(T0930-12-80) Regulatory Challenges with Formulation Assessment of Parenteral Drug Products During ANDA Review: Case Studies and Considerations

Purpose: According to 21 CFR § 314.94(a)(9)(iii), a drug product intended for parenteral use is required to contain the same inactive ingredients in the same concentration as the Reference Listed Drug (RLD) but may differ from the RLD in the use of preservatives, buffers, or antioxidants provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety and efficacy of the proposed drug product. It has been challenging in certain circumstances for applicants to develop a generic that is qualitatively (Q1) and quantitatively (Q2) the same as the RLD to meet this inactive ingredient requirement. The waiver provision at 21 CFR 314.99(b) enables some flexibility in the generic approval process by allowing an applicant to “ask FDA to waive under this section any requirement that applies to the applicant under 314.92 through 314.99”, including 21 CFR 314.94(a)(9)(iii), with appropriate scientific justification. Regulatory challenges, scientific considerations of Q1/Q2 evaluation, and waiver requests are summarized to enhance review consistency and efficiency based on the Agency’s current thinking.

Methods: Cases evaluated from 07/2018 to 10/2022 with regulatory challenges related to Q1/Q2 formulation assessment and waiver requests were summarized and categorized by different scenarios. Two main categories were identified including pH adjuster related issues and RLD/Reference Standard (RS) related issues.

Results: From 07/2018 through 10/2022, a total of 44 abbreviated new drug application (ANDA) for parenteral drug products with regulatory challenges were analyzed and summarized. Representative cases were summarized for pH adjuster related issues including scenarios with Q1 difference and Q2 difference between test and RLD. Representative cases were also summarized for RLD/RS related issues including scenarios when the test formulation is not Q1/Q2 the same to the RLD and scenarios when the test formulation is Q1/Q2 to the RLD but in different dosage forms or strengths. The scientific considerations were also summarized for each challenge/scenario.

Conclusion: This study identified two common categories of regulatory challenges related to Q1/Q2 evaluation and waiver request consideration for parenteral drug products. By summarizing different case studies and assessment considerations, it could provide a clear guideline to follow based on the Agency’s current thinking. This will ultimately support better drug product development for generic industry and increase efficiency and consistency for ANDA assessment.

Acknowledgements: This abstract/poster reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Representative case study for pH adjuster related issues

Representative case study for RLD/RS related issues