Design, Development, and Execution of a Continuous‐flow‐Enabled API Manufacturing Route

Mini-Monoplant Technology for Pharmaceutical Manufacturing

“…Continuous flow at the micro- or milliscale provides several advantages compared with typical large-scale batch production processes, including improved heat and mass transfer, lower solvent requirements, better process control, enhanced reaction homogeneity, and safer handling of hazardous materials. − Productivity (defined as the amount of product generated with a finite amount of resources, including labor) comparable to that in large-scale batch operation can be achieved when the system is run continuously in a smaller-scale unit, leading to a drastically smaller footprint. Several examples of continuous pharmaceutical production have been developed and published by researchers at Eli Lilly, including high-temperature continuous crystallization and continuous active pharmaceutical ingredient (API) production under cGMP conditions, − and there are also reports detailing collaborations and technology transfer between pharmaceutical companies and contract manufacturing organizations. , Of key importance to the intensification of pharmaceutical processes and due to the enhanced rates of heat and mass transfer is the ability to perform reaction chemistries that would normally be considered “forbidden” under standard batch operation. , Intensified reactions run at high temperature, pressure, and concentration result in higher reaction rates and larger productivities, especially with the implementation of automation and RTRT. In addition, higher-energy reagents may be employed, which can facilitate more direct synthesis routes with fewer steps and higher-purity products. , For example, microreactors have previously shown success in the generation of explosive nitroglycerin and can significantly broaden the safe operating window with explosive substances .…”