Federal GMPs for Dietary Supplements

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 thandietary 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

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:

• Visitor & FDA Inspection policies and procedures
• SOP on SOP
• Change control
• Quality unit authorities and responsibilities
• Internal audits
• Personnel health, disease control, qualifications and GMP training
• Product review, approval, release or rejection
• Vendor selection and qualification
• Sample storage and retention
• 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.

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.