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Developing and optimizing a quench-crystallization operation in drug substance manufacturing

By Dr. James D. Fostinis, Ph.D.
Drug Substance Technologies Engineer, Amgen

Quench crystallization approaches provide unique opportunities to design and control crystallization of pharmaceutically-relevant compounds, which can help streamline end-to-end processes by integrating reaction quench and downstream crystallization operations. A well-designed, single step quench-crystallization can neutralize an activated-state crude reaction stream, while providing conditions for the desired free product to crystallize in a controlled manner. Process performance indicators, such as impurity rejection, crystal size, crystal form, and filtration time targets can be optimized during the characterization of the quench-crystallization. The development of such a quench-crystallization differs from the traditional cooling/antisolvent crystallization, and the described case study offers an approach to systematically develop this type of reactive crystallization. The case study was successfully applied and scaled to 400 kg for commercial manufacturing, while also reducing the filtration time on scale from multiple days to hours.

Keywords: KRAS, sotorasib, quench-crystallization, process analytical technology, process development
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