D2S11-Kaur+Guo-v1.2-FINAL.pdf

1、Bioequivalence Recommendations for Bridging Pre-and Post-Mitigation Formulations of Nitrosamine-Impacted Drug Products:Case StudiesParamjeet Kaur,Ph.D.,Lead PharmacokineticistMin Guo,Ph.D.,PharmacokineticistOffice of Bioequivalence/Office of Generic DrugsSBIA Generic Drug Forum April 23,20262Disclai

2、merThis presentation reflects the views of the authors and should not be construed to represent FDAs views or policies.3Outline Background on Nitrosamine Impurities and Mitigation Strategies Bioequivalence(BE)Approaches for Drug Products Reformulated to Control Nitrosamines Case Studies Summary Ackn

3、owledgements4Background-Nitrosamine Impurities in Drug Products Unacceptable levels of nitrosamines have been detected in commonly prescribed medications Nitrosamines are potent genotoxic agents;classified as probable or possible human carcinogens;“cohort of concern”compounds in the ICH M7(R1)This i

4、ssue impacts diverse drug products and dosage forms,affecting both New Drug Applications(NDAs)and Abbreviated New Drug Applications(ANDAs),with ANDAs representing the majority of cases Types of Nitrosamine Impurities Small molecule nitrosamines:N-nitrosodimethylamine(NDMA),N-nitrosodiethylamine(NDEA

5、),and related compounds;do not share structural similarity to the active pharmaceutical ingredient(API);found in many different drug products Nitrosamine drug substance-related impurities(NDSRIs):Structurally related to the API or API fragmentsReference:FDA Guidance-Control of Nitrosamine Impurities

6、 in Human Drugs(September 2024)5Regulatory Strategies to Mitigate Nitrosamine ImpuritiesMitigation Strategy Examples of Changes API Source/Process Modifications Modify route of synthesis or select new API suppliers Optimize manufacturing processes to minimize nitrosamine formation Control nitrite le