Since July 2018, more than thousands of drug products have been recalled due to presence of nitrosamine impurities (NIs). There was high regulatory concern because <i>N</i>-nitrosamines are potential human carcinogens and are toxic at extremely low levels, i.e., ng/day levels. Initially, the issue was restricted to <i>N</i>-nitrosodimethylamine (NDMA) contamination of valsartan from Chinese active pharmaceutical ingredients (APIs) suppliers. However, it soon became apparent that use of other common secondary or tertiary amines in API syntheses could also introduce other types of NIs besides NDMA. The occurrence of NIs has shown that pharmaceutical companies and regulatory agencies did not focus on these substances in the past during drug development. Based on ICH M7(R1), Assessment and control of DNA reactive (Mutagenic/genotoxic) impurities in pharmaceuticals to limit potential carcinogenic risk, N-Nitrosamines are compounds of concern due to their mutagenic carcinogenic effect. Hence, they are to be controlled at or below the acceptable cancer risk levels. Regulators, including the FDA, expect that manufacturers of APIs and drug products take reasonable steps to prevent higher levels or eliminate N-nitrosamines. Until recently, nitrosamines were not expected to be formed during the manufacture of most APIs outside the class of sartans with a tetrazole ring. However, based on the new knowledge, the impurities can form during production under certain conditions and when certain solvents, reagents, and other raw materials are used. The most significant challenge is a lack of understanding and knowledge surrounding by-product chemistry, i.e., impurities and degradants. This perspective provides a critical account of establishing Acceptable Intakes (AIs) for structural group of NIs, without carcinogenic data of NIs, predicting carcinogenic potency using metabolism/computational models and risk assessment for NIs.

Safety assessment of potential risks associated with nitrosamine impurities in Human drugs and pharmaceuticals

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.