manual for Participants

© March 2009 United States Pharmacopeial Convention, All rights reserved.

U.S. Pharmacopeia Dietary Supplement Verification Program

MANUAL FOR PARTICIPANTS

i

Notice

This manual provides guidance to dietary supplement1 manufacturers who intend to participate in the United States Pharmacopeia’s Dietary Supplement Verification Program (USP-DSVP or Program). Additional requirements and criteria that are not included in this manual, including those in the DSVP Certification Mark Usage Manual, must be satisfied for participation. Prospective participants are advised to discuss these additional requirements with USP. The USP-DSVP is designed to assist participants in assuring their customers that the manufactured product is produced in accordance with Good Manufacturing Practices and that the participant’s other quality control and systems comply with the product label and meet other program requirements. USP considers this a cooperative effort between USP and participants. Participants who meet the requirements of this Program will receive permission to use the special USP verified mark on participant’s product labels. Barring safety concerns, or other special circumstances (see section 20 “Product Recall”), USP maintains the confidentiality of information gained through the verification process in accordance with the provisions of the Program License Agreement, provided separately.

1 USP understands that the term dietary supplement in the US has different meanings in other countries. Non-US terms include: botanicals, herbals, herbal medicines, and nutraceuticals.




1

Contents

Notice ........................................................................................................ i

1. Overview .................................................................................................. 2

2. Criteria for Participation ......................................................................... 3

3. Required Process and Submissions ..................................................... 4

4. Process Overview Chart ......................................................................... 5

5. USP-DSVP Product Category-Family Matrix ......................................... 6

6. Product Acceptance ............................................................................... 8

7. Evaluation of Initial Audit Documentation ............................................ 9

8. Sampling and Submission of Product Documentation ..................... 13

9. Evaluation of Quality Control Documentation .................................... 16

10. Evaluation of Manufacturing Documentation ..................................... 20

11. Testing of Product Samples ................................................................. 21

12. Specifications for Dietary Supplement Raw Material and/or Finished Product ................................................ 23

13. USP-DSVP Notification of Findings ..................................................... 26

14. Issuance and Use of the USP Verified Program Mark ....................... 28

15. Need for Re-Evaluation......................................................................... 30

16. Participant’s Internal Audit and Annual Product Reports ................. 32

17. Market Surveillance .............................................................................. 34

18. Appeals ................................................................................................. 38

19. Product Recalls ..................................................................................... 39

Glossary................................................................................................. 41

Forms and Checklists ................................................................................... 45

Checklist for Quality Control Documentation Checklist for Manufacturing Documentation Checklist for On-Site Audit

20. Legal Notices……………….…………………………………………………78




2

1. Overview

he USP’s Dietary Supplement Verification Program (USP-DSVP) is one of several public health programs of the United States Pharmacopeia (USP).

Participation is voluntary and open to participants manufacturing dietary supplement products. The USP-DSVP covers dietary supplement products legally marketed under the Dietary Supplement Health and Education Act (DSHEA)-including vitamins, minerals, amino acids, botanical, and other non botanical dietary supplement products. The USP-DSVP complements FDA’s regulation of dietary supplements under DSHEA and 21 CFR Part 111. The USP-DSVP includes:

Evaluation of manufacturers’ quality systems through audit for compliance with Good Manufacturing Practices.

Review of manufacturing and quality control documents for products submitted for certification.

Laboratory evaluation of product samples from selected lots for compliance with label claim and program requirements.

Grant of the USP-DSVP Verified mark

Post-verification surveillance of products bearing the USP-DSVP Verified mark

The use of the distinctive USP-DSVP Verified mark is granted for dietary supplement products that successfully meet USP-DSVP requirements. The mark indicates the verification of ingredient quality by a trusted and established authority. It provides assurance that:

The manufacturer’s quality system helps to ensure that the dietary supplement evaluated contains the declared ingredients of the correct identity in the declared amount or strength on the product label.

The dietary supplement is prepared under accepted manufacturing practices.

The dietary supplement meets requirements for acceptable limits of contaminants.

The dietary supplement meets disintegration and/or dissolution standards.

T




3

2. Criteria for Participation

Participants in the USP-DSVP agree to:

Complete the license agreement.

Submit requested data and documentation.

Subject their products and facilities to all reviews, inspections, and audits specified in the program.

Abide by the decisions made in accordance with the rules and requirements of the DSVP.

Operate in accordance with the provisions of the DSHEA and other relevant federal regulations.

Ensure that single-ingredient and multi-ingredient dietary supplements submitted for review meet the requirements specified in USP–NF or provide data that support the company’s decision not to comply. USP suggests that participants monitor proposed changes to the requirements specified in USP–NF that affect the manufacturers’ products and facilities, via Pharmacopeial Forum.

Have a written test protocol or procedure that assesses the stability of prospective products at the declared storage conditions and in the container-closure system in which they are marketed. The protocol or procedure should include sample size, test intervals, storage conditions (temperature, humidity, etc.), test methods, and specifications. This procedure should form the basis of the product’s shelf life.

Collect stability data, according to their stability protocol or procedure, for all prospective products at time intervals up to and including the products’ declared shelf life. If during these studies data are obtained that indicate that the product will fail to meet specifications before the declared shelf life, the participant will immediately notify USP’s staff.

Comply with applicable federal requirements on nutritional structure-function claims and other labeling requirements.

Pay all fees required by USP agreements or by documents executed between the participant and USP.




4

3. Required Process and Submissions

Participants in the USP-DSVP shall:

Appoint a duly authorized representative to execute a “License Agreement”

Provide the list of products for which verification is sought, with a list of ingredients for each product, and the lot history for all lots of the products manufactured under the current quality system

Enable USP to sample products or product lots specified by USP Staff

Submit the following documentation as described in this manual (see following sections)

1. Initial Audit Documentation: See Section 7 2. Quality Control Documentation: See Section 8

3. Manufacturing Documentation: See Section 8

Enable USP to perform on-site audits




5

4. Process Overview Chart

Yes

Participant completes License Agreement with USP

USP staff reviewdetermines product (s) to be appropriatefor inclusion, based on USP policies and

guidelines

No Product not entered into

verification program

Potential Participant submits application withselected product list and product information

USP coordinates and conducts on-site audit, analytical testing,and review of QC and manufacturing documentation

On-sitemanufacturing audit indicates

acceptance criteriamet

Participant addresses deficiencies withcorrective action plan

Participant submits product samples, and QC and manufacturingdocumentation for all randomly selected product lots

Yes

No

Yes

Yes

Yes

No

Yes

No

No

Participant takes corrective actionand/or appeals decision

QA Director reviewsand approves report

USP reviewscorrective action and/or appeal

and approves productverification

Verification process stopsfor product

VP Verification Programsreviews report and approves

product verification

USP staff conducts surveillancetesting of product(s)

USP staff conducts recurringon-site audit (3-year intervals)

Participant conducts internal audit(annual) and reports results to USP

ResubmitUSP Staff correct any errors/non-conformances

USP staff prepares summary reportof all findings for review by VP

Verification Programs

No

USP staffreview determines data and

documentation to be acceptable

Participant submits additionaldocumentation requested by USP

Yes

Analytical testresults conform to product

specifications

USP coordinates additional testing andreview to confirm original results

Product approved to carryUSP Verification Mark

Yes

No

Yes

No




6

5. USP-DSVP Product Category-Family Matrix

Category Description Sampling Family

1. Single Vitamins

Single Vitamin—oil soluble and/or water soluble vitamin—preparations

The number of products chosen will be [ n + 1] as a minimum, where n = # of products in the product class. The number of products is dependent on dietary ingredients, and are independent of dosage strength, of serving size, or of the servings per container. Consequently, it is possible for several stock-keeping units (SKUs) to be considered as one product. Each combination of product category and family equals a unique and separate product class. For each chosen product, one (1) random product lot will be selected. From the selected product lots, three (3) lots receive complete documentation review and testing; and the remaining [ n – 2] lots receive at minimum limited documentation review and testing on key parameters. The products not initially chosen will receive master batch record, product specification, and label review. However, all products may be subject to market surveillance. If n ≤ 3, products and/or product lots will be chosen such that three (3) product sample lots will receive complete review and testing.

Tablet or Hard Gelatin Capsule

Soft Gelatin Capsule

Liquid

Powders

Teas

2. Multivitamin Multivitamin—oil soluble and/or water soluble vitamin—preparations

3. Minerals Single and/or multiple mineral preparations

4. Amino Acids Single and/or multiple amino acid preparations

5. Vitamins and Minerals

Combinations of vitamin and mineral preparations

6. Vitamins, Minerals, and Amino Acids

Combinations of vitamins, minerals, and amino acid preparations

7. Botanicals Single or multiple botanical species preparations

Each botanical species will be treated as a separate subcategory. Three (3) product lots from each subcategory-family will receive complete documentation review and testing.

8. Other Non Botanical Dietary Supplements

Single or multiple other non botanical dietary ingredient preparations

Each other non botanical dietary supplement will be treated as a separate subcategory. Three (3) product lots from each subcategory-family will receive complete documentation review and testing.

Product category is determined as a function of dietary ingredient type, whereas product family is determined as a function of dosage form. Botanicals and other non botanical dietary supplements are further divided into subcategories according to the species or type of the other non botanical dietary ingredient. Each combination of product category/subcategory and family will be treated as a unique and separate product class.

Standardized ingredients are used to determine product category. For botanicals and other non botanical dietary supplements, standardized ingredients contain a defined amount of a particular chemical constituent or group(s) of constituents, known as marker compounds. In other cases, dietary ingredients may be “standardized” according to a percent daily value (%DV), as with vitamins.

Continued on following page




7

□ Examples of the determination of product category-family and product class

1. Echinacea purpurea hard gels, Goldenseal hard gels, and Echinacea purpurea and Goldenseal combination hard gels would be considered three (3) different subcategories within category 7.

2. Multivitamin and mineral tablets, containing three non-standardized botanical ingredients (Ginkgo biloba powder, Eleuthero root powder, and Grape Seed extract), would belong in category 5.

3. Vitamin C 250 mg tablets, with Green Tea extract, standardized to 50% polyphenols, would belong in category 7.

4. Vitamin E 200 IU capsules containing Lecithin from Glycine max (bean), with no quantitative label claim, would belong in category 1.

5. Botanical teas would belong in category 7.

6. Powdered protein drinks with vitamin and mineral claims would belong in category 6.




8

6. Product Acceptance

pon completion of the license agreement, the participant submits to USP a list of products, with a list of ingredients for each product, for which verification is

sought. USP Staff, in consultation with USP’s Council of Experts, will review the list of product ingredients to confirm that the ingredients are appropriate for inclusion in the program. The participant submits to USP the product lot history (lot number, description of the lot number coding system, date of manufacture, manufacturing facility, and lot size) for all lots of the products seeking verification, manufactured under the current quality systems.

Dietary supplements or ingredients for which there are official or proposed USP–NF standards are on the current “Approved” list for inclusion in the USP-DSVP.

All dietary supplements or ingredients for which there are no official or proposed USP standards will require an evaluation before the product can be included in the USP-DSVP. USP’s Dietary Supplements Information Expert Committee (DSIEC) will establish inclusion criteria.

If all ingredients in the dietary supplement product submitted are on the “Approved” list, or meet USP’s DSIEC inclusion criteria, USP will accept the product into the USP-DSVP and move forward with the verification process.

If a dietary ingredient is currently on the “Not Approved” list, or does not meet USP’s DSIEC inclusion criteria, all supplements containing these ingredients will not be considered for the USP-DSVP.

U




9

7. Evaluation of Initial Audit Documentation

he On-Site Audit Checklist (see Forms and Checklists) is used by USP-DSVP as a tool to ascertain information about the participating company, its quality

systems, and critical manufacturing information.

Prior to the on-site audit, the participant should provide USP with a copy of the company’s SOP index and a copy of the site map/layout.

During the on-site audit, the participant should be able to provide the information on the list for Initial Audit Documentation (see below) to USP auditors, upon request during the on-site audit. The USP auditor performs preliminary review of the information In evaluating the Initial Audit Documentation, the absence of any of the following may be deemed as deficiencies for corrective actions to be taken by the participant.

Initial Audit Documentation

Flow chart of the manufacturing process

Site map/layout

Organizational chart

Training program

Table of contents from SOP manual

Incoming materials control system

Document management system

List of process equipment requiring calibration, preventive maintenance, and cleaning

Calibration and preventive maintenance program for process equipment

Change control program

Program to determine process performance (e.g., validation)

Label control program

Deviation program/ Policy

Laboratory control procedures

Sample tracking system

Program for evaluating shelf life of marketed product

T




10

Supplier certification program

Contract manufacturer certification program

Contract laboratory certification program

Complaint Handling and Recall Procedures

In certain cases, the participant may not have a formally established program for some of the quality systems. If so, the participant can provide a description of their informal process along with a proposed plan and schedule to formalize it.

Deficiencies, if any, will be noted and provided to the participant in the on-site audit report. The participant should develop corrective action plans within 30 calendar days of receipt of notification. Corrective Actions target dates for implementation should be within six calendar months. If information on the corrective action is found acceptable by USP, the verification process will continue. If the participant fails to develop and implement corrective action, the verification process will be discontinued.

USP-DSVP uses USP Staff and/or approved contract auditors to perform the on-site audit of the participant.

The initial certification on-site audit and re-certification on-site audit will be conducted once every three years, lasting two to three days, depending on the size of the manufacturing facility and operations. In the intervening years, USP will conduct a surveillance audit, typically lasting one day. All audits will be conducted around the anniversary date of the initial certification on-site audit conducted by USP.

Notification of audit must be given to the participant’s Quality Assurance contact at least two weeks ahead of time. USP Staff will communicate any plan/agenda for the audit of a particular area to the management of that area to ensure the availability of required personnel during the audit. Safety procedures for the laboratory or area being audited will be followed.

The auditors will evaluate the findings of the on-site audit, according to compliance with the following two guidance documents:

1. USP <2750> Manufacturing Practices for Nutritional Supplements 2. 21 CFR Part 111- Current Good Manufacturing Practice in Manufacturing, Packing, Labeling, or

Holding Operations for Dietary Supplements

Auditors will look for the following mandatory criteria:




11

Organization/Personnel Dedicated Quality Assurance/Quality Control department Training program for the competency of all employees

Document Management Program for control of Standard Operating Procedures (SOPs), lot records, test methods, and specifications that include required approvals and revision/archival control, where appropriate

Equipment/Facilities Adequate security to prevent access for unauthorized personnel Adequate size and design of facility Maintenance and calibration of equipment to ensure consistent performance for its intended use

Documentation of use, calibration, cleaning, and preventive maintenance of equipment

Sample/Component Control Program for receipt, quarantine, disposition, release, and distribution of incoming materials

Designation of materials as to their status System of material reconciliation

Deviations

Maintenance of deviation logs Written policy—with time frame—for the disposition of deviations SOP for investigating and analyzing non-conforming results and trends

Laboratory Controls Written test methods and specifications Use of compendial methods where applicable Use of validated/qualified and appropriate methods Review of data and qualifications Monitoring/tracking of media/reagents prior to use Appropriate maintenance and calibration of laboratory equipment/instruments

Label Control Program for controlling label revision Program for monitoring and use of incoming labels Assurance of accountability of labels Monitoring of regulations as required

Shelf-Life Evaluation Program to evaluate product shelf life




12

Testing within defined time frames Formal program for resolution of discrepancies in testing Data to support shelf life of products submitted to USP-DSVP for certification

Quality Assurance Review System to ensure product quality prior to release

Process Performance Evaluation Demonstrated for products submitted to USP-DSVP for verification

Electronic Records/Computerized Systems Demonstrated proof of performance Appropriate security Appropriate backup

The on-site audit will be conducted according to the Checklist for On-Site Audit (see Forms and Checklists). Upon completion of the on-site audit, USP Staff will evaluate the on-site audit findings summarized in an audit report, which will include a list of any deficiencies. The audit report will then be forwarded to the participant along with the USP-DSVP report of any actions that it believes the participant needs to take. The participant will have 30 business days to reply to reported deficiencies with a corrective action plan. Failure to do so will result in the discontinuation of the verification process. Proof of corrective action, with the date of completion or progress made, must be submitted to USP-DSVP with the participant’s first self-audit report.




13

8. Sampling and Submission of Product Documentation

or each product seeking verification, USP-DSVP will randomly select, from the lot history for the product manufactured under the current quality system, the

lot(s) of the product to be used in the certification process.

USP will select, at minimum, three products or product lots from each category- family for which certification is being sought.

USP will request that the participant sample the product lot(s) and send them via express mail to USP. Alternatively, USP may decide to send a USP-DSVP representative to perform the sampling.

Products submitted to USP-DSVP should be sampled in the commercial packaging for the product. In the case of a bulk product that has not been packaged for sale, the product should be sampled in a container closure system similar to that of the commercial packaging. The product needs to be labeled, at minimum, with the following information: Company Name, Product Name, Material Resource Code, Material Lot Number, Sample Date, Sampler’s Initials, and Number of Serving Units.

After the product lot has been sampled, USP-DSVP will request that the participant submit the following documentation for the chosen lot(s).

1. Checklist for Quality Control Documentation 2. Checklist for Manufacturing Documentation

Note that the requested information must be submitted in the format indicated in the outline for “Documentation for USP-DSVP.” The requested information can be submitted in electronic format. Complete documentation needs to be received before the review process can begin. If the requested information is found inadequate (for example, incomplete or not in the requested format), USP-DSVP may request additional information from the participant.

Initial Verification Documentation for USP-DSVP:

The following is an outline of the documentation to be provided for products undergoing initial verification. Please provide the documentation organized and labeled according to the major sections listed below. Sections II.A. and II. B. apply to all products selected for initial verification. Sections II.C., II.D., II.E., III.A. and III.B. apply to individual products; the participants has the option of submitting documents in these latter sections on a per product or per product category basis.

F




14

Requested Format of Documents Section II. Quality Control Documentation

A. Specifications for raw material, packaging, and finished product, related to products undergoing verification.

1. Raw material specifications for raw material used to prepare finished products undergoing verification.

2. Packaging and labeling specifications for primary and/or secondary packaging used for finished products undergoing verification.

3. Release and shelf-life specification for finished products undergoing verification.

B. Test methods and reference standards used for testing of raw material used to

prepare finished products and testing of finished products undergoing verification.

1. Written method. 2. Data demonstrating suitability of method for intended use (e.g. method

validation protocol and method validation data/report). 3. Reference materials used for testing a. Description (name, source, quality) of the standard (if not included in the

written method). b. Data to support the suitability of standard for intended use. C. Release documentation for the lots of raw material used to prepare the finished

product lots undergoing verification. 1. Test results and the corresponding raw data from in-house testing (i.e.,

laboratory notebook pages, spectra, chromatograms, etc.). 2. Certificate of Analysis (CoA) from the supplier. D. Release Documentation for the finished product lots undergoing verification. 1. QC laboratory release form for the finished product (CoA, if applicable).

2. Test results and the corresponding raw data (i.e., laboratory notebook pages, spectra, chromatograms, etc.).

E. Stability Data for the finished products undergoing verification. 1. Stability protocol. 2. Test results summary to support the marketed shelf-life.




15

Section III. Manufacturing Documentation A. Master Formula and Batch Record 1. Include master batch records for manufacturing, including any premixes and

subassemblies. 2. Include any approval signatures and date(s) for master batch records

submitted. B. Executed Batch Records 1. Include premix or subassembly executed batch records. 2. Include copies of incoming inspection and release of labels, and packaging

materials used in the batches. 3. Include verification that the shelf-life calculation was verified and correct. 4. Include scale print-outs verifying measured weights of raw materials. 5. Include final QA testing and approval of finished lots.

Request for supplemental information: If the quality control/manufacturing documentation is considered inadequate, due to missing information, USP-DSVP will send a written Observations(s)/Corrective Action Plans/Supplemental Information form (See Forms and Checklists) to the participant, requesting additional information.

If the quality control/manufacturing documentation is considered inadequate but, upon discussion with the participant, USP-DSVP determines that there is sufficient cause to confirm any supplied methods and/or analytical results, the product samples submitted by the participant will be analyzed in USP-DSVP approved, contracted laboratories. If the laboratory results support the acceptance of the quality control documentation, USP-DSVP will proceed to the next step in the verification process. If the laboratory results support the acceptance of the quality control documentation, but lead to other issues, USP will request additional information from the participant. If the laboratory results do not support the acceptance of the quality control/manufacturing documentation, the verification process will be discontinued for the product category under consideration.

If the quality control/manufacturing documentation is considered inadequate and, upon discussion with the participant, USP-DSVP determines that evaluation of additional product samples submitted by the participant will not add useful data, the entire quality control/manufacturing documentation will be deemed unacceptable and the verification process will be discontinued for the product category under consideration.




16

9. Evaluation of Quality Control Documentation

SP staff will review all quality control documentation submitted (See Checklist for Quality Control Documentation under Forms and Checklists) for products

accepted into the USP-DSVP. They will determine whether the specifications (tests, methods, and acceptance criteria) provided are sufficient to demonstrate consistent and appropriate product quality. USP Staff will review specifications relating to raw materials, in-process specifications, final products, packaging and labeling materials, stability data/shelf life, method verification, certificate of analysis, data from selected lots, and reference materials.

Note that the requested information must be submitted in the format indicated in the outline for “Documentation for USP-DSVP,” in Section 8. The requested information can be submitted electronically. Complete documentation needs to be received before the review process can begin. If the requested information is found inadequate (for example, incomplete or not in the requested format, (see page 14), USP-DSVP may request additional information from the participant.

Raw materials: For dietary ingredients for which a USP–NF monograph exists, USP-DSVP will verify conformance to the requirements specified in the monograph. If a product does not comply with the USP–NF monograph, USP-DSVP requests submission of data as explanation for the deviation. USP Staff will evaluate the data for acceptance.

For dietary ingredients for which there is no USP–NF monograph, USP-DSVP may verify that the specifications provided by the participant are adequate to ensure identity, purity, quality, and content in accordance with the labeling. The specifications must include tests for

Identification by chemical, spectroscopic, or chromatographic tests, and/or by macroscopic/microscopic methods

Content of specific entity or marker(s)

Heavy metals

Residual solvents/organic volatile impurities

Known toxic components

Pesticide residue as applicable

Microbial limits

Other undesirable components as applicable

Other quality standards (Water, Loss on Drying, Ash, Residue on Ignition, pH, etc., as appropriate)

U




17

Please refer to the section titled “Specifications for Dietary Supplement Raw Material and/or Finished Product” for further details on raw material specifications.

Packaging and labeling materials: USP will review descriptions and specifications provided by the participant for packaging materials in direct contact with the product, as well as samples and specifications provided for labels and labeling (i.e., secondary printed packaging components).

Note that in terms of the relationship between marker compounds and label claims, federal regulations 21 CFR part 101.9(g)(3), 101.9(g)(4), and 101.36(f)(1) require that products be truthfully labeled with respect to their contents. The FDA has established two different minimum levels that label claims must meet depending on the type of ingredient. Fortified or fabricated (Class I) nutrients, whose content has been controlled in some fashion must meet 100% of label claim. Naturally occurring (Class II) nutrients, whose constituents occur naturally in an ingredient and whose level is not controlled must meet at least 80% of label claim. For DSVP, a botanical or “other dietary supplement” extract with declared chemical marker constituents on the label is considered a Class I (standardized) nutrient, whereas a powdered botanical or “other” dietary supplement is considered a Class II (nonstandardized) nutrient. In both cases, the rule applies to the product throughout its shelf life.

Reference to the USP–NF, other Pharmacopeias and standards on labels or labeling must be completely accurate. Other marks or seals cannot be used on the label without USP approval. Labeling must comply completely with all federal labeling regulations.

The current edition of Herbs of Commerce, published by the American Herbal Products Association (AHPA), should be consulted regarding the proper Latin Binomial and Standardized Common Name for each botanical species.

Final product: For dietary supplement products for which a USP–NF monograph exists, USP-DSVP will verify conformance to the requirements specified in the monograph. If a product does not comply with the USP–NF monograph, USP-DSVP requests submission of data as explanation for the deviation. USP Staff will evaluate the data for acceptance.

For dietary supplement products for which there is no USP–NF monograph, USP-DSVP will verify that the specifications provided by the participant are adequate to ensure purity, quality, and content in accordance with the labeling.

The participant provides for USP-DSVP review, release, and shelf-life specifications for the finished product that include:




18

Physical examination

Identification by chemical, spectroscopic, or chromatographic tests

Content of dietary ingredient

Performance characteristics according to dosage form type (e.g., disintegration/dissolution)

Undesirable components

Other quality standards (friability, hardness, water, pH)

Please refer to the section entitled “Specifications for Dietary Supplement Raw Material and/or Finished Product” for further details on final product specifications.

Method validation: USP-DSVP will review documentation for each analytical method. If the analytical method is a procedure from USP–NF, AOAC International Official Methods of Analysis (OMA), AOAC International Peer Verified Method (PVM), American Herbal Pharmacopeia (AHP) method, or the Food Chemical Codex (FCC), there is no need for a complete validation report. In this case, the suitability of the method for testing the specific product must be supported by analytical data. The data should check the accuracy and precision of the analyte determination and lack of interference from other components/excipients with the analyte.

If the analytical method is not a procedure from USP–NF, AOAC International Official Methods of Analysis or an AOAC Peer Verified Method (PVM), American Herbal Pharmacopeia (AHP) method, or the Food Chemical Codex (FCC), the method shall be validated according to the USP–NF General Chapter <1225> Validation of Compendial Methods. If the validation data provided by the company does not demonstrate that the method is suitable for its intended use, DSVP will provide recommendations.

Reference materials: USP-DSVP will check the source of reference materials used to support the product specifications. If USP Reference Standards have been used for USP–NF tests, no additional information is needed, other than indication of the lot number of the USP Reference Standard used. For non-USP Reference Standards, USP-DSVP will check to ensure that the characterization data submitted supports the suitability of the material for its intended use.

Stability data/shelf life: Procedures used in stability studies will be reviewed to determine if they are able to evaluate product quality attributes such as appearance, content, performance characteristics, microbial counts, etc. that are susceptible to change during storage and likely to influence product quality. USP-DSVP will check that the product stability protocol or procedure and supporting data follow a logical




19

and predefined plan indicating test specifications, testing intervals, storage conditions, and packaging to support the proposed shelf life of the product.

For new dietary supplement products, the initial shelf life should be based upon accelerated stability studies on the commercial formulation in the commercial container-closure system (a minimum of 1 lot, 3 months at 40°C/75% RH supporting the shelf life). For the accelerated stability studies, USP-DSVP prefers that commercially manufactured batches be used; however, a pilot batch that is of suitable size and that uses equipment consistent with what will be used in commercial manufacturing can also be used. Participants in the USP-DSVP must commit to providing USP-DSVP with one-year stability data for products stored consistent with the labeled storage conditions, as well as stability data at the end of the declared shelf life of the product.

If a new product has the same dietary ingredients and similar formulation and container-closure systems as an existing product, real-time data from the existing product may be sufficient initially to support the declared shelf life of the new product for immediate product launching. Participants in the USP-DSVP must commit to providing USP-DSVP with side-by-side accelerated stability data, comparing the new and the existing product, to further support the declared shelf life of the new product. Also, participants in the USP-DSVP must commit to providing USP-DSVP with one-year stability data for products stored consistent with the labeled storage conditions, as well as stability data at the end of the declared shelf life of the product.

For existing dietary supplement products, comparing test data from suitable retained samples, which have been manufactured under the current quality control system and have been stored under controlled conditions, for necessary quality attributes against the initial release data may be sufficient to support the declared shelf life of the product.

After initial certification of a product, supplemental stability data shall be reviewed to ensure that the data support the declared shelf life of the product.

Certificate of analysis: USP-DSVP will verify that the analytical results on the certificates of analysis, from actual dietary supplement product lots of which USP-DSVP has requested samples, are in compliance with the specifications. In case of non-compliance, USP-DSVP will provide recommendations.

Data for sample lots: USP-DSVP will evaluate data collected from dietary supplement samples on the basis of the criteria described in the quality control documentation.




20

10. Evaluation of Manufacturing Documentation

SP-DSVP will review all manufacturing documentation (submitted per Checklist for Manufacturing Documentation under Forms and Checklists, with

associated data) for products accepted into the USP-DSVP.

Note that the requested information must be submitted in the format indicated in the outline for “Documentation for USP-DSVP,” in Section 8. The requested information needs to be submitted in a three-ring binder, preferably with no stapled pages. Complete documentation needs to be received before the review process can begin. If the requested information is found inadequate, (for example, incomplete or not in the requested format), USP-DSVP may request additional information from the participant.

The documentation submitted must include

Manufacturing process directions

Master formula for each product for which certification is sought

Reprocessing information (if performed)

Executed lot records for lots from which USP-DSVP has taken samples The lot records include

Manufacturing instructions Packaging instructions In-process data related to the manufacturing quality control checkpoints Labeling for the subject lot Indication of QA final release approval

In-process control: USP-DSVP will review specifications provided by the participant for in-process control steps defined in their internal manufacturing and process directions.

U




21

11. Testing of Product Samples

esting of product samples will begin after the USP Staff has determined that the quality control documentation and manufacturing documentation for the product

is complete and in the requested format, based on an initial review of the documentation.

Products as applicable will be tested for identification, contamination [microbial, heavy metals, pesticides, known toxic components], performance characteristics [weight variation and/or content uniformity, disintegration and/or dissolution (per monograph)], and assay content of label claim [for standardized ingredients and percent daily value (%DV)].

For non-standardized ingredients, minimum testing will include ingredient identification, verification of correct weight input as per the lot records, along with participant’s process verification to confirm content uniformity. Testing of any declared marker also will be performed in accordance with participant’s specifications and label claims.

Please refer to the section titled “Specifications for Dietary Supplement Raw Material and/or Finished Product” for further details on specifications for testing of product samples.

USP-DSVP will follow USP procedures for testing, as applicable, unless instructed otherwise by the participant to use a validated alternate method that is listed in the current product specification.

USP-DSVP will coordinate testing of product samples either in the USP laboratories or by one or more approved contract laboratories. A single analysis will be performed for each product specification. Test data will then be evaluated for accuracy and to determine if the product conforms to the specifications reported by the participant.

If the test data received conform to the product specifications and there are no other issues arising from the test results, USP-DSVP will proceed to the next step in the verification process.

If the test data do not conform to the product specifications or if there are other issues arising from the test results, USP-DSVP will reevaluate the raw data submitted by the laboratory to confirm the accuracy of test results. If specific analytical errors are found, a sample retest will be requested from the laboratory. The laboratory will be requested to reanalyze the original sample, if possible, in duplicate. If the reanalyzed

T




22

results agree with the initial test result, all results will be averaged and reported. If the reanalyzed results confirm the suspected analytical error, the nonconforming test result is invalidated and the average of the reanalyses reported.

In the case of nonconforming results, in which there is no determinant error, the laboratory will be requested to reanalyze the original sample, if possible, in duplicate, along with a newly submitted sample of the product lot, in duplicate. Testing on each sample set will be performed by different experienced analysts. If the four reanalyzed results disagree with the initial test result, the average of the four reanalyzed test results will be reported. If the four reanalyzed results agree with the initial test result, all results will be averaged and reported.

In all cases, the reported result will be compared to participant’s specifications for determining compliance to label claim(s). In the event of a question regarding compliance to participant’s specification(s) or label claim(s), the decision by USP-DSVP shall be final.




23

12. Specifications for Dietary Supplement Raw Material

and/or Finished Product

s previously indicated, for dietary ingredients for which a USP–NF monograph exists, USP-DSVP will verify conformance to the requirements specified in the

monograph. If a product does not comply with the USP–NF monograph, USP-DSVP requests submission of data as explanation for the deviation. USP Staff will evaluate the data for acceptance.

For dietary ingredients for which there is no USP–NF monograph, USP-DSVP will verify that the specifications provided by the participant are adequate to ensure identity, purity, quality, and content in accordance with the labeling.

In regards to identification testing for, and to potential adulterants in botanical material, one should consult the FDA CFSAN’s 25JUN99 Draft Report of the Food Advisory Committee (FAC) Dietary Supplement Working Group on “Ingredient Identity Testing Records and Retention.” Participants should take care to eliminate any known toxic components in their products. Two recent issues concerning toxicity involve aristolochic acid and bovine spongiform encephalopathy (BSE). For information regarding aristolochic acid, refer to FDA’s document regarding the “Listing of Dietary Ingredients of Concern” (revised 09APR01). In responding to the requirements for material of animal origin, the European Pharmacopoeia (EP) General Chapter 5.2.8 “Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Medicinal Products,” and FDA’s Web site should be consulted.

Pesticide testing should be conducted according to USP <561>, and should comply with applicable federal regulations. Dietary supplements are subject to the statutory provisions of the Federal Food, Drug, and Cosmetic Act that governs foods but not drugs. Limits for pesticides for foods are determined by the EPA and where no limit is set, the limit is zero. For practical reasons, the limit that one can establish for the level of a pesticide in a dietary ingredient or supplement is governed by the detection limit of the chosen analytical method. In some cases, analytical methods for pesticides have been specially developed, with guidance from FDA’s Pesticide Analytical Manual (PAM), to achieve lower detection limits than that achievable by USP <561>. For example, the validated analytical method developed for the CRN-AHPA Joint Task Force on Pesticides, for detecting quintozene and lindane pesticides in Ginseng raw material, powders, and/or extracts needs to be employed for any Ginseng product seeking USP-DSVP certification. For pesticides, when feasible, analytical methods that can achieve lower detection limits should be employed.

A




24

Please refer to the following table regarding participant specifications for dietary supplement raw material and finished product. The specifications are provided for guidance; the applicability of the various tests can vary for different articles (raw materials and/or finished products). For questions or clarification please contact the USP Staff.

Table continued on following page.

i Refer to glossary for definition of acronyms, and to section text for additional details.

ii Aflatoxin AOAC Official Methods include 991.31 and 999.07.

iii A. Dried or powdered botanicals; B. Powered botanical extracts; C. Nutritional supplements with botanicals; D. Botanicals to which boiling water is added before use (i.e., teas); E. Other raw materials and dietary supplement ingredients; F. Nutritional supplements with synthetic or highly refined ingredients.

Specifications for Dietary Supplement Raw Material and/or Finished Product (AS APPLICABLE) Analyte—Containment—Test Reference—Method Acceptance Criteria

RAW MATERIAL SPECIFICATIONS Identification of ingredient or marker(s) USP–NF, AHP, AOAC, FCC, Verified As per method Purity or content of specific entity or marker compound(s) USP–NF, AHP, AOAC, FCC, Verified As per method Absence of adulterants USP–NF, AHPA, FAC As per reference Known toxic, or undesirable components EP, FAC, FDA As per reference Insects/Foreign organic matters USP–NF <561> As per monograph, or manufacturer criteria Organic Volatile Impurities USP–NF <467> As per monograph, or manufacturer criteria Pesticides USP–NF <561>, PAM Not detected Quintozene in Ginseng CRN-AHPA Not detected, < 10 ppb Mycotoxins (e.g., Aflatoxins) USP–NF <561>, AOACii < 20 ppb

RAW MATERIAL and FINISHED PRODUCT SPECIFICATIONS (continued on next page) Microbial enumeration tests USP–NF <2021>, USP–NF <2023>, BAM Upper limit, in units of cfu per g or mL

Total aerobic microbial count

Aiii B C D E F 105 104 104 105 103 103

Molds and yeasts 103 103 103 103 102 102 Bile-tolerant Gram-negative bacteria 103

Viable specific microorganisms Salmonella species USP–NF <2022> Absent per 10g or 10 mL Escherichia coli USP–NF <2022> Absent per 10g or 10 mL Clostridium species (for chondroitin sulfate) USP–NF <2022> Absent per 10g or 10 mL Staphylococcus aureus USP–NF <2022> Absent per 10g or 10 mL

Heavy Metals USP–NF <231> As per monograph, or <10 ppm




25

Specifications for Dietary Supplement Raw Material and/or Finished Product (continued) Analyte—Containment—Test Reference—Methodi Acceptance Criteria

RAW MATERIAL and FINISHED PRODUCT SPECIFICATIONS (continued from previous page) Other quality standards As per monograph, or manufacturer criteria

Water USP–NF <921> Loss On Drying USP–NF <731> Ash (total, acid-soluble ash) USP–NF <561> Residue On Ignition USP–NF <281> pH USP–NF <791>

FINISHED PRODUCT SPECIFICATIONS Strength or content of specific entity or marker

compounds USP–NF, AOAC, FCC, Verified As per method

Performance characteristics As per monograph, or manufacturer criteria Disintegration USP–NF <2040> Dissolution USP–NF <2040> Weight Variation USP–NF <2091> Friability USP–NF <1216>




26

13. bservation and Corrective Action/Supplemental Information Forms will be issued to participants listing the determination and status of the issues

regarding the various elements of the Dietary Supplement Verification Program (DSVP), as it pertains to the participant. The reports will be segregated according to the following elements of the program, as applicable

Pre-Audit Documentation

On-Site Audit

Product(s) Quality Control Documentation Manufacturing Documentation Analytical Results

The results for the Pre-Audit Documentation and the On-Site Audit apply to the manufacturing site audited and the products manufactured at that site, whereas the results for the product section(s) will be product specific.

The status of the issues or deficiencies within each program element may be divided into three categories: Action Level 1, Action Level 2, and Action Level 3. These three categories differ according to the nature of the issue or deficiency. All Action Levels require some action to be taken by the company.

ACTION LEVEL 1 issues involve a lack of a quality system program element, or products identified as having critical deficiencies. Action Level 1 issues may be resolved by supplying essential information, or by making major changes to a product/process. Action Level 1 issues involve changes to the current quality system. Action Level 1 issues must be adequately resolved before certification can be given to the product, and may require that the product be resubmitted for certification.

ACTION LEVEL 2 issues involve a lack of information regarding a quality system program element, or products identified as having major deficiencies. Action Level 2 issues can be resolved by supplying substantial information, or by making minor changes to the product/ process. Action Level 2 issues do not involve changes to the current quality system. Action Level 2 issues must be adequately resolved before certification can be given to the product.

ACTION LEVEL 3 issues involve the need for clarifying information or newly requested information regarding a quality system element, requested improvements to product criteria, or products identified as having minor deficiencies. Action Level 3 issues can be resolved by supplying additional information or by making requested changes to product/process. Action Level 3 issues would allow the DSVP certification mark to be

O USP-DSVP Notification of Findings




27

issued subject to the firm’s commitment to address the issues cited within the specified time period.

Note: All Action Level 3 issues that are not resolved by the next internal audit will be upgraded to Level 2.

Justification for citing the Action Levels is based on the USP-DSVP Standard Operating Procedures (SOPs), which were developed in consultation with representatives of the Industry Advisory Group (IAG) companies. In addition, the following two documents will also be consulted: (1) USP <2750> Manufacturing Practices for Nutritional Supplements; and/or (2) 21 CFR Part 111 Current Good Manufacturing Practice in Manufacturing, Packing, Labeling or Holding Operations for Dietary Supplements.

The status of each category (Pre-Audit Documentation, On-Site Audit, and Products) is indicated by an overall Assessment of Pass,or Fail, depending on the nature of the issues/deficiencies within each category. The grading system of Pass, and Fail are based on the following determination:

PASS indicates that only Action Level 3 issues or deficiencies need to be resolved. Certification would be considered without further qualification, and will be reconsidered based on the company’s first self-audit report.

FAIL indicates that one or more Action Level 1 issues or deficiencies need to be resolved. The company would need to make the appropriate change(s) to the product/process and most likely will need to resubmit the product for verification.

The participant understands that compliance with USP-DSVP does not constitute compliance with state requirements. The participant agrees that any sampling, inspections, or tests conducted by USP-DSVP are designed only to verify compliance with USP-DSVP requirements and do not relieve the participant of its responsibility to ensure the quality of its products in the marketplace or to comply with applicable federal, state, or local laws or regulations.




28

14. On satisfactory completion of the:

Evaluation of pre-audit documentation

Evaluation of quality control documentation

Evaluation of manufacturing documentation

Testing of product samples

Evaluation of on-site audit report

For each product that successfully completes the Program, USP will issue a approval letter. The letter will specify which of the participant’s product(s) are entitled to the use of the USP Verified Dietary Supplement Mark and other limiting information (such as manufacturing site information) as appropriate.

USP will review all labeling that will include the USP Dietary Supplement Verified Mark for the prospective product. USP reserves the right to ask for additional documentation as necessary.

The USP Verified Dietary Supplement Mark must be used in accordance with the guidelines in the USP DSVP Certification Mark Usage Manual and the Program License Agreement, which will be provided by USP along with the notification of approval to use the mark. These guidelines relate to

Size and color of the USP Verified Mark

Acceptable format and materials

Specifications for reproduction

Examples of appropriate and inappropriate use

Acceptable and unacceptable usage of the USP Verified Dietary Supplement Mark in advertising and promotional materials, exhibit signage, speaking engagements, presentations, educational materials and events, and on websites

USP requires submission of artwork for product labels, advertising, promotions, or other materials that include the USP Verified Dietary Supplement Mark for pre-approval. The artwork must be submitted in final mock-up form in color, along with stock (paper) samples and bindery details, if applicable. A specification sheet outlining the strategy/goals of the materials, the target audience, and the number of pieces—if any—to be mailed must be provided along with the artwork. USP may also require actual production copies of artwork using the USP Verified Dietary Supplement to be submitted for evaluation.

Issuance and Use of the USP Verified Program Mark




29

Written approval or disapproval of the materials submitted will be provided by USP to the participant. USP may, if necessary, request additional materials from the participant.

Materials must conform to the recommended guidelines to be approved by USP. If the materials are not approved by USP, the participant will be given an opportunity to correct or adjust deficiencies and resubmit the materials to USP. The participant must obtain USP’s final written approval before using the USP Verified Dietary Supplement Mark.

News releases and associated references to the Program must be submitted to USP for approval prior to release. If desired, USP, at its discretion, also will work with the participant on joint news releases. USP will draft, edit, and coordinate approvals of the joint news release and work with the participant to determine the media list(s) for distribution.

A list of licensed participants and licensed products under the Program will be made available to the public on the USP website.

If the USP Verified Dietary Supplement Mark is misused or improperly used, USP will work with the participant licensed to use the USP Verified Dietary Supplement Mark to resolve the problem(s) or any related dispute(s). USP and the licensed user will agree on a written plan to bring the usage into required conformance. However, if the problem cannot be resolved to USP’s satisfaction, USP will issue a written warning of proposed revocation or suspension of the license to use the USP Verified Dietary Supplement Mark either in its entirety or on a product-specific basis. The warning should specify the steps required for the participant to come into conformance and avoid revocation or suspension, and a reasonable time period for achieving conformance. In case of continued nonconformance, USP will make a final decision to revoke or suspend the participant’s license to use the USP Verified Dietary Supplement Mark, either in its entirety or on a product-specific basis. Such a decision may not be appealed by the participant.

Participants are reminded, however, that the terms and conditions set forth in the Program License Agreement have precedence over this manual.




30

15.

fter USP has granted approval to use the verification mark, a particpant might make changes to a product’s specifications, process control data, raw material

source, manufacturing site change, testing, or any other criteria deemed by the participant to be essential or significant to product quality.

Major changes must immediately be reported in writing to USP-DSVP. Minor changes must be reported in the Annual Products Report (APR), under a section that covers product “Changes Effected.” A list of the products that are impacted by such changes, along with the rationale for the changes, needs to be clearly indicated.

During the re-evaluation or re-testing period, the participant may continue to use the verification mark on product batches manufactured with the change(s) in accordance with approved specifications, so long as sufficient supporting documentation for the change has been provided to USP-DSVP. The participant must provide batch details that include batch/lot number, date of manufacture, and date of expiry of products manufactured under such changed conditions.

Major Site Changes: Major site changes include, but are not limited to, the following: (1) a move to a site that has not been audited and found to be acceptable by USP-DSVP; (2) the addition of a new manufacturing operation, such as manufacture of a liquid line where only tablet and/or capsules have been manufactured previously, for manufacturing USP verified products; and (3) the manufacture of a USP verified product from a product class that the site has not been approved to manufacture.

Major Changes to Equipment: A change to equipment different in design and operating principle.

Major Changes in Composition and Components: Major changes in composition and components include, but are not limited to, the following: (1) addition of a new product to a USP-DSVP verified product class; (2) the addition of a new dietary ingredient to a formulation; (3) changes to excipient concentration that are likely to have any detectable impact on formulation quality and performance.

Major Process Changes: Changes to the type of process used in the manufacturing of the product, such as change from wet granulation to direct compression of dry product.

Major Changes to Specification: Major changes to specifications include, but are not limited to, the following: (1) the assay range or some other significant test

Need for Re-Evaluation

A




31

parameter is broadened by a significant amount, usually as a result of a formulation change; and (2) a change in the analytical methodology employed for a given test that provides less assurance that the product meets its specification.

Major Change to Label: Any change to the supplement facts panel, the ingredient list, the order of ingredients listed on the label, or claims on the label.

Minor Changes: All other changes not specified.

If re-evaluation is required, USP-DSVP will immediately notify the participant by phone, with follow-up in writing. USP may also require, if necessary, under special circumstances, the participant to cease continued use of the verification mark until the re-evaluation has been completed.

The participant may appeal the decision to require re-evaluation or re-testing; however, the participant shall not have the right to appeal the decision requiring them to cease using the verification mark until re-evaluation or re-testing has occurred.




32

16.

esults reported from the participant’s internal audit are used to monitor the state of operations within the company after the on-site audit conducted by

USP.

The on-site audits will be conducted by USP once every three years. In the intervening years, USP will conduct a surveillance audit, typically lasting one day.

The internal audit must be conducted by the participant annually. To conduct the internal audit, the participant’s internal audit SOP should be used. The participant’s internal audit SOP should cover all quality systems addressed in the On-Site Audit Checklist (See Forms and Checklists). The report must include progress on corrective actions against observations noted during the on-site audit conducted by USP, or during the particpant’s internal audit. USP may ask to review the internal audits when conducting the surveillance audit.

An Annual Products Report (APR) must also be submitted to USP-DSVP. The report must include progress on corrective actions against observations noted during the product verification. The report must also include an analysis of product quality-related deviations. The report must include a section for product “Changes Effected.” The list of products that are impacted by such change(s), along with the rationale for the change(s), needs to be clearly indicated.

If any compliance issues arise during the review of these reports, USP-DSVP reserves the right to conduct an on-site audit, and/or re-evaluate and re-test the product(s). If an on-site audit or re-evaluation of the product(s) is required, USP-DSVP will immediately notify the participant by phone, with follow-up in writing. USP may also require the participant to cease continued use of the verification mark until the compliance issues have been satisfactorily addressed.

USP reserves the right to reclassify a change, reported by the participant in the Annual Products Report to be a minor change, as a major change based on scientific considerations. During the re-evaluation or re-testing period, the participant may continue to use the verification mark on product batches manufactured with the change(s) in accordance with licensed terms, so long as sufficient supporting documentation for the change has been provided to USP-DSVP.

The DSVP Annual Summary Report (ASR) should include a cover page listing the USP verified products in the order in which their Annual Products Report (APR) are submitted. The list should include a matrix indicating for each product whether or not there are any issues of concern to which USP should pay particular attention.

Participant’s Internal Audit and Annual Product Reports

R




33

Annual Product Review for each product should include the following information in a format that best suits the participant:

1. Copy of Current Specification

2. Complaints

3. Nonconformances

4. Stability

5. Changes Effected (major and minor) on processes and/or formulation

6. Any other relevant information concerning the product carrying the USP verified mark, such as reports of any regulatory agency and their findings.

The standard submission for each section should contain an appropriate level of detail to describe the current status of the product, in twenty-five words or less if possible. Initially, no data is requested to be submitted for any changes, but instead just the rationale for the changes.

USP-DSVP reserves the right to request additional information or data, if necessary.




34

17.

fter the USP-DSVP Verified mark is awarded to products, USP will perform a periodic “off-the-shelf” evaluation of the products to ensure that they continue

to meet the criteria to carry the mark.

Surveillance testing will commence after the USP-DSVP certification has been awarded to a product class. Products not originally verified in the product class will be tested such that all unique products are tested at least once over the course of the initial three years, from the date the product class is certified. The number of products not originally verified is divided equally between the remaining time of the initial three-year period. A minimum of one product is evaluated per calendar year, regardless of whether all the products have been tested.

After the initial three-year verification period, a number of products equal to the square root of the number of products per class is selected and evaluated every year. Different products are selected every year until all products in a product class have been evaluated. The cycle is then repeated.

The participant may be contacted to determine the outlets through which the product is being distributed. National sampling will be conducted as appropriate. USP-designated representatives will be asked to select specific products from various marketing locations, via Internet or other marketing channels. They will ship the products to USP headquarters in Rockville, MD.

USP-DSVP will request that the participant submit the necessary quality control and manufacturing documentation so that USP Staff can conduct limited documentation and label review for the product lot of interest. The information required is listed below:

Limited Documentation:

The following is an outline of the documentation to be provided for products undergoing market surveillance. Please provide the documentation organized to the major sections listed below; the documentation can be provided electronically. Sections II.A, III.A. and III.B. apply to each product lot selected for market surveillance.

Market Surveillance

A




35

Section II. Quality Control Documentation

A. Release and Shelf-life Specification for Finished Product 1. Specification for the finished product. 2. QC laboratory release form for the finished product (CoA, if applicable).

3. Test results and the corresponding raw data (i.e., laboratory notebook pages, spectra, chromatograms, etc.).

Section III. Manufacturing Documentation A. Master Formula and Batch Record 1. Include master batch records for manufacturing, including any premixes

and subassemblies. 2. Include approval signatures and date(s) for master batch records

submitted. B. Executed Batch Records 1. Include premix or subassembly executed batch records. 2. Include verification that the shelf-life calculation was verified and

correct. 3. Include scale print-outs verifying measured weights of raw materials. 4. Include final QA testing and approval of finished lots.

Market surveillance testing on the selected product lots may include assay content of label claim and selected parameters for contamination and performance characteristics. Test data will then be reviewed to determine whether continued use of the certification mark should be approved or withdrawn. The participant will be notified of surveillance results. In the event of an issue, USP will work with the participant to resolve the issue. If the issue cannot be resolved to USP’s satisfaction then USP may suspend or revoke use of the certification mark.

Problems detected during market surveillance can be categorized as either a Critical Deficiency, a Major Deficiency, or a Minor Deficiency, as follows.

Critical Deficiencies There is a reasonable probability that the use of, or exposure to, the product may cause serious adverse health consequences or death.




36

And/or there is a remote probability that the use of, or exposure to, the product may cause temporarily or medically reversible adverse health consequences.

And/or a non-hazardous ingredient not listed on the label is detected during testing at a concentration that exceeds those allowed by federal regulations.

Major Deficiencies An ingredient tested is less than 100% of label claim, outside normal analytical variance.

Significantly crushed capsules, leaking capsules, or broken tablets that affect the dosage.

An ingredient is detected in an amount that exceeds those allowed in a USP monograph, or that is greater than 150% of label claim when not allowed in USP. Ginkgo biloba and liquid products are exempt from this requirement.

Other non-compliance with label or specifications.

Minor Deficiencies An ingredient tested is greater than 125% of label claim and is not a recommended overage.

And/or physical appearance of the sample indicates minor product deterioration such as excessive dust in container (tablets), crushed capsules (hard gelatin), etc.

And/or any other minor deviations that may be observed.

If a critical deficiency is observed, USP-DSVP will inform the company representative of the product problem, within 24 hours of detection, via conference call. USP-DSVP will present all test data and information that was used to determine the severity of the deficiency and will recommend recall of the product. USP-DSVP will notify the FDA of its findings.

If a major deficiency is observed and the non-conforming result investigation confirms the original result, then USP-DSVP will obtain samples from three (3) different lots of product. These lots will be tested to determine if the major deviation was an isolated incident or a pervasive processing problem.

If the testing indicates that the lot failure was an isolated incident, USP-DSVP will notify the participant and request them to conduct a thorough internal investigation and report to USP-DSVP any observations and proposed corrective actions taken to prevent future occurrence of the deviation. USP will recommend recall of this lot of product.




37

If the testing indicates that the failure is not an isolated incident and is a major processing problem, USP-DSVP will immediately inform the company representative of the problem, within 24 hours of detection, via conference call. USP-DSVP will present all the test data and information that was used to determine the severity of the deviation and will recommend recall of the product. USP-DSVP will request the participant to conduct a thorough internal investigation and report to USP-DSVP any observations and proposed corrective actions taken to prevent future occurrence of the deviation. If the participant fails to demonstrate corrective action within 30-days from notification, USP-DSVP may suspend/revoke the USP Verified mark for that product. The participant may appeal USP-DSVP’s decision to suspend or revoke the mark within 30 days from notification. If the participant does not provide corrective action, show sufficient evidence of appropriate action, or request an appeal, the USP Verified mark will be revoked for that product.

If a minor deviation is observed, USP-DSVP will inform the company representative of the observations detected during the market surveillance testing. USP-DSVP will verify that appropriate corrective action is taken by the participant.




38

18.

n certain situations USP may suspend, withdraw, or refuse to issue the verification mark to participants in the USP-DSVP. Participants have the

opportunity to appeal the following:

Rejection of quality control and/or manufacturing documentation, test results, or audit reports

Product recalls

Suspension of the verification mark

Rejection due to documentation, test results, or audit reports

USP may reject as insufficient:

Documentation that fails to meet the requirements for pre-audit, quality control, or manufacturing documentation (for initial certification and market surveillance)

Test results that fail to demonstrate that the product contains the claimed ingredient in the labeled amount or other product specifications (for initial verification and market surveillance)

Audit reports that show deficiencies or deviations from good manufacturing practices at the facility

USP will send written notification of rejection to the participant, along with any relevant findings or reports. The participant will have the opportunity to appeal the rejection or take corrective action(s). Subsequently, if USP rejects the corrective action(s), the participant may appeal that rejection. The participant must send a written notice of appeal, along with any supporting evidence, within 30 days from the date of receiving the written notification from USP.

USP’s Appeals Board will review the evidence received with the appeal and decide to accept or reject the participant’s data and/or audit reports. In either case, written notification of the decision will be sent to the participant. If the data and/or audit reports are accepted, USP will resume evaluation of the participant and data at the appropriate step in the USP-DSVP process. If the data and/or reports are rejected, the participant can re-enter the program after correcting the deficiencies.

I

Appeals




39

19.

SP is entitled to recommend a product recall if critical product deficiencies are detected. Product deficiencies are considered critical if:

There is reasonable probability that the use of, or exposure to, the product may cause serious adverse health consequences or death

There is even a remote probability that the use of, or exposure to, the product may cause temporary or medically reversible adverse health consequences

An official from the participating company has submitted fraudulent documents to the USP-DSVP

The FDA has recommended a voluntary recall

Upon recommending a recall, USP will immediately notify the participant. Within 24 hours of such recall recommendation, USP will convene a hearing—by conference call—with the participant’s representative(s), who must answer any questions and provide the requested information about the product problem. USP will then affirm or overturn its recommendation to recall the product. If USP decides that a recall is not to be recommended, it will immediately notify the participant. If USP decides that a recall is appropriate, it will immediately contact the FDA and notify the participant to discontinue use of the USP-DSVP certification mark on the product. The participant must take immediate action to do so but may appeal the decision to discontinue use of the mark.

Suspension of the mark USP may suspend a participant’s right to use the USP-DSVP Verified mark due to:

Violation of any USP-DSVP participation criteria, policies, or procedures by the manufacturing company, its affiliates, or agents.

Major product deficiencies, which include a major deviation from product standards, or the lack of essential product criteria.

Major product deficiencies on a new, unreleased product.

Major changes to a product’s specifications, process control data, raw material source, manufacturing site change, testing, or any other change deemed essential by the participant, which must immediately be reported in writing to USP-DSVP. USP-DSVP will review the information and determine whether to suspend use of the certification mark during re-evaluation or re-testing of the product. Such work may include review of analytical data or additional audits at the participant’s expense.

Minor product deficiencies to a product bearing the USP-Verifed mark. Minor product deficiencies include significant deviations from product standards that

U

Product Recalls




40

do not show evidence of manufacturing problems or health risk. The participant must notify USP of minor product deficiencies. USP will work with the participant to ensure that the minor product deficiencies are resolved. If the participant has repeated minor product deficiencies, USP may suspend use of the mark.

The participant may appeal USP’s decision to suspend use of the certification mark. The appeal, along with any supporting evidence, must be made within 30 days from the receipt of notification of suspension from USP. If no appeal is made within this period, the suspension becomes a revocation of the use of the certification mark with no further rights of appeal.

While submitting the appeal, the participant may request a review of analytical methods data, documentation, or an audit. USP will conduct such a review or audit at the participant’s expense and provide a written report of findings to the participant.

The participant may, on appeal, also request a hearing. USP will set a place, time, and date—not more than 60 days after receiving the request for an appeal—for the hearing and notify the participant. USP and the participant may present evidence at the hearing. The participant may be represented by a counsel. The participant shall pay all reasonable expenses incurred by USP, including, but not limited to, travel expenses.

USP will make a recommendation and provide explanations within 30 days, if in the hearing it is found that the participant:

Is substantially out of compliance with the USP-DSVP criteria—in which case USP will revoke use of the certification mark.

Is substantially in compliance with the USP-DSVP criteria—in which case USP will reverse the suspension and reinstate use of the mark.

Can conduct corrective action within six months to become substantially compliant with USP-DSVP criteria—in which case USP will affirm the suspension until further review. The participant must notify USP, within 30 days, that it will seek the review. The participant will bear the cost of such review by USP. The participant’s failure to notify USP within 30 days, or to be in substantial compliance within six months, will result in revocation of use of the mark

Upon revocation of the verification mark, a participant may re-enter the program one year from such revocation, on payment of full fees.




41

Glossary

Acceptance Criteria: predetermined limits against which sample data are compared to determine compliance with standards of quality.

Adequate: item/area/system/knowledge that meets basic minimum requirements.

AHP: American Herbal Pharmacopeia is a tax-exempt, educational 501(c)(3) foundation, started in 1995, whose mission is to disseminate authoritative and comprehensive information to the herbal industry, pharmacists, health care practitioners, educational institutions, regulatory agencies, and the general public.

AHPA: American Herbal Products Association is a national trade association of the herbal products industry, which is composed of growers, processors, manufacturers, and marketers of herbs and herbal products.

AMB-EC: USP’s Analytical Microbiology Expert Committee.

AOAC: AOAC International, formerly the Association of Official Analytical Chemists, is an independent scientific association of analytical scientists, with members located throughout the world. AOAC publishes Official Methods of Analysis of AOAC International, which contains validated chemical and microbiological analytical methods in the area of foods, beverages, agriculture, and drugs.

Appeals Panel: a group consisting of two (2) members from appropriate USP Expert Committees; the USP Director of Quality Assurance; and additional USP staff. The Panel will have the authority to review appeals submitted by companies participating in the Program regarding: (1) rejection of data, process controls, or audit reports; (2) product recalls; or (3) suspension of the use of the mark.

Auditor: any Program staff member or USP approved audit firm/consultant that performs the on-site audit.

BAM: The FDA’s Bacteriological Analytical Manual is a collection of procedures preferred by analysts in FDA laboratories for the detection in food and cosmetic products of pathogens (bacterial, viral, parasitic, plus yeast and mold) and of microbial toxins. BAM is published and distributed by AOAC International, and is being placed on FDA’s Web site.

Batch (or Lot): a specific quantity of a finished product or other material that is intended to have uniform character and quality, within specified limits and is produced according to a single manufacturing order during the same cycle of manufacture.

CFSAN: FDA’s Center for Food Safety and Applied Nutrition.

Council of Experts (CoE): USP Convention’s group of elected scientific standard-setting bodies.




42

Current Quality System: the quality control system and manufacturing process in place since the last instituted change to the product manufacturing operation.

Dietary Ingredient: as defined in section 201(ff) of the Federal Food, Drug, and Cosmetic Act, a dietary ingredient can be a vitamin, a mineral, an herb or other botanical, an amino acid, a botanical, 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 the aforementioned ingredients.

Dietary Supplement: as defined in section 201(ff) of the Federal Food, Drug, and Cosmetic Act, a dietary supplement is a product that complies with or is intended for ingestion in a form described in section 411(c)(1)(B)(I) of the Federal Food, Drug, and Cosmetic Act; is not represented for use as a conventional food or as a sole item of a meal or the diet; and is labeled as a dietary supplement.

DSHEA: Dietary Supplement Health and Education Act of 1994.

DSIEC: Dietary Supplement Information Expert Committee.

DSVP: Dietary Supplement Verification Program.

EP: European Pharmacopoeia.

EC: USP’s Expert Committee. One of USP Convention’s elected scientific standard-setting bodies.

EPA: U.S. Environmental Protection Agency.

FAC: CFSAN’s Food Advisory Committee.

FCC: Food Chemical Codex is a publication under the administrative supervision of the Food and Nutrition Board of the Institution of Medicine/National Academy of Sciences.

FDA: U.S. Food and Drug Administration.

Federal FDC Act: the Federal Food, Drug, and Cosmetic Act.

IAG: the Industry Advisory Group is composed of representatives from dietary supplement manufacturing companies that provide advice for the guidelines and requirements of the USP-DSVP. The number of participating companies, at any particular time, is limited to four. The participating companies are selected by USP, on an annual basis.

LOD: Loss On Drying.

Manufacturing Documentation: the manufacturing directions, master formulation, and executed batch records.




43

Method: a procedure used to generate analytical data.

NF: National Formulary, current edition, including its supplements.

Non-Standardized Dietary Ingredients: include botanical or “other” dietary ingredient raw material, or traditional-style extracts made according to historical or traditional practices. The dietary ingredient tends to be one whose composition is complex, containing groups of chemical compounds, many of which are not identified and for which no analytical method exists. Naturally occurring botanicals or “other” dietary ingredients for which no label claim is made regarding the chemical constituents (e.g. ground botanicals or ground oyster shells) are considered non-standardized dietary ingredients.

OMA: Official Methods of Analysis of AOAC International is a publication of validated methods under the supervision of the AOAC.

OVI: Organic Volatile Impurities as defined by USP General Chapter <467>.

PAM: FDA’s Pesticide Analytical Manual is a repository of the analytical methods used in FDA laboratories to examine food for pesticide residues for regulatory purposes (40 CFR 180.101 (c)). The manual is organized according to the scope of the analytical methods in a two-volume set, available in Adobe Acrobat pdf format on FDA’s Web site.

Participant: a company that has qualified to participate in the USP-DSVP.

PF: Pharmacopeial Forum is a bimonthly publication of the USP. It is the working vehicle of the USP Council of Experts. It also provides interested parties an opportunity to review and comment as the Council of Experts develops or revises standards for the USP–NF.

Product Deficiencies (Major): include the following: (1) there are major deviations from product standards that are judged would render the product unusable for its intended purpose; or (2) there is a lack of essential product criteria that are judged would render the product unusable for its intended purpose; or (3) the company, affiliates, or agents engage in violation of any USP-DSVP participation criteria, policy, or procedure.

Product Deficiencies (Critical): include the following: (1) there is a reasonable probability that the use of, or exposure to, the product may cause serious adverse health consequences or death; (2) there is even a remote probability that the use of, or exposure to, the product may cause temporary or medically reversible adverse health consequences; (3) a company official has submitted fraudulent documents to the USP-DSVP program; or (4) the FDA has recommended a voluntary recall.

Product Deficiencies (Minor): substantial deviations from product standards that show evidence of significant manufacturing and/or quality control problems.

PVM: AOAC International Peer Verified Method.




44

QA: Quality Assurance.

QC: Quality Control.

Raw Material: any ingredient intended for use in the manufacture of a dietary supplement including those that may not appear in the finished product.

Recall: a company’s removal or correction of its marketed product that USP-DSVP, FDA, or the company initiates due to critical product deficiency.

Reference Standard: characterized chemical substances, used to test for compliance in order to demonstrate identity, strength, quality, and purity for drugs and dietary supplements.

Shall: used to state mandatory requirements.

Shelf Life: the interval of time for which the product must conform to applicable specifications when stored under labeled conditions. The shelf life period should be supported by stability data and be indicated on the product label and exterior commercial packaging.

Should: used to state recommended or advisory procedures or to identify recommended equipment.

Specification: includes the test, test method, and acceptance criteria that define the standard of quality for a material.

SOP: Standard Operating Procedure.

Standardized Dietary Ingredients: For the purposes of this manual, a limited definition of standardized dietary ingredients is being used. Standardized ingredients are tested to verify that products are truthfully labeled with respect to their contents. For botanicals and “other dietary supplements”, standardized ingredients contain a defined amount of a particular chemical constituent or group(s) of constituents, known as marker compound(s). In other cases, as with vitamins, ingredients may be “standardized” according to a percent daily value (%DV). Note that a complete definition of standardization includes the information and controls needed to produce a material of predetermined and defined consistency.

USP: United States Pharmacopeia, current edition, including its supplements.

USP–NF: the current official volume of the United States Pharmacopeia–National Formulary.




45

Forms and Checklists

Checklist for Quality Control Documentation SECTION I

Checklist for Manufacturing Documentation SECTION II

Checklist for On-Site Audit


Checklist for Quality Control Documentation SECTION I

Company Information

COMPANY NAME YEAR ESTABLISHED OWNER

ADDRESS

NAME AND TITLE OF MANUFACTURING CONTACT PHONE NUMBER

NAME AND TITLE OF QA CONTACT PHONE NUMBER

PRODUCT NAME MANUFACTURER PRODUCT CODE USP VER BARCODE

Product Information—Quality Control Methods and Data

Complete documentation, in the requested format, must be received before review begins. SHADED AREA TO BE

COMPLETED BY USP STAFF AC = Acceptable NAC = Not Acceptable MI = Missing Information N/A = Not Applicable

A. Specifications for all raw materials (dietary ingredients and excipients) and packaging/labeling materials

1. Raw Material Specification (must be in compliance with USP–NF standards, when applicable, otherwise statistical justification needs to be provided)

a. Identification by spectroscopic, organoleptic, chemical, and/or chromatographic test. Materials of botanical origin must be labeled with Latin binomial as per Herbs of Commerce and plant part(s) used. If applicable, they must conform to macro/microscopic description in addition to chemical and/or chromatographic identification test.

AC NAC MI N/A

b. Content of specific entity/marker compound by chemical and/or biological procedure. AC NAC MI N/A

c. Undesirable contaminants and components. (1) Heavy metals (<10ppm per USP <231>, or limit set by USP–NF monograph when

applicable). AC NAC MI N/A

(2) Residual solvents (OVIs or other hazardous solvents when applicable). AC NAC MI N/A

(3) Known toxic components as mentioned in the specifications (e.g., aristolochic acid). AC NAC MI N/A

(4) Insects/foreign matter (for botanicals or other products as applicable). AC NAC MI N/A

(5) Pesticides analysis for materials of botanical origin. AC NAC MI N/A

(a) For Ginseng, FDA Pesticide Analytical Manual Vol. 1, Section 303, 1/94, modified—CRN/AHPA.

AC NAC MI N/A

(6) Microbial counts and absence of specified microorganisms. Materials of botanical origin may also require a test for Aflatoxins.

AC NAC MI N/A

(7) Absence of adulterants (for botanicals in compliance with guidelines set by AHPA and FAC).

AC NAC MI N/A

(8) Other undesirable components. AC NAC MI N/A

d. Other quality standards (water, Loss on Drying, Ash, Residue on Ignition, ph) AC NAC MI N/A

2. Packaging and Labeling Materials

a. Description and specifications for packaging materials in direct contact with the product. AC NAC MI N/A

b. Samples and specifications for labels and labeled packaging. AC NAC MI N/A

B. Release and shelf-life specifications for the finished product (must be in

compliance with USP–NF standards, when applicable, otherwise statistical justification needs to be provided)

SHADED AREA TO BE COMPLETED BY USP STAFF

AC = Acceptable NAC = Not Acceptable MI = Missing Information N/A = Not Applicable

1. Physical Examination

a. Appearance (e.g., dosage form type, shape, and size). AC NAC MI N/A

b. Color AC NAC MI N/A

2. Identification by spectroscopic, chemical, or chromatographic test. Materials of botanical origin must be labeled with atin binomial and plant part(s) used.

AC NAC MI N/A

3. Content of dietary ingredient by specific entity/marker by chemical and/or biological procedure.

AC NAC MI N/A

4 Performance characteristics according to dosage form type

a. Tablets and Capsules—Weight variation or content uniformity and dissolution or disintegration.

AC NAC MI N/A

b. Powders—Appearance on reconstitution. AC NAC MI N/A

c. Liquids—Appearance, pH. AC NAC MI N/A

d. Suspensions—Appearance on resuspension, homogeneity. AC NAC MI N/A

5. Undesirable components—(not needed if absence is demonstrated through raw materials and process control).

AC NAC MI N/A

a. Heavy metals AC NAC MI N/A

b. Known toxic components AC NAC MI N/A

c. Microbial count and absence of specified microorganisms AC NAC MI N/A

6 Other quality standards (friability, hardness, water, pH) AC NAC MI N/A

C. Testing Method(s) Verification

1. Analytical method(s) from USP–NF, AOAC International’s Official Methods of Analysis, a Peer-Verified Method, or the Food Chemical Codex should demonstrate suitability for product testing.

a. Lack of interference of other components and/or excipients with analyte determination. AC NAC MI N/A

b. Accuracy and precision for analyte determination. AC NAC MI N/A

c. Raw data/chromatograms. AC NAC MI N/A

2. Analytical method(s) not from USP–NF, AOAC International’s Official Methods of Analysis, a Peer-Verified Method, or the Food Chemical Codex should be verified as per USP <1225> as applicable. Full verification is required for parent member of product family (additional products need only demonstration of suitability). If full verification is not possible, sufficient information must be provided to verify the method(s) suitability for the intended use.

a. Linearity across a suitable range AC NAC MI N/A

b. Accuracy AC NAC MI N/A

c. Precision AC NAC MI N/A

d. Limit of detection/Limit of quantitation AC NAC MI N/A

e. Specificity AC NAC MI N/A

f. Raw data/chromatograms AC NAC MI N/A

3 If analytical testing is performed by a contracted laboratory, method verification needs to be submitted by the lab as it pertains to subsection C1 or C2 above; and/or lab verification by manufacturer or USP is needed.

AC NAC MI N/A

D. Reference Materials SHADED AREA TO BE

COMPLETED BY USP DSVP AC = Acceptable NAC = Not Acceptable MI = Missing Information N/A = Not Applicable

1. A list of all reference standard materials needed for raw material and product testing, indicating the quality and source if not a USP Reference Standard used for a USP test.

AC NAC MI N/A

2. For non-USP Reference Standards or reference standards for non-USP tests, characterization data to support the suitability of the reference material for its intended use.

AC NAC MI N/A

E. Stability Data

1. Stability protocol describing the product, product packaging, test specifications, test intervals, and storage conditions.

AC NAC MI N/A

2. Data to support the marketed shelf-life period in the commercial package at the storage conditions recommended on the product labeling.

a. For new products containing new dietary ingredients of unknown stability, 1 batch, 3 months at 40°C/ 75% RH supporting the shelf life. A commitment to provide 1-year data at the labeled storage conditions is required with a commitment to provide stability data at the end of the declared shelf-life period.

AC NAC MI N/A

b. For new products similar to existing products, real-time data along with side-by-side accelerated stability data comparing the new and existing product may be sufficient data to support the shelf life period of the new product.

AC NAC MI N/A

c. For existing products, comparing test data from suitable retained samples, which have been manufactured under the current quality control system and have been stored under controlled conditions, for necessary quality attributes against the initial release data may be sufficient to support the shelf-life period.

AC NAC MI N/A

3. Data should be provided for appearance, content, performance characteristics, and microbial count.

AC NAC MI N/A

4. Specifications for product stability. AC NAC MI N/A

F. Documents for Product Under Review

1. Certificates of analysis for submitted product. AC NAC MI N/A

2 Copies of raw data, including spectra and chromatograms of samples and standards as applicable.

AC NAC MI N/A

Name and Signature of USP Staff Reviewer and Date

Reported By: ______________________________ ____________________________ __________ Printed Name Signature Date

Reviewed By: ______________________________ ____________________________ __________ Printed Name Signature Date


Checklist for Manufacturing Documentation Submitted for Review Under USP DSVP

SECTION II

Company Information

COMPANY NAME

ADDRESS

NAME AND TITLE OF MANUFACTURING CONTACT PHONE NUMBER

NAME AND TITLE OF QA CONTACT PHONE NUMBER

PRODUCT NAME MANUFACTURER PRODUCT CODE USP VER BARCODE

Product Information—Manufacturing Records

Complete documentation, in the requested format, must be received before review begins. SHADED AREA TO BE

COMPLETED BY USP STAFF AC = Acceptable NAC = Not Acceptable MI = Missing Information N/A = Not Applicable

A. Master formula/manufacturing directions for each product containing

1. A complete list of raw materials/packaging components used in the manufacture of the product, including positive identification of all labeling to be used; designated by names or codes sufficiently specific to indicate any special quality characteristic(s).

AC NAC MI N/A

2. A statement of the weight or measure of each raw material used in the manufacture of a typical batch of the product, including ingredients not found in the final product. Each claimed dietary ingredient must be at least 100% of label claim.

AC NAC MI N/A

3. The name and weight or measure of each dietary ingredient per unit or per unit of weight or measure, or percentage of the supplement.

AC NAC MI N/A

4. A statement of the total weight or measure of the dietary supplement unit. AC NAC MI N/A

5. A statement of theoretical/actual weight or measure of the dietary supplement expected at the conclusion of manufacture. Include the maximum and minimum percentages of actual yield beyond which justification to release the batch is required.

AC NAC MI N/A

6. A statement concerning any calculated overage of dietary ingredients contained in the product. AC NAC MI N/A

7. Acceptable procedures for reprocessing, which have demonstrated that the product from a reprocessed batch meets label declaration and stability or a statement that reprocessing is not performed.

AC NAC MI N/A

8. A statement of shelf-life print specifications for labeling and any calculations associated with determining the shelf-life dates.

AC NAC MI N/A

9. A list of all processes, operations, and process/environmental controls to be performed at each step during the manufacture.

AC NAC MI N/A

10. Identification of steps requiring a Quality Control check. AC NAC MI N/A

11. A description of all equipment and production lines to be used during the manufacture. AC NAC MI N/A

12. List of references for appropriate equipment cleaning procedures, indicating SOP# and description.

AC NAC MI N/A

13. Signature(s) of responsible authoring person(s), signature(s) of responsible review/approval person(s) other than author, and effective date.

AC NAC MI N/A

B. Executed lot records for the requested lots of product

SHADED AREA TO BE COMPLETED BY USP STAFF

AC = Acceptable NAC = Not Acceptable MI = Missing Information N/A = Not Applicable

1. Production order with lot number, manufacturing start date, expiration date, and responsible signatures (production operators, supervisor, and final QA review).

AC NAC MI N/A

2. Evidence that the raw materials, packaging containers, closures and labels, etc., were verified as released and acceptable for use. Copies of the labeling used, including labels issued and labels with lot numbers and shelf-life dates. Evidence that the shelf-life calculation was verified as correct according to the specifications.

AC NAC MI N/A

3. Record of all pertinent weights and measures. AC NAC MI N/A

4. All pertinent in-process control data. AC NAC MI N/A

5. Identification (by code, lot #, or serial #) of actual raw materials, in-process materials, equipment, and lines used.

AC NAC MI N/A

6. Environmental control records, as required by manufacturing process directions. AC NAC MI N/A

7. Product yield calculation. AC NAC MI N/A

8. Complete description of any deviation from the written procedures, including justification. AC NAC MI N/A

9. Reprocessing information, if applicable. AC NAC MI N/A

10. Demonstration that Quality Assurance provides final disposition of product lot. AC NAC MI N/A

Name and Signature of USP Staff Reviewer and Date

Reported By: ______________________________ _________________________ ___________ Printed Name Signature Date

Reviewed By: ______________________________ _________________________ ___________ Printed Name Signature Date


VER Form 31, Version 2 Form VER-31-02

USP DIETARY SUPPLEMENT VERIFICATION PROGRAM ON-SITE AUDIT CHECKLIST

COMPANY: DATE: LOCATION: ESCORTS: AUDITORS: NOTE: THIS CHECKLIST IS DESIGNED AS GUIDANCE FOR EXPERIENCED AUDITORS TO USE IN CONDUCTING AUDITS. IT IS NOT NECESSARILY INTENDED TO BE ALL-

INCLUSIVE, OR TO LIMIT THE SCOPE OF THE AUDIT. ONE PRODUCT MUST BE TRACKED FROM RAW MATERIAL RECEIVING TO FINISHED PRODUCT RELEASE. THIS CHECKLIST, CONTAINS THE INFORMATION REQUIRED IN SECTIONS OF THE USP CHAPTER <2750> AND THE REQUIREMENTS OF 21 CFR PART 111 – CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PACKAGING, LABELING OR HOLDING OPERATIONS FOR DIETARY SUPPLEMENTS.

INDEX TO GUIDELINE A. GENERAL INFORMATION B. ORGANIZATION AND PERSONNEL C. PHYSICAL PLANT AND GROUNDS D. EQUIPMENT AND UTENSILS E. REQUIREMENTS TO ESTABLISH A PRODUCTION AND PROCESS CONTROL SYSTEM F. REQUIREMENTS FOR QUALITY CONTROL G. REQUIREMENTS FOR COMPONENTS, PACKAGING, AND LABELS RECEIVED H. REQUIREMENTS FOR MASTER MANUFACTURING RECORDS

I. REQUIREMENTS FO R BATCH PRODUCTION RECORDS J. REQUIREMENTS FOR LABORATORY OPERATIONS K. REQUIREMENTS FOR MANUFACTURING OPERATIONS L. REQUIREMENTS FOR PACKAGING AND LABELING OPERATIONS

M. HOLDING AND DISTRIBUTION N. RETURNED DIETARY SUPPLEMENTS

O. PRODUCT COMPLAINTS P. RECORDS AND RECORDKEEPING

© March 2009 United States Pharmacopeial Convention, All rights reserved. 52

Form VER-31-02

USP DIETARY SUPPLEMENT VERIFICATION PROGRAM ON-SITE AUDIT CHECKLIST

S =SATISFACTORY; IN = INADEQUATE; NA =NOT APPLICABLE S IN

NA COMMENTS

A. GENERAL INFORMATION

Brief company history

When was the last FDA or other regulatory inspection, What were the results of the inspection?

Have the inspection issues been resolved?

Does this company perform all operations at this site? (Yes, No)

If not, what other sites/companies are used and for what functions?

Are there adequate laboratory facilities for the testing and approval or rejection of all components?

Is testing out-sourced? (Yes, No)

Is there a policy of client notification of subcontracting?

B. ORGANIZATION AND PERSONNEL

Are there written Standard Operating Procedures (SOPs) for Personnel Requirements?

Approximately how many employees are in the company? At this site?

Is there capacity for additional work?

Is there a separate Quality Control Unit that has the responsibility and authority to approve or reject all raw materials, product containers, closures, in-process materials, packaging material, labeling, and finished dietary supplements.

Does the Quality Control Unit have the responsibility for the approval or rejecting of all SOPs and product specifications?

Do all personnel have the proper education, training, and or experience to perform their assigned functions?

Is there a written Training Program? Does it ensure that personnel are trained prior to performing their assigned functions? Is training documented?


Form VER-31-02 USP DIETARY SUPPLEMENT VERIFICATION PROGRAM

ON-SITE AUDIT CHECKLIST


NA COMMENTS

Are there written job descriptions describing the required qualifications and training needed for each job?

HYGIENIC PRACTICES

• Is there a written hygiene plan? Does it cover prevention of microbiological contamination, wearing protective garments, hand washing, personnel cleanliness, and removal of jewelry, use of gloves, wearing hair covers, proper storage of personnel belongings, no food, drink or smoking in production areas.

• Are there written requirements that prevent microbial contamination from sick or infected personnel and contamination with filth, or other extraneous materials?

C. PHYSICAL PLANT AND GROUNDS GROUNDS

Are the grounds maintained in such a manner that protects against the adulteration of dietary supplements?

Are the grounds maintained in such a manner to prevent breeding places, or harborage areas for pests?

Is there adequate drainage areas which prevent product adulteration by seepage, foot-borne filth, or breeding places for pests

Are operational systems for waste treatment and disposal properly controlled to ensure that they do not constitute a source of adulteration in areas where product is exposed?

BUILDINGS DESIGN

How old are the facilities?

Is there adequate security to assure there is no entry by unauthorized persons?

Are facilities maintained in a clean and orderly manner and in a good state of repair?

Are facilities suitable in size, construction, and design to facilitate the maintenance, cleaning, and sanitizing operations?

Provide adequate space for the orderly placement of equipment and holding of materials as is necessary for maintenance, cleaning, and sanitizing operations and to prevent contamination and mix-ups of components and dietary supplements during manufacturing, packaging, labeling, or holding of a dietary supplement?





NA COMMENTS

Permit the use of proper precautions to reduce the potential for mix-ups or contamination of components, dietary supplements, or contact surfaces, with microorganisms, chemicals, filth, or other extraneous material.

Does the plant have, and or use, separate or defined areas of adequate size or other control systems, such as computerized inventory controls or automated systems of separation, to prevent contamination and mix-ups of components and dietary supplements during all manufacturing operations of receiving, identifying, manufacturing, packaging, labeling, cleaning and sanitizing, laboratory analyses , and holding components or dietary supplements?

Design and construction include: Floors, walls, and ceilings that can be adequately cleaned and kept clean and in good repair

Design and construction include: Fixtures, ducts, and pipes that do not contaminate components, dietary supplements, or contact surfaces by dripping or other leakage, or condensate.

Design and construction include: Adequate ventilation or environmental control equipment such as airflow systems, including filters, fans, and other air-blowing equipment, that minimize odors and vapors (including steam and noxious fumes) in areas where they may contaminate components, dietary supplements, or contact surfaces.

Design and construction include: (iv) Equipment that controls temperature and humidity, when such equipment is necessary to ensure the quality of the dietary supplement;

Design and construction include: Aisles or working spaces between equipment and walls that are adequately unobstructed and of adequate width to permit all persons to perform their duties and to protect against contamination of components, dietary supplements, or contact surfaces with clothing or personal contact?

Provide adequate light in all manufacturing areas, including hand-washing areas, dressing and locker rooms, and bathrooms?

Provide effective protection against contamination of components and dietary supplements in bulk fermentation vessels, by, for example: Use of protective coverings, Placement in areas where you can eliminate harborages for pests over and around the vessels; Placement in areas where you can check regularly for pests, pest infestation, filth or any other extraneous materials; and Use of skimming equipment?

Is there an adequate pest control program? Use of adequate screening or other protection where necessary?

Are there provisions for power backup sources for critical systems if main power should fail, and/or an SOP for recovery from power failure?

Is there an environmental monitoring program that includes qualification and monitoring of all utilities?





NA COMMENTS

How are temperature and humidity excursions handled?

D. EQUIPMENT AND UTENSILS

MAINTENANCE AND CALIBRATION

Is the equipment and utensils used are of appropriate design, construction, and workmanship to enable them to be suitable for their intended use and to be adequately cleaned and properly maintained? For example: Equipment used to hold or convey; to measure; compressed air or gas; pipes and vessels automated, mechanical, or electronic systems?

Are there established written procedures for:(a) Calibrating instruments and controls used in manufacturing or testing a component or dietary supplement;(b) Calibrating, inspecting, and checking automated, mechanical, and electronic equipment; and(c) Maintaining, cleaning, and sanitizing, as necessary, all equipment, utensils, and any other contact surfaces that are used to manufacture, package, label, or hold components or dietary supplements?

Is there a master list of all equipment that specifies those requiring maintenance and/or calibration?

Is there a master list of the last calibration of all equipment?

Are there SOPs for inspection (monitoring the condition), maintenance of equipment, measuring, and testing instruments? Do SOPs assign responsibilities; include schedules; describe procedures, equipment, and materials to be used; and require maintenance of records?

If equipment and instruments malfunction are determined to be defective, are they immediately taken out of use per an SOP?

Do SOPs assign responsibilities; include schedules; describe procedures, equipment, and materials to be used, including calibration over actual range of use and standards traceable to national standards; and include specifications and tolerances?

If calibration operations are performed in-house, do SOPs specify proper handling and storage conditions for the traceable standards?

Are the calibration intervals based on the manufacturers’ specified frequencies or personal experience?

Does an SOP specify that equipment cannot be used if it is beyond the calibration due date, and describe actions to be taken if equipment is used that is found to have been beyond the due date or is found to be out of calibration limits?

Is calibrated equipment labeled with date calibrated and date next calibration is due?





NA COMMENTS

Is equipment in use observed to be within calibration dating?

Are periodic verifications performed on balances and scales (using a range of weights) to assure that they remain within calibration in the time between full calibrations? Is this documented?

Are records maintained for maintenance and calibration operations?

EQUIPMENT CLEANING

Are there written procedures for cleaning, specifying cleaning agents and procedures?

Are there data to show that cleaning procedures for non-dedicated instruments are adequate to remove the previous materials?

Are there data to show that the residues left by the cleaning and/or sanitizing agent are within acceptable limits when cleaning is performed in accordance with the approved method?

Is there an adequate system to assure that unclean equipment/utensils are not used (e.g., labeling with clean status)?

Is there proper storage of cleaned equipment to prevent contamination?

Is the equipment and utensils in use: installed and maintained to facilitate cleaning; corrosion-resistant; made of nontoxic materials?

Is the use of equipment and utensils of appropriate design and construction so that use will not result in the contamination with: lubricants; fuel; coolants; metal or glass fragments; filth or any other extraneous material; contaminated water; or any other contaminants?

E. REQUIREMENTS TO ESTABLISH A PRODUCTION AND PROCESS CONTROL SYSTEM

Are there production and process controls that covers all stages of manufacturing, packaging, labeling, and holding of the dietary supplement?

Is the production and in-process control system designed to ensure that the dietary supplement is manufactured, packaged, labeled, and held in a manner that will ensure the quality of the dietary supplement?

Has the manufacturer implemented quality control operations to ensure the quality of the dietary supplement?

Are written specifications established to include the following:





NA COMMENTS

• A specification for any point, step, or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record.

• An identity specification for each component

• Component specifications which ensure that specifications for the purity, strength and composition of dietary supplements manufactured using the components are met

• Specifications which establish limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch

• Establish in-process specifications for any point, step, or stage in the master manufacturing records where control is necessary to ensure product specifications

• Provide adequate documentation of the basis for meeting the in-process specifications, in combination with meeting component specifications, will help ensure that the specifications are met for the identity, purity, strength, and composition of the dietary supplements and for limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch

• Ensure that Quality control personnel review and approve the documentation that is provided for in-process control

• Establish specifications for dietary supplement labels (label specifications) and for packaging that may come in contact with dietary supplements (packaging specifications). Packaging that may come into contact with dietary supplements must be safe and suitable for its intended use and must not be reactive or absorptive or otherwise affect the safety or quality of the dietary supplement

• For each dietary supplement manufactured the establishment of product specifications for the identity, purity, strength, and composition of the finished batch of the dietary supplement, and for limits on those types of contamination that may adulterate, or that

may lead to adulteration of, the finished batch of the dietary supplement to ensure the quality of the dietary supplement

• Establishment of specifications for product from a supplier for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier), the to provide sufficient assurance that the product received is adequately identified and is consistent with purchase order

• Establishment of specifications for the packaging and labeling of the finished packaged and labeled dietary supplements, including specifications that ensure that you used the specified packaging and that you applied the specified label?





NA COMMENTS

• Established specifications for labels (label specifications) and for packaging that may come in contact with dietary supplements (packaging specifications). Packaging that may come into contact with dietary supplements must be safe and suitable for its intended use and must not be reactive or absorptive or otherwise affect the safety or quality of the dietary supplement?

• Established product specifications for the identity, purity, strength, and composition of the finished batch of the dietary supplement, and for limits on those types of contamination that may adulterate, or that may lead to adulteration of, the finished batch?

If the manufacturer receives a product from a supplier for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier), does the manufacturer establish specifications to provide sufficient assurance that the product received is adequately identified and is consistent with the purchase order?

Before the manufacturer uses a component, do they ensure that they:

• Conduct at least one appropriate test or examination to verify the identity of any component that is a dietary ingredient?

• Confirm the identity of other components and determine whether other applicable component specifications are established?

If the manufacturer relies on a certificate of analysis from the supplier of the components that they receive, do they ensure that:

• Confirm the identity of other components and determine whether other applicable component specifications are established?

• Qualify the supplier by establishing the reliability of the supplier's certificate of analysis through confirmation of the results of the supplier's tests or examinations

• The certificate of analysis includes a description of the test or examination method(s) used, limits of the test or examinations, and actual results of the tests or examinations

• Maintain documentation of how they qualified the supplier

• Periodically re-confirm the supplier's certificate of analysis





NA COMMENTS

• Quality control personnel review and approve the documentation setting forth the basis for qualification (and re-qualification) of any supplier

Does the manufacturer monitor the in-process points, steps, or stages to determine whether the in-process specifications are met and detect any deviation or unanticipated occurrence that may result in a failure to meet specifications?

Does the manufacturer verify that the finished batch of the dietary supplement meets product specifications?

Does the manufacture conduct appropriate tests or examinations to determine compliance with one or more established specifications?

Does the manufacturer have adequate documentation for determining the basis for compliance with one or more specification(s), through the use of appropriate tests or examinations, conducted to ensure that the finished batch of the dietary supplement meets all product specifications for identity, purity, strength, and composition?

Do quality control personnel reject components that do not meet specifications, and is there assurance that the component will not be used in manufacturing the dietary supplement?

Are representative samples collected of each unique lot of components, packaging, and labels that are received from each unique lot within each unique shipment?

Are representative samples collected of in-process materials for each manufactured batch at points, steps, or stages, in the manufacturing process as specified in the master manufacturing record?

Are representative samples collected of finished batches through a sound statistical sampling plan, before releasing for distribution to verify that the finished batch of dietary supplement meets product specifications established?

Are representative samples collected of packaging and labeling material to determine whether the packaging and labeling of the finished packaged and labeled dietary supplements meet specifications established?

Does Quality control personnel conduct all required material reviews and make all required disposition decisions?

Does the system assure that changes receive the proper review and approval with regard to potential effects before being instituted and that only authorized personnel can make such changes?

If necessary, are personnel trained subsequent to changes?





NA COMMENTS

Is a log of system and program changes maintained?

SECURITY

Is there appropriate security to limit access to computerized systems, protect records from tampering, and prevent data alteration?

If passwords are used as a security measure, are there provisions for periodic changing of passwords? Does a responsible person (e.g., system administrator) have a list of all passwords in case of emergency?

If anyone leaves the department or company or otherwise loses authority to access the systems, are there procedures to immediately remove that person’s access codes from the system?

Is there a verification / qualification Program for equipment software?

F. REQUIREMENTS FOR QUALITY CONTROL

Are there established and followed written procedures for the responsibilities of the quality control operations, including written procedures for conducting a material review and making a disposition decision, and for approving or rejecting any reprocessing?

Do Quality control personnel ensure that the manufacturing, packaging, labeling, and holding operations have been conducted as specified in the master manufacturing record in a quality manner?

Do quality control personnel perform operations that include:

• Approving or rejecting all processes, specifications, written procedures, controls, tests, and examinations, and deviations from or modifications to them, that may affect the identity, purity, strength, or composition of a dietary supplement;

• Reviewing and approving the documentation setting forth the basis for qualification of any supplier

• Reviewing and approving the documentation setting forth the basis for why meeting in-process specifications, in combination with meeting component specifications, will help ensure that the identity, purity, strength, and composition of the dietary supplement are met

• Reviewing and approving the documentation setting forth the basis for why the results of appropriate tests or examinations for each product specification selected will ensure that the finished batch of the dietary supplement meets product specifications?





NA COMMENTS

• Reviewing and approving the basis and the documentation for why any product specification is exempted from the verification requirements, and for why any component and in-process testing, examination, or monitoring, or other methods will ensure that such exempted product specification is met without verification through periodic testing of the finished batch

• Ensuring that required representative samples are collected

• Ensuring that required reserve samples are collected and held

• Determining whether all specifications established are met

Do Quality control operations for laboratory operations associated with the production and process control system include:

• Reviewing and approving all laboratory control processes associated with the production and process control system

• Ensuring that all tests and examinations required under these regulations are conducted;

• Reviewing and approving the results of all tests and examinations required of these regulations?

Do Quality control operations require a material review and disposition decision?

Does material review and disposition decisions include the following:

Quality control personnel must conduct a material review and make a disposition decision if :

• Specification established is not met

• A batch deviates from the master manufacturing record, including when any step established in the master manufacturing record is not completed and including any deviation from specifications

• There is any unanticipated occurrence during the manufacturing operations that adulterates or may lead to adulteration of the component, dietary supplement, or packaging, or could lead to the use of a label not specified in the master manufacturing record

• Calibration of an instrument or control suggests a problem that may have resulted in a failure to ensure the quality of a batch or batches of a dietary supplement

• A dietary supplement is returned





NA COMMENTS

When there is a deviation or unanticipated occurrence during the production and in-process control system that results in or could lead to adulteration of a component, dietary supplement, or packaging, or could lead to the use of a label not specified in the master manufacturing record, quality control personnel must reject the component, dietary supplement, packaging, or label unless it approves a treatment, an in-process adjustment, or reprocessing to correct the applicable deviation or occurrence.

When a specification established is not met, quality control personnel must reject the component, dietary supplement, package or label, unless quality control personnel approve a treatment, an in-process adjustment, or reprocessing, as permitted.

The person who conducts a material review and makes the disposition decision must, at the time of performance, document that material review and disposition decision?

Do Quality control operations for equipment, instruments, and controls include:

• Reviewing and approving all processes for calibrating instruments and controls • Periodically reviewing all records for calibration of instruments and controls • Periodically reviewing all records for calibrations, inspections, and checks of automated,

mechanical, or electronic equipment

• Reviewing and approving controls to ensure that automated, mechanical, or electronic equipment functions in accordance with its intended use?

Quality control operations for components, packaging, and labels before use in the manufacture of a dietary supplement must include:

• Reviewing all receiving records for components, packaging, and labels • Determining whether all components, packaging, and labels conform to specifications

established

• Conducting any required material review and making any required disposition decision • Approving or rejecting any treatment and in-process adjustments of components,

packaging, or labels to make them suitable for use in the manufacture of a dietary supplement

• Approving, and releasing from quarantine, all components, packaging, and labels before they are used?

Do Quality control operations for the master manufacturing record, the batch production record, and manufacturing operations include:

• Reviewing and approving all master manufacturing records and all modifications to the master manufacturing records

• Reviewing and approving all batch production-related records • Reviewing all in process monitoring and controls • Conducting any required material review and making any required disposition decision





NA COMMENTS

• Approving or rejecting any reprocessing • Determining whether all in-process specifications established are met • Determining whether each finished batch conforms to product specifications established • Approving and releasing, or rejecting, each finished batch for distribution, including any

reprocessed finished batch

Quality control personnel must not approve and release for distribution:

• Any batch of dietary supplement for which any component in the batch does not meet its identity specification

• Any batch of dietary supplement, including any reprocessed batch, that does not meet all product specifications established

• Any batch of dietary supplement, including any reprocessed batch, that has not been manufactured, packaged, labeled, and held under conditions to prevent adulteration

• Any product received from a supplier for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier) for which sufficient assurance is not provided to adequately identify the product and to determine that the product is consistent with the purchase order?

Do Quality control operations for packaging and labeling operations include:

• Reviewing the results of any visual examination and documentation to ensure that specifications established are met for all products that you receive for packaging and labeling as a dietary supplement (and for distribution rather than for return to the supplier)

• Approving, and releasing from quarantine, all products that you receive for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier) before they are used for packaging or labeling

• Reviewing and approving all records for packaging and label operations • Determining whether the finished packaged and labeled dietary supplement conforms to

specifications established

• Conducting any required material review and making any required disposition decision • Approving or rejecting any repackaging of a packaged dietary supplement • Approving or rejecting any re-labeling of a packaged and labeled dietary supplement; • Approving for release, or rejecting, any packaged and labeled dietary supplement

including a repackaged or relabeled dietary supplement) for distribution?

Do Quality control operations for returned dietary supplements include:

• Conducting any required material review and making any required disposition decision

• Determining whether tests or examination are necessary to determine compliance with product specifications established;





NA COMMENTS

• Reviewing the results of any tests or examinations that are conducted to determine compliance with product specifications established

• Approving or rejecting any salvage and redistribution of any returned dietary supplement

• Approving or rejecting any reprocessing of any returned dietary supplement • Determining whether the reprocessed dietary supplement meets product specifications

and either approving for release, or rejecting, any returned dietary supplement that is reprocessed?

Do Quality control operations for product complaints include reviewing and approving decisions about whether to investigate a product complaint and reviewing and approving the findings and follow-up action of any investigation performed?

G. REQUIREMENTS FOR COMPONENTS, PACKAGING, AND LABELS RECEIVED FOR PACKAGING OR LABELING AS A DIETARY

SUPPLEMENT

Are there established and followed written procedures for fulfilling the requirements for Components, Packaging, and Labels and for Product That Are Received for Packaging or Labeling as a Dietary Supplement, including the following:

• Visually examine each immediate container or grouping of immediate containers in a shipment that you receive for appropriate content label, container damage, or broken seals to determine whether the container condition may have resulted in contamination or deterioration of the components

• Visually examine the supplier's invoice, guarantee, or certification in a shipment you receive to ensure the components are consistent with your purchase order

• Quarantine components before you use them in the manufacture of a dietary supplement until:

• The collection of representative samples of each unique lot of components (and, for components that you receive, of each unique shipment, and of each unique lot within each unique shipment)

• Quality control personnel review and approve the results of any tests or examinations conducted on components

• Quality control personnel approve the components for use in the manufacture of a dietary supplement, including approval of any treatment (including in-process adjustments) of components to make them suitable for use in the manufacture of a dietary supplement, and

• releases them from quarantine





NA COMMENTS

• Identify each unique lot within each unique shipment of components that is received and any lot of components that is produced in a manner that allows you to trace the lot to the supplier, the date received, the name of the component, the status of the component (e.g., quarantined, approved, or rejected); and to the dietary supplement that you manufactured and distributed.

• Is this unique identifier used when recording the disposition of each unique lot within each unique shipment of components that you receive and any lot of components that is produce, and

• The holding of components under conditions that will protect against contamination and

deterioration, and avoid mix-ups?

Do established requirements for packaging and labels received include the following:

• Visually examine each immediate container or grouping of immediate containers in a shipment for appropriate content label, container damage, or broken seals to determine whether the container condition may have resulted in contamination or deterioration of the packaging and labels.

• Visually examine the supplier's invoice, guarantee, or certification in a shipment to ensure that the packaging or labels are consistent with your purchase order.

• Quarantine packaging and labels before they are used in the manufacture of a dietary supplement until:

• The collection of representative samples of each unique shipment, and of each unique lot within each unique shipment, of packaging and labels and, at a minimum, conduct a visual identification of the immediate containers and closures

• Quality control personnel review and approve the results of any tests or examinations conducted on the packaging and labels;

• Quality control personnel approve the packaging and labels for use in the manufacture of a dietary supplement and release them from quarantine.

• Identify each unique lot within each unique shipment of packaging and labels in a manner that allows you to trace the lot to the supplier, the date received, the name of the packaging and label, the status of the packaging and label (e.g., quarantined, approved, or rejected); and to the dietary supplement that you distributed;

• Use a unique identifier when recording the disposition of each unique lot within each unique shipment of packaging and labels.





NA COMMENTS

• The holding of packaging and labels under conditions that will protect against contamination deterioration, and avoid mix-ups?

Has the manufacturer established requirements, which apply to a product received for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier)?

Has the manufacturer established requirements, which apply to rejected components, packaging, and labels, and to rejected products that are received for packaging or labeling as a dietary supplement?

H. REQUIREMENTS FOR THE MASTER MANUFACTURING RECORDS

Are written master manufacturing records prepared and followed for each unique formulation of dietary supplement manufactured, and for each batch size, to ensure uniformity in the finished batch from batch to batch?

Does the master manufacturing record include the following:

• Identify specifications for the points, steps, or stages in the manufacturing process where control is necessary to ensure quality

• Establish controls and procedures to ensure that each batch manufactured meets the established specifications

• The name of the dietary supplement to be manufactured and the strength, concentration, weight, or measure of each dietary ingredient for each batch size

• A complete list of components to be used • An accurate statement of the weight or measure of each component to be used • The identity and weight or measure of each dietary ingredient that will be declared on

the Supplement Facts label and the identity of each ingredient that will be declared on the ingredients list of the dietary supplement

• A statement of any intentional overage amount of a dietary ingredient • A statement of theoretical yield including the maximum and minimum percentages of

theoretical yield beyond which a deviation investigation is necessary

• A description of packaging and a representative label, or a cross-reference to the physical location of the actual or representative label

Written instructions, including the following: • Specifications for each point, step, or stage in the manufacturing process where control

is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record

• Procedures for sampling and a cross-reference to procedures for tests or examinations





NA COMMENTS

• Specific actions necessary to perform and verify points, steps, or stages in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record

Such specific actions must include verifying the weight or measure of any component and verifying the addition of any component

• For manual operations, does such specific actions include: One person weighing or measuring a component and another person verifying the weight or measure;

• One person adding the component and another person verifying the addition.

• Special notations and precautions to be followed; and corrective action plans for use when a specification is not met?

I. REQUIREMENTS FO R BATCH PRODUCTION RECORDS

Has the manufacturer established a system for the preparation of batch production

records in accordance with the following:

• A batch production record is prepared every time a batch of a dietary supplement is manufactured

• Do batch production records include complete information relating to the production and control of each batch?

• Do batch production records accurately follow the appropriate master manufacturing record?

• Does the manufacture make and keep batch production records?

Does the batch production record include the following:

• The batch, lot, or control number of the finished batch

• The identity of equipment and processing lines used in producing the batch

• The date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producing the batch, or a cross-reference to records, such as individual equipment logs, where this information is retained

• The unique identifier that is assigned to each component (or, when applicable, to a product that is received from a supplier for packaging or labeling as a dietary supplement), packaging, and label used

• The identity and weight or measure of each component used; • A statement of the actual yield and a statement of the percentage of theoretical yield at

appropriate phases of processing

• The actual results obtained during any monitoring operation





NA COMMENTS

• The results of any testing or examination performed during the batch production, or a cross-reference to such results

• Documentation that the finished dietary supplement meets specifications established • Documentation at the time of performance, for each step of manufacturing, including

the date and initials of the persons performing each step, i.e. weighing and measuring of components, verifying the weight or measure of components, adding and verifying the addition of components to the batch.

• Documentation, at the time of performance, packaging and labeling operations including, assigning a unique identifier to packaging and labels used, the quantity of the packaging and labels used, and, when label reconciliation is required, reconciliation of any discrepancies between issuance and use of labels

• An actual or representative label, or a cross-reference to the physical location of the actual or representative label specified in the master manufacturing record

• The results of any tests or examinations conducted on packaged and labeled dietary supplements (including repackaged or relabeled dietary supplements), or a cross-reference to the physical location of such results;

• Documentation at the time of performance that quality control personnel reviewed the batch production record, and any in process monitoring, results of any tests and examinations, including tests and examinations conducted on components, in-process materials, finished batches of dietary supplements, and packaged and labeled dietary supplements

• Approved or rejected any reprocessing or repackaging • Approved and released, or rejected, the batch for distribution, including any reprocessed

batch

• Approved and released, or rejected, the packaged and labeled dietary supplement, including any repackaged or relabeled dietary supplement.

• Documentation at the time of performance of any required material review and disposition decision.

• Documentation at the time of performance of any reprocessing?

J. REQUIREMENTS FOR LABORATORY OPERATIONS





NA COMMENTS

Has the manufacturer established and followed written procedures for laboratory operations, including written procedures for the tests and examinations conducted to determine whether specifications are met?

Does the manufacturer have adequate laboratory facilities to perform all testing and examinations as necessary to determine whether components used meet specifications, in-process specifications are met and the dietary supplements manufactured meet specifications?

Are laboratory control processes established, followed, reviewed and approved by quality control personnel, including the following:

• Use of criteria for establishing appropriate specifications;

• Use of sampling plans for obtaining representative samples of components, packaging, and labels: In-process materials, bulk batches, packaged and labeled supplements and purchased bulk received for packaging or labeling.

• Use of criteria for selecting appropriate examination and testing methods

• Use of criteria for selecting standard reference materials used in performing tests and examinations

• Use of test methods and examinations in accordance with established criteria?

Are there established requirements, which apply to laboratory methods for testing and examination, including:

• Verification that the laboratory examination and testing methodologies are appropriate for their intended use

• Identification and the use of an appropriate scientifically valid method for each established specification for which testing or examination is required to determine whether the specifications are met?

ANALYTICAL & MICROBIOLOGY LABORATORIES

Control of Supplies

Is there a vendor qualification policy for laboratory supplies?

Is there a list of approved vendors for laboratory supplies?

Is reference standards (primary and secondary) appropriately prepared, identified, tested, approved, and stored in a proper manner to ensure stability?

Are expiration dates adequately monitored so they are not used beyond the expiration dates?





NA COMMENTS

If reference standards are not USP Reference Standards, has appropriate characterization (including purity and stability) been performed? Are material grades appropriate?

Are reagents adequately controlled and monitored to assure that they are periodically replaced and that old reagents are not used?

Are all containers of materials or solutions adequately labeled to determine identity, preparer, and dates of preparation and expiration (if applicable)?

Are preparations logs maintained, including manufacturer and lot number, preparer and date?

Are there certificates of analysis available for inspection for reagents?

Are reagents and microbiological media adequately controlled and monitored to assure that they are periodically replaced and that old reagents are not used?

Based on an SOP, is growth support testing with low levels of organisms performed on all media lots, and is it documented?

Is an expiration date assigned to prepared media and are prepared media stored at the manufacturers’ recommended storage temperatures?

Is each lot of microbial Identification systems checked with positive and negative controls?

Testing

Is there an SOP describing how numbers are to be rounded?

Are data and calculations reviewed, verified, and signed by a second person?

Are investigations of Non Conforming Results completed and matters resolved within a period per an SOP? Do conclusions and actions appear to be adequate?

Is environmental monitoring of the lab conducted? Has the microbial profile of the laboratory been developed?

Based on an SOP, is the laboratory cleaned and disinfected, including rotation of disinfectants?

Are procedures verified based on an SOP?

Are there complete written instructions for testing, including procedures, equipment, operating parameters, and acceptance specifications?

Are test procedures readily available?

Is testing conducted with adequate technique and in such a manner and place to preclude laboratory contamination of samples?





NA COMMENTS

Are positive and negative controls used for testing? Are their results recorded?

Are data and calculations reviewed, verified, and signed by a second person?

Are investigations of Non Conforming Results completed and matters resolved within a reasonable period per an SOP? Do inclusions and actions appear to be adequate?

Are trend analyses performed?

Are periodic reports of complaints and investigations provided to the appropriate parties, including management per an SOP?

Stability Testing

Has the manufacturer established a written protocol designed to assess the stability characteristics of dietary supplements?

Is the manufacturer using the results of stability testing to determine appropriate storage conditions and shelf life?

Does the stability protocol include the following:

•

• Sample size and test intervals based on statistical criteria for each attribute should be examined to ensure valid estimates of stability

• storage conditions for samples retained for testing

• Reliable, meaningful, and specific test methods should be used

• The dietary supplement should be tested in the same type of container-closure system as that in which the dietary supplement is marketed?

Is the manufacturer testing an adequate number of batches of each dietary supplement to determine an adequate shelf-life, and is a record of the data maintained?

Does the manufacturer use accelerated studies to tentative shelf-life for raw materials, dietary supplements, and container-closure systems?

Where data from similar product formulations are available to support a shelf-life estimation of a new product is the manufacturer conducting simplified stability testing?

Where data from accelerated studies are used to project a tentative shelf life date that is beyond a date supported by actual shelf-life studies, does the manufacturer conduct stability studies including dietary supplement testing at appropriate intervals, until the tentative shelf life is verified or the adequate shelf life is determined?





NA COMMENTS

K. REQUIREMENTS FOR MANUFACTURING OPERATIONS

Has the manufacturer established and followed written procedures for manufacturing operations Does the manufacturer take all the necessary precautions during the manufacture of a dietary supplement to prevent contamination of components or dietary supplements? Do these precautions include

• Performing manufacturing operations under conditions and controls that protect against the potential for growth of microorganisms and the potential for contamination

• Washing or cleaning components that contain soil or other contaminants • Using water that, at a minimum, complies with the applicable Federal, State, and local

requirements and does not contaminate the dietary supplement when the water may become a component of the finished batch of dietary supplement

• Performing chemical, microbiological, or other testing, as necessary to prevent the use of contaminated components

• Sterilizing, pasteurizing, freezing, refrigerating, controlling hydrogen-ion concentration (pH), controlling humidity, controlling water activity (a<INF>w</INF>), or using any other effective means to remove, destroy, or prevent the growth of microorganisms and prevent decomposition

• Holding components and dietary supplements that can support the rapid growth of microorganisms of public health significance in a manner that prevents the components and dietary supplements from becoming adulterated;

• Identifying and holding any components or dietary supplements, for which a material review and disposition decision is required, in a manner that protects components or dietary supplements that are not under a material review against contamination and mix-ups with those that are under a material review

• Performing mechanical manufacturing steps (such as cutting, sorting, inspecting, shredding, drying, grinding, blending, and sifting) by any effective means to protect the dietary supplements against contamination, by, for example: cleaning and sanitizing contact surfaces, using temperature and time controls

• Using effective measures to protect against the inclusion of metal or other foreign material in components or dietary supplements, by, for example: filters or strainers, traps, magnets, or electronic metal detectors.

• Segregating and identifying all containers for a specific batch of dietary supplements to identify their contents and, when necessary, the phase of manufacturing

• Identifying all processing lines and major equipment used during manufacturing to indicate their contents, including the name of the dietary supplement and the specific batch or lot number and, when necessary, the phase of manufacturing?





NA COMMENTS

Does the manufacturer have written requirements, which apply to rejected dietary supplements?

Does the manufacturer have written requirement which clearly identify, hold, and control under a quarantine system for appropriate disposition any dietary supplement that is rejected and unsuitable for use in manufacturing, packaging, or labeling operations?

Do written procedures include the design requirements for manufacturing operations, which ensure that product specifications are consistently met?

Do written procedures include requirements for sanitation?

Are all manufacturing operations conducted in accordance with adequate sanitation principles?

L. REQUIREMENTS FOR PACKAGING AND LABELING OPERATIONS

Ensure packaging meets specifications so that the condition of the packaging will ensure the quality of your dietary supplements?

Are the issuance and use of packaging and labels controlled and reconciled after use? Label reconciliation is not required for cut or rolled labels if a 100-percent examination for correct labels is performed by appropriate electronic or electromechanical equipment during or after completion of finishing operations.

Does the manufacturer examine packaging and labels before packaging and labeling operations begin?

Is the manufacturer able to determine the complete manufacturing history and control of the packaged and labeled dietary supplement through distribution?

Does the manufacturer have written requirements which apply to filling, assembling, packaging, labeling, and related operations?

Does the manufacturer fill, assemble, package, label, and perform other related operations in a way that ensures the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record?

Does the manufacturer use effective means to ensure product quality by:

• Cleaning and sanitizing all filling and packaging equipment, utensils, and dietary supplement packaging, as appropriate

• Protecting manufactured dietary supplements from contamination, particularly airborne contamination

• Using sanitary handling procedures





NA COMMENTS

• Establishing physical or spatial separation of packaging and label operations from operations on other components and dietary supplements to prevent mix-ups

• Identifying, by any effective means, filled dietary supplement containers that are set aside and held in unlabeled condition for future label operations, to prevent mix-ups

• Assigning a batch, lot, or control number to each lot of packaged and labeled dietary supplement from a finished batch and each lot from a finished batch of dietary supplement that are distributed to another person for packaging or labeling.

• Examining a representative sample of each batch of the packaged and labeled dietary supplement to determine whether the dietary supplement meets specifications established

• Suitably disposing of labels and packaging for dietary supplements that are obsolete or incorrect to ensure that they are not used in any future packaging and label operations?

Does the manufacturer have requirements, which apply to repackaging and re-labeling?

• Do these requirements address repackage or re-label dietary supplements only after quality control personnel have approved such repackaging or re-labeling.

• Do the requirements provide for the examination of a representative sample of each batch of repackaged or relabeled dietary supplements to determine whether the repackaged or relabeled dietary supplements meet all specifications established

• Do Quality control personnel approve or reject each batch of repackaged or relabeled dietary supplement prior to its release for distribution?

Does the manufacturer have requirements, which apply to a packaged and labeled dietary supplement that is rejected for distribution?

Do these requirements clearly identify, hold, and control under a quarantine system for appropriate disposition any packaged and labeled dietary supplement that is rejected for distribution?

M. HOLDING AND DITRIBUTION

Does the manufacturer have written requirements, which apply to holding components, dietary supplements, packaging, and labels?

Do these written requirements include the following:

• The holding of components and dietary supplements under appropriate conditions of temperature, humidity, and light so that the identity, purity, strength, and composition of the components and dietary supplements are not affected.





NA COMMENTS

• The holding of packaging and labels under appropriate conditions so that the packaging and labels are not adversely affected.

• Holding of components, dietary supplements, packaging, and labels under conditions that do not lead to the mix-up, contamination, or deterioration of components, dietary supplements, packaging, and labels?

Does the manufacturer have written requirements, which apply to holding of in-process material, including the following:

• Identification and holding in-process material under conditions that protect against mix-up, contamination, and deterioration;

• Holding in-process material under appropriate conditions of temperature, humidity, and light?

Does the manufacturer have written requirements, which apply to holding reserve samples of dietary supplements, which includes the following:

• Hold reserve samples of dietary supplements in a manner that protects against contamination and deterioration.

• Holding the reserve samples under conditions consistent with product labels or, if no storage conditions are recommended on the label, under ordinary storage conditions;

• Using the same container-closure system in which the packaged and labeled dietary supplement is distributed, or if distributing dietary supplements to be packaged and labeled, using a container-closure system that provides essentially the same characteristics to protect against contamination or deterioration as the one in which you distribute the dietary supplement for packaging and labeling elsewhere.

Retain reserve samples for 1 year past the shelf life date (if shelf life dating is used), or for 2 years from the date of distribution of the last batch of dietary supplements associated with the reserve samples, for use in appropriate investigations?

Does the manufacturer ensure that distributed dietary supplements are conducted under conditions that will protect the dietary supplements against contamination and deterioration?

N. RETURNED DIETARY SUPPLEMENTS

Establishes and follows written procedures for returned dietary supplements, which include the identification and quarantine of returned product until quality control personnel conduct a material review and make a disposition decision?

Does the manufacturer ensure destruction or otherwise suitably dispose of any returned dietary supplement, unless the outcome of a material review with quality control approval is to salvage the returned dietary supplement for redistribution or reprocessing?





NA COMMENTS

Has the manufacturer established written requirements, which ensure that a returned dietary supplement must have quality control approve reprocessing that include the following?

• Ensure that any returned dietary supplements that are reprocessed meet all product specifications established

• Quality control personnel must approve or reject the release for distribution of any returned dietary supplement that is reprocessed

Does the manufacturer conduct an investigation if the reason for a dietary supplement being returned implicates other batches?

If so, does the manufacturer conduct an investigation of the manufacturing processes and each of those other batches to determine compliance with specifications?

O. PRODUCT COMPLAINTS

Has the manufacturer established written procedures for the handling of product complaints, which include the following:

• Review all product complaints to determine whether the product complaint involves a possible failure of a dietary supplement to meet any of its specifications, or any other requirements, including those specifications and other requirements that, if not met, may result in a risk of illness or injury

• Investigate any product complaint that involves a possible failure of a dietary supplement to meet any of its specifications.

• Quality control personnel must review and approve decisions about whether to investigate a product complaint and review and approve the findings and follow-up action of any investigation performed.

• All complaints, investigations and follow up must be documented.

P. RECORDS AND RECORDKEEPING

Does the manufacture keep written records of all requirements of these regulations, which include the following:

• Written records required by these regulations for 1 year past the shelf life date, if shelf life dating is used, or 2 years beyond the date of distribution of the last batch of dietary supplements associated with those records.

• Records must be kept as original records, as true copies (such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records), or as electronic records.

All electronic records must comply with 21 CFR Part 11?


20. Legal Notices

The information in this manual, including but not limited to text and images herein and their arrangement, is copyrighted. Copyright 2009 The United States Pharmacopeial Convention. All rights reserved. This manual is provided for informational purposes only. It does not constitute a legal and binding contract between USP and the participant. In the event of a conflict between this manual and the Program License Agreement, the terms and conditions of the Program License Agreement shall take precedence over the terms and conditions of this manual. USP does not endorse, guarantee, or warrant the goods and services offered by Program participants. The License Agreement provides that USP shall not be liable for any damages whatsoever, including bodily harm and/or property damage that may result from an ingredient of a participant verified in the Program. USP reserves the right to change or terminate the Program at any time without notice. USP reserves the right to disqualify participants that fail to comply with any of the Program’s requirements from participating in the Program.



DSVP147M_2013-10

USP Headquarters� 12601 Twinbrook Parkway Rockville, MD 20852 USA

1-800-227-8772��+1-301-881-0666

Europe/Middle Eas�t/Africa Münchensteinerstrasse 41 CH-4052 Basel, Switzerland

+41�(0)61�316�30�10

USP–India Private Limited IKP Knowledge Park Turkapally Village, Genome Valley Shameerpet, Ranga Reddy District Hyderabad 500�078, A.P. India

+91-40-4448-8888�

USP–China Building 11� Lane 67 Libing Road Zhangjiang Hi-Tech Park 201203�Shanghai China

+86-21-51370600

USP–Brazil Avenida Ceci, 1600-Tamboré� Barueri-SP 06460-120�Brazil

+55-11-3245-6400 www.us�p.org