D2S12-2-Shakleya-v1.2-FINAL.pdf

1、FDA Perspectives on Nitrosamine Risk Reduction in Manufacturing Diaa Shakleya,Ph.DSr.Research Scientist,OPQR/OPQCDER|US FDASBIA-Generic Drugs Forum April 23,2026www.fda.gov2www.fda.gov3Disclaimer“This presentation is not intended to convey formal FDA policy”www.fda.gov4Presentation Outline Identifyi

2、ng the risk factors and the control strategies Mitigation strategies Case study:Bumetanide&Metformin DPwww.fda.gov5Risk factorsRisk Factors for nitrosamine formation:A susceptible nitrogen containing compound(secondary or tertiary amines)A nitrosating agent(e.g.,introduced from nitrite present as im

3、purities in excipients)pH conditions to achieve the nitrosating reactionManufacturing conditions(Blending,Drying,granulation,etc.)Storage conditions&PackagingStudy Objectives:the primary objective of this work is to mitigate the risk of the formation of N-nitroso impurities by evaluating the role of

4、 different inhibitors in different formulations prepared by FDA formulation scientists using bumetanide&metformin as model drugs.www.fda.govControl Strategies API manufacturing control Supplier qualification program that takes into account potential nitrite impurities across excipient suppliers and

5、excipient lots to reduce the risk of nitrosamine formation in the drug product Antioxidants(Vitamin C,Vitamin E,etc.)and pH modifiers(Sodium carbonate,etc.)Manufacturing control(Blending control,Drying control,etc.)Packaging control(example:using inert,non-reactive materials)www.fda.gov pH Control A

6、cidic conditions facilitate the nitrosating reaction to form the nitrosating agent Maintaining neutral pH of the drug product will serve as a protection strategy against nitrosamine formationMitigation strategies Heat and Moisture Control Elevated heat and moisture increase risk:Nitrosamine formatio