(322g) Risk Assessment of Encrustation in Continuous Pharmaceutical Crystallization Process – a Case Study

Authors: 
Acevedo, D. A., U.S. Food and Drug Administration
Yang, X., U.S. Food and Drug Administration
Zhang, J., U.S. Food and Drug Administration
Mazumder, S., Office of Testing and Research, U.S. Food and Drug Administration
O'Connor, T., U.S. Food and Drug Administration
Cruz, C. N., U.S. Food and Drug Administration
Encrustation is a risk factor that can cause product and process failure in continuous crystallization processes. Various risk mitigation strategies proposed in the literature, such as coating of crystallizer walls, use of additives to control encrustation kinetics, and periodic steady state operation show promising results in delaying or preventing encrustation.1-3 Due to increased interest in the use of continuous crystallization in industrial applications, it is important to understand this risk factor further. Recent developments on dynamic models, mechanisms and risk factors of encrustation in continuous crystallization processes will be discussed. Methodologies for detection, mitigation, or control of encrustation will be evaluated. Cooling crystallization of carbamazepine will be used as a case study to evaluate detection methodologies (visual, process analytical technology, etc.). Various design and control strategies to mitigate the encrustation risk are also proposed. Appropriate control strategies should be implemented during continuous crystallization to avoid the impact of encrustation on drug substance quality.

  1. Wu, T.; Sun, Y.; Li, N.; de Villiers, M. M.; Yu, L., Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir 2007, 23 (9), 5148-5153.
  2. Powell, K. A.; Saleemi, A. N.; Rielly, C. D.; Nagy, Z. K., Monitoring Continuous Crystallization of Paracetamol in the Presence of an Additive Using an Integrated PAT Array and Multivariate Methods. Organic Process Research & Development 2016, 20 (3), 626-636.
  3. Koswara, A.; Nagy, Z. K., On-Off Feedback Control of Plug-Flow Crystallization-A Case of Quality-by-Control in Continuous Manufacturing. IEEE Life Sciences Letters