(673g) Quality Control by QbD-Guided Optimization of Reaction and Crystallization

Under the QbD paradigm, costs of rework and inspection are minimized by assuring product quality based on control of critical process parameter variation. The case study presented highlights an approach used to identify, quantify, and manage / control risk to product quality by: (1) conducting a Failure-Mode Events Analysis (FMEA) of the process as a quality risk assessment, (2) quantifying risk by determining the impact of multivariate parameter variation on product quality, and (3) developing a control strategy to manage risk to product quality based on scientific understanding of the multivariate design space.

This approach was applied to the manufacture of an advanced intermediate product. The step involves a chlorination reaction, a coupling reactive crystallization, and a reactive recrystallization. The process FMEA highlighted parameter variation for both the chlorination reaction and the reactive recrystallization as potential risks. Experimental design around the chlorination reaction revealed slight increases in a key reagent resulted in lower quality intermediate and much slower reaction kinetics. Product crystallization during the coupling reaction results in substantial residual intermediate entrapment within the product crystals. A 2³ full-factorial experimental design was implemented to map the reactive recrystallization design space. These and other experiments provided an understanding of the fate of residual intermediate in the reactive recrystallization. Control strategies for both the chlorination reaction and reactive recrystallization were developed to ensure product quality. The effectiveness of the control strategy was demonstrated at manufacturing scale to produce high quality product.