013: Impacts of Bio-Batch Adequacy on Bioequivalence Assessment of Generic Drug Product Applications

Statement of Purpose: Generic drug product applicants must demonstrate, among other things, that the test product is bioequivalent to the Reference Listed Drug (RLD) product. All bioequivalence (BE) studies conducted between the test and reference products are considered unacceptable if the Office of Pharmaceutical Quality (OPQ) determines that the test product batch used in the BE studies (i.e., the “bio-batch”) is unacceptable. In recent years, we have observed that the BE evaluation process was interrupted for an increasing number of ANDAs due to bio-batch acceptability issues. Consequently, this resulted in an extended BE assessment time due to unacceptable BE studies. The objective of this project was to summarize the issues related to the bio-batch acceptability and highlight the recommendations for the BE data needed in each scenario.

Description of Methods & Materials: We collected available information from 82 ANDAs submitted from 2010 until 2022 containing BE study data with potential issues of bio-batch adequacy, analyzed the data, and identified the specific issues pertaining to bio-batch acceptability for each of these ANDAs. The BE recommendations communicated for each of the identified bio-batch issues from the Agency were then identified. The BE assessment time and number of assessment cycles resulting from each issue of bio-batch acceptability were also assessed.

Data & Results: The most common issue for bio-batch adequacy identified was related to the validity of the API lot (e.g., cGMP compliance issue) used to manufacture the original bio-batch, which was observed in 67% of the aforementioned ANDAs. Other common issues that affected the bio-batch adequacy included drug product critical quality attributes (e.g., compliance with USP, 23%), and manufacturing process issues (e.g., contamination during manufacturing process, 10%). The Office of Bioequivalence (OB)’s BE recommendations pertaining to each type of bio-batch adequacy issue are listed in Figure 1. As the generic drug applicants needed to re-submit new BE studies due to an unacceptable bio-batch, the number of ANDA assessment cycles increased and the review process was prolonged for the impacted applications. The average assessment time to achieve BE adequacy is shorter for applications with acceptable bio-batches (18 months) as compared to those with unacceptable bio-batches (44 months). The number of assessment cycles (average of 1.7) needed to achieve BE adequacy when OPQ determined that the bio-batch was acceptable was shorter compared to that when the bio-batch was found to be unacceptable (average of 3.0).

Interpretation, Conclusion or Significance: Our findings indicate that bio-batch adequacy is a critical element that impacts the length of the BE evaluation process. The results described above may improve the generic drug industry’s understanding of the impact of bio-batch adequacy on the BE assessment timelines and thereby facilitate the ability of applicants to make strategic decisions that will avoid unnecessary additional assessment time and thus lead to faster ANDA approvals.

Disclosures: This presentation reflects the views of the authors and should not be construed to represent FDA’s views or policies.