D2S10-Fu-v1.2-FINAL.pdf

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1、Nitrosamine Safety Assessment in Generic Drugs:A Pharm/Tox PerspectiveXin Fu,PhD,DABTDivision of Pharmacology&Toxicology Review(DPTR)Office of Safety and Clinical Evaluation(OSCE)Office of Generic Drugs(OGD)CDER|US FDA2026 SBIA Generic Drug ForumApril 22 23,20262DisclaimerThis presentation reflects

2、the views of the author and should not be construed to represent FDAs views or policies.www.fda.gov3Nitrosamine Safety Assessment Overview Common pitfalls Summary and recommendationswww.fda.gov4Nitrosamine Safety Assessment Overview Small molecule nitrosamines and complex nitrosamines(NDSRIs)Potent

3、rodent carcinogens,probable human carcinogens Metabolic activation necessary for downstream effects Belong to cohort of concern(CoC)in ICH M7 Require tighter control limits than typical mutagenic impurities(1500 ng/day:additional(-)in vivo mutagenicity(transgenic rodent assay)Read-across(RaX)to surr

4、ogate:structurally relevant nitrosamine,robust carcinogenicity data(-)in vivo mutagenicity ICH Q3A/Q3B qualification thresholdwww.fda.gov9Nitrosamine Safety Assessment Common Pitfalls Inadequate EAT to assess mutagenicity Alternate AI limit solely based on negative EAT Inappropriate surrogate to est

5、ablish AI limitwww.fda.gov10Common Pitfalls Inadequate EAT Inadequate dose selection of test article,low top dose Selected solvent concentration interfering with metabolic activation Lack proper nitrosamine positive controls Insufficient metabolic activation conditionwww.fda.gov11Common PitfallsAlte

6、rnate Limit Based on Negative EAT only FDA recommends additional studies In vitro mammalian mutation assay In vitro metabolism study focusing on-hydroxylation Support alternative AI 1500 ng/daywww.fda.gov12Common Pitfalls Inappropriate Surrogate for RaX Structure consideration:N-nitroso alert in the