(270b) Disturbance Studies of Continuous Cooling Crystallization of Carbamazepine

Yang, X., U.S. Food and Drug Administration
Acevedo, D. A., U.S. Food and Drug Administration
Mohammad, A., U.S. Food and Drug Administration
Pavurala, N., Office of Testing and Research, U.S. Food and Drug Administration
Wu, W. L., Food and Drug Administration
Wong, E., FDA
O'Connor, T., U.S. Food and Drug Administration
Cruz, C. N., U.S. Food and Drug Administration
Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector. Continuous crystallization is important in an integrated CM process and may significantly affect the drug substance critical quality attributes (CQAs), such as particle size distribution and polymorphism. However, few publications have been focused on potential manufacturing disturbances, the impact on drug substance quality and how the risks can be mitigated. Here, we designed and built an automated two-stage Mixed Suspension Mixed Product Removal (MSMPR) crystallization platform for a model compound (Carbamazepine, CBZ) that exhibits multiple polymorphs. The crystallization process includes integration of Process Analytical Technology (PAT) tools (on-line Raman microscopy and Focused Beam Reflectance Microscopy, FBRM) for real-time monitoring. We performed continuous runs and evaluated the effects of typical manufacturing disturbances, such as temperature fluctuations, agitation rate change, and feed concentration hikes, on process dynamics. This talk will discuss our results and findings.