Analytical Quality By Design Based Method Development For The Analysis Of Valsartan And Nitrosamines Impurities Using UPLC-MS

By Fadi L. Alkhateeb and Paul D. Rainville, Waters Corporation

The primary concern related to genotoxic impurities that they have the potential to interact with human cells to cause mutations and cancer, even at the lowest levels. As such, genotoxic impurities should be avoided all at once and if not possible, reduced below a defined level. The advent of these impurities in various angiotensin receptor blocker drugs (ARB) such as valsartan, losartan, and irbesartan has caused broad recalls of these drugs from the markets and made this issue a focus for regulatory agencies including the FDA and the European Medicines Agency (EMA). In order to comply with regulations, it is critical that analytical methods that are used for the analysis of these compounds are accurate, robust, and sensitive. One way to develop robust and accurate methods is employing the Analytical Quality by Design principles (AQbD) in the method development process.

The AQbD is a systematic approach for method development that starts with predefined objectives and provides rational understanding of the effects of chromatographic factors on the method performance. The outcome of this approach is a fit for purpose, well designed, understood, and robust method that delivers the expected performance throughout its lifecycle.

In this paper we demonstrate how using the AQbD approach and automated software helps gaining a deep knowledge about the method and as a result developing a highly robust and reproducible method.