Presentation Title: Enabling Robust Impurity Rejection and Form Control in the Crystallization of a Small Molecule API by Switching from Batch to Continuous Processing

Abstract: Within the past decade the pharmaceutical industry has embraced the implementation of continuous processing as part of a concerted effort to modernize the methods by which therapeutic products are developed and manufactured (Burcham et al., 2018). In the production of small molecule active pharmaceutical ingredients (APIs), numerous product quality, safety, sustainability, and cost benefits can be realized by parting ways with antiquated batch processing methods and focusing new synthetic routes towards continuous processing infrastructure. In this presentation, APC discusses the opportunity landscape for continuous processing in API crystallization and how continuous crystallizers can be used to enable robust control of critical quality attributes (CQAs) (e.g., crystal purity, form, and size) that can be difficult to consistently deliver through a batch operation, particularly as production volumes scale with progression through clinical development. These advantages are further explored through a case study on an industrial crystallization process to isolate a Janus kinase 1 (JAK1) inhibitor, where the purging of a key impurity had become challenging in the batch production-scale process and an alternative continuous crystallization process was developed to improve the robustness of the impurity rejection (Morris et al., 2022). References Burcham, C.L., Florence, A.J., Johnson, M.D., 2018. Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing. Annu. Rev. Chem. Biomol. Eng. 9, 253–281. https://doi.org/10.1146/annurev-chembioeng-060817-084355 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