Bio: Hairuo Wen, Ph.D/Professor, Study Director of National Institute of Food and Drug Control, engaged in preclinical safety evaluation research. She is currently a member of the Board of the Beijing Environmental Mutagen Society, the Committee of Genotoxicity of the Chinese Toxicology Society, SAC/TC279/WG12, SAC/TC248/SC1. She is the first author of GB/Z 42246-2022 and YY/T 1897-2023, and participated in the drafting and revision of varies non-clinical research technical guidelines and ADC drugs.

Abstract: N-nitrosamines, known as drug impurities and suspected carcinogens, have drawn significant public concern. Due to their prevalence, the large individual differences in carcinogenicity risk, as well as the lack of carcinogenic data, EMA and FDA U.S. have proposed that the acceptable intake (AI) limits of N-nitrosamines could be established based on their structure-activity relationships and using cross-reference methods. However, the resulted AI are often overestimated their risks. As reported previously, compared with NDIPA, the mutagenicity and DNA damage potencies of NEIPA (which contains one more α-hydrogen) were much greater. The AI of N-nitroso bumetanil, a N-nitrosamine drug substance related impurities (NDSRIs) is defined as1.5 mg/d (considering as a common mutagenic impurity) based on its structural characteristics, while showed no mutagenicity in varies tests. Furthermore, for most degradation impurities (e.g.), the calculated AIs place much higher requirements on the drug production process. In addition, the updated mutagenic risk evaluation test methods (enhanced Ames test, Pig-a assay, and second-generation sequencing method for low frequency mutation) for N-nitrosamine impurities will be introduced, so as to provide reference for research and supervision.