(34e) Process Design and Intensification of a Continuous Modular Crystallization System

Recently there has been a transition from batch to continuous manufacturing to further intensify the standard manufacturing process. Continuous processes in general have shown many promising results such as increased product uniformity, quality, and safety due to minimal human involvement and no batch-to-batch variation, as well as easier scale-up and reduced operating volumes allowing for better control and reduced overall footprint and cost (Su et al., 2019). Using process intensification further improves the robustness and decreases the scale of these processes enabling high degree of automation, modularization, and autonomous operation. The concept of modular manufacturing has gained recognition recently in various academic and industrial communities. Containing continuous manufacturing processes in reconfigurable, automated modular and mobile units can minimize disruptions in the supply chain of various critical products, such as pharmaceuticals and energetic materials, that the current centralized batch manufacturing systems cannot do due to more rigid operation at fixed locations requiring complex logistics for transferring and storing the active ingredients. Modular manufacturing systems are reconfigurable and can be customized to changing process needs.

Current literature has shown few modular manufacturing units, including a Pharmacy on Demand (PoD) portable continuous manufacturing factory containing downstream units for producing battlefield medicines instantly and locally (Capellades et al., 2021). In this work, a modular automated and autonomous continuous crystallization unit is presented consisting of a mixed-suspension mixed-product removal (MSMPR) cascade system. This unit was designed for energetic materials with the motivation of improving personnel safety by eliminating the transport of the energetic compound due to local manufacturing and only requiring raw material transportation. The modular unit is constructed in an intelligent containment unit (ICU) with increased safety including blast-resistant plexiglass, sensors, cameras, and alarms for process monitoring and automated fault detection. It is controlled via custom built LabVIEW software for remote management of all enclosed equipment and allowing the ability to switch between closed-loop (automated design of experiments) and open-loop operation (end-to-end manufacturing). In-situ process analytical technology (PAT) tools are integrated in the continuous crystallization system for further control to ensure the desired critical quality attributes (CQAs) are being achieved. Applying this modular design to continuous crystallization achieves robust, efficient, and flexible manufacturing.

1. Su, Q.; Ganesh, S.; Moreno, M.; Bommireddy, Y.; Gonzalez, M.; Reklaitis, G. V.; Nagy, Z. K. A Perspective on Quality-by-Control (QbC) in Pharmaceutical Continuous Manufacturing. Chem. Eng. 2019, 125, 216–231.
2. Capellades, G.; Neurohr, C.; Briggs, N.; Rapp, K.; Hammersmith, G.; Brancazio, D.; Derksen, B.; Myerson, A. S. On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and In Situ Control of Downstream Production. Org. Process Res. Dev. 2021, 25 (7), 1534–1546.