(382e) Continuous Manufacturing As an Enabler for Intensified Process Design and an Integrated Control Strategy in Pharmaceutical Synthesis
For the case study herein, the transition from laboratory development to a continuous process demonstration operating at 50â100% of the commercial-scale in walk-in fume hoods is described. Scale-up efforts integrating multiple unit operations in flow and leveraging process analytical technology (PAT) are demonstrated to test process robustness and generate process knowledge that directly informs the target conditions and operating ranges for the commercial-scale manufacturing process. In this example, transfer of the process for a late-stage clinical supply campaign within the external manufacturing network is detailed, culminating in a continuous route with two plug flow reactor (PFR) transformationsâan amidation and a high-temperature deprotectionâoperating in conjunction with a continuous mixed-suspension, mixed-product-removal (MSMPR) crystallization and parallel filtration with in situ solids dissolution. Genotoxic impurity control is afforded through process design and engineering controls and is verified with online and offline analyses. The process is shown to operate in continuous mode for 18 days, affording more than 150 kg drug substance in exceptional purity. These steps will be at the core of a multi-step continuous unit operations sequence in the commercial process.