Status of and Challenges in End-to-end Synthesis of APIs

Klavs F. Jensen Ph.D.

The status and challenges in integrating reaction and work-up equipment in end-to-end production of active pharmaceutical ingredients (APIs) is discussed along with scaling strategies. State-of the equipment is discussed along with challenges in integrating reaction and work-up, including equipment availability, matching residence times and hold-ups, handling solids, start-up and shut down.  Scaling strategies are based on combining automated systems for extracting kinetic data and yield optimization combined with engineering process models.  Secondly, as an example of process integration for on demand manufacturing, a plug-and-play, reconfigurable, refrigerator-sized manufacturing platform is presented for on-demand API synthesis. This flexible system is capable of complex multi-step synthesis, in-line purification, post-synthesis work-up and formulation. Multistep synthesis occurs at elevated temperatures and pressures to enhance reaction rates, and the resulting residence times are a few minutes, in contrast to the multiple hour-long synthesis typically needed for batch.