PAT-Enabled Automated Feedforward Control: An Application to the Continuous Manufacture of Apremilast

Previously, we reported the development and characterization of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance of Otezla. Herein, we report the application of closed-loop control to this CM process as a case study. A Python-based feedforward closed-loop controller is developed that uses infrared (IR) process analytical technology (PAT) to monitor incoming feed concentrations and then automatically adjusts the downstream feed flow rates in response to disturbances such that near optimal product yield is maintained through the continuous operation. The closed-loop controller was developed and demonstrated on a lab system that replicates the continuous manufacturing skid for apremilast production. In reporting this demonstration, we aim to (1) provide an example of how PAT-based closed-loop control could be beneficially applied to a drug substance CM process and (2) highlight areas where we believe further technical advancement is required to enable such closed-loop control to be successfully deployed in a manufacturing setting.