White paper on approaches for addressing Nitrosamines

Abstract

In 2018 N-nitrosodimethylamine (NDMA) was detected in a batch of valsartan at levels exceeding ICH acceptable intake limits for mutagenic impurities. Since then, 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 white paper reviews the evolution of the regulatory landscape and discusses the development of analytical methods for the determination of nitrosamine impurities referenced by regulatory authorities. The development of a separation of these compounds from the active pharmaceutical ingredient (API) is discussed, together with application of mass spectrometry (MS) to ensure that the required detection limits can be reached. Additionally, the potential for interference, notably from N,N- dimethylformamide (DMF), is considered, along with strategies for mitigating the risks of inaccurate quantification that arises.