Get Full Government Meeting Transcripts, Videos, & Alerts Forever!
Get email alerts on the Nitrosamines Be Guidance topic
No spam. Unsubscribe anytime.
FDA office outlines bioequivalence expectations for nitrosamine-mitigation reformulations
Summary
FDA Office of Bioequivalence staff summarized how nitrosamine contamination has affected applications since 2018 and reviewed mitigation categories and recommended bioequivalence data for reformulated products, stressing case-by-case review and early engagement with the agency.
Paramjeet Kaur of the Office of Bioequivalence in the Office of Generic Drugs told attendees that "since 2018, unacceptable levels of nitrosamines have been detected in commonly prescribed medications," creating a significant regulatory concern for both the agency and manufacturers.
Kaur summarized three broad mitigation strategies recommended in FDA's nitrosamine guidance: changing the API source or synthesis route, reformulating the drug product (for example by adding antioxidants or pH modifiers), and implementing manufacturing or packaging controls. She said the choice of mitigation affects what bioequivalence (BE) data FDA expects, and that decisions depend on BCS class, dosage form, and the specific reformulation approach.
On the most commonly used reformulation approach, Kaur said the guidance supports using certain antioxidants and pH modifiers but recommends specific testing. "Drug products reformulated with FDA research antioxidants at an amount no more than 10 milligram per dose ... recommend comparative dissolution data on pre and post change products," she said, adding that dissolution should be tested in QC medium and in three pH conditions (1.2, 4.5 and 6.8).
Kaur and her colleague Ming Guo noted that alternative BE approaches (IVIVC, PBPK modeling, or in vivo BE) may be required for some products, including modified-release forms, narrow therapeutic index drugs, or when changes exceed guidance limits. Both presenters emphasized that the nitrosamine guidance is general and that "every drug product is unique," so agency review remains case-by-case and applicants should engage early with FDA via meeting requests or controlled correspondence.
The presentation directed industry to the FDA guidance "Control of nitrosamine impurities in human drugs" for detailed recommendations and examples.
