Quality by design-based method development for the determination of related substances of ezetimibe by high performance liquid chromatography

Abstract

Abstract The pharmaceutical industry is one of the fastest developing industries, and therefore, the chromatographic methods used to ensure the quality of products are constantly evolving, based on current regulatory requirements. Relevant guidelines state that a good understanding of the effects of all parameters on method performance should be predicted and controlled to ensure that test methods are safe and reliable. This quality by design-based approach is increasingly applied in chromatography. One of the pillars of this method development is the design space that results from pre-designed and systematically realized experiments, which contributes to a better understanding of the separation processes and provides flexibility and robustness to the final method. Modeling softwarewares can be used to experimental design and data evaluation, providing possibilities that empirical development does not allow, such as predicting optimal operating conditions or in silico robustness testing, to understand the separation process. This paper describes the steps of chromatographic method development according to the ICH Q14 guideline, keeping in mind the quality by design principles and taking advantage of the possibilities offered by the DryLab chromatographic modeling software. As an example, the development of an analytical method for the determination of the related substances of ezetimibe is presented, including the design of experiments, method optimization, robustness testing, validation, method specification and lifecycle management, and finally testing of the method applicability. We have demonstrated that experimental design-based retention modeling is an effective way of method development, and the in silico robustness testing is a reliable approach to identifying critical method parameters and setting up control strategies. In chromatographic method development, instead of using a rigid system based on strict and fixed rules, the understanding of separation processes offers higher flexibility. This paper aims to present and promote this new approach to those involved in chromatographic method development.