Low-Level Determination of Mutagenic Nitrosamine Impurities in Drug Substances by LC–MS/MS

Abstract

Since the detection of N-nitrosodimethylamine (NDMA) in a batch of valsartan in 2018, at levels exceeding ICH acceptable intake limits for mutagenic impurities, the analysis of nitrosamines has become an intense focus point for the pharmaceutical industry. The identification and low-level determination of nitrosamines in potentially affected materials is challenging and requires the application of highly sensitive analytical techniques. This article reviews the chronological development of the story and the regulatory landscape that has evolved. It will then discuss the development of analytical methods for the determination of a series of nitrosamines referenced by regulatory authorities, demonstrating separation of these compounds from the active pharmaceutical ingredient (API) and looking at how mass spectrometry (MS) can be applied to ensure that the required detection limits can be reached.