Nitrosamine Ames Data Review and Method Development: Proceedings of a US FDA/HESI Workshop

Detection of N-nitrosamine (NA) in pharmaceuticals became a point of interest due to the mutagenic and carcinogenic potential of some compounds of this class, and their identification as nitrosated forms of marketed drugs, otherwise known as NA Drug Substance-Related Impurities (NDSRIs). The Ames test is used to assess the mutagenic potential of drug impurities, including NAs. Concerns over the sensitivity of the Ames test, as recommended in OECD Test Guideline 471, in predicting the rodent carcinogenic potential of NAs has prompted optimization of several test parameters used for detecting the mutagenicity of NAs (e.g., methods used for metabolic activation and the selection of tester strains). In order to discuss optimal Ames test conditions for the evaluation of NAs, including NDSRIs, the Office of New Drugs (OND) in the US Food and Drug Administration’s Center for Drug Evaluation and Research (US FDA/CDER) and the Health and Environmental Sciences Institute’s Genetic Toxicology Technical Committee (HESI/GTTC) co-organized and co-sponsored a workshop entitled “Nitrosamines: Ames Data Review and Method Development Workshop”. The workshop featured five sessions addressing charge questions pertinent to the Ames test conditions and performance through the presentation of data and panel discussions. This report outlines the key takeaway points from the workshop.