By Courtney Cavaliere and Mark Blumenthal
The US Food and Drug Administration’s (FDA) final regulations for Good Manufacturing Practices (GMPs) for dietary supplements (DS) were published on June 25, 2007, providing new requirements that manufacturers, packagers, labelers, and holders of DS will have to use in their operations to ensure the proper identity, purity, strength, composition, and overall quality of their products.1 Several trade organizations sponsored teleseminars and webinars regarding these new GMPs soon after the rule was published, during which experts attempted to analyze and clarify the new rule. In light of the importance of the new rule, this article provides a summary of some of the main aspects of the GMPs, based in part on some of the presentations made during the American Herbal Products Association’s (AHPA) teleseminar on July 12, 2007, and the Council for Responsible Nutrition’s (CRN) webinar on July 16, 2007.
Requirements of the New GMPs
Under the new GMP rule, manufacturers will be required to implement a system of production and process controls for all stages of the manufacturing, packaging, labeling, quality control, record-keeping, storing, and distributing of DS to ensure the quality and proper identification of those supplements. FDA set a staggered schedule for compliance with this new rule, so that the largest DS companies, with 500 or more employees, must conform within 1 year, while those with fewer than 500 but more than 20 employees will have 2 years to comply, and the smallest companies, with less than 20 employees, will have until June 25, 2010. Experts have argued that the new regulations provide companies with many options in developing a production and process controls system, so long as manufacturers are able to justify the specific procedures that they choose to implement.
An important aspect of the new GMPs is the relative flexibility afforded to manufacturers. They will be required to establish their own specifications and conduct appropriate in-process and end-product tests and examinations to verify that all quality specifications for identity, purity, strength, and composition are met. However, the GMP rule also provides flexibility for the manufacturer to test either every batch of finished products or a subset of finished batches to determine that all quality specifications are met, or document why testing of dietary ingredients (DI) and monitoring of manufacturing processes will ensure that these specifications are met. This requirement also pertains to non-DI components.* Specifications are also required for in-process production, labels and packaging components, and finished products.
Testing subsets of finished batches would have to be based on a statistical sampling plan with a justifiable rationale for why such a plan ensures the products’ quality.
DI suppliers are not required to conform to the new GMP rule; the responsibility to determine DI quality rests with the manufacturer of the finished DS product. Therefore, DS manufacturers must ensure the proper identity of any DI (and non-DI) components used in their products. The identity specification of any DI can only be verified by actual testing or examination, unless FDA grants an exemption from testing 100% of the time. To determine whether DI specifications are met, (a) identity tests must be carried out on components prior to use; (b) in-process points, steps, or stages where control is necessary to ensure the quality of the DS finished product must be monitored; and (c) a subset of finished batches must be tested for one or more of the established specifications for identity, purity, strength, composition, and contamination limits, using “appropriate, scientifically valid methods.”
Manufacturers could confirm DI identity by conducting at least one appropriate scientifically valid test or examination (e.g., gross organoleptic analysis [analysis based on taste, smell, color, morphology, etc.]; macroscopic analysis; microscopic analysis; chemical analysis; or other scientifically valid methods). Identity of other (non-DI) components may also be confirmed by conducting appropriate tests or examinations or by relying on a Certificate of Analysis (C of A) from the supplier, provided that certain conditions are met.
The C of A will be sufficient only if it includes information on test methods, limits, and actual results; if the manufacturer establishes the reliability of the supplier’s C of A through confirmation of the supplier’s tests; if the manufacturer documents how the supplier was qualified as reliable and verifies that this qualification was reviewed and approved by the manufacturer’s quality assurance personnel; and if the manufacturer periodically reconfirms the C of A.
With respect to contaminants, FDA declined to establish upper limits. Therefore, manufacturers are required to determine what, if any, contaminants are likely or certain to be present in raw materials and to establish limits, as appropriate, to prevent adulteration of the finished product.
Under the FDA’s interim final rule, also released on June 25, 2007, with a 90-day comment period, manufacturers can petition the agency for exemption from testing DI 100% of the time.2 The deadline for submitting comments about the interim final rule was September 24, 2007. Assuming that the interim final rule is accepted in its current form, the FDA will not accept a petition from a manufacturer for an exemption to the 100% testing requirement until that company is required to be in compliance with the new GMP rule (i.e., the 1, 2, or 3 years, as noted above, depending on company size). The petition would have to set forth the scientific rationale for why testing less than 100% of a specific DI from a specific supplier would not result in reduced assurance of identity or quality and it would have to be accompanied by supporting data and information.
The final rule does not provide specific guidelines or requirements for the tests that a company would need to conduct to verify the identity, purity, strength, and composition of ingredients and finished products. The tests or analyses that a manufacturer chooses to employ, however, must be “scientifically valid,” as previously described. The final rule also does not require the use of any specific quality or grade designation of DI, e.g., DI for which standards have been established by the United States Pharmacopeia (USP). It is entirely up to the manufacturer to establish its own specifications for the identity, purity, strength and composition of components, as well as contamination limits specifications. Therefore, there is nothing in the final rule to prevent the use of low quality DI, as long as the manufacturer establishes accurate specifications that define the DI and it fulfills its responsibility to determine whether the (potentially low) specifications are met.
Manufacturers will also have to establish and follow written procedures for their operations and facilities, which are specified in the final GMP rule. (Of course, many or most DS manufacturers already have written procedures documenting standard operating and other manufacturing-related processes; these manufacturers will most likely have to adjust their current record-keeping processes to comport with the new requirements and/or add new written procedures, as required.) They will need to keep written product records for 1 year past the expiration date (if the company chooses to affix an expiration date on its products) or 2 years beyond the date of distribution of the last batch of supplements associated with those records, and these records must be available to the FDA upon request. Eugene Lambert of Covington and Burling LLP pointed out during CRN’s webinar that the FDA does not necessarily have explicit authority for records inspection and that the FDA has essentially claimed a necessity requirement for records inspection.3 He stated that other industries—including the seafood and juice industries—have not challenged FDA’s claimed authority in this regard, and it remains to be seen whether the DS industry will raise such a challenge.
Entities and Procedures Outside the Scope of the Final Rule
Suppliers of DI will not have to follow the new GMPs for DS, but they will instead continue to follow conventional food GMPs. The burden of verifying the identity of DI—as stated previously—will now rest entirely on the manufacturers of finished DS products. However, those companies that manufacture DI that are sold directly to consumers or supplied to other companies that “simply package” the DI as a final product, will be subject to the new GMPs. Some experts have stated that this may require manufacturers to work closely with DI suppliers, and some manufacturers may at least find it necessary to become knowledgeable of how certain ingredients are produced.
The new rule does not require expiration dates on DS. However, any company that does put such a date on its label will have to maintain records with supporting data to substantiate the choice of such a date. According to experts participating in CRN’s webinar, during the public comment period on the proposed GMPs issued by FDA in 2003, numerous members and experts from the DS industry objected to FDA’s refusal to require expiration dating. They argued that expiration dates are already required within retail markets and that a lack of an expiration date seemingly implies that a product’s lifespan is infinite. FDA, however, concluded that there was not enough data to support regulations about expiration dating in the final rule.
Differences between the Final Rule and the Proposed Rule of 2003
In his presentation during the CRN webinar, Paul Bolar, vicepresident of regulatory affairs for Pharmavite LLC, a leading manufacturer of DS in the mainstream market, enumerated several differences between the final rule for DS GMPs and the proposed rule of 2003.4 According to Bolar, several of these changes are less restrictive and offer more flexibility to manufacturers. For instance, the FDA modified the definition of “sanitize” that was given in the proposed rule, eliminated some prescriptive requirements for bathroom and hand-washing facilities, and changed the term “quality control unit” to “quality control personnel.” Under the final rule, personnel and supervisors must now prove that they have education, training, or experience—as opposed to education, training, and experience. The final rule further gives manufacturers more flexibility as to the testing of supplement components, provides provisions for reliance on C of A’s, and has reduced finished product testing requirements. Reserve samples and records for products must now be kept for 1 year after a product’s expiration date or 2 years after last distribution, instead of the 3 years suggested in the proposed rule. The final rule also contains less restrictive salvaging requirements for returned product.
Bolar also noted several additional requirements in the final rule that were absent from the proposed rule. The definition of “product complaint” now includes “illness or injury,” which Bolar argued could cause companies to consider even minor illness complaints as having possibly been manufacture-related. The final rule further requires that companies keep training records and develop standard operating procedures for all operations, and a section regarding “grounds” was added to the final rule. Moreover, the final rule differs from the proposed rule in that manufacturers must document a basis for the adequacy of their specifications for ensuring the quality of their finished products.
The final rule also eliminated some redundant requirements for component compliance already specified in the Food, Drug and Cosmetic Act. During CRN’s webinar, Dave Schoneker, director of global regulatory affairs at Colorcon and chairman of the International Pharmaceutical Excipients Council (IPEC), stressed that all excipients used in DS must be approved food additives or generally recognized as safe (GRAS) materials—which he said is currently not the case for many supplements on the market.5 The FDA included specific language about this requirement in its proposed rule for GMPs but eliminated such language in the final rule. According to Schoneker, this elimination was merely to remove redundant requirements and does not reflect a change in the FDA’s expectations for excipients. Schoneker stated that the FDA expects all excipients to be manufactured using food GMPs at a minimum, and the agency may expect additional controls and documentation in some cases. He added that IPEC has published an Excipient Information Protocol, which is available on the organization’s Web site at www.ipecamericas.org.
Implications for Industry
The final GMPs became effective on August 24, 2007. For many companies, the new rules are likely to have minimal impact. Some companies, in anticipation of the new rules, have invested millions of dollars over the past decade in creating in-house laboratories and hiring qualified technical personnel for testing the ingredients and final products produced in their facilities. Many have also instituted newly enhanced procedures and record-keeping necessary for ensuring product quality. Those that have not already taken such measures will have to develop the necessary operating and recordkeeping procedures in time for the compliance dates mandated for their company’s size.
The FDA will begin to conduct inspections of manufacturers’ facilities and records beginning in 2008. Companies overseas that sell their products in the US market will also need to comply with the new GMPs, and they will be subject to inspections as well. Some manufacturers may choose to enlist the services of thirdparty certification programs to assist in confirming the quality of their products; however, such certification will not substitute for an FDA inspection. The FDA will consider such a certification as it performs its own inspection, although the agency does not recognize or recommend particular certification programs.
AHPA President Michael McGuffin noted during AHPA’s teleseminar that the new GMPs will almost certainly prove a barrier to under-funded start-up companies and that one-person operations will now be a thing of the past.6 All operations will have to have at least two individuals involved in product manufacturing simply for the verification of quality control procedures, and some of the requirements will likely prove too expensive for young, earlystage companies. According to McGuffin, some of the industry’s smallest companies will probably disappear as a result of the new GMPs.
All rulemaking requires an analysis of impacts (e.g., economics, health, regulatory), including the cost-benefit analyses that are required for significant rules. As such, the FDA has estimated that “the final rule will lead to quantifiable costs of $16 million in the first year it takes effect, $120 million in the second year, and $190 million in the third year. After 3 years, the annual costs will be about $164 million.”1 Later in the document, the agency has added that, “Using plausible assumptions about the uncertain variables, we estimate that total quantified costs most likely will fall within a range of $104 million to $322 million per year.” The agency also acknowledges that the rule will have a significant economic impact on small businesses, and it estimates that annual costs will be approximately $46,000 for a company with fewer than 20 employees and $184,000 for companies with 20 to 499 employees.
Questions asked by attendees at AHPA’s teleseminar and CRN’s webinar indicate that there may be some confusion that companies will have to investigate and resolve as they attempt to comply with the new rules. One area of confusion seems to be the distinction between DS and DI in some cases. For instance, some attendees asked whether merely encapsulating an ingredient or blending ingredients would cause a company to qualify as a DI supplier or a DS manufacturer. Some attendees also indicated confusion as to how companies of different sizes—and therefore having different compliance deadlines—may be affected in their relationships with one another as they attempt to comply with the new GMPs.
New AHPA Petition
In light of some of the confusion and concerns that have been expressed by various industry members, AHPA submitted a petition for reconsideration to the FDA on July 25, 2007, requesting that the agency reconsider and amend 7 elements of the GMP final rule.7 The FDA Commissioner will have the sole discretion to accept or reject the petition. AHPA has requested that the FDA:
- Clarify that a DI manufacturer or supplier cannot be made subject to the final rule based on how its customers use its ingredients;
- Remove a potential loophole that would allow companies that package products made by someone else to avoid some parts of the rules on verifying that product specification are met;
- Add definitions for the terms “manufacturing,” “packaging,” “labeling,” and “holding;”
- Allow master manufacturing records to include a range of batch sizes, rather than be limited to a specific batch size;
- Remove language that would bar single-employee companies from being in the DS business and replace it with appropriate options that will ensure product quality even in such small firms;
- Allow personnel to conduct 100% examinations for correct labels (currently limited to electronic or electromechanical examination) to qualify for an exemption to label reconciliation;
- Require that the batch, lot or control number that must be assigned to DS actually appears on finished products.
At HerbalGram’s press time there was no response from FDA on AHPA’s petition.
Resources for Manufacturers Adjusting to the New GMPs
As companies analyze and implement the new GMPs, trade organizations will undoubtedly continue to serve as invaluable resources in answering questions and helping companies reach compliance. AHPA has announced that it will soon update its FDA Inspection Guidance in light of the new GMPs.
Likewise, various certification programs will probably be increasingly used as resources by companies in their efforts to reach GMP compliance. One such program is the independent organization NSF International, which audits registered companies twice each year to ensure that those companies are following all necessary regulations for operating procedures and product quality. Kendle Regulatory Affairs (formerly AAC Consulting Group), also performs audits and provides consulting and training support to companies regulated by the FDA. The USP is yet another independent organization that offers a verification program to DS manufacturers. USP tests the purity, potency, and quality of member companies’ finished DS products, performs audits, and awards use of the USP Verified Dietary Supplement Mark to those DS that pass its stringent criteria for display on their product labels. Additionally, the USP has proposed revisions to its USP General Chapter 2750 “Manufacturing Practices for Dietary Supplements.” This revision is proposed in order to include the requirements described in both “Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements (21 CFR Part 111)” and “Dietary Supplement and Nonprescription Drug Consumer Protection Act (21 USC Section 760 [21USC379]).” USP’s goal is to provide proper standards that comply with the current US law.8
Contrarian View and Concerns about Economic Impact on Industry
Jonathan Emord, an attorney with considerable experience with FDA policies as they relate to DS, argues that the costs generated by the new GMPs are substantial and threaten the viability of at least 30% of the DS industry, according to an economic analysis of the rule commissioned by Emord from Steve Hanke, PhD, former senior economist on President Reagan’s Council of Economic Advisors (J. Emord, oral communication to M. Blumenthal, August 3, 2007). Emord predicts that the new rule will prevent market entry of new DS manufacturers—thereby decreasing innovation—and will increase the cost of supplements, decrease the diversity and availability of them, and likely result in the elimination of at least 150 DS companies between 2008 and 2012. Dr. Hanke predicted that the costs for compliance with the rule will probably be 10 times higher than the FDA has estimated (i.e., that the costs will likely be around $3.2 billion per year rather than $322 million, the FDA’s estimate noted in the GMP publication). Moreover, Emord has argued that the majority of the new costs imposed by the GMP rule will be borne by small to very small companies (those that have 500 or fewer full-time equivalent employees), representing about 90% of the entire DS industry. Emord predicts that all but the largest supplement companies will be forced to raise the prices of their products, resulting in a reduced demand for them.
Emord added that any violation of the final rule by a DS manufacturer—even record-keeping violations—will be construed as product adulteration, without need for proof that products present an actual risk of illness or injury to the public, enabling FDA at its whim to go so far as to shut companies down. All products being produced by the company in question would be considered adulterated and might be subject to an FDA-ordered recall.
“The cGMP rule is the most extensive and devastating regulation that has ever been imposed on the dietary supplement industry,” Emord said.
Despite concerns expressed by Emord and others, many industry leaders believe that the GMPs are an important step in helping to ensure that herb and other DS products are manufactured according to uniform and reliable methods. DS industry leaders have been calling for the promulgation of DS GMPs for more than 12 years, during which there have been numerous delays since 1994, when they were initially authorized by Congress by the passage of the Dietary Supplement Health and Education Act.
When the new GMP rule is compared to GMPs currently required for comparable natural products by other national authorities (for example, among others, the GMP requirements for manufacture of complementary medicine products by the Australia New Zealand Therapeutic Products Authority (ANZTPA), the GMPs for natural health products by Health Canada Natural Health Products Directorate (NHPD), and GMPs for herbal medicinal products in the EU-27 Member States by the European Medicines Agency (EMEA)), FDA’s new rule is, on the surface, relatively easier for manufacturer compliance. Whether the implementation of these new GMPs will actually result in higher quality herb products in the United States or whether some manufacturers will simply adjust the GMPs to their own needs so they can continue to produce low quality products remains to be seen.
The authors gratefully acknowledge the assistance of the following industry experts who have reviewed and made suggested edits for this article: Paul Bolar, senior vice-president of regulatory and legal affairs at Pharmavite, Northridge, California, and chair of the GMP committee at the Council for Responsible Nutrition; Josef Brinckmann, vice-president of research and development at Traditional Medicinals, Sebastopol, California; and Michael McGuffin, president of the American Herbal Products Association.
- Food and Drug Administration. 21 CFR Part 111 Current good manufacturing practice in manufacturing, packaging, labeling, or holding operations for dietary supplements: final rule. Federal Register. June 25, 2007;72(121):34751-34958.
- Food and Drug Administration. 21 CFR Part 111 Petition to request an exemption from 100 percent identity testing of dietary ingredients: current good manufacturing practice in manufacturing, packaging, labeling, or holding operations for dietary supplements: interim final rule. Federal Register. June 25, 2007:72(121):34959-34969.
- Lambert EI. Dietary supplement GMPs: the legal perspective. Power point presentation for: CRN Dietary Supplement GMPs Webinar. July 16, 2007.
- Bolar P. The evolution of dietary supplement cGMPs. Powerpoint presentation for: CRN Dietary Supplement GMPs Webinar. July 16, 2007.
- Schoneker DR. Excipients used in dietary supplements. Powerpoint presentation for: CRN Dietary Supplement GMPs Webinar. July 16, 2007.
- McGuffin M. Presentation for: Good Manufacturing Practice: the Final Rule Tele-seminar. July 12, 2007.
- AHPA petitions FDA to reconsider some parts of cGMP [press release]. Silver Spring, MD: American Herbal Products Association; July 26, 2007.
- United States Pharmacopeial Convention. Briefing: <2750> Manufacturing practices for dietary supplements. Pharmacopeial Forum. 2007;33(5):1035.
* DI is defined in the Federal Food, Drug and Cosmetics Act [21 U.S.C. 321, Sect. 201(ff)(1)] as a vitamin, mineral, herb or other botanical, amino acid, a dietary substance to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any of the aforementioned ingredients. Non-DI components can be excipients or substances used in the manufacture of a DS, including those that may not appear in the finished product.