Development of an automated multi-stage continuous reactive crystallization system with in-line PATs for high viscosity process

Pharmaceutical synthesis remains one of the last industrial processes to use “batch” or non-continuous approaches.1 Conversely, other industries, such as petrochemicals, automobiles, electronics, and food, have moved forward with automated and continuous operations. Pharmaceutical companies generally manufacture the active pharmaceutical ingredient (API) at one company plant, and formulate the API with excipients into the final drug product at a separate plant. It is a fragmented process with a long lead-time and a large plant footprint. This time–space inefficiency has led to an increased interest in integrated continuous manufacturing (ICM) of APIs and drug products as a seamless end-to-end process. Advantages of continuous manufacturing include:

1. Flexibility,
2. Speeding up the supply chain,
3. Agility and reduced scale-up efforts,
4. Real-time quality assurance and better engineered systems,
5. Recentralized and individualized manufacturing,
6. Reduced footprint and investment costs, and
7. Societal benefits

Continuous manufacturing processes of pharmaceuticals can include the following steps: reaction, crystallization, filtration, drying, and hot melt extrusion (HME).