Transitioning from Batch to Continuous API Crystallization to Establish a More Scalable Means to Kinetically Control the Purging of a Co-Precipitating Impurity

In this presentation, APC discuss the application of continuous crystallization to control drug substance purity and crystal form in the isolation of Genentech’s JAK1 inhibitor, GDC-4379 (Morris et al., 2022). Motivated by challenges encountered with the reliable purging of a regioisomer impurity in production-scale batch recrystallizations of crude GDC-4379, the adaptation of this impurity purging recrystallization to a continuous mixed suspension, mixed product removal (MSMPR) crystallizer enabled superior kinetic rejection of the regioisomer (97.9%) in comparison to the batch operation (32.4%). Furthermore, by operating the MSMPR crystallizer at sufficient water content and temperature, the ability to selectively crystallize the required hydrate form A of GDC-4379 for the active pharmaceutical ingredient (API) directly from the solvent system of the impurity purging recrystallization (DMSO/MeOH) was confirmed. The results of the development effort provided proof of concept that a continuous crystallization process could achieve the regioisomer purge and API form control requirements of the GDC-4379 drug substance and provide a more scalable and streamlined alternative to the two-step batch recrystallization process used in production.

References

Morris, G., Keogh, A.P., Farid, U., Stumpf, A., 2022. Development of an impurity and hydrate form controlling continuous crystallization to telescope a two-step batch recrystallization in the GDC-4379 drug substance process. Chem. Eng. Res. Des. 183, 608–622. https://doi.org/10.1016/j.cherd.2022.02.022

Biography

Brian Glennon is a Professor of Chemical Engineering in University College Dublin (UCD) and co-founder of APC and VLE Therapeutics. He holds a BE and PhD in Chemical Engineering from UCD. Prior to joining UCD, he worked with Merck in Ireland. Since joining UCD in 1995, his research interests have focused on pharmaceutical process engineering, with particular emphasis on crystallization, bioprocess design and continuous manufacturing. In his role as Chief Technology Officer in APC and VLE, he leads the internal research programmes and is charged with driving innovation across both organisations.