FDA's Frankos Discusses Agency's GMP Expectations

LAS VEGASVasilios Frankos, Ph.D., director of the division of dietary supplement programs at FDA, provided details about the agencys expectations for supplier qualification to a packed room of more than 200 executives at SupplySide West Nov. 12. He emphasized that the burden to ensure that all components used in the manufacture of a dietary supplement rests with the finished product manufacturer.

In the best of both worlds, the dietary supplement GMPs would apply to both the dietary supplement and the ingredient suppliers, Frankos said. But, he said following review by the Office of Management and the Budget (OMB) and budgetary issues, the agency made the decision the GMPs (good manufacturing practices) would apply to dietary supplement manufacturers.

For dietary ingredients, manufacturers must conduct an appropriate identity test on the ingredient 100 percent of the time. For dietary components, such as excipients and other components that are not dietary ingredients, manufacturers can rely on a certificate of analysis if the vendor has been appropriately qualified, according to Frankos. Manufacturers cannot rely on a certificate of analysis in lieu of 100% identity testing for dietary ingredients unless first petitioning the agency for an exception to this requirement and receiving an affirmative response. Manufacturers must qualify their suppliers of both components and dietary ingredients, and Frankos spent significant time explaining the agencys expectations for this vendor qualification.

At a minimum, Frankos said manufacturers must establish the reliability of a component suppliers COA through confirmation with tests and examinations. He also said that the COA must include a description of the test or examination methods used, limits of the tests or examinations, and it must contain actual results for the lot received and not just a specification sheet. The dietary supplement manufacturer must also maintain documentation of how it qualified a supplier, must maintain records of any audits conducted, must periodically reconfirm the COA (for components), and the manufacturers QC personnel must review and approve the documentation setting forth the basis for the supplier qualification and requalification. He also said that manufacturers should be sure to qualify the water source used by the ingredient supplier. Again, he emphasized that 100% identity testing is required for dietary ingredients.

Throughout his presentation, Frankos emphasized the need for written records, at one point stating that if it isnt written down, it didnt happen.

He also discussed the challenges manufacturers face in qualifying foreign suppliers, but clearly stated the agency expects firms to meet the requirements of the regulation. He did say FDA anticipates the industry will be creative in qualifying its global supply chain, suggesting that standardized programs such as the SIDI protocol and shared auditing is something that should be looked at.

Frankos said FDA expects consultant audits to be used as part of a manufacturers supplier qualification records, but that such reports must be complete, and not simply an opinion letter. He also said the third party audits must be specific to the manufacture of each ingredient and not a generic evaluation of the overall facility. Vendor questionnaires cannot be used as audit reports, and FDA will not defer or otherwise excuse these audit reports from examination during a GMP inspection as they are part of the qualification records that manufacturers must retain.

Heavy metals were another area of focus in Frankos presentation. He said the onus is again on the manufacturer to establish specifications for incoming raw ingredients to assure the final product is safe under the recommended conditions of use. A single heavy metal limit for an ingredient is not appropriate because dietary supplements vary dramatically in the amounts of each ingredient they may contain and in the daily recommended serving sizes. While FDA does not establish limits for heavy metal  concentrations in dietary supplements or dietary ingredients, Frankos said the manufacturer is expected to use authoritative sources to determine a safe level of exposure for each heavy metal.

Frankos also discussed FDAs expectation for complaints versus adverse events. While federal law requires firms to report all serious adverse events to FDA, he said voluntary reporting of other complaints is encouraged. And, all complaints, whether related to adverse health effects or product quality, must be evaluated to determine if a failure in the manufacturing process caused the complaint. From the GMP perspective, manufacturers must maintain procedures for handling, investigating and keeping records of complaints. The manufacturers quality control personnel must review and approve decisions about whether to further investigate a product complaint and any follow up action taken as a result.

He emphasized manufacturers must make and keep a written record of every consumer complaint related to GMPs, and said based on the FDAs early inspections, this does not seem to be happening as methodically as we hoped.

Frankos also shared his thoughts on the implementation of the GMPs with INSIDER in the video below.