Learning from GMP Mistakes

In the four years since FDA released its final rule on dietary supplement GMPs (good manufacturing practices) and began a staggered start for compliance, from large companies to the smallest firms, the supplement industry has exerted great energy into preparing for FDA GMP inspections. Experts in all things FDA, GMP, quality control (QC) and supplements wrote articles, spoke at seminars and workshops, and offered one-on-one consulting. Industry organizations created or furthered third-party GMP certification programs and compliance training in an effort to give supplement companies some hands-on experience in bringing their firms into compliance.

Despite these great efforts, early results from the first few years of inspections have highlighted some common violations of the GMP regulation (21 CFR 111). Whether a sign of the breadth of the supplement industry or of a lack of urgency among numerous companies, the failures during these first rounds of inspections offer the greater industry some potentially useful lessons in helping those yet-uninspected companies prepare for a visit from FDAs inspectors. Given the recent wave of FDA warning letters for inadequate responses to the 483 inspection reports, the lessons learned may also help those recently or currently undergoing inspection to more appropriately respond to 483s.

Bradford Williams, manager of the Division of Dietary Supplement Programs at FDAs Center for Food Safety and Nutrition (CFSAN), confirmed FDA has significantly increased its inspection rate, from just one inspection in 2008 to 84 inspections in 2010; as of May 2011, there were 66 supplement GMP inspections conducted, with a projected 2011 total of around 191 or more.

Alarmingly, he reported fiscal year 2010 violation rates were nearly 25 percent, which was higher than FDA expected. He explained the agency expected noncompliance to grow as firm size decreased, but noncompliance has been across the board of company sizes and types, including own-label distributors, contract manufacturers and re-packers and -labelers.

The chronology of GMP inspection events goes generally like this: FDA sends GMP inspectors to a facility to conduct investigations. All records relevant to GMPs must be available for inspectors. After the inspection, a form 483 inspection report is delivered to the inspected firm, detailing any violations found and what FDA expects from the company in response to these violation notices. It is advisable to try to respond adequatelydetailed written plans for corrective action, including a timelinewithin 15 days of receiving the 483. If FDA decides the response to the 483 report is inadequate, it can issue a warning letter to the company, which usually comes with a requirement to respond within 15 days of the letter. If the companys response is still inadequate, or even defiant, FDA can take further enforcement action such as product seizure, injunction and prosecution. However, for some corrective actions reported by those responding to 483s, FDA seems to be content to promise a close inspection of these items in its next inspection of those facilities.

Highlighting one of the common mistakes found in FDA GMP inspections, Williams said FDA has found failure to maintain adequate MMR and BPR content and recordkeeping is one of the top violations it has found in these first waves of GMP inspections. More specifically, numerous companies have been cited for failing to prepare and follow a written MMR for each unique formulation of a dietary supplement it manufactures and for each batch size.

Williams reminded specifications must be established and followed for: any point, step or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement; labels; and packaging materials. Specs are also needed for finished products; and packaging and labeling of the finished packaged and labeled dietary supplement, and they are regardless of whether the company manufactures the component(s) itself, contracts with another firm to manufacture the component(s), or buys the component(s) from another company.

A serious case of MMR violation was in the 483 report given to Cerebral Health of Jupiter, FL. FDA highlighted the same failure to establish an MMR for each formulation and batch size, but noted the company verbally admitted to the inspector it does not have written MMRs for any of its dietary supplements.

In this case, the missing records and procedures were so extensive, the companys response to the 483 was that it decided to contract out all its manufacturing to third-party GMP-compliant manufacturers. While this might be the best corrective this company could take given the circumstancesthe lack of preparation suggests ignorance, neglect or defianceFDA still took issue with Cerebral Healths response for failing to include detailed plans for the companys manufacturing operations before the contract manufacturing is in place, which the company said might take six months.

This situation with Cerebral Health might be an indication of how GMP-compliant contract manufacturers may see increased business from firms that are unable or unwilling bring their own operations into compliance. Still, other similar cases have seemingly awakened the real need for investment in GMP compliance.

A 483 report delivered to San Diego-based Gods Garden Pharmacy, which manufactures, packages, labels and holds dietary supplements, detailed complete lack of MMRs and BPRs, in addition to failure to provide written procedures for QC responsibilities, raw material review, cleaning, pest control and other critical operations. However, in this case the company responded to FDA with assurances it was in the process of preparing written records and procedures required by GMPs; FDA still took issue with the companys failing to include written documentation while the corrective actions were being taken.

The number of 483s and subsequent warning letters indicating failure to establish and maintain MMRs and BPRs has been increasing at a high rate, but there are other major findings from recent GMP inspections that concern FDA. Some companies had specifications for manufacturing points and steps, but failed to adequately test to ensure products met these specifications. A number of 483s noted the inspected company released product before QC personnel confirmed the product met specifications.

The failure to establish component specifications to ensure purity, strength and composition of dietary supplements was a common theme among those releasing product too early. Columbine Specialty Products, a Denver-based contract manufacturer, told GMP inspectors it does not test any finished goods, but FDA noted the companys status as a contract manufacturer does not exempt it from having to comply with these GMP regulations, including ensuring the final product meets established specifications for identity, purity, strength and composition.

Two other important issues emerged in the warning letter FDA sent to Columbine. The companys response that it is in the process of establishing the missing specs and implementing a finished product testing program were inadequate because the response lacked documentation that demonstrates these corrective steps. Further, the documentation to exempt any one product specification for a finished product must state why, any component and in-process testing, examination or monitoring, and any other information, will ensure that such exempted product specification is met without verification through periodic testing of the finished batch.

Another major problem in numerous GMP inspection reports was failure to adequately test products and ingredients for identity. This was an oft-discussed issue at many GMP workshops and seminars, but still numerous companies have been cited for such violations.

For Derry, NH-based BioSan Laboratories, the manufacturing of its Women Over 40 One Daily supplement, which includes vitamin, mineral and herbal ingredients, did not include at least one appropriate test or examination to verify the identity of a dietary ingredient prior to its use, according to its 483 report.

Williams explained a dietary ingredient firm must, at minimum, conduct an appropriate identity test on the dietary ingredient, but may rely on a Certificate of Analysis (CofA) for other specifications, such as compliance of a non-dietary ingredient, if the vendor has been qualified.

Supplier qualification has been another big issue for Industry. Williams relayed FDAs recommendations for qualifying suppliers, including running tests to verify the CofA. He said a real CofA should contain: a description of the test or examination methods used; limits of the tests or examinations; and actual results for the lot received (not just a specification sheet). FDA further recommends manufacturers maintain documentation of how they qualified the supplier and any audits conducted on the supplier. It is also important to periodically reconfirm the CofA, with qualification and requalification reviewed and approved by the manufacturers QC team. In the case of botanical ingredients, FDA advised manufacturers to confirm the use of good agricultural practices (GAPs) in the growth and harvest.

When it comes to supply chain qualification, especially involving overseas suppliers, FDA recognizes industry has been out in front of the agency on recommendations and programs. In fact, the industrys collaborative efforts on SIDI (standardized information on dietary ingredients) address many of the agencys supplier qualification concerns. The protocol was developed jointly by a working group including the Council for Responsible Nutrition (CRN), United Natural Products Association (UNPA) and the Consumer Health Products Association (CHPA), and offers guidelines and templates for sharing information including CofAs. This voluntary standard for the exchange of important ingredient information between suppliers and finished products manufacturers were intended to help simplify the qualification process.

In addition to SIDI, there are tons of resources available to companies in the industry interested in learning how to achieve compliance with the regulation and handle FDA inspection and reports. The Natural Products Association (NPA) was the first to offer a GMP certification program for dietary supplements, utilizing third-party auditors. Created before FDAs supplement GMP final rule, NPA has since integrated all the final rule requirements into its program. NSF International also offers a third-party GMP certification program, as does the US Pharmacopeia (USP), which calls its program USP Verified. FDA has said it is aware of these programs and may someday consider using third-parties to help with the GMP inspection program, but not until the supplement GMP program matures.

Beyond certification opportunities, industry can take advantage of several training sessions for some hands-on experience with the regs. This fall, NPA is conducting an Advanced Course on the Final FDA GMP Rule for Dietary Supplements, which will help prepare companies for FDA GMP inspection and how to respond to 483s and other related agency communications and actions.

And at this years SupplySide West trade show in Las Vegas, NSF DBA will present several levels of GMP training courses utilizing much of the information learned from FDA inspections conducted over the past few years. In addition to a GMP overview course featuring and in-depth look at the reg and case studies of recent inspections, additional courses will cover the specifications and evidence involved in vendor qualification and auditor training, and the development of and supporting data required for stability testing.

Stability testing is not a requirement of the GMPs, but if a manufacturer chooses to use a shelf life statement on the product label, it must have scientific data and testing results to back up the dating. NSF organized a working group of industry trade groups and representatives from top supplement companies to help create voluntary Stability Testing Guideline for Dietary Supplements. FDA and the Office of Dietary Supplements (ODS) participated as observers. The resultant document is freely available to industry via NSF.org, and provides recommendations on what dietary supplement companies should consider when developing their voluntary written shelf-life study protocols for expiration dating of finished products, including strategies for gathering stability testing data of their products.

FDAs increasing rate of GMP inspections and warning letters demonstrates the attention the agency plans to focus on quality supplement manufacturing. Dietary supplement companies of all types and sizes are beginning to realize the depth of the GMP regulation and FDA expectations, as reflected in the common violations noted in numerous 483s and subsequent interactions between the agency and manufacturers. Heeding the lessons these case studies offer and making use of the extensive industry resources for education and training on the regulation specifics, preparing for inspection and responding appropriately to follow-up requests will go along way toward GMP compliance.

NOTE: The official GMP training workshops at SupplySide are designed as interactive training courses that delve into the actual processes and procedures you must understand and implement to ensure GMP compliance. Presented by DBA/NSF, these courses will be held during the first two days of the SupplySide West trade show in Las Vegas, which takes place Oct. 10 14, 2011. For more detailed information on the course subjects and fees, visit the SupplySide West website.