MATTHEW WEBBERLEY
Associate Director, Analytical Research and Development, SK biotek Ireland, SK pharmteco Company, Swords, Ireland

Abstract

Development of chromatographic methods for the determination of genotoxic (GTI) or potential genotoxic (PGI) impurities can be time consuming and laborious. Having a generic approach to a method development strategy can aid in the generation of a suitable method in a shorter space of time. Several different approaches to method development are possible. This paper provides an overview of method development strategies to generate a suitable, reliable, robust, and even validatable method for the determination of genotoxic impurities. The discussion includes several examples of successfully developed and validated methods for a range of genotoxic impurities, including nitrosamines, by liquid chromatography (LC) and gas chromatography (GC).

INTRODUCTION
The development of chromatographic methods to determine potential genotoxic impurities (GTIs) can be time consuming and laborious. While there are several approaches to method development (1), having a generic method development strategy can help streamline the process. This article provides an overview of method development strategies to help analysts, chromatographers, and researchers develop suitable, reliable, robust, and potentially validatable methods to determine GTIs. It includes several examples of successfully developed and validated methods for a range of GTIs, including nitrosamines, by liquid chromatography (LC) and gas chromatography (GC).

GTI METHOD DEVELOPMENT
GTIs are intermediates, reactants, or related substances from the synthetic pathway of a drug substance that must be monitored at very low levels, typically ppm or even ppb levels, 1,000 times lower than limits for classical impurities. Both the EMEA (2) and ICH (3) provide regulatory guidance to assess and characterize GTIs. Analytical methods used for their analysis include GC (4, 5) or LC (6, 7), often combined with mass ...