USP Quality Systems GMP Audited Verification Program

a USP Quality Systems GMP Audited Verification Program. © January 2016, U.S. Pharmacopeial Convention. All rights reserved.

USP Quality Systems GMP Audited Verification Program

Manual for Participants

a USP Quality Systems GMP Audited Verification Program. © January


Manual for ParticipantsManual for Participants

2016, U.S. Pharmacopeial Convention. All rights reserved.20162016USP Quality Systems GMP Audited Verification Program. © January 2016


B U I L D I N G T R U S T a n d C O N F I D E N C E


b USP Quality Systems GMP Audited Verification Program. © January 2016, U.S. Pharmacopeial Convention. All rights reserved.



Notice

This manual provides guidance to dietary supplement1 manufacturers who intend to participate in the United States Pharmacopeia’s Quality Systems GMP Audited Verification Program (USP QS GMP Audited Program, or Program). Additional requirements and criteria that are not included in this manual, including those in the USP Quality Systems GMP Audited Mark Usage Manual, must be satisfied for participation. Prospective Participants are advised to discuss these additional requirements with the United States Pharmacopeial Convention (USP).

The USP QS GMP Audited Program is designed to assist Participants in assuring their customers that a manufactured product is produced in accordance with current Good Manufacturing Practices (GMPs) and that the Participant’s GMP quality systems comply with the 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 Quality Systems GMP Audited Mark on the Participant’s business-to-business website, trade promotion, and advertising.

Barring safety concerns or other special circumstances, USP maintains the confidentiality of information gained through the quality systems GMP audited process in accordance with the provisions of the Program License Agreement, provided separately.

1 USP understands that the term dietary supplement as used in the United States has different meanings in other countries. Non-U.S. terms include botanicals, herbals, herbal medicines, nutraceuticals, food supplements, and natural health products.

c USP Quality Systems GMP Audited Verification Program. © January 2016, U.S. Pharmacopeial Convention. All rights reserved.






Table of Contents

Notice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

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

Required Process and Submissions . . . . . . . . . . . . . . . . . . . . . . . 2

Process Overview Chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Evaluation of Intitial Quality Systems Audit Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

On-Site Qualtiy Systems GMP Audit. . . . . . . . . . . . . . . . . . . . . . . .7

USP Notification of Nonconformties. . . . . . . . . . . . . . . . . . . . . . 12

Issuance of the USP Quality Systems GMP Audited Mark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Need for Annual Quality Systems GMP Audits . . . . . . . . . . . . . 16

Need for Re-evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Appeals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Product Recalls and Suspension of the Mark . . . . . . . . . . . . . . 18

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Forms and Checklists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

• Section I: Participant’s Declaration of Information Fulfilling Initial

Quality Systems Audit Documentation Request

• Section II: Checklist for On-Site Quality Systems GMP Audit

Legal Notices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42


Manual For Participants

1 USP Quality Systems GMP Audited Verification Program. © January 2016, U.S. Pharmacopeial Convention. All rights reserved.



1. Overview

The USP Quality Systems GMP Audited Verifi cation Program (USP QS GMP Audited Program, or Program) is one of several public health programs of the USP. Participation is voluntary and open to companies manufacturing dietary supplement products.

The USP QS GMP Audited Program covers the quality systems used in a facility to manufacture dietary supplements legally marketed under the Dietary Supplement Health and Education Act (DSHEA), including vitamins, minerals, amino acids, botanicals, and other non-botanical dietary supplement products. The Program complements the United States Food Drug Administration’s (U.S. FDA’s) regulation of dietary supplements under DSHEA and the Good Manufacturing Practice (GMP) regulations contained in 21 Code of Federal Regulations Part 111 (21 CFR Part 111).

The USP QS GMP Audited Program includes: Evaluation of manufacturers’ quality systems by an audit to establish conformity with USP and FDA GMPs.

Granting use of the USP Quality Systems GMP Audited Mark and issuance of a Certifi cate of Standards Compliance upon obtaining conformity with the Program requirements.

Annual Quality Systems GMP audits of facilities using the USP Quality Systems GMP Audited Mark (Mark) to ascertain continuing conformity with Program requirements.

The use of the distinctive USP Quality Systems GMP Audited Mark is granted for dietary supplement manufacturing facilities that successfully meet USP QS GMP Audited Program requirements. The Mark indicates verification that the manufacturing facility quality system has met USP’s requirements under the Program. It provides assurance that the manufacturer’s quality system helps to ensure that dietary supplements will be manufactured in accordance with applicable GMPs.




2. Criteria for Participation

Participants in the USP Quality Systems GMP Audited Program agree to:

Sign the license agreement.

Submit requested documentation.

Subject their facilities to all reviews, inspections, and audits specifi ed in the Program.

Abide by the decisions made in accordance with the requirements of the USP Quality Systems GMP Audited Verifi cation Program as specifi ed in this manual, the USP Quality Systems GMP Audited Mark Usage Manual, and the Program License Agreement.

Operate in compliance with applicable laws and regulations.

Register the facility under the provisions of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002.

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

3. Required Process and Submissions

Participants in the USP Quality Systems GMP Audited Program shall:

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

Provide the list of manufacturing sites for which quality systems GMP auditing is sought.

Enable USP to enter manufacturing facilities and perform on-site audits.




4. Process Overview Chart

No

On-sitequality systems GMP audit

indicates acceptancecriteria met

Participant executes LicenseAgreement with USP

Participant addresses nonconformitieswith corrective action plan (CAP) report

Participant takes further correctiveaction and/or appeals decision

No

Yes

Yes

USP staff submit status report of all audit findings forreview by Department Head, Verification Programs

Department Head,Verification Programs

reviews status report and approvesmanufacturing site quality systems

GMP certification

Manufacturing site approved to useUSP Quality Systems GMP Audited Mark

USP conducts recurringon-site audit annually

Certification process stops formanufacturing site

USP reviewscorrective action and/or

appeal and approves manufacturingsite quality systemsGMP certification

Manufacturing site notentered into GMP audit program

Potential participant submits applicationwith manufacturing site information

Potential participantaccepts price quote

USP conducts on-site audit and issues auditreport citing nonconformities, if any

No

USP reviews corrective action plan (CAP)report and sends Participant a report of

USP’s assessment of CAP

USP sends price quote letterto potential participant

Yes

No

Yes




5. Evaluation of Initial Quality Systems Audit Documentation

Upon completion of the license agreement and prior to the initial on-site audit, the Participant must submit to USP an electronic (e.g., PDF) copy of the information for Initial Audit Documentation (see below) for each manufacturing site for which a quality systems GMP audit is sought.

The following quality systems GMP audit documentation is needed before the initial USP QS GMP audit. The requested pre-audit documentation is organized according to the six quality systems. The Participant is requested to complete the Participant’s Declaration of Information Fulfi lling Initial Quality Systems Audit Documentation Request, to assist USP in identifying the relevant documents associated with each system.

The USP auditor performs preliminary review of the information in evaluating the initial quality systems audit documentation. The absence of any of the following may be deemed a nonconformity for which corrective actions need to be taken by the Participant. Nonconformities, if any, will be noted and reported to the Participant in the on-site audit report.

1) Quality Management System ensures overall compliance with GMPs and internal procedures and specifi cations.

Table of contents for all company standard operating procedures (SOPs)

Employee training program SOP

Organizational chart

Job description for the key quality unit staff and the key manufacturing/operations staff

Personnel hygiene SOP

Documentation control and record-keeping SOP

Corrective action preventative action (CAPA) program SOP

Complaint handling SOP

Deviation and failure investigations SOP

Recalls SOP

Change control SOP




2) Facilities and Equipment System includes activities that provide an appropriate physical environment and resources used in the production of products.

Plant/site map

Pest control SOP

Facility cleaning and sanitation SOP

Purifi ed water system diagram

Equipment maintenance, calibration, and cleaning SOP

Equipment cleaning validation SOP

Computer system validation, backup, change control, and security for GMP applications SOP

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

3) Material System includes measures and activities to control raw material ingredients, other components, intermediates, containers, and labels.

Receipt, sampling, storage, and release of components, containers, and labels SOP

Specifi cations for components, containers, and labels SOP

Supplier qualifi cation program SOP

Rejected and returned product management SOP

4) Production System includes measures and activities to control the manufacture of products.

Flow chart of manufacturing process

Master production and control records SOP

Manufacturing process validation SOP

Reprocessing and/or reworking SOP

Contract manufacturer qualifi cation SOP

5) Packaging and Labeling System includes measures and activities that control the packaging and labeling of products.

Label control SOP

Packaging and labeling of dietary supplements SOP




6) Laboratory Control System includes measures and activities related to testing raw materials and fi nished product for conformity to specifi cations.

Receipt, storage, and documentation of reagents, reference standards, and samples SOP

Instrumentation maintenance and calibration SOP

Laboratory test procedures SOP

Analytical method validation or verifi cation SOP

Out-of-specifi cation investigation SOP

Stability program SOP

7) General Information includes general metrics not associated with a specifi c quality system.

Year the facility went into operation

Number of employees (total staff, manufacturing staff, quality control/quality assurance [QC/QA] staff )

Square footage of facility

Proof of facility registration as required by the Public Health Security and Bioterrorism Preparedness and Response Act of 2002

USP requests that the Participant have readily available a list of analytical instrumentation, analytical instrumentation DQ/IQ/OQ/PQ reports, the analytical instrumentation calibration/maintenance schedule, analytical test procedures, analytical method validation/verifi cation reports, nonconformities and out-of-specifi cation investigations, and stability studies. A sampling of reports from these lists will be selected for review.

On the last day of the audit, in the afternoon:

Auditor prepares the closing meeting report (1/2 to 1 hour)

Audit closing meeting (about 1/2 hour)

During the audit closing meeting, the USP auditor will inform the Participant of the audit fi ndings with a preliminary indication of their Action Level rating. (See Section 7 for details on Action Level ratings.)

Upon completion of the on-site audit, the USP auditor will prepare a brief narrative audit report, which will include a list of any nonconformities and their Action Level rating, for USP staff review and approval. The audit report will then be sent to the Participant. The Participant will have thirty (30) calendar days to reply to reported nonconformities with a corrective action plan. Failure to do so will result in the discontinuation of the verifi cation. Objective evidence of corrective action, with the date of completion or progress made, must be submitted to USP with the Participant’s corrective action plan report.




6. On-Site Quality Systems GMP Audit

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

Nonconformities, if any, will be noted and provided to the Participant in the on-site audit report. The Participant should develop corrective action plans within thirty (30) calendar days of receipt of notification. Target dates for implementation of corrective actions should be within six (6) calendar months. If information on the corrective action is found acceptable by USP, the quality systems audit process will continue. If the Participant fails to develop and implement corrective action, the quality systems audit process will be discontinued or suspended until the nonconfor-mities are corrected to USP’s satisfaction.

USP uses USP staff and/or approved contract auditors to perform the on-site audit of the Participant.

The initial verifi cation on-site audit and re-verifi cation on-site audits will be conducted on an annual basis, lasting two to three days, depending on the size of the manufacturing facility and operations. The re-verifi cation audits will be conducted around the anniversary date of the initial on-site audit conducted by USP.

Notification of audit will be given to the Participant’s designated Quality Unit contact at least one month ahead of time. USP staff will communicate the plan/agenda for the audit to ensure the availability of required personnel during the audit. Safety procedures for the manufacturing area or laboratory being audited will be followed by auditors.

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

1. USP General Chapter <2750> Manufacturing Practices for Dietary Supplements

2. 21 CFR Part 111 – Current Good Manufacturing Practice in Manufacturing, Packing, Labeling, or Holding Operations for Dietary Supplements

Ideally, the audit will be conducted each day between the hours of 8:00 a.m. and 5:00 p.m.; however, the auditors will adapt to existing circumstances and reserve the right to modify the hours and schedule, as needed.

A typical quality systems GMP audit generally will be conducted according to the following agenda; however, each year special attention will be given to selected topics that have been the focus of recent industry regulatory audits.

Opening Meeting (1/2 to 1 hour, repeated on the fi rst day of the audit of each site)

Introduction of personnel

Purpose of the USP audit

Description of manufacturing plant operations (Participant presentation)




Organizational chart

Site layout

Overview of facility, processes, and operational capacity

Plant Tour (following the process fl ow)

Raw materials, packaging, and labels receipt and storage area

Warehouse area(s)

Production area(s)

Purifi ed or deionized water system and utilities area

Label control

Packaging area

Laboratory area

Bulk and fi nished goods control, storage, and release area

On-site lunch (each day – about 1/2 hour)

Review of FDA investigations/Form 483 observations, if any, under 21 CFR Part 111

The auditor will then conduct a detailed review of the following six quality systems.

Note: At the end of each of the six quality system sections is a request for the Participant to provide specifi c documentation and/or have it readily available for review. The information below is provided solely for guidance. The auditor will select the specifi c quality systems documentation to be reviewed while on site.

1) Quality Management System ensures overall compliance with GMPs and internal procedures and specifi cations.

Bulk and fi nished goods control, storage, and release area

Quality manual and policy

Employee training program, e.g., job descriptions, training standard operating procedures (SOPs), personnel training records, qualifi cations and verifi cations, personnel hygiene

Documentation control and record keeping

Internal quality audit program

Corrective action preventative action (CAPA) program

Complaint reviews




Discrepancy and failure investigations

Reprocessing and/or reworking

Recalls

Change control

Validation master plan, including protocols and reports, as applicable, for equipment design, installation, operational, and performance qualifi cation (DQ, IQ, OQ, PQ), manufacturing process validation, analytical method validation or verifi cation, computer system validation, cleaning validation

Annual product review

Quality unit approval oversight

Contract manufacturers and laboratories

USP requests that the Participant provide a copy of the quality manual and the table of contents for all company SOPs and have readily available a list of training records, internal audits, CAPAs, customer complaints, deviations, returns, recalls, and contract manufacturers and laboratories.

2) Facilities and Equipment System includes activities that provide an appropriate physical environment and resources used in the production of products.

Facility and Grounds Maintenance• Physical plant sanitation • Grounds keeping• Pest control• Water supply and plumbing• Sewage and trash disposal• Bathrooms and hand-washing facilities

Purifi ed water system

HVAC system

Equipment• Construction• Installation, operational, performance qualifi cation (IQ, OQ, PQ)• Maintenance, calibration, and cleaning procedures• Automated, mechanical, or electronic equipment application

Computer system• Verifi cation of GMP-related applications• Backup, change control, and security

USP requests that the Participant have readily available a plant/site map, water system diagram, a list of manufacturing equipment, manufacturing equipment calibration/maintenance/cleaning schedule, and computer systems for GMP-related activities.




3) Material System includes measures and activities to control raw material ingredients, other components, intermediates, containers, and labels.

Receipt, sampling, storage, and records of components, containers, and labels

Specifi cations of components, containers, and labels

System of release of raw materials

Validation of computerized and inventory control processes

Storage and distribution controls

Supplier qualifi cation program

Rejected and returned product management

USP requests that the Participant have readily available a copy of component specifi cations, component handling SOPs, a list of approved suppliers, and supplier qualifi cation records.

4) Production System includes measures and activities to control the manufacture of products.

Master production and control records

Major operations or steps in the process, e.g., raw material weighing, blending, compression, encapsulation, coating, packing, labeling, and testing

In-process sampling and testing

Manufacturing process validation

Reprocessing and reworking production and control records

Upon request, USP expects the Participant to have readily available the lot history for products, a copy of the master and executed production control records for selected lots, and a list of manufacturing process validation reports for products.

5) Packaging and Labeling System includes measures and activities that control the packaging and labeling of products.

Label control

Packaging and labeling of dietary supplements

USP requests that the Participant have readily available a copy of label and packaging specifi cations and SOPs, and the master and executed packaging control records for selected lots of products.




6) Laboratory Control System includes measures and activities related to testing raw materials and fi nished products for conformity to specifi cations.

Receipt, storage, and documentation of reagents, reference standards, and samples

Laboratory notebooks and instrument logbooks

Instrumentation maintenance and calibration

SOPs and specifi cations for testing

Laboratory test procedures

Out-of-specifi cation investigation procedures

Analytical method validation or verifi cation

Stability program

Reserve samples

Waste disposal of samples

USP requests that the Participant have readily available a list of analytical instrumentation, analytical instrumentation DQ/IQ/OQ/PQ reports, the analytical instrumentation calibration/maintenance schedule, analytical test procedures, analytical method validation/verifi cation reports, nonconformities and out-of-specifi cation investigations, and stability studies. A sampling of reports from these lists will be selected for review.

On the last day of the audit, in the afternoon:

Auditor prepares the closing meeting report (1/2 to 1 hour)

Audit closing meeting (about 1/2 hour)

During the audit closing meeting, the USP auditor will inform the Participant of the audit fi ndings with a preliminary indication of their Action Level rating. (See Section 7 for details on Action Level ratings.)

Upon completion of the on-site audit, the USP auditor will prepare a brief narrative audit report, which will include a list of any nonconformities and their Action Level rating, for USP staff review and approval. The audit report will then be sent to the Participant. The Participant will have thirty (30) calendar days to reply to reported nonconformities with a corrective action plan. Failure to do so will result in the discontinuation of the verifi cation. Objective evidence of corrective action, with the date of completion or progress made, must be submitted to USP with the Participant’s corrective action plan report.




7. USP Notifications of Nonconformities

Quality Systems GMP Audit Report will be issued to the Participant listing the determination and status of the nonconformities regarding the various quality system program elements of the audit as it pertains to the Participant. The report will be segregated according to the aforementioned six (6) quality systems, as applicable.

The status of the nonconformities (also referred to as observations or findings) may be divided into three ratings: 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 Participant.

ACTION LEVEL 1 observations involve a lack of a quality system program element, or a quality system program element identifi ed as having a critical nonconformity involving consumer safety. An Action Level 1 rating represents a critical observation that must be adequately resolved before a facility can be eligible to obtain the USP Quality Systems GMP Audited Mark, and may require that the manufacturing site be re-audited.

ACTION LEVEL 2 observations involve a quality system program element identifi ed as having major nonconformity, or a lack of information regarding a quality system program element. An Action Level 2 rating represents a major observation that must be adequately resolved before a facility can obtain the USP Quality Systems GMP Audited Mark.

ACTION LEVEL 3 observations involve a quality system program element identifi ed as having a minor nonconformity, or the need for clarifying information or newly requested information regarding a quality system program element. An Action Level 3 rating represents a minor observation that requires a commitment from the Participant to implement appropriate corrective action within a specifi ed time period before a facility can obtain the USP Quality Systems GMP Audited Mark.

Note: An Action Level 3 observation that is not resolved by the next annual audit will be upgraded to an Action Level 2 observation. Conversely, an Action Level 2 observation for which a Participant has taken remedial corrective action to address not all but at least the major concerns of the nonconformity may be downgraded to an Action Level 3 observation. In certain cases, the USP auditor may provide the Participant with an Opportunity for Improvement (OFI) based on the auditor’s knowledge and experience with general industry practices. An OFI represents a suggestion for consideration that requires no response from the Participant and does not adversely impact facility GMP verifi cation.

Justification for citing the Action Levels is based on the following two documents:

1. USP General Chapter <2750> Manufacturing Practices for Dietary Supplements; and/or

2. 21 CFR Part 111 – Current Good Manufacturing Practice in Manufacturing, Packing, Labeling or Holding Operations for Dietary Supplements.




The USP Quality Systems GMP Audited compliance status is indicated by an overall assessment of Pass or Fail, depending on the nature of the nonconformities within each category. The grading system is based on the following determinations:

PASS indicates that only Action Level 3 nonconformities need to be corrected within a specifi ed time period. Verifi cation would be considered without further qualifi cation, and will be reconsidered based on the next annual quality systems GMP audit of the Participant’s facility and operations.

FAIL indicates that one or more Action Level 1 nonconformities need to be corrected. The Participant would need to make the appropriate change(s) to the quality system program element and the Participant’s facility and operations would need to be re-audited.

During an annual re-audit of a Participant’s facility that has obtained a USP Quality Systems GMP Audited Mark, the facility may be cited for having Action Level 2 major nonconformities and Action Level 3 minor nonconformities. Under these circumstances the Participant will have thirty (30) calendar days to correct the Action Level 2 major nonconformities while still retaining the USP Quality Systems GMP Audited Mark to the point at which only Action Level 3 nonconformities remain to be corrected within a time period specified by USP. If the Participant does not correct the Action Level 2 major nonconformities within thirty (30) calendar days, the Participant’s use of the USP Quality Systems GMP Audited Mark will be suspended. Once the Participant has corrected the Action Level 2 major nonconformities, the Participant’s use of the Mark may be reinstated by USP.

The Participant understands that compliance with the requirements of the USP Quality Systems GMP Audited Program does not constitute compliance with federal or state requirements. The Participant agrees that any audit(s) or inspection(s) conducted by USP is designed only to verify compliance with the requirements of the USP Quality Systems GMP Audited Verifi cation Program for the sole purpose of awarding use of the USP Quality Systems GMP Audited Mark to the Participant. It is the Participant’s responsibility to ensure that all of its manufacturing operations and marketed products are in compliance with all applicable federal, state, or local laws or regulations.




8. Issuance of the USP Quality Systems GMP Audited Mark

Use of the USP Quality Systems GMP Audited Mark will be awarded to a Participant upon satisfactory completion of the following:

Evaluation of initial audit documentation;

Evaluation of the on-site audit report; and

Evaluation of corrective action plan for cited nonconformities.

For each facility that successfully completes the Program, USP will issue an approval letter and a certificate of Quality Systems GMP Audited compliance. The letter and the certificate will specify which of the Participant’s facility(ies) are entitled to use the USP Quality Systems GMP Audited Mark and other limiting information (such as manufacturing site information and/or activities) as appropriate.

USP will review all use of advertisements and/or websites utilizing the USP Quality Systems GMP Audited Mark. USP reserves the right to ask for additional documentation as necessary.

The USP Quality Systems GMP Audited Mark must be used in accordance with the guidelines in the USP Quality Systems GMP Audited Mark Usage Manual and the Program License Agreement, which will be provided to Participants by USP. These guidelines relate to:

Size and color of the USP Quality Systems GMP Audited Mark

Acceptable format and materials

Specifi cations for reproduction

Examples of appropriate and inappropriate use

Acceptable and unacceptable usage of the USP Quality Systems GMP Audited Mark in advertising and promotional materials, exhibit signage, speaking engagements, presentations, educational materials, and events, and on websites

USP requires submission of artwork for pre-approval for advertising, promotions, or other materials that include the USP Quality Systems GMP Audited Mark. 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 Quality Systems GMP Audited Mark to be submitted for evaluation.

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 Quality Systems GMP Audited 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, 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 manufacturing sites under the Program will be made available to the public on the USP website.

If the USP Quality Systems GMP Audited Mark is misused or improperly used, USP will work with the Participant licensed to use the USP Quality Systems GMP Audited 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 conformity. 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 Quality Systems GMP Audited Mark either in its entirety or on a manufacturing-site-specific basis. The warning should specify the steps required for the Participant to come into conformity and avoid revocation or suspension of the Mark, and a reasonable time period for achieving conformity. In case of continued nonconformity, USP will make a final decision to revoke or suspend the Participant’s license to use the USP Quality Systems GMP Audited Mark, either in its entirety or on a manufacturing-site-specific basis. Such a decision is final and cannot 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.




9. Need for Annual Quality Systems GMP Audits

After the USP Quality Systems GMP Audited Mark is awarded to a manufacturing facility, USP will perform annual GMP audits of the facility and operations to ensure that they continue to meet the Program requirements to use the Mark.

The on-site audits will be conducted by USP on an annual basis for all Participants.

USP will provide notice of not less than three (3) business days, requesting access to a Participant’s facility to conduct the initial GMP audit or annual re-audit, except that USP may, in its sole discretion, conduct unannounced audits of a Participant’s facility at any time to determine whether the facility complies with the USP QS GMP Audited Program requirements.

10. Need for Re-evaluation

After USP has granted approval to use the USP Quality Systems GMP Audited Mark, a Participant might make changes to its quality systems such as 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 its manufacturing process.

Major Quality Management Changes: Major quality management changes include, but are not limited to, the following: (1) purchase of the company by another company; (2) a change in senior quality and/or manufacturing management staff; (3) the addition of a new computerized resource management system; and (4) the addition of a new document control management system.

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; (2) the addition of a new manufacturing operation, such as manufacture of soft gelatin capsules where only tablet and/or hard gelatin capsules have been manufactured previously; and (3) the addition of a new laboratory, such as a microbiology lab where only a chemistry laboratory previously existed.

Major Changes to Equipment: Major changes to equipment include, but are not limited to (1) a change to equipment different in design and operating principle and (2) the addition of new analytical instrumentation, such as inductively coupled plasma–mass spectrometry (ICP-MS) where only atomic absorption spectroscopy (AAS) was previously used.

If an on-site audit is required, USP will immediately notify the Participant by phone, with a follow-up in writing. USP may also require the Participant to cease continued use of the USP Quality Systems GMP Audited Mark until the re-audit has been successfully completed.

The Participant may appeal the decision to require a re-audit; however, the Participant shall not have the right to appeal the decision requiring them to cease using the USP Quality Systems GMP Audited Mark until the re-audit has been successfully completed.




11. Appeals

In certain situations USP may suspend, revoke, or refuse to issue the USP Quality Systems GMP Audited Mark to Participants in the Program. Participants have the opportunity to appeal the following:

Rejection of quality system audit report fi ndings

Refusal, revocation, or suspension of the use of the Mark

Rejection due to quality system audit report findings

USP may reject as insufficient:

Documentation that fails to meet the requirements for initial quality systems audit and for on-site audits

Audit reports that show nonconformities or deviations from GMPs at the facility

USP will send a 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 thirty (30) calendar days from the date of receiving the written notification of rejection from USP.

USP’s Appeals Panel will review the evidence received with the appeal and decide to accept or reject the Participant’s supporting evidence. In either case, written notification of the decision will be sent to the Participant. If the Participant’s supporting evidence is accepted, USP will resume evaluation of the Participant’s facility at the appropriate step in the auditing process. If the Participant’s supporting evidence is rejected, the Participant can reapply to the Program after correcting the nonconformities.




12. Product Recalls and Suspension of the Mark

USP is entitled to recommend a product recall if critical product deficiencies are detected. Product deficiencies are considered critical if in USP’s discretion:

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

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

An offi cial from the participating company has submitted fraudulent documents to the USP.

FDA has recommended a voluntary recall of the Participant’s product(s ).

USP may recommend that the Participant issue a product recall in the event of a critical product deficiency. Within twenty-four (24) hours of USP’s recall recommendation, USP will convene a hearing—by conference call—with the Participant or Participant’s representative(s), who must answer any questions and provide the requested information about the product problem. Such conference call shall be confidential and not subject to public disclosure, absent a judicial or administrative decree. Based on the information obtained from the Participant, USP will either affirm or overturn its recommendation for the Participant to issue a product recall. If USP decides that a recall is not necessary, it will immediately notify the Participant. If USP decides that a recall is appropriate, it will immediately contact FDA and notify the Participant to discontinue use of the USP Quality Systems GMP Audited Mark. The Participant must take immediate action to do so, but may appeal to USP the decision to discontinue use of the Mark.

Suspension of the Mark

USP may suspend a Participant’s right to use the USP Quality Systems GMP Audited Markdue to:

Violation of any USP Quality Systems GMP Audited participation criteria, policies, or procedures by the manufacturing company, its affi liates, or agents.

Major quality systems nonconformities, i.e., Action Level 2 nonconformities.

The Participant may appeal USP’s decision to suspend use of the Mark. The appeal, along with any supporting evidence, must be made within thirty (30) calendar 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 Mark with no further right of the Participant to appeal.

The Participant may, on appeal, also request a hearing in person or by teleconference. All in-person hearings will be held at USP headquarters in Rockville, Maryland. USP will set a place, time, and date—not more than sixty (60) calendar days after receiving the request for a hearing—and will notify the Participant accordingly. USP and the Participant may present evidence at the hearing. The Participant may be represented by counsel. The Participant shall pay all reasonable expenses incurred by USP to hold the hearing.




USP will make a recommendation and provide explanations within thirty (30) calendar days after the hearing. If USP determines that the Participant:

Is substantially out of compliance with the USP Quality Systems GMP Audited Program criteria—USP will revoke use of the Mark.

Is substantially in compliance with the USP Quality Systems GMP Audited Program criteria—USP will reverse the suspension and reinstate use of the Mark.

Can conduct corrective action within six (6) months to become substantially compliant with USP Quality Systems GMP Audited Program criteria—USP will affirm the suspension until further review. The Participant must notify USP within thirty (30) calendar 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 thirty (30) calendar days, or to be in substantial compliance within six (6) months, will result in revocation of the use of the Mark.

Upon revocation of the use of the USP Quality Systems GMP Audited Mark, a Participant may re-enter the Program one year after such revocation, on payment of full fees.




13. Glossary

Acceptance Criteria: the product specifications and predetermined acceptance or rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch.

Actual Yield: the quantity that is actually produced at any appropriate step of manufacture or packaging of a particular dietary supplement.

Appeals Panel: a group consisting of USP Senior Legal Counsel, USP Senior Director of Global Quality Assurance, and USP Vice President of Strategic Marketing and Program Operations. The Panel will have the authority to review appeals submitted by companies participating in the Program regarding: (1) rejection of quality system audit report findings; or (2) refusal, withdrawal, or suspension of the use of the Mark.

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

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.

Batch Number, Lot Number, or Control Number: any distinctive group of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacturing, packaging, labeling, and/or holding of a batch or lot of material can be determined.

Component: any substance intended for use in the manufacture of a dietary supplement, including those that may not appear in the finished batch of the dietary supplement.

Contact Surface: any surface that contacts a component or dietary supplement, and those surfaces from which drainage onto the component or dietary supplement, or onto the surfaces that contact the component or dietary supplement, occurs during the normal course of operations. Examples of contact surfaces include containers, utensils, tables, contact surface of equipment, and packaging.

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 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 these 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.

Dietary Supplement Health and Education Act (DSHEA): 1994 act that set the regulatory framework for dietary supplements in the U.S.

Federal Food, Drug, and Cosmetic Act (FFDCA): a set of laws passed by Congress in 1938 giving authority to U.S. FDA to oversee the safety of food, drugs, and cosmetics. The FFDCA has undergone several significant amendments. FDA enforces the laws enacted by Congress and issues regulations as authorized by Congress under the FFDCA to implement its statutory authority. The regulations have the force of law and are fully enforceable by FDA.




Food Chemicals Codex (FCC): a publication acquired by USP from the National Academy of Sciences in 2006. USP formed a Food Ingredients Expert Committee within its Council of Experts that is responsible for approving all new and revised standards in the FCC. The FCC contains more than 1,200 food-ingredient-specific standards, including monographs, provisional monographs, and FCC identity standards. It also contains more than 150 General Tests and Assays, providing procedures frequently cited in ingredient-specific standards. Additionally, the FCC includes a General Information section with up-to-date relevant informational materials on method validation and various analytical techniques, reference tables, and information on current GMPs.

Ingredient: any substance that is used in the manufacture of a dietary supplement and is intended to be present in the finished batch of the dietary supplement.

In-Process Material: any material that is fabricated, compounded, blended, ground, extracted, sifted, sterilized, derived by chemical reaction, or processed in any other way for use in the manufacture of a dietary supplement.

National Formulary (NF): the National Formulary, current edition, including its supplements. In 1975, USP acquired the NF, which now contains excipients standards that also call for reference materials.

Participant: a company that has qualified to participate in the USP Quality Systems GMP Audited Verification Program by signing a Quality Systems GMP Audited Verification Program License Agreement with USP.

Pest: any objectionable insect or other animal including birds, rodents, flies, mites, and larvae.

Pharmacopeial Forum (PF): a bimonthly publication of USP. It is a freely available public forum that invites comments on proposed USP–NF standards. It provides interested stakeholders with the opportunity to review and comment as the Council of Experts develops or revises standards for the USP–NF.

Physical Plan: all or any part of a building or facility used for or in connection with manufacturing, packaging, labeling, or holding a dietary supplement.

Product Complaint: any communication that contains any allegation—written, electronic, or oral—expressing concern, for any reason, with the quality of a dietary supplement that could be related to current manufacturing practices.

Quality: means that the dietary supplement consistently meets the established specifications for identity, purity, strength, and composition, limits on contaminants, and performance, and has been manufactured, packaged, labeled, and held under conditions to prevent adulteration under the FFDCA.

Quality Control Operation: a planned and systematic operation or procedure for taking all actions necessary to ensure the quality of a dietary supplement.

Quality Control Unit: any person, persons, or group, within or outside the organization, designated by the Participant to be responsible for the duties relating to quality control operations.

Raw Material: any ingredient intended for use in the manufacture of a dietary ingredient or 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, FDA, or the company initiates due to critical product deficiency.

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

Representative Sample: a sample that consists of a number of units that are drawn based on rational criteria such as random sampling and is intended to ensure that the sample accurately portrays the material being sampled.

Sanitizing: adequately treating equipment, containers, or utensils by a process that is effective in destroying vegetative cells of microorganisms of public health significance and in substantially reducing other undesirable microorganisms but without affecting the product or its safety to the consumer.

Shall: used to state mandatory requirements under the provisions of this manual and the Program License Agreement.

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 actions or procedures.

Specification: includes the test, test method, and acceptance criteria that define a standard of quality for a particular test for material. Product specifications include test specifications for identity, purity, strength, limits on contaminants, and performance that define a standard of quality for a material.

Theoretical Yield: the quantity that would be produced at any appropriate step of manufacture or packaging of a particular dietary supplement, based on the quantity of components or packaging to be used, in the absence of any loss or error in actual production.

U.S. Food and Drug Administration (FDA): an agency within the U.S. Department of Health and Human Services responsible for protecting the public health by ensuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices. FDA is also responsible for the safety and security of most of the nation’s food supply, all cosmetics, dietary supplements, and products that give off radiation.

United States Pharmacopeia (USP): the United States Pharmacopeia, current edition, including its supplements. The USP is a compendium of documentary standards for identity and quality that typically involve reference materials used as comparison standards in specified tests and assays.

USP–NF: the current official volume of the United States Pharmacopeia–National Formulary. Although USP and NF are published under one cover and share General Notices and Requirements, they are separate compendia. The General Notices and Requirements section presents the basic assumptions, definitions, and default conditions for the interpretation and application of the USP and the NF.




14. Forms and Checklists

SECTION I: Participant’s Declaration of Information Fulfi lling Initial Quality Systems Audit Documentation Request

SECTION II: Checklist for On-Site Quality Systems GMP Audit



Manual for Participants System/DocumentDocument Name and Number or File Name Provided

Quality Management System

Table of Contents for SOPs

Employee Training Program SOP(s)

Organizational Chart

Job Descriptions – Quality Unit & Manufacturing/Operations Staff

Personnel Hygiene SOP(s)

Document Control and Record-Keeping SOP(s)

CAPA Program SOP(s)

Complaint Handling SOP(s)

Deviation and Investigation SOP(s)

Recall SOP(s)

Change Control SOP(s)

Facilities and Equipment System

Plant/Site Map

Pest Control SOP(s)

Facility Cleaning and Sanitation SOP(s)

Purifi ed Water System Diagram

Equipment Maintenance, Calibration, and Cleaning System SOP(s)

Equipment Cleaning Validation SOP(s)

Computer System Validation, Backup, Change Control, and Security SOP(s)

Comprehensive List of Processing Equipment Requiring Calibration and/or Preventive Maintenance

Section I: Participant’s Declaration of Information Fulfilling Initial Audit Documentation Request

Please complete the table below and return it with the requested documentation.




System/DocumentDocument Name and Number or File Name Provided

Material System

Receipt, Sampling, Storage, and Release of Components, Containers, and Labels SOP(s)

Specifi cations for Components, Containers, and Labels SOP(s)

Supplier Qualifi cation Program SOP(s)

Rejected and Returned Product Management SOP(s)

Production System

Flowchart(s) of Manufacturing Process(es)

Master Production and Control Records SOP(s)

Manufacturing Process Validation SOP(s)

Reprocessing and/or Reworking SOP(s)

Contract Manufacturer Qualifi cation SOP(s)

Packaging and Labeling System

Label Control SOP(s)

Packaging and Labeling of Dietary Supplements SOP(s)

Laboratory Control System

Receipt, Storage, and Documentation of Reagents, Reference Standards, and Samples SOP(s)

Instrumentation Maintenance and Calibration SOP(s)

Laboratory Test Procedures SOP(s)

Analytical Method Validation or Verifi cation SOP(s)

Out-of-Specifi cation Investigation SOP(s)

Stability Program SOP(s)




System/DocumentDocument Name and Number or File Name Provided

General Information

Year the Facility Went into Operation

Square Footage of Facility

Total Staff Manufacturing QC QA Administrative

Proof of Facility Registration under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002




Section II: Checklist for On-Site Audit

DIETARY SUPPLEMENT QUALITY SYSTEMS GMP AUDITED Verification PROGRAMON-SITE AUDIT CHECKLIST

COMPANY NAME:

LOCATION [ADDRESS]:

DATE(S) OF AUDIT:

ESCORT(S) [NAME(S) AND TITLE(S)]:

AUDITOR(S) [NAME(S) AND TITLE(S)]:

Note: This checklist is designed as a reporting tool to be used by USP auditors in conducting USP Quality Systems (QS) Good Manufacturing Practice (GMP) Audits. It is not necessarily intended to be all-inclusive or to limit the scope of the audit. It is also not intended to supplant or be a substitute for an FDA inspection but is only for the purpose of determining whether or not to award use of the USP Quality Systems GMP Audited Mark to the Participant. Ideally, one lot of a dietary supplement (DS) should be tracked from the start of production to release of the final product. In subsequent annual audits, USP will target different quality systems for emphasis, to focus on those aspects of the quality systems that have been the focus of recent FDA inspections. (Note: S.No. equals section number.)

The audit follows the general scheme of systems approach associated with the auditing of the manufacture of DSs including coverage of the following systems: Quality

Systems

QualityManagementSystem

Facility and EquipmentSystems

MaterialsSystem

ProductionSystem

Packaging and LabelingSystem

Laboratory ControlSystem

1

2

3

4

5

6




S. No. GMP QUALITY SYSTEM ELEMENT

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1.0 QUALITY MANAGEMENT SYSTEM

1.1 Principles

a. There is an organizational chart that refl ects the current reporting structure and responsibilities.

b. Job descriptions for positions throughout the company are available.

c. A Quality Management System (QMS) is implemented.

d. The Quality Unit (QA and/or QC) is independent of production.

e. There is/are authorized person(s) for the release of raw materials and DSs.

f. Deviations from established procedures are documented and explained. Critical deviations are investigated, and the investigation and its conclusions documented.

g. No materials are released or used before the satisfactory completion of evaluation by the Quality Unit, unless there are appropriate systems in place to allow for such use.

h. Procedures exist for notifying responsible management in a timely manner of inspections, serious GMP defi ciencies, product defects, and related actions (e.g., complaints, recalls, regulatory actions).

Comments:

1.2 Training

a. Procedures are established and used for identifying training needs. Training procedure(s) include part-time and temporary staff, management, visitors, contract/construction personnel, consultants, and government and customer auditors.

b. Procedures address training schedules such as upon hire, future training requirements, follow-up, and/or retraining frequencies.

c. Training effectiveness is evaluated on a periodic basis.

d. Employee training covers general topics such as GMP, sanitation, safety, environment, and SOPs. In addition, training is provided on specifi c work instructions, procedures, equipment operations, and specifi c job function.

e. Qualifi cations (education, training, experience) and training records are maintained for all personnel.

f. Qualifi cations and experience requirements for trainers are defi ned in job description training procedures.

g. Training records are maintained for all personnel and include: date, topic, name of instructor, employee signatures, tests, quizzes, etc.

h. Specifi c training requirements are defi ned for each unique job description or job function.

Comments:





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1.3 Internal Audits (Self-Inspection)

a. There is a documented procedure for conducting internal quality audits. Auditors are independent of the area that they are auditing.

b. Internal audits are conducted annually or scheduled on the basis of status and importance of activity.

c. Internal audits include work environment and general housekeeping.

d. Internal audit fi ndings and corrective actions are documented and brought to the attention of management.

e. Agreed corrective actions are completed in a timely and effective manner.

Comments:

1.4 Product Quality Review

a. Regular quality reviews of DSs are conducted with the objective of verifying the consistency of the process. Such reviews are normally conducted and documented annually.

b. The outcomes of this review are evaluated and an assessment made of whether corrective action or any revalidation needs to be undertaken. Reasons for such corrective action are documented. Agreed corrective actions are completed in a timely and effective manner.

Comments:

1.5 Validation Policy

a. The company has an overall policy, intentions, and approach to validation, including the validation of production processes, cleaning, analytical methods, computerized systems, and persons.

b. A written validation protocol is established that specifi es how validation of a particular process is conducted.

c. A validation report that cross-references the validation protocol is prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct defi ciencies.

d. Systems and processes are periodically evaluated to verify that they are still operating in a valid manner.

Comments:

1.6 Qualifi cation

a. Before starting process validation activities, appropriate qualifi cation of critical equipment and ancillary systems is completed.

b. Qualifi cation covers the design, installation, operation, and performance of the critical equipment.

Comments:





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1.7 Process Validation

a. Process validation is documented providing evidence that the process operated within established parameters, and performed effectively and reproducibly to produce DSs meeting predetermined specifi cations and quality attributes.

b. The number of process runs for validation depends on the complexity of the process or the magnitude of the process change being considered.

c. Critical process parameters are controlled and monitored during process validation studies.

d. Process validation is performed prospectively, concurrently, or retrospectively.

Comments:

1.8 Cleaning Validation

a. Cleaning procedures are normally validated. In general, cleaning validation is directed to situations or process steps where contamination or carryover of materials poses the greatest risk to DS quality.

b. Validation of cleaning procedures refl ects actual equipment usage patterns. If various DSs are manufactured using the same equipment and the equipment is cleaned by the same process, a representative DS can be selected for cleaning validation.

c. The cleaning validation protocol describes the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, sampling procedure, sampling locations, and analytical methods.

d. Validated analytical methods having sensitivity to detect residues or contaminants are used.

Comments:

1.9 Change Control

a. A formal change control system is established to evaluate all changes that may affect the production and control of the DS.

b. Written procedures provide for the identifi cation, documentation, appropriate review, and approval of changes in standard operating/manufacturing/test procedures, raw materials, specifi cations, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software.

c. The potential impact of proposed changes on the quality of the DS is evaluated.

Comments:





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1.10 Complaints and Recalls

a. All quality-related complaints, whether received orally or in writing, are recorded and investigated according to a written procedure.

b. Records of complaints are retained in order to evaluate trends, product-related frequencies, and severity with a view to taking additional and, if appropriate, immediate corrective action.

c. There is a written procedure that defi nes the circumstances under which a recall of a DS should be considered.

d. Mock recalls are performed on a specifi ed frequency, with a written report.

e. In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities are informed and their advice sought.

Comments:

1.11 Contract Manufacturers and Laboratories

a. All contract manufacturers and laboratories comply and are evaluated in line with GMP requirements.

b. There is a written and approved contract or formal agreement between the contract giver and the contract acceptor that defi nes in detail the GMP responsibilities, including the quality measures, of each party.

c. Where subcontracting is allowed, the contract acceptor does not pass to a third party any of the work entrusted to it under the contract without the contract giver’s prior evaluation and approval of the arrangements.

d.Changes in the process, equipment, test methods, specifi cations, or other contractual requirements are notifi ed to and approved by contract giver.

Comments:

2.0 FACILITY AND EQUIPMENT SYSTEM

2.1 Design and Construction

a. There is adequate space provided for orderly placement of equipment and materials to prevent mix-ups and contamination.

b. Appropriate environmental controls are established and maintained (e.g., controlled temperature, air fi ltration, humidity, and lighting). Records are maintained of these conditions if they are critical to the quality of DSs.

c. All water systems are adequately protected against back fl ow.

d. There are adequate hand-washing facilities for restrooms, break areas, and manufacturing areas.

e. There are adequate controls for maintaining the grounds of the physical plant to protect against the contamination of components, DSs, and contact surfaces.

f. Floors, walls, ceilings, doors, and windows are completely sealed to prevent entry of pests.

g. There is separation of defi ned areas and adequate controls to prevent contamination.

Comments:





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2.2 Process Equipment

a. Equipment is constructed so that surfaces that contact raw materials, in-process materials, or DSs do not alter the quality of the DSs beyond the offi cial or other established specifi cations.

b. Major equipment (e.g., blenders, coaters) and permanently installed processing lines used during the production of a DS is appropriately identifi ed.

c. Loading dock doors are fl ush to the fl oor when closed.

d. A set of current drawings is maintained for equipment and critical installations (e.g., instrumentation and utility systems).

e. Written procedures are established for cleaning of equipment and its subsequent release for use in the manufacture of DSs. Cleaning procedures contain suffi cient details to enable operators to clean each type of equipment.

f. Control, weighing, measuring, monitoring, and test equipment that is critical for ensuring the quality of DSs is calibrated according to written procedures and an established schedule.

Comments:

2.3 Construciton and Maintenance

a. Non-toxic and corrosion-resistant materials such as stainless steel are used in the manufacturing process.

b. Seams are well bonded and smooth.

c. Any substances associated with the operation of equipment, such as lubricants, heating fl uids, or coolants, do not contact in-process material or DSs. Wherever possible, food-grade lubricants and oils are used.

d. Schedules and procedures (including assignment of responsibility) are established for the preventative maintenance of equipment. Any deviations are investigated and evaluated.

Comments:

2.4 Computerized Systems

a. GMP-related computerized systems comply with 21 CFR Part 11.

b. GMP-related computerized systems are validated.

c. Computerized systems have suffi cient controls to prevent unauthorized access or changes to data.

d. Written procedures are available for the operation and maintenance of computerized systems.

e. If a computerized system breakdown or failure would result in the permanent loss of records, a backup system is provided.

f. Data can be recorded by a second means in addition to the computer system.

Comments:





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2.5 Pest Control Program

a. A documented pest control program is in place.

b. Appropriate contractual agreements are established if the pest control program is outsourced.

c. Building exterior is protected from rodent and pest entry.

d. There is a map with the locations of all traps identifi ed.

e. The pest control program includes frequent inspections.

f. All chemicals used in pest control are accurately labeled and stored securely.

Comments:

2.6 Cleaning and Sanitation

a. There is a written and comprehensive plant and equipment sanitation program.

b. Facility and equipment maintenance ensures safe manufacture of DSs.

c. Written procedures are established assigning responsibility for cleaning and sanitation and describing the schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.

d. When necessary, written procedures are established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labeling materials, in-process materials, and DSs.

e. There are cleaning and usage logs established for major equipment, to include: dates, products, number of lots, person who used/cleaned the equipment.

f. Hoppers and tanks are properly covered.

Comments:

2.7 Water

a. Water used in the manufacture of DSs is demonstrated to be suitable for its intended use.

b. Where the manufacturer of a DS either intends or claims that water is suitable for use in processing to produce a DS, water used is monitored and controlled for total microbial counts and objectionable organisms.

c. Where water used in the process is treated by the manufacturer to achieve a defi ned quality, the treatment process is validated and monitored with appropriate action limits.

d. Where the manufacturer of a DS either intends or claims that the water complies with compendial requirements for Purifi ed Water, it demonstrates so.

Comments:





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2.8 Hygenic Practices

a. Hygienic practices are in place to protect against contamination of DSs.

b. Personnel wear clean clothing suitable for the manufacturing activity. Additional protective apparel, such as head, face, hand, and arm coverings, are worn when necessary.

c. Any person, by medical examination or supervisory observation, that is shown to have, or appears to have, an illness or open lesions, is excluded from any operations until the condition is corrected. Personnel are instructed to report such conditions to supervisors.

d. Designated areas outside of processing zones are provided for clothing and other personal belongings.

e. Consumption of food and beverages, chewing of gum, or the use of tobacco products is strictly prohibited in processing areas.

f. Proper hand-washing practices are reinforced with signs posted in break rooms, production areas, and washrooms.

g. Written procedures exist that address and include the control and proper supervision of the above practices.

Comments:

3.0 MATERIALS SYSTEM

3.1 General Controls

a. There are written procedures describing the receipt, identifi cation, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

b. There is a system for evaluating suppliers of critical materials.

c. Materials are purchased against an agreed specifi cation, from a supplier(s), approved by the Quality Unit.

Comments:

3.2 Traceability

a. Each container or grouping of containers (batches) of materials is assigned and identifi ed with a distinctive code, batch, or receipt number. This number is used in recording the disposition of each batch. A system is in place to identify the status of each batch.

b. First-in/First-out (FIFO) or First-expiry/First-out (FEFO) procedures for materials and goods are established and documented.

Comments:





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3.3 Storage and Distribution

a. Materials are stored under conditions and for a period that have no adverse effect on their quality, and are normally controlled so that the oldest stock is used fi rst.

b. Rejected materials are stored and controlled in a segregated area so as to prevent usage.

c. Materials are re-evaluated, as appropriate, to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).

d. DSs and in-process materials are released for distribution to third parties after they have been released by the Quality Unit(s).

e. DSs and in-process materials are transported in a manner that does not adversely affect their quality.

Comments:

4.0 PRODUCTION SYSTEM

4.1 Production Operations

a. Raw materials for in-process material and DS manufacturing are weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices are of suitable accuracy for the intended use.

b. If a material is subdivided for later use in production operations, the container receiving the material is suitable for use and identifi ed.

c. Critical weighing, measuring, or subdividing operations are witnessed or subjected to an equivalent control. Prior to use, production personnel verify that the materials are those specifi ed in the batch record for the intended DS.

d. Actual yields are compared with expected yields at designated steps in the production process.

e. Any deviation is documented and explained. Any critical deviation is investigated.

f. The processing status of major units of equipment is indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.

g. Materials to be reprocessed or reworked are appropriately controlled to prevent unauthorized use.

Comments:

4.2 Contamination

a. Residual materials can be carried over into successive batches of the same DS if there is adequate control. Such carryover does not result in the carryover of degradants or microbial contamination that may adversely alter the established DS impurity profi le.

b. Production operations are conducted in a manner that prevents contamination of in-process materials or DSS by other materials.

Comments:





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4.3 Manufacturing Process Controls

a. Identity and usage of all containers, processing lines, and major equipment during production is recorded.

b. Filling, assembling, packing, and other operations are performed in such a way that products are not adulterated.

c. Written procedures are established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of in-process materials and DSs.

d. Control points and methods for establishing and monitoring critical process control points are stated in writing.

e. In-process mixing of fractions from single batches (e.g., collecting several loads from a single batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.

f. Finished product sub-batches within the same specifi cation are combined to produce a homogeneous material.

g. Out-of-Specifi cation batches are not blended with other batches for the purpose of meeting specifi cations. Each batch incorporated into the blend is manufactured using an established process and is individually tested and found to meet appropriate specifi cations prior to blending.

Comments:

4.4 Batch Records

a. Batch production records are prepared for each in-process material and DS and include complete information relating to the production and control of each batch. If the batch production record is produced from a separate part of the master document, that document includes a reference to the current master production instruction being used.

b. Batch production records are numbered with a unique batch or identifi cation number, dated, and signed when issued.

Comments:





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4.5 Rejection and Reuse of Materials

a. In-process materials and DSs failing to meet established specifi cations are identifi ed as such and quarantined. The fi nal disposition of rejected materials is recorded.

b. Reprocessing: introducing a DS, including one that does not conform to standards or specifi cations, back into the process and reprocessing by repeating a step or other appropriate chemical or physical manipulation steps (e.g., milling, coating) that are part of the established manufacturing process is generally considered acceptable.

c. Reworking:1) Before a decision is taken to rework batches that do not conform

to established standards or specifi cations, an investigation into the reason for nonconformity is performed.

2) Batches that have been reworked are subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Rework procedure is validated concurrently.

d. Recovery of Materials:1) Recovery of in-process materials is considered acceptable,

provided that approved procedures exist for the recovery and the recovered materials meet specifi cations suitable for their intended use.

2) The use of recovered materials is adequately documented.

e. Returns:1) If the conditions under which returned in-process materials or

DSs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned in-process materials or DSs are reprocessed, reworked, or destroyed, as appropriate.

2) Records of returned in-process materials or DSs are maintained.

Comments:

5.0 PACKAGING AND LABELING SYSTEM

5.1 General Controls

a. There are written procedures describing the receipt, identifi cation, quarantine, sampling, examination and/or testing and release, andhandling of packaging and labeling materials.

Comments:





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5.2 Label Issuance and Control

a. Access to the label storage areas is limited to authorized personnel.

b. Procedures are established on how to investigate/evaluate any discrepancies found between number of containers labeled and number of labels issued.

c. Procedures are established for the destruction of obsolete and outdated labels.

d. Printing devices used to print labels for packaging operations are controlled to ensure that all imprinting conforms to the print specifi ed in the batch production record.

e. A printed label representative of those used is included in the batch production record.

Comments:

5.3 Packaging and Labeling Operations

a. There are documented procedures designed to ensure that correct packaging materials and labels are used.

b. Components, in-process materials, and DSs are identifi ed with a lot number that permits determination of history and control of batch.

c. Packaged and labeled in-process materials or DSs are examined to ensure that containers and packages in the batch have the correct label. This examination is part of the packaging operation. Results of these examinations are recorded in the batch production or control records.

d. Proper line clearance procedures are in place and utilized during changeovers.

Comments:

6.0 LABORATORY CONTROL SYSTEM

6.1 Process Quality Control Plan (Packaging/Raw Materials)

a. There are documented procedures describing sampling, testing, approval or rejection of materials, and recording and storage of laboratory data.

b. Any out-of-specifi cation result obtained is investigated and documented according to a procedure.

c Systems are in place to ensure that staff have and are following the approved specifi cation and most current customer specifi cation.

d. Adequate resources (e.g., qualifi ed people, testing instrumentation) are available.

e. Laboratory analysts are properly trained on test procedures.

f. There is a procedure for maintenance of laboratory standards and reagents.

g. Reagents and standard solutions are prepared and labeled following written procedures. “Use by” dates are applied as appropriate for analytical reagents and standard solutions.





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h. Primary reference standards are obtained as appropriate for the manufacture of DSs. The source of each primary reference standard is documented. Consumption and storage records are maintained.

i. Secondary reference standards are appropriately prepared, identifi ed, tested, approved, qualifi ed, and stored. Each secondary reference standard batch is requalifi ed periodically in accordance with a written protocol.

j. Instrument calibration and maintenance programs are established and followed.

Comments:

6.2 Testing of Dietary Supplements

a. For each batch of components, in-process material, and fi nished DS, appropriate laboratory tests are conducted to determine conformity to specifi cations.

b. Appropriate tests are performed for identifi cation, strength or content, limit of specifi ed contaminants, performance, and specifi c tests (e.g., pH, peroxide value, anisidine value) as needed.

c. Appropriate tests are established for all dietary ingredients for which a quantitative claim is made on the DS product label.

d. Limits are established on those types of contaminants (i.e., contaminant profi le) that may adulterate or may lead to adulteration of the fi nished batch of DS.

e. Tests are performed on components and DSs at appropriate intervals to demonstrate conformity to specifi cations and are compared against historical data in order to detect changes to the DS resulting from modifi cations in raw materials, equipment operating parameters, or the production process.

Comments:

6.3 Quality Control Microbiology Lab

a. Microbiology quality control laboratory has updated product specifi cations.

b. Adequate resources (e.g., qualifi ed people, testing instrumentation, and supplies) are available.

c. There is a documented effective laboratory cleaning and sanitization program with environmental monitoring.

d. Appropriate microbiological tests are conducted on each batch of components, in-process material, and fi nished DS where microbial contamination is of concern.

e. The validity of results from microbial tests are adequately demonstrated by data showing that the test specimens to which they are applied do not, of themselves, inhibit the multiplication under the test conditions of microorganisms that may be present (i.e., preparatory testing).

Comments:





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6.4 Stability Monitoring of Dietary Supplements

a. A documented, ongoing testing program is designed to monitor the stability characteristics of DSs. Ideally, the stability program follows recognized standards (e.g., ICH Q1). The results are used to confi rm appropriate packaging and storage conditions and expiry dates.

b. The test procedures used in stability testing are validated and stability indicating.

c. Ideally the fi rst three commercial production batches, but at least one batch initially, and one batch per year thereafter of DS manufactured is submitted to the stability monitoring program and tested.

d. If similar DSs (e.g., multivitamin mineral supplements) are grouped together and bracketed into a family of products and submitted to the stability monitoring program and tested, justifi cation for the product grouping and bracketing is documented.

e. Accelerated stability testing is performed to determine the effect of short-term excursions outside the label storage conditions (such as might occur during shipping).

Comments:

6.5 Expiry Dating

a. When an in-process material (e.g., granulated premix, bulk packaged DSs) is intended to be transferred outside the control of the manufacturer’s material management system, an expiry or retest date is assigned and supported by stability information (e.g., published data, test results).

b. Expiry dates for DSs are based on an evaluation of data derived from stability studies.

c. A representative sample is taken for the purpose of performing tests for a stability time point.

d. When accelerated stability testing is used to establish an initial estimated expiry date, it is followed by long-term stability testing to confi rm the validity of the expiry date.

Comments:

6.6 Reserve/Retention Samples

a. Packaging and holding of reserve samples are for the purpose of potential future evaluation of the quality of batches of DS and not routinely for future stability testing purposes.

b. Appropriately identifi ed reserve samples of each DS batch are retained for one year after the expiry date of the batch assigned by the manufacturer.

c. Reserve samples are stored in the same packaging system in which the DS is marketed or in one that is equivalent to or more protective than the marketed packaging system. Suffi cient quantities are retained to conduct at least two full compendial monograph analyses or, when there is no pharmacopeial monograph, two full product specifi cation analyses.

Comments:





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6.7 Validation and Verifi cation of Analytical Methods

a. Analytical methods are validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference.

b. The suitability of all test methods used is verifi ed under actual conditions of use and is documented.

c. Appropriate qualifi cation of analytical equipment and analysts is considered before starting validation of analytical methods.

d. Complete records are maintained of any modifi cation of a validated analytical method. Such records include the reason for the modifi cation and appropriate data to verify that the modifi cation produces results that are as accurate and reliable as the established method.

Comments:




15. Legal Notices

The information in this manual, including but not limited to text and images herein and their

arrangement, is copyrighted. Copyright 2016 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 manufacturing

facility and operations of a Participant 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.




USP Quality Systems GMP Audited Verification Program. © January 2016, U.S. Pharmacopeial Convention. All rights reserved.43 USP Quality Systems GMP Audited Verification Program. © January



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QS_GMP012M_2016-04

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