NPA GMP Certification Program

NPA has always taken a leadership role in promoting quality standards and has developed proactive certification programs for that purpose. NPA was the first organization to offer a third-party GMP certification program for the manufacturing of dietary supplements and dietary ingredients. NPA established GMP standards for dietary supplements in 1999 and updated the standard in 2000. At time of publication, these GMP standards represented industry’s best practices and served as the basis of the NPA GMP Certification Program as well as establishing a higher level of control than was currently required by the FDA.

In June 2007, the FDA published the final GMP regulation specific to dietary supplements (21 CFR 111). In order to keep the NPA GMP Certification Program relevant and reflect the highest level of industry good manufacturing practices, the NPA GMP Standard has been revised to include all of the FDA GMP requirements of 21 CFR Part 111 and certain requirements from the 2000 version of the NPA GMP standard that exceed requirements of the FDA GMPs, or reflect best industry practices, and/or are necessary for the evaluation of compliance to the NPA GMP standard.

The NPA GMP Standard serves as the basis for the GMP Certification Program. All program requirements and support materials relate to the NPA GMP Standard. The NPA GMP Standard is a living document and will be reviewed and potentially updated to reflect current best practices, advances in technology, and ingredient and product knowledge.

The NPA GMP Standard established good manufacturing practices requirements for dietary supplement manufacturers, dietary ingredient manufacturers, and distributors that want to be certified through NPA’s GMP Certification Program. All companies, including dietary ingredient suppliers, that are seeking certification through the NPA GMP Certification Program will be required to meet the NPA GMP Standard in all areas that are applicable to the manufacturer’s, distributor’s or supplier’s operations.

NPA has always taken a leadership role in promoting quality standards and has developed proactive certification programs for that purpose. NPA was the first organization to offer a third-party GMP certification program specific to the manufacturing of dietary supplements and dietary ingredients. In addition, NPA established GMP standards for dietary supplements in 1999 and updated the standard in 2000. At time of publication, these GMP standards represented industry’s best practices served as the basis of the NPA GMP Certification Program as well as establishing a higher level of control than was currently required by FDA.

In June 2007, the FDA published the final GMP regulation specific to dietary supplements (21 CFR 111). In order to keep the NPA GMP Certification Program relevant and reflect the highest level of industry good manufacturing practices, the NPA GMP Standard has been revised to include all of the FDA GMP requirements of 21 CFR Part 111 and certain requirements from the 2000 version of the NPA GMP standard that exceed requirements of the FDA GMPs, or reflect best industry practices, and/or are necessary for the evaluation of compliance to the NPA GMP standard.

The NPA GMP Certification Program is designed to verify that member suppliers’ manufacturing practices for dietary supplements conform to a standardized set of good manufacturing practices (GMPs) developed and approved by NPA. This program is based upon comprehensive third-party inspections of the manufacturing facilities and GMP-related documentation to verify compliance to the requirements of NPA GMP standards. This program ensures that all elements of the manufacturing process are reviewed to provide reasonable assurance that processes are sufficiently controlled so that products meet their established specification for quality, including identity, purity, strength and composition.

NPA member suppliers that meet a high level of compliance to the NPA GMP Standard and have received an “A” compliance rating after an NPA GMP audit will qualify for GMP certification and use of the NPA GMP certification seal. NPA GMP certification and display of the GMP certification seal demonstrates to suppliers, retailers, consumers and the public that products have been manufactured using good manufacturing practices and provide a means of self-assessment and independent evaluation of GMP compliance to the dietary supplement industry. NPA GMP certification represents facility and process certification versus product certification.

To maintain their NPA GMP certification status, certified companies must remain active NPA members, comply with all NPA supplier membership requirements, maintain compliance to the NPA GMP standards and terms of certification, pay an annual certification fee, and be re-audited every two years.

To ensure appropriate and adequate ongoing oversight of the NPA GMP certification program, NPA established a GMP advisory committee that provides input on current program materials and activities. The GMP Advisory Committee, under the direct supervision of NPA, is comprised of experts selected for their extensive knowledge and training in GMPs. Whenever possible, the committee members will have a diverse background, including food, dietary supplements, pharmaceuticals, and botanicals, representing the needs of the membership.

The functions of the Advisory Committee include:

• Periodic review of the NPA GMPs
• Review and revision of suggested programs, procedures and records, necessary to meet GMPs
• Review and revision of the Audit Checklist and Performance Rating System
• Selection of auditing companies and assessment of their performance
• Resolution of any disagreements between auditors and member suppliers

Third-party auditors are utilized to conduct audits of supplier members according to established program audit protocol, utilizing the NPA GMP standards and audit documents. Auditors are selected by the Advisory Committee and approved by NPA, based on qualifications and prior experience conducting audits and inspections of food or dietary supplement manufacturers. Auditors must be trained in the NPA GMP standards and performance rating system, and have the required education, experience and training to conduct on-site audits. For more information about the NPA third-party auditors, see Third-Party Auditors for the NPA GMP Certification Program.

Third-party auditors are utilized to conduct audits of supplier members according to established program audit protocol, utilizing the NPA GMP standards and audit documents. Auditors are selected by the Advisory Committee and approved by NPA based on qualifications and prior experience conducting audits and inspections of food or dietary supplement manufacturers. Auditors must be trained in the NPA GMP standards and performance rating system, and have the required education, experience and training to conduct on-site audits. Typical education and experience of auditors is:

• A four year college degree, or higher, in biology, chemistry, or food science
• Expertise in food or pharmaceutical GMPs
• Experience in the manufacturing processes for foods or dietary supplements
• Experience in conducting audits of food, dietary supplement or drug manufacturers
• Successful completion of training in the NPA GMPs

Auditors have been trained to conduct GMP audits only according to the NPA audit protocol using the approved audit checklist and performance rating system developed by NPA.

Arrangements for the initial audit, resolution of any findings, and any follow-up audits, are to be made jointly by the auditing company and the member supplier, but must follow the protocol developed by NPA.

Auditing companies are limited to the determination of compliance of a member supplier to NPA GMPs, and any decision with regard to GMP certification is at the sole discretion of NPA.

Auditing companies shall provide NPA with copies of all audit and corrective action reports. They must also agree to the accompaniment of members of NPA staff and/or GMP Advisory Committee on a specified number of audits each year so that NPA may assess the quality of audits and the need for revision of the audit checklist and/or performance rating system.

Conflict of Interest Policy
Auditing companies must be independent, with no known or potential conflict of interest, for each company for which they are contracted to complete an audit review. It is a conflict of interest for an auditing company to currently consult with any member supplier for which it conducts an audit; or to have consulted with that member supplier for a three-year period prior to the audit.

The purpose of the third-party audit is to verify a company’s compliance with the requirements of the NPA GMP standards. It also provides an opportunity for the exchange of information between the company and the auditor that will identify areas for improvement required to meet the requirements of NPA GMP standards. The auditor will inspect all facilities involved with the manufacturing, packaging, labeling, testing, holding and/or distributing of dietary supplements to ensure that all elements of the manufacturing process are reviewed to provide reasonable assurance that appropriate procedures are in place and that processes are sufficiently controlled so that products meet their established specifications for quality, including for identity, purity, strength and composition. Auditors assign a performance rating and submit their report to NPA for the final review and certification decision.

A member supplier has the ability to appeal audit finding or an assigned performance rating. The appeal must be in writing and must address each of the deficiencies and the reasons for the appeal. The written appeal must be submitted directly the GMP Advisory Committee c/o Natural Products Association along with the required fees.

For more detail about the on-site audit, compliance/performance rating, and appeal process please see the On-Site Inspections for the NPA Certification Program.

NPA GMP certification is based on based upon comprehensive third-party inspections of the manufacturing facilities and GMP-related documentation to verify compliance to the requirements of NPA GMP standards. These audits ensure that all elements of the manufacturing process are reviewed to provide reasonable assurance that appropriate procedures are in place and that processes are sufficiently controlled so that products meet their established specifications for quality, including for identity, purity, strength and composition.

On-Site Audits
The purpose of the third-party audit is to verify a company’s compliance with the requirements of the NPA GMP standards. It also provides an opportunity for the exchange of information between the company and the auditor that will identify areas for improvement required to meet the requirements of NPA GMP standards.

The auditor will inspect all areas of the facilities that are involved with the manufacturing, packaging, labeling, testing, warehousing, and/or distributing of dietary supplements. The auditor will observe the general direction of materials flow through the facility, cleanliness, space requirements, equipment and adherence to procedures. Additionally, the auditor will spend a significant amount of time reviewing required GMP-related documentation. The member supplier must have a qualified representative available to answer the auditor’s questions during the on-site audit.

Auditors are responsible for all phases of the audits, including completion of the audit checklist, the audit report, follow-up on corrective actions, and any secondary audits.

A fee will be charged for the audit according to fee schedules submitted by the auditing companies. There will be additional charges to cover the auditor’s travel and lodging expenses; these expenses are to be determined by the member supplier and auditing company in advance of the audit.

Communication will occur directly between the auditing company and the member supplier during all aspects of the auditing process following guidelines developed by NPA. Any disputes that cannot be resolved within these guidelines shall be referred to the GMP Advisory Committee for resolution.

At the close of the onsite audit, the auditor will meet with the company representative and discuss any deficiencies or areas of non-compliance. The company and the auditor will establish a corrective action list and timeline to complete the required follow-up action items. The company must complete any outstanding corrective action items within the agreed upon timeline and communicate its progress to the auditor on a regular schedule compliant with the NPA audit protocol. Should a company fail to communicate with the auditor on a timely basis and/or fail to complete the corrective actions within the set timeline, the audit will be closed and an incomplete audit report will be submitted to NPA. Once the audit is closed, the company will have to start the audit process from the beginning to become NPA GMP certified.

Deficiencies
During the audit, the auditor will note deficiencies and rank them and assign an internal numerical value to the deficiency, based severity and criticality to the manufacturing process and the potential impact on the finished dietary supplement product. The auditor will use this information as part of his or her overall evaluation and to assign a performance rating. NPA has identified three levels of deficiencies, defined below.

Minor Deficiency
A deficiency that, in and of itself, is not of serious nature. A minor deficiency is one that is a departure from established standards having little bearing on the effective use or operation of a product and is unlikely to reduce the material usability of a product for its intended purpose. Several minor deficiencies, or a combination of major and minor deficiencies may prevent a member supplier from receiving an “A” compliance rating.

Major Deficiency
A serious deficiency. A major deficiency is one, other than a critical deficiency, that represents substantial non-compliance to, or a violation of, a GMP-mandated requirement, procedure or documentation. Major deficiencies may be sufficient to prevent the member supplier from receiving an “A” compliance rating.

Critical Deficiency
A deficiency so severe that a single critical deficiency is sufficient to prevent the member supplier from receiving an “A” compliance rating. A critical deficiency is one that judgment and experience indicate would result in hazardous or unsafe conditions for individuals using, maintaining, or depending on a product, a deficiency that judgment and experience indicate is likely to result in product recall due to economic fraud, or a deficiency that could result in the distribution of a product that is 1) contaminated or toxic, or 2) constitutes a risk to human health.

Performance Rating System
The performance rating assigned to a company is based on the level of compliance the company exhibits to the NPA GMP standards. The levels of compliance are as follows:

1. A member supplier demonstrates excellent compliance with NPA GMPs.
2. A member supplier demonstrates good compliance with NPA GMPs, but several significant deficiencies were noted and corrected.
3. A member supplier demonstrates fair or poor compliance with NPA GMPs, many deficiencies were noted and corrected; a re-audit of the facility required.

When a company has earned an “A” rating, the audit will be closed and auditor submits his or her audit report NPA. Upon review and acceptance of the audit report, the company will immediately qualify for NPA GMP certification. NPA will send a letter stating the terms of certification. When the company returns the certification agreement letter, signed by an officer of the company, with the certification fee the company is officially certified and the association will provide a GMP certificate and GMP graphic files. NPA will list the company on its GMP certification program web page.

Note: To obtain certification, a member company must be audited under the NPA audit process described above. Compliance with other programs (e.g., ISO) will not be accepted as a substitute for the NPA audit process.

Appeal Process
A member supplier has the ability to appeal audit finding or an assigned performance rating. The appeal must be in writing and must address each of the deficiencies and the reasons for the appeal. The written appeal must be submitted directly the GMP Advisory Committee c/o Natural Products Association along with the required fees.

The GMP Advisory Committee will review the appeal within 30 working days and attempt to resolve the issue through discussion with the member supplier and auditing company. If this is not possible, a site visitation will be arranged.

The Advisory Committee’s review of any appeal is contingent upon prior payment of a fee to offset the expenses associated with appeal process.

NPA has provided Good Manufacturing Practices (GMP) guidance and certification to its members since 1999. Now, the association raises GMP support to another level: NPA Dietary Supplement GMP Notes, compiled by the team of NPA GMP advisors, auditors and staff.

Dietary Supplement GMP Notes’ content is based on NPA GMP standards, addressing GMP topics related to the GMP program as well as topics like FDA activities, guidance and proposed rule-making; laboratory issues; and policy issues. GMP Notes provide inspection and compliance points to consider that could be valuable in your everyday activities, and clarify existing policies and regulations central to your operations.

GMP Notes cover the basics of GMPs as well as focusing on issues like documenting policies and procedures, change control, record keeping, good documentation practices, quality assurance and quality control, and internal audits.

NPA’s GMP program, the first large-scale effort of its kind in the supplement industry, was launched in January 1999. Since then, NPA, working with its advisors and auditors, is responsible for certifying more than 60 companies and providing GMP educational programming for representatives from more than 600 dietary supplement suppliers and manufacturers.

The content of NPA’s Dietary Supplement GMP notes is based on the NPA GMP Standard. As always we welcome your feedback about the GMP program. We will consider brief articles that NPA supplier members may wish to contribute to NPA Now, our bi-monthly newsletter for all NPA members. Subjects should be cGMP related. Your input would be especially valuable if it addresses emerging new technologies. Note: NPA reserves the right to edit submissions for clarity and length.

NPA’s GMP program, the first large-scale effort of its kind in the supplement industry, was launched in January 1999. Since that time, NPA, working with its advisors and auditors, is responsible for certifying more than 60 companies and providing GMP educational programming for representatives from more than 600 dietary supplement suppliers and manufacturers.

What is the role of testing in the new FDA GMPs for dietary supplements?
NPA believes the FDA was responsive to the many industry comments submitted in response to the proposed FDA GMPs in 2003 objecting to the heavy emphasis on finished product testing, especially the requirements for testing every batch of finished dietary supplements for identity, quality, strength, purity and composition, the understanding being you cannot test quality into the product at the end. The agency has modified the testing requirements in the final rule, providing more flexibility and reducing the finished product testing burden, making it more consistent with current quality systems principles, which uses testing as an element of quality control, not the central focus or tool to ensuring quality. Basically, in the final CGMPs, the role of testing is to verify compliance to specifications set by the manufacturer and confirm that the manufacturing processes are sufficiently controlled to prevent adulteration.

In the preamble, the FDA states:

• Consistent with basic CGMP principles, ensuring the quality of the dietary supplement product requires that the manufacturer establish precisely what it will produce (specifications for its product), how it will make the product (processes), and which process controls and tests it will use to ensure reliable, reproducible results. 21 CFR 111 Preamble (page 113)
• Under the final FDA GMPs for dietary supplements, testing and/or examinations are used to confirm incoming components and in-process materials meet their specifications. Additionally, testing and examination are required to ensure that the manufacturing processes were sufficiently controlled to ensure that the finished product meets its specifications and was not unintentionally contaminated or adulterated during its manufacture.

Can you describe the testing requirements for incoming components?
First, the manufacturer is responsible for establishing specifications for identity, purity, strength and composition related to incoming components as well as limits on those types of contaminants that may adulterate or lead to adulteration of the finished product. (21 CFR 111.70) The manufacturer must then verify through appropriate, scientifically valid testing or examination that these specifications have been met. (21 CFR 111.75)

While there is some flexibility in determining what tests and examinations you will use to substantiate that established specifications are met, you must conduct at least one appropriate test or examination to verify the identity of any incoming component that is a dietary ingredient. (21 CFR 111.17(a)(1)). For companies that are certified through the Natural Products Association GMP Certification Program, you already perform 100 percent identity testing of incoming ingredients in most instances and may already be in compliance to this provision.

Can you explain the purpose of the interim final rule on 100 percent identity testing?
On the same day as the final FDA GMP rule was published, the FDA published an interim final rule, “Petition to Request an Exemption From 100 Percent Identity Testing of Dietary Ingredients; Interim Final Rule (IFR).” The IFR outlines a procedure for requesting (by petition to, and review by FDA) an alternative to the required 100 percent identity testing of dietary ingredients. The FDA states they recognize it may be possible for a manufacturer to demonstrate an alternative approach to 100 percent identity testing for verifying the identity of a dietary ingredient. This procedure would be consistent with the agency’s stated goal of providing flexibility in the cGMP requirements. The provisions outlined in the IFR clarify the agency’s willingness to consider such petitions on a case-by-case basis. FDA is requesting comments on the IFR to Docket No. 2007N-0186, and has extended the submission date to October 24, 2007.

What is the procedure outlined in the interim final rule (IFR) for petitioning FDA for an exemption from 100 percent identity testing requirement?
First, the IFR notes that the FDA will not consider a manufacturer’s petition until after the FDA CGMP compliance date for that company and suggests that a manufacturer who may want to submit a petition could begin immediately to gather the data and information needed to support the petition for exemption. The petition must include the scientific rationale, supported by data and information, that the alternative to the 100 percent identity testing will demonstrate that there is no material decrease of assurance, compared to the assurance provided by 100 percent identity testing, when the dietary ingredient is sourced from one or more suppliers identified in the petition. The FDA will considered such petitions under § 10.30 (21 CFR 10.30), the citizen petition process. The petition must include:

• The action requested (a request for an exemption from requirements of § 21 CFR 111.75(a)(1)(i);
• A statement of grounds (this is the section that outlines your scientific rationale and supporting data and information);
• A section on environmental impact;
• A statement certifying that you have presented all information and views on which the petition relies, including representative date and information which are unfavorable to the petition.

If granted, the manufacture will have to implement the system identified in the petition and the exemption would apply only to the specific dietary ingredient (and any of its attributes) and the specific supplier or suppliers as provided in the petition, under the circumstances outlined in the petition.

The IFR contains background information that will be useful to manufacturers wishing to develop petitions under the IFR. Additionally, FDA state it will issue a guidance on the information and type of data it recommends be included in the citizen petition and how the petition will be processed.

I’ve heard I can use a certificate of analysis (COA) to qualify my components. Is this true, and if so, are there any special requirements to do so?
The rule does allow manufacturers to rely on certificates of analysis to verify the identity specifications for components other than dietary ingredients. Additionally, the certificate of analysis can be used to verify compliance to other established specifications for components. However, in order to use a COA as an alternative to conducting your own tests and examinations to verify component specifications, you must establish the reliability of the COA by confirming supplier tests or examinations. The COA must describe the test or examination method used, test or examination limits, and provide actual tests or examination results. Additionally, you must maintain documentation regarding how you qualify the supplier and periodically re-confirm the supplier’s COA, and your quality control personnel must review and approve the documentation setting forth the basis for qualification and re-qualification of any supplier. (21 CFR 111.75)

Do I have to conduct in-process testing?
The final rule does not identify specific in-process testing that must be performed. However, under the new rule you are required to set (21 CFR 111.70) and monitor (21 CFR 111.75) in-process specifications for any point, step, or stage in the manufacturing process (documented in the master manufacturing record) where control is necessary and for limits on those types of contamination that may adulterate or lead to adulteration of your finished dietary supplement products.

Does the new rule require finished product testing?
Yes, the final FDA GMPs requires you to verify that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition and for limits on contamination that may adulterate your product. Specifically, under 21 CFR 111.75(c) and (d), you must select and test or examine one or more established finished product specifications (for identity, purity, strength, composition, and limits on contaminants that may adulterate your product) to verify that your manufacturing process has yielded a finished batch that meets all product specification except those exempted by quality control personnel under §111.75(d). You must also provide adequate documentation for why meeting these specifications will ensure your finished batch meets all product specifications and quality control personnel must review and approve such documentation.

The rule provides some flexibility in this area, requiring testing of every finished batch or alternatively, allowing for testing a subset of batches identified using a sound statistical sampling plan. The rule also allows you to exempt one or more product specifications from the verification (testing or examination) requirements if you determine and document that the specification cannot verified through testing because there is no scientifically valid method for testing the exempted product specification at the finished product stage and the specification can be verified through component and in-process testing or examination. Additionally, the rule allows you to select one, two, three or more specifications that could be used to demonstrate compliance with specifications if testing these specifications will verify that the other untested specifications are met. Once again, you must document your basis for why this is so and your quality control personnel must review and approve such documentation.

What is an appropriate test or examination? Do I have to use a compendial or official method for my testing?
In the preamble to the new rule, FDA states that they agree with comments that companies should have the flexibility to decide what methods are most appropriate or suitable for testing or examining their ingredients and dietary supplements. They go on to note that the appropriateness of the test will depend on the nature of the material being testing and the manufacturer is responsible for choosing the appropriate test.

Specifically, 21 CFR 111.75 (h)(2) of the new rule states that the tests and examinations that you use have to include at least one of the following methods: gross organoleptic analysis; macroscopic analysis; microscopic analysis; chemical analysis; or other scientifically valid methods. Once again, It is your responsibility to determine the appropriateness of the test and/or examination you will use based on suitability for the material and purpose of the test. For example, an organoleptic examination of a powdered herbal extract may not be a suitable identity test, and a macroscopic and/or microscopic evaluation to confirm identity would have to be performed by personnel that have been trained and qualified to do such.

The final rule does not dictate the use of compendial or official test methods, and although the FDA recommends their use where appropriate, the actual regulatory requirement is that the test or examination be scientifically valid. In the preamble to the final GMP rule, FDA discusses what they consider a scientifically valid test or examination. They note that although a method has not been “formally validated,” meaning that it has not been subject to collaborative studies using multiple laboratories, it may in fact be a scientifically valid method because it has been tested multiple times in a single lab and is suitable for its intended use. They also note that typical validation characteristics include accuracy, precision, specificity, detection limits, quantification limits, linearity, range and robustness. The preamble to the 2003 proposed FDA GMPs for Dietary Supplements cites several references that companies might use to conduct internal method validation studies including USP, AOAC and ICH guidance documents. FDA offers guidance, though not specific to Dietary Supplements/Dietary Ingredients, which may be useful on how to scientifically validate chromatographic methods:

• www.fda.gov/Cder/guidance/cmc3.pdf
• www.fda.gov/ora/science_ref/priv_lab/comp_liq_chro/jaoac.htm

The purpose of the third-party audit is to verify a company’s compliance with the requirements of the NPA GMP standards. It also provides an opportunity for the exchange of information between the company and the auditor that will identify areas for improvement required to meet the requirements of NPA GMP standards. The auditor will inspect all facilities involved with the manufacturing, packaging, labeling, testing, holding and/or distributing of dietary supplements to ensure that all elements of the manufacturing process are reviewed to provide reasonable assurance that appropriate procedures are in place and that processes are sufficiently controlled so that products meet their established specifications for quality, including for identity, purity, strength and composition. Auditors assign a performance rating and submit their report to NPA for the final review and certification decision.

A member supplier has the ability to appeal audit finding or an assigned performance rating. The appeal must be in writing and must address each of the deficiencies and the reasons for the appeal. The written appeal must be submitted directly the GMP Advisory Committee c/o Natural Products Association along with the required fees.

For more detail about the on-site audit, compliance/performance rating, and appeal process please see the On-Site Inspections for the NPA Certification Program.

NPA GMP certification is based on based upon comprehensive third-party inspections of the manufacturing facilities and GMP-related documentation to verify compliance to the requirements of NPA GMP standards. These audits ensure that all elements of the manufacturing process are reviewed to provide reasonable assurance that appropriate procedures are in place and that processes are sufficiently controlled so that products meet their established specifications for quality, including for identity, purity, strength and composition.

On-Site Audits
The purpose of the third-party audit is to verify a company’s compliance with the requirements of the NPA GMP standards. It also provides an opportunity for the exchange of information between the company and the auditor that will identify areas for improvement required to meet the requirements of NPA GMP standards.

The auditor will inspect all areas of the facilities that are involved with the manufacturing, packaging, labeling, testing, warehousing, and/or distributing of dietary supplements. The auditor will observe the general direction of materials flow through the facility, cleanliness, space requirements, equipment and adherence to procedures. Additionally, the auditor will spend a significant amount of time reviewing required GMP-related documentation. The member supplier must have a qualified representative available to answer the auditor’s questions during the on-site audit.

Auditors are responsible for all phases of the audits, including completion of the audit checklist, the audit report, follow-up on corrective actions, and any secondary audits.

A fee will be charged for the audit according to fee schedules submitted by the auditing companies. There will be additional charges to cover the auditor’s travel and lodging expenses; these expenses are to be determined by the member supplier and auditing company in advance of the audit.

Communication will occur directly between the auditing company and the member supplier during all aspects of the auditing process following guidelines developed by NPA. Any disputes that cannot be resolved within these guidelines shall be referred to the GMP Advisory Committee for resolution.

At the close of the onsite audit, the auditor will meet with the company representative and discuss any deficiencies or areas of non-compliance. The company and the auditor will establish a corrective action list and timeline to complete the required follow-up action items. The company must complete any outstanding corrective action items within the agreed upon timeline and communicate its progress to the auditor on a regular schedule compliant with the NPA audit protocol. Should a company fail to communicate with the auditor on a timely basis and/or fail to complete the corrective actions within the set timeline, the audit will be closed and an incomplete audit report will be submitted to NPA. Once the audit is closed, the company will have to start the audit process from the beginning to become NPA GMP certified.

Deficiencies
During the audit, the auditor will note deficiencies and rank them and assign an internal numerical value to the deficiency, based severity and criticality to the manufacturing process and the potential impact on the finished dietary supplement product. The auditor will use this information as part of his or her overall evaluation and to assign a performance rating. NPA has identified three levels of deficiencies, defined below.

Minor Deficiency
A deficiency that, in and of itself, is not of serious nature. A minor deficiency is one that is a departure from established standards having little bearing on the effective use or operation of a product and is unlikely to reduce the material usability of a product for its intended purpose. Several minor deficiencies, or a combination of major and minor deficiencies may prevent a member supplier from receiving an “A” compliance rating.

Major Deficiency
A serious deficiency. A major deficiency is one, other than a critical deficiency, that represents substantial non-compliance to, or a violation of, a GMP-mandated requirement, procedure or documentation. Major deficiencies may be sufficient to prevent the member supplier from receiving an “A” compliance rating.

Critical Deficiency
A deficiency so severe that a single critical deficiency is sufficient to prevent the member supplier from receiving an “A” compliance rating. A critical deficiency is one that judgment and experience indicate would result in hazardous or unsafe conditions for individuals using, maintaining, or depending on a product, a deficiency that judgment and experience indicate is likely to result in product recall due to economic fraud, or a deficiency that could result in the distribution of a product that is 1) contaminated or toxic, or 2) constitutes a risk to human health.

Performance Rating System
The performance rating assigned to a company is based on the level of compliance the company exhibits to the NPA GMP standards. The levels of compliance are as follows:

1. A member supplier demonstrates excellent compliance with NPA GMPs.
2. A member supplier demonstrates good compliance with NPA GMPs, but several significant deficiencies were noted and corrected.
3. A member supplier demonstrates fair or poor compliance with NPA GMPs, many deficiencies were noted and corrected; a re-audit of the facility required.

When a company has earned an “A” rating, the audit will be closed and auditor submits his or her audit report NPA. Upon review and acceptance of the audit report, the company will immediately qualify for NPA GMP certification. NPA will send a letter stating the terms of certification. When the company returns the certification agreement letter, signed by an officer of the company, with the certification fee the company is officially certified and the association will provide a GMP certificate and GMP graphic files. NPA will list the company on its GMP certification program web page.

Note: To obtain certification, a member company must be audited under the NPA audit process described above. Compliance with other programs (e.g., ISO) will not be accepted as a substitute for the NPA audit process.

Appeal Process
A member supplier has the ability to appeal audit finding or an assigned performance rating. The appeal must be in writing and must address each of the deficiencies and the reasons for the appeal. The written appeal must be submitted directly the GMP Advisory Committee c/o Natural Products Association along with the required fees.

The GMP Advisory Committee will review the appeal within 30 working days and attempt to resolve the issue through discussion with the member supplier and auditing company. If this is not possible, a site visitation will be arranged.

The Advisory Committee’s review of any appeal is contingent upon prior payment of a fee to offset the expenses associated with appeal process.

Good Manufacturing Practices (GMPs) provide a framework of controls that are intended to:

• Protect the product from adulteration or contamination.
• Prevent mix-ups and errors.
• Let you and other personnel know what to do before you or they do it.
• Ensure consistency and control throughout the manufacturing process.
• Ensure quality is designed into the manufacturing process and products.
• Document what really occurred throughout the production cycle.
• Provide an independent group to make the final decisions regarding approval and release or rejection.
• Provide mechanisms for companies to solve problems, learn from mistakes, monitor operations, and continually improve.
• Provide products that meet their established quality specifications.

GMPs provide for documented evidence that a manufacturer maintains a level of quality by design and quality systems to ensure product quality, strength, purity, and identity. GMPs require specifications to be established for raw materials, packaging materials, labeling and finished products. These specifications must address quality issues as well as potential adulteration and contamination issues. GMPs require procedures for the review, approval and release or rejection of raw materials, packaging materials, labeling and finished products based on conformity to established specifications. Additionally, GMPs provide for a mechanism for investigation of deviations, deficiencies and/or failures to determine root cause(s) and to implement corrective and preventative actions as necessary. GMPs ensure that companies promote a culture of ‘continuous improvement’.

SOPs define how a company will meet GMP requirements. SOPs are your company’s internal regulations; their role is to describe departments’ roles, responsibilities and activities. SOPs are written documents that describe in detail, step-by-step, how a procedure, task, operation or function should be done. SOPs are intended to standardize the performance of the procedure to ensure consistent outcome or results each time. Once established, SOPs should be followed as written as they are intended to describe the company-approved method for performing the procedure, task, operation or function. Changes to SOPs should be made under a change control program that includes a review of the impact of the change(s) and approval by appropriate management and the Quality Unit.

An extremely important part of GMPs is documenting every aspect of manufacturing processes, activities, and operations. You could say that SOPs are the foundation of the GMP framework. The purpose of SOPs is to ensure uniformity in the performance of GMP-related operations to assure safe, quality products that meet their established specifications and minimize the potential of adulteration, contamination and/or mix-ups during manufacturing and distribution. SOPs are usually the first item reviewed in a regulatory inspection, and the Natural Products Association third-party auditors will focus the majority of their audit time on reviewing your SOPs for our GMP certification program. Your SOPs and other GMP-documentation such as records are used by FDA and third-party auditors to see how your company operates and to evaluate your GMP compliance.

Additionally SOPs make good business sense because they tell your employees what they are supposed to do, when and how. They can minimize or eliminate contamination, mix-ups and errors which saves time and other resources, improves efficiency, and results in consistent products that meet their established specifications.

A well-written SOP answers the Who, What, Where, When, Why and How questions. Use a standard format or template to ensure that each of these questions is addressed consistently and adequately within company SOPs. Consider developing an SOP on SOPs and good documentation practices.

Every FDA-regulated company should have these 10 standard operating procedures in place:

1. Visitor & FDA Inspection policies and procedures
2. SOP on SOPs
3. Change control
4. Quality unit authorities and responsibilities
5. Internal audits
6. Personnel health, disease control, qualifications and GMP training
7. Product review, approval, release or rejection
8. Vendor selection and qualification
9. Sample storage and retention
10. Customer complaints and product recall procedures

This list is not all-inclusive and the actual number of SOPs a company may develop and establish to address the above issues will be dependent upon company philosophies and complexity of operations. This list is reflective of those SOPs that will define the company’s management philosophy and policies related to these issues, and also addresses how certain functions or activities will be performed to ensure essential tasks are performed correctly, consistently and in conformance with internally approved procedures. The list does not include operational SOPs, which are dependent upon the actual functions and operations conducted by individual companies within specific facilities.

Additionally, for the purposes of NPA GMP certification, where NPA’s GMP standards state that there shall be written procedures—it must be taken as a mandatory requirement to establish one or more SOPs that address that particular GMP requirement.

A controlled document is one that is required by GMP standards or regulations or that otherwise falls under the scope of GMPs. Controlled documents include company program or policy documents that address GMP-related issues or requirements, GMP-related SOPs and records, etc.

When a manufacturer makes permanent changes or modifications to procedures or documentation to address regulatory changes or improvements or modifications in or with their own procedures or facilities, the changes should be reviewed, justified, documented, approved and implemented in a defined, systematic way. This system of documenting and approving permanent changes has become known in GMP parlance as “change control.” Temporary changes are considered deviations and should be addressed in conformity with appropriate documented procedures. Change control with its components of review, justification, documentation, approval and implementation allows us to evaluate the potential impact of change on regulatory guidance, previously approved procedures and documentation as well as on product quality and in some cases safety. Change control procedures must be formalized and identify what is and what isn’t covered by the procedure and how proposed changes will be identified or recommended, processed, reviewed and approved. While the cGMPs assign approval responsibility to the Quality Unit, other specialty groups may also be assigned or required to review procedures, e.g., engineers, chemists, computer experts, etc.

We believe FDA was responsive to the many industry comments submitted in response to the proposed FDA GMPs in 2003 objecting to the heavy emphasis on finished product testing, especially the requirements for testing every batch of finished dietary supplements for identity, quality, strength, purity and composition; the understanding being that you cannot test quality into the product at the end. The agency has modified the testing requirements in the final rule, providing more flexibility and reducing the finished product testing burden, making it more consistent with current quality systems principles, which uses testing as an element of quality control, not the central focus or tool to ensuring quality. Basically, in the final CGMPs, the role of testing is to verify compliance to specifications set by the manufacturer and confirm that the manufacturing processes are sufficiently controlled to prevent adulteration. In the preamble, the FDA states:

Consistent with basic CGMP principles, ensuring the quality of the dietary supplement product requires that the manufacturer establish precisely what it will produce (specifications for its product), how it will make the product (processes), and which process controls and tests it will use to ensure reliable, reproducible results. 21 CFR 111 Preamble (page 113)

Under the final FDA GMPs for dietary supplements, testing and/or examinations are used to confirm incoming components and in-process materials meet their specifications. Additionally, testing and examination are required to ensure that the manufacturing processes were sufficiently controlled to ensure that the finished product meets its specifications and was not unintentionally contaminated or adulterated during its manufacture.

The rule does allow manufacturers to rely on certificates of analysis to verify the identity specifications for components other than dietary ingredients. Additionally, the certificate of analysis can be used to verify compliance to other established specifications for components. However, in order to use a COA as an alternative to conducting your own tests and examinations to verify component specifications, you must establish the reliability of the COA by confirming supplier tests or examinations. The COA must describe the test or examination method used, test or examination limits, and provide actual tests or examination results. Additionally, you must maintain documentation regarding how you qualify the supplier and periodically re-confirm the supplier’s COA, and your quality control personnel must review and approve the documentation setting forth the basis for qualification and re-qualification of any supplier. (21 CFR 111.75)

The final rule does not identify specific in-process testing that must be performed. However, under the new rule you are required to set (21 CFR 111.70) and monitor (21 CFR 111.75) in-process specifications for any point, step, or stage in the manufacturing process (documented in the master manufacturing record) where control is necessary and for limits on those types of contamination that may adulterate or lead to adulteration of your finished dietary supplement products.

Yes, the final FDA GMPs requires you to verify that every finished batch of dietary supplement meets each product specification for identity, purity, strength, composition and for limits on contamination that may adulterate your product. Specifically, under 21 CFR 111.75(c) and (d), you must select and test or examine one or more established finished product specifications (for identity, purity, strength, composition, and limits on contaminants that may adulterate your product) to verify that your manufacturing process has yielded a finished batch that meets all product specification except those exempted by quality control personnel under §111.75(d). You also must provide adequate documentation for why meeting these specifications will ensure your finished batch meets all product specifications and quality control personnel must review and approve such documentation.

In the preamble to the rule, FDA states that they agree with comments that companies should have the flexibility to decide what methods are most appropriate or suitable for testing or examining their ingredients and dietary supplements. They go on to note that the appropriateness of the test will depend on the nature of the material being testing and the manufacturer is responsible for choosing the appropriate test.