(422d) PAT-Enabled Automated Process Control: Application to Otezla Continuous Manufacturing

Continuous manufacturing (CM) has the potential to realize some of the visions of Industry 4.0 like lights-out manufacturing where processes run for significant periods of time with minimal manual oversight or intervention. However, to get there, advances in monitoring and control must be proposed, approved, and implemented under GMP drug substance manufacturing.

We report the development and lab-scale demonstration of a feedforward control loop that can adapt to input disturbances to maintain optimal operation during the continuous synthesis of Apremilast, the drug substance of the commercial product Otezla®. The closed-loop control strategy applies process analytical technology (PAT)—mid-infrared spectroscopy, in this case—to monitor feed tank solution compositions in real-time. It then adapts to off-setpoint compositions by automatically adjusting pump flow rates using a Python-based controller to maintain optimal equivalency of the reactants going into the plug flow reactor.

This demonstration helps make concrete the potential for PAT-enabled process control to maintain optimal operation in drug substance CM processes. We will also highlight areas where technical progress is still needed to implement closed-loop control in a manufacturing environment.