Nitrite testing in excipients – Industry best practices

Abstract

NNitrosamine risk assessment and control are essential components of pharmaceutical drug development and product evaluation. Nitrites present in excipients pose a risk to vulnerable amines that are present in APIs, API impurities or other process related amines, as they can be nitrosated to form N-nitrosamines. Detection and quantification of nitrite in excipients is an essential undertaking within the pharmaceutical industry to inform nitrosamine risk assessment and related risk mitigation strategies. An industry consortium and Lhasa Nitrites database was established to collaborate on this challenge, share knowledge, and reduce the testing burden. This article demonstrates the existing understanding of analytical techniques within this consortium for the quantification of nitrite in excipients incorporating IC with conductivity or UV detection, Griess derivatisation (with subsequent HPLC-UV or MS/MS detection or as PCD after IC), DAN derivatisation (with FL and MS detection) and cyclamate derivatisation (with GC-FID or GC–MS detection). We aim to highlight a variety of best practices as well as detailing their techniques principles, performance characteristics and sample preparation. Utilising the nitrite results in the database has highlighted a range in LOQs of nitrite that can be achieved, as well as knowledge of the advantages and disadvantages of using each analytical technique. This publication aims to facilitate the selection of an appropriate analytical method when considering nitrite in excipient determination.