亚硝胺相关指南-Cantave.pdf

1、Nitrosamine Related GuidanceReynolds Cantave,PharmDSr.Regulatory Business Process ManagerOffice of Quality Assurance,Office of Pharmaceutical QualityCDER|US FDAGeneric Drug Forum April 10,2025fda.gov/cdersbiafda.gov/cdersbia2Learning ObjectivesDefine Nitrosamines and describe the two structural clas

2、ses of these impurities.Describe purpose of predicted carcinogenic potency categorization approach(CPCA)framework introduced with 2023 Guidance.Describe four key updates published in 2024 Guidance for Industry:Control of Nitrosamine Impurities in Human Drugs.Describe control strategy recommendations

3、 described in 2024 Guidance for Industry:Control of Nitrosamine Impurities in Human Drugs.List elements of the three-step mitigation strategy.Describe recommendations NDSRI mitigation strategies and recommended supporting stability data for reformulation.fda.gov/cdersbiafda.gov/cdersbia3 June 2018,C

4、DER Alerted to presence of NDMA in Valsartan Prompted global regulatory response and industry-wide action Subsequently,scope expands to include additional drugs and new nitrosamines Ongoing investigations into other drug productsBrief Historical Backgroundfda.gov/cdersbiafda.gov/cdersbia4 N-nitroso

5、compounds:formed by nitrosation of susceptible amines Genotoxic,probable human carcinogens Commonly found in the environment,rubber,foods(cured meats,beer,and cheese),and pharmaceuticalsWhat are Nitrosamines?fda.gov/cdersbiafda.gov/cdersbia5Small molecule Nitrosamines(not associated with API.e.g.,ND

6、MA,NDEA,NMPA,NDIPA,NDBA,and NBMA etc.)Nitrosamine drug substance related impurities NDSRIs(associated with API)“Small Molecule”vs.“NDSRI”N-Nitrosodimethylamine(NDMA)N-nitroso-phenylephrinefda.gov/cdersbiafda.gov/cdersbia6Challenge Question#1FDAs recommended three-step mitigation strategy include all