Application of a Statistical Approach to Process Development of Futibatinib by Employing Quality-by-Design Principles. Part 3: Development of Design Space for Control of Particle Size Distribution

This study constructs a control strategy with a design space of the particle size distribution for futibatinib using a design of experiment and statistical approach without an additional milling process to save resources for validating consistency and equivalence. First, an L12 orthogonal experiment of the Plackett–Burman type is designed to identify the risk of whether 11 potential critical process parameters in the recrystallization process are in fact critical process parameters. Next, the effect of particle size distribution is confirmed by changing the levels of the process parameters of agitated drying in the two-trial manufacturing; we find that the agitated drying time is a critical process parameter. Then, we prove that there is little out-of-specification risk of the particle size distribution considering manufacturing error and analytical error using the Monte Carlo approach. Finally, this study confirms the reimplementation of failure mode and effect analysis as risk evaluation improves the understanding of the manufacturing process and reduces the particle size distribution risk of futibatinib by clarifying the process. Based on the quality-by-design concept, we construct a design space and control strategy for the particle size distribution, focusing on experimental design and statistical analysis. This study clarifies that the agitated drying process affects the particle size more than other parameters do. By examining the overall process, this study demonstrates that particle size can be controlled sufficiently without the milling process. It proves that the commercial manufacturing method is a robust process, and futibatinib can be stably produced.