The Division of Scientific Investigations (DSI) and FDA field investigators conduct inspections of clinical and analytical sites that perform bioavailability (BA) and bioequivalence (BE) testing for drug manufacturers seeking approval of a drug product. One of the most common findings from these inspections is the absence of retention samples by the testing facility where the study was conducted. The regulations regarding retention samples of test articles can be found in 21 CFR 320.38 and 320.63. The final rule on these regulations can be found in the Federal Register Notice, Vol. 58, No. 80, April 28, 1993.
The purpose of these regulations is to make available to the Food and Drug Administration (FDA) reserve samples of the tested products administered to study subjects. The Agency may then analyze these retention samples to ensure that the BA/BE results upon which FDA bases approval of New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDAs) are reliable. For an ANDA, reserve samples of both the test article and the reference standard should be retained at the study site for a period of 5 years. The test article means the drug product for which the applicant is seeking approval. The reference standard means an approved drug product identified by the FDA as the drug product upon which the applicant relies in seeking approval of its ANDA, usually the innovator product.
Retention samples should be kept at the testing facility where the study was conducted. The study sponsor should provide the testing facility with a supply of the test article and the reference standard sufficient to complete the study and retain the appropriate number of dosage units as reserve samples. The study sponsor should not separate out the samples to be reserved prior to sending the batches to the testing facility. The testing facility will randomly select the reserve samples from the supply sent by the sponsor. This is to ensure that reserve samples are in fact representative of the same batches provided by the study sponsor for the testing. The testing facility should retain enough quantify to permit FDA to perform five times all of the release tests required in the application.
It is important to be aware of this regulation because the approval of your application depends on assurance to the FDA that the study was conducted with the appropriate products. The purpose is to eliminate the possibility for sample substitution by the study sponsor or to preclude the sponsor from altering a reserve sample after a contract research organization completes the study. In the event that a testing facility is unable to retain the reserve samples, a third party should be contracted to retain the samples. It is the responsibility of the sponsor to comply with the regulations cited above.