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Ensuring Integrity: USFDA's Proposes change on BA/BE Sample Retention quantities

The FDA has recently released a draft guideline “Handling and Retention of BA and BE Testing Samples” concerning the retention of bioavailability (BA) and bioequivalence (BE) samples (here).  Number of Retention Samples for both test and reference product (more so for Reference Product) has always been a sore point for Generic Industry, both for cost associated and storage at the BE testing sites,. The updated guideline provides handling number of samples and the retention of BA/BE samples, based on Industry requests, advancement in analytical techniques and better understanding by the agency on enforcement policy. As agency states in the guidance “ It revises and supersedes the agency’s compliance policy related to the quantity of BA  and BE samples retained under § 320.38(c) described in the final guidance Compliance Policy  for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 51 320.38(c) (August 2020) (“the 2020 Compliance Policy”), which is hereby withdrawn”, The guidance highlights:

(1) How the test article (T) and reference standard (RS) for BA and BE studies should be distributed to the testing sites.

(2) How testing sites should randomly select samples for testing and material to maintain 30 as reserve samples.

(3) How the reserve samples should be retained. 


(4) Addresses the requirement at 21 CFR 320.38(c) to retain reserve samples of sufficient quantity to permit FDA to perform five times all the release tests required in an  application or supplemental application.

 (5) Describes the conditions under which the Agency does not generally intend to take enforcement action against an applicant or CRO for retaining less than the quantity of reserve samples of the test article and reference standard that were used in the BA or  BE study as specified in 21 CFR 320.38(c).

The Applicant, or CRO (if contracted out), must retain identified quantities of T and RS reserve samples, both for In-Vivo and In-vivo Studies. However, the agency also clarifies that reserved samples are not required for all Studies, and studies as such, irritation study, adhesion studies for transdermal products, In-vitro comparative characterization (if not part of Product Specific Guidance) and dissolution studies.

Section on sampling for Reserved sample provides specific instances/examples for sampling different type of product (Single dose, Multi-dose container, repackaged, blinded samples)

The recommendation for number of samples are as follows-

For in vivo studies: A minimum quantity of 30 single-dose (SD) or 3 multi-dose (MD) units each of the T and RS (and P if applicable) in the original container in total across all testing sites with at least 1 unit in the original container per treatment (or blinded kit, as applicable) retained from each shipment used in the BA or BE study.

For in vitro studies:  A minimum quantity of 30 SD or 3 MD units in the original container per batch each of the T and RS in total for all in vitro studies conducted at the testing site with at least 1 unit in the original container each of the T and RS retained from each shipment used in the BE studies.

This compliance policy is applicable to all reserve samples for BA and BE studies held to date, including reserve samples from previously completed BA or BE studies.

In accordance with §§ 320.38(e) and 320.63, reserve samples must be stored for a period of at least 5 years following the date on which the application or supplemental application is approved, or the date of completion of the BA or BE study if such application or supplemental \application is not approved.

Additionally, Guidance provides the agency's thinking, requirement and recommendation on different points, which is based on the agency’s experience in many years. Overall, this guidance provides much needed relief to the generic industry on sample retention and at the same, it is very comprehensive and should help sponsors/applicants avoid any potential compliance issue.

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