N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP

Abstract

The finding of N -nitrosodiethylamine (NDEA) and N -nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N -nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N -nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N -nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N -nitrosamines with model N -nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N -nitrosamines by providing in vivo TGR mutation data for N -nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N -nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day. • Practical strategies are needed to establish exposure limits for N -nitrosamines. • In vivo TGR mutation study provides compound specific data for novel N -nitrosamines. • Relative potency comparison of in vivo TGR data provides basis for exposure limit. • NPIP in vivo TGR data adds to the database of well-studied, model N -nitrosamines. • Relative potency comparison supports the safety of NTTP exposures ≥1500 ng/day.