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FDA: API source changes made to fix cGMP issues require new bioequivalence data
Summary
In a hypothetical case study, FDA staff said if original API batches were produced at facilities with unresolved cGMP deficiencies, data generated with those batches are unreliable and applicants should run new BE studies with material from the new API source.
In a hypothetical case study presented by Paramjeet Kaur, the applicant had conducted BE studies on the highest strength and requested waivers for lower strengths, but the agency subsequently found the original API's DMF had unresolved cGMP deficiencies. Kaur said that when the quality of the bio‑batch cannot be assured, "the BE studies and the waiver requests cannot be deemed adequate."
She advised that if the original API is not adequate, "the API source change to address nitrosamine impurities cannot be supported by dissolution testing only" and recommended that applicants conduct new BE studies and dissolution testing using batches manufactured with the new API source. The example underscored that cGMP concerns can invalidate prior BE evidence and require repeat studies with material from the new supplier.
The case illustrates FDA's position that analytical or dissolution comparisons alone may be insufficient when upstream quality problems (for example unresolved facility cGMP deficiencies) call into question the reliability of previously generated batches. Kaur suggested that applicants engaging in API-source changes tied to nitrosamine mitigation consult early with reviewers to determine the appropriate scope of studies.
