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FDA GMP Warning Letters to Target Finished Product Testing

According to Dr. Daniel Fabricant, Director of FDA’s Division of Dietary Supplement Programs, the agency is going through an evolution concerning its enforcement of dietary supplement good manufacturing practice (“GMP”) violations.  Since the dietary supplement GMPs were rolled out five years ago, FDA’s main focus has been on enforcement against basic violations, such as the lack of a master manufacturing record or the failure to set specifications.  Dr. Fabricant expects that to change, however, as was reported by on November 13, 2012, in a video interview by Stephen Daniells.  In that interview Fabricant indicated that FDA will issue warning letters for technical GMP violations, and he specifically identified finished product testing violations as an example of a technical violation FDA will be looking for in the near future.  As a result, finished product testing is expected to be big on FDA’s radar in 2013.

The purpose of finished product testing is to ensure that each finished batch of dietary supplements meets established product specifications for identity, purity, strength, composition, and limits on types of contamination that may adulterate it.  Under 21 C.F.R. § 111.75(c), to determine whether one or more product specifications are met, dietary supplement manufacturers must test or examine either: (1) a subset of finished dietary supplement batches identified through a sound statistical sampling plan; or (2) every finished batch.  FDA does not require any specific tests, such as testing for marker compounds.  The test or examination, however, must be scientifically valid.  21 C.F.R. § 111.75(h)(1).  The test or examination must also be capable of “verify[ing] that the production and process control system is producing a dietary supplement that meets all product specifications[.]”  Id. at § 111.75(c)(1)-(2).  Manufacturers are required to provide adequate documentation of their basis for determining that compliance with the established specifications, as established through the use of tests, will ensure that finished batches of dietary supplements meet all product specifications.  Id. at § 111.75(c)(3).  Additionally, the manufacturer’s quality control personnel must review and approve such documentation.  Id. at § 111.75(c)(4).

Limited flexibility is allowed when testing is not feasible due to the lack of a valid test.  Under section 111.75(d)(1), a manufacturer can exempt one or more product specifications from verification requirements if the manufacturer determines that the exempted specification(s) cannot “verify that the production and process control system is producing a dietary supplement that meets the exempted product specification and there is no scientifically valid method for testing or examining such exempted product specification at the finished batch stage[.]”  In such a case, FDA requires manufacturers to “document why, for example, 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[.]”  Id. at § 111.75(d)(1).

Because each product’s specifications are unique, when FDA evaluates a firm’s finished product testing for GMP compliance, it will likely ask firms for an explanation of why they use certain tests, why they do not use other tests, and why they test for some things and not others others.   Such questions must be answered in order for FDA to determine if the testing is adequate.

Dietary supplements that were manufactured without sufficient finished product testing are adulterated under 21 U.S.C. § 342(g).  As Jonathan Emord explained in his recent blog post, any GMP violation, regardless of whether the dietary supplement is unsafe, will render it adulterated.  That is particularly troubling considering that the introduction into interstate commerce of any food that is adulterated is punishable under 21 U.S.C. § 333(a)(1) with civil and criminal sanctions, including up to one year in prison and a fine of up to $1,000 for every violation, up to one year in prison, or both.   It also carries a prison sentence of not more than three years and a fine of up to $10,000 for every subsequent violation of section 331 and any violation of section 331 committed with the intent to defraud or mislead.  21 U.S.C. § 333(a)(2).  Because of the harsh penalties for GMP violations, manufacturers must ensure that their finished product testing is adequate.

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