Brought to you by: GMP Inspection Lessons Early results from the first few years of inspections have highlighted some common violations of the GMP regulation (21 CFR 111). July, 2011

FDA: More Violations than Expected Fiscal year 2010 violation rates were nearly 25 percent, which was higher than FDA expected. 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.

Inspection Steps 1.FDA sends GMP inspectors to a facility to conduct investigations. a. All records relevant to GMPs must be available for inspectors. 2. 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.

Recordkeeping Problems FDA has found failure to maintain adequate Master Manufacturing Record (MMR) and Batch Production Record (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.

Specification Requirements 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; Finished products; and Packaging and labeling of the finished, packaged and labeled dietary supplement. Specs are needed 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. 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.

Testing Problems Another major problem in numerous GMP inspection reports was failure to adequately test products and ingredients for identity. 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.

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’s Suggestions for Qualifying Suppliers 1.Run tests to verify the CofA. 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). 2.Maintain documentation of how a supplier was qualified and any audits conducted on the supplier. 3.Periodically reconfirm the CofA, with qualification and requalification reviewed and approved by the manufacturer’s QC team. 4.In the case of botanical ingredients, manufacturers should confirm the use of good agricultural practices (GAPs) in the growth and harvest.

FDA Recognizes Industry Efforts The industry’s collaborative efforts on SIDI (standardized information on dietary ingredients) address many of the agency’s supplier qualification concerns. SIDI 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. 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). For more information, visit: CRNusa.org/SIDI/

Other Industry Resources NPA was the first to offer a GMP certification program for dietary supplements, utilizing third-party auditors. Created before FDA’s supplement GMP final rule, NPA has since integrated all the final rule requirements into its program. NPA is also 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. NSF International also offers a third-party GMP certification program, as does the US Pharmacopeia (USP), which calls its program USP Verified.

SupplySide 2011 GMP Training 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 to 14, For more detailed information on the course subjects, visit the SupplySide West website: SupplySideShow.com/2011/west/

For a more in-depth look at what recent GMP inspections can teach supplement manufacturers facing future inspections, check out the INSIDER article, “Learning from GMP Mistakes,” at: from-gmp-mistakes.aspx.