Highly Sensitive and Robust LC-MS/MS Method for Determination up to 15 Small Molecule Nitrosamine Impurities in Pharmaceutical Drug Substances.

Abstract

Nitrosamine impurities have been classified as probable human carcinogens for decades. These impurities were reported in water, food, tobacco, pesticides, and plastics but received attention in mid-2018 when N-nitrosodimethylamine (NDMA) was reported in valsartan drug products. Subsequently, it was revealed that several small molecule and complex nitrosamine impurities can form in any active pharmaceutical ingredient (API) or drug product in which secondary or tertiary amines are present (as API or as impurities) along with a nitrosating agent. Consequently, regulators have provided several guidelines for the risk assessment of nitrosamine formation during manufacturing, storage, or from contaminated supply chains. This has led to a demand for validated analytical methods that quantify N-nitrosamine impurities in pharmaceutical products. In this study, a highly sensitive and robust analytical method was developed and validated for quantitatively determining up to 15 small nitrosamines at low levels (0.01 ppm) in sartan drug substances. The study also suggests that this method can be extended not only to corresponding sartan drug products but could also be used as a generic screening method to test a variety of drug substances, and drug products with the minimum required optimization of method conditions.