Application of a Statistical Approach to Process Development of Futibatinib by Employing Quality-by-Design Principles. Part 1: Identification of Critical Process Parameters for Impurities

We focus on a novel experimental design and statistical analysis to identify the critical process parameters (CPPs) of impurities in futibatinib, which is a fibroblast growth factor receptor inhibitor. First, using failure mode and effects analysis, we identify 11 potential CPPs as the process parameters to be investigated. Next, an L-12 orthogonal experiment of the Plackett-Burman type is designed for risk analysis to check whether the 11 potential CPPs are in fact CPPs. Finally, for each impurity, analysis of variance, regression analysis, and regression diagnosis are carried out, enabling the CPPs to be analyzed correctly. Based on the quality-by-design concept, we identify three impurities that impact the impurity profile of the active pharmaceutical ingredient and five CPPs of the impurities, focusing on design of experiment and statistical analysis. We also clarify the process parameters to be examined in more detail for commercial production.