FDA official discusses common deficiencies derailing ANDAs

Regulatory NewsRegulatory News | 27 April 2022 |  By 

The US Food and Drug Administration (FDA) rejected a fewer number of abbreviated new drug applications (ANDAs) in FY 2021 through its refuse-to-receive (RTR) mechanism compared to previous years, said Peter Enos, a reviewer with the agency’s Office of Generic Drugs. He attributed the improvement to increased transparency with industry, better filing practices and enhanced communication with applicants.
Enos also addressed how industry can improve their submissions to avoid RTRs during the second day of FDA’s Generic Drug Forum on 27 April. The forum was sponsored by FDA’s Small Business and Industry Assistance (SBIA) program.
FDA numbers show that in FY 2021, 4.7% of the 808 ANDA applications were deemed RTR, lower than the 8.33% rejection rate of the 1,057 applications submitted in FY 2018.
Major deficiencies in FY 2021 triggering an RTR included inadequate stability data and insufficient Q1/Q2 sameness studies with the reference-listed drug (RLD). Other major problems were inadequate dissolution studies, insufficient identification of impurities and inadequate bioequivalence studies, as well as lax justification for using certain inactive ingredients.
To ensure the acceptability of stability data, Enos said that “it is imperative to provide at least three test batches using two [active pharmaceutical ingredient] API lots of each strength, and the data should include at least six months of accelerated and long-term study data with three time points.”
Intermediate studies should be performed if there is a stability failure at any time point in accelerated studies.
Stability studies should also be studied for both worst-case and non-worst-case scenarios.
To avoid inadequate Q1/Q2 comparisons, sponsors should ensure parenteral drug products contain the same inactive ingredients and in the same concentration as the RLD. He pointed out that exception excipients that diverge from the RLD are permitted if used in buffers, thickening agents, or antioxidants. Exception excipients are not permitted in ophthalmic products.
To ensure that dissolution studies are adequate, sponsors were advised to consult FDA’s product-specific guidances (PSGs), which include dissolution study recommendations and other advice for developing specific generic products.
Such dissolution studies should include a minimum of 12 dosage units for each strength of both the test product and the RLD. The most recent PSG guidance was issued in February. (RELATED: FDA releases 43 new and revised product-specific guidances, Regulatory Focus 17 February 2022)
In other logistical areas, Enos said that ANDAs should be in English. In addition, submissions in the electronic Common Technical Document (eCTD) should be legible, pages should be oriented correctly, and submissions should include adequate and descriptive bookmarks or hyperlinks.


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