FDA reduces number of samples to retain for BA/BE testing

In a part-draft, part-final guidance issued on Tuesday, the US Food and Drug Administration (FDA) finalized its policy on the quantity of reserve samples to be retained for bioequivalence (BE) and bioavailability (BA) testing to ensure that samples are comparable to reference listed drugs (RLD) and to deter fraud in such testing.

Section IV.B of the guidance, which covers the quantity of the reserve samples to be tested has been issued as a final guidance, and supersedes an August 2020 compliance policy; the remainder of the guidance has been issued in draft form. (RELATED: FDA trims reserve testing quantity requirements, Regulatory Focus 18 August 2020)

The draft portion of the guidance describes how the test and reference drug should be distributed to the testing sites, how testing sites should select samples for testing, which samples should be held in reserve, and how the reserve samples should be retained. It also discusses the roles of each stakeholder in handling and retaining reserve samples.

The guidance applies to applicants submitting new drug applications (NDAs), abbreviated new drug applications (ANDAs), supplemental applications, and contract research organizations (CROs) conducting BA/BE studies.

The finalized portion of the guidance states that that sponsors and CROs must set aside 30 single-dose or 3 multi-dose units each of the test and reference products in the original container across all testing sites with at least 1 unit in the original container.

The guidance is meant to provide clarification on FDA’s expectations for the handling and retention of BA/BE testing samples, which stem from a 1990 interim rule and a 1993 final rule on the topic and its implementing regulations related to the final rule.

FDA said that “the interim rule was intended to help ensure BE between generic drugs and their reference listed drug and to help FDA investigate possible fraud in BA and BE testing.” The final rule specified that the quantity to be retained for testing would be five times the amount required for release testing.

Yet applicants and CROs complained that the testing requirements set in the regulation were onerous and expensive. In response, FDA determined that it is no longer necessary to require sponsors to set aside such aside this quantity, and that it would not enforce this testing limit set in regulation.

A notice states that “FDA has determined that, using the Agency’s current testing methodology, the updated recommended minimum quantities of reserve samples described in this guidance are sufficient for FDA to conduct the necessary testing of the T [test] and RS [reserve samples] samples used in a BA or BE study as intended by the regulation.”

FDA said that “this reduced quantity will provide a less burdensome approach for applicants and CROs but remains consistent with the Agency’s mission to ensure public health.”

The guidance further specifies that reserve samples must be stored for at least five years from the date the application or supplement was approved. In addition, reserve samples should be stored under conditions that are consistent with product labeling, with limited access to these samples by authorized personnel only.

It further notes that “when there are multiple shipments, reserve samples selected from each shipment should not be commingled, but rather should be segregated and labeled to identify the shipment from which the samples were pulled.”

An independent third party should ensure that samples are not substituted. In addition, testing sites “should ensure that any reserve samples transferred to a separate storage facility are not commingled with reserve samples from other testing sites so that any given reserve sample can be unambiguously associated with the testing site from which it came.”

The deadline to comment is 27 June.

Guidance, Notice

FDA reduces number of samples to retain for BA/BE testing

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