(M1430-08-54) Analysis of Manufacturing Deficiencies for Immediate Release Tablets in Abbreviated New Drug Applications

Purpose: Generic drugs have significantly contributed to public health, but the initial approval rate for Abbreviated New Drug Applications (ANDAs) for generic drugs is typically low. Among the solid oral drug categories, Immediate Release (IR) tablets have the largest number of ANDAs each year. To understand the reasons for the low first review cycle approval rate of IR tablet ANDAs, we have gathered and examined review recommendations from multiple review disciplines. Additionally, we have conducted a detailed analysis of the manufacturing deficiencies of the drug product (DP), including the process and facility, in the original ANDAs for IR tablets.

Methods: We queried the FDA CDER informatics platform for data on original IR tablet ANDAs from January 1, 2017, to December 31, 2019, excluding applications that were refused or withdrawn. For each review discipline, we recorded the recommendations after completing the first review cycle. We collected, classified, and analyzed deficiencies related to manufacturing assessments cited in information requests, discipline review letters, and complete responses.

Results: We analyzed 405 ANDAs for IR tablets in the dataset and found that only ~15% were approved in the first review cycle, while ~85% received complete responses (CR). Among the 345 CR applications, most ANDAs were deemed inadequate by multiple review disciplines. Of these, 127 received process CR and 117 received facility CR. Of the 117 ANDAs with facility CR, 82% were due to CGMP withhold, 10% due to Preapproval inspection (PAI)-withhold, and 8 % due to lack of facility readiness for inspection. The first review cycle resulted in approximately 2,700 DP manufacturing process deficiencies being issued to the 345 ANDAs, with approximately 61.2% of them citing unit operations-related deficiencies. We also identified common DP manufacturing process category deficiencies across IR tablets ANDAs.

Conclusion: From 01/01/2017 to 12/31/2019, the first cycle approval rate for IR tablet ANDAs was only 15%, which can be attributed to deficiencies identified in multiple review disciplines, particularly those related to the manufacturing process. Unit operations-related deficiencies were the most common manufacturing process-related issues. The purpose of this project is to communicate with ANDA applicants about the most frequent manufacturing deficiencies, clarifying regulatory expectations for the DP manufacturing section. Addressing these common DP manufacturing deficiencies can potentially improve the quality of applications, increase the first review cycle approval rate for IR tablet ANDAs, and provide earlier access to generic drugs.

Acknowledgements: Disclaimer: The content reflects the views of the authors and should not be construed to present FDA’s views or policies. The work was supported by FDA CDER Regulatory Science and Review Enhancement Program. This project was supported in part by an appointment to the Research Participation Program at the U.S. Food and Drug Administration administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.