Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine

Abstract

Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance and is considered a critical process step in achieving the continuous manufacturing of drug substances. Although many publications previously focused on various innovative techniques to continuously make crystals with desired properties, engineering difficulties such as system design, automation, and integration with process analytical technology (PAT) tools have not been thoroughly discussed. Here, we focus on how to develop a continuous crystallization system, from the perspective of process engineering, and the related risk considerations on product quality. Specifically, 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 the integration of PAT tools (online Raman microscopy and focused beam reflectance microscopy, FBRM) for real-time monitoring. A series of case studies were done to evaluate the performance of the continuous system and PAT tools. Specifically, the drawing schemes, slurry transport, and variations on process variables are considered as the three key risk areas for continuous crystallization process development. Our proof-of-concept continuous crystallization system uses feedback/feedforward controls to achieve constant levels in crystallizers, a centralized automation program coded in LabVIEW, and PAT monitoring for polymorphs and particle size distribution (Raman and FBRM). To the best of our knowledge, this is also the first study on continuous crystallization of carbamazepine for form III and its polymorphic transition (between form II and form III).

The Role of Residence Time Distribution in the Continuous Steady-State Mixed Suspension Mixed Product Removal Crystallization of Glycine

“…This suggests that intermittent withdrawal may not be as efficient for suspensions containing coarse crystals. Other researchers 58 have observed similar behaviour using an intermittent pneumatic withdrawal method, whereby the mean particle size of the isolated sample was slightly smaller than in the crystallizer.…”

Continuous protein crystallisation platform and process: Case of lysozyme

“…Continuous stirred tank reactor (CSTR) or multi-stage MSMPR (Alvarez et al, 2011;McGlone et al, 2015) had been introduced in crystallisation of small organic molecules which can achieve a better plug flow with increase of the stages or parallel reactors. These designs are suitable for systems that require longer residence times, but its strong agitation and nonuniform temperature profile may cause problems for particle size and polymorphism control as reported in crystallization of small organic molecules (Yang et al, 2017).…”

“…The steady-state operation of a continuous crystallisation stabilizes variability in the product, reduce capital costs, and improve control over the CSD of the API (Baxendale et al, 2015). Many research on continuous crystallizers have been investigated in mixed-suspension, mixed-product removal (MSMPR) crystallizer (Su et al, 2015;Yang et al, 2017), i.e. continuous stirred tank reactors (CSTRs) (Lai et al, 2015), plug flow reactor (PFR) (Neugebauer and Khinast, 2015), continuous (baffled) oscillatory flow reactor/crystalliser (OBR)/(COFC) (Chew et al, 2004;Jian and Ni, 2005;Yang et al, 2016).…”

Continuous manufacturing – the Green Chemistry promise?

“…As such they have started incorporating key waste contributors into their life cycle assessment tools to help prioritize areas for improvement. 19…”

“…the integration and subsequent approval of these methodologies by regulatory agencies. 19 Thus, focus on process robustness and product quality is essential. Hazards identified for a continuous manufacturing process differ from their batch counterparts and therefore, understanding the associated risks of continuous manufacturing will be of critical importance.…”