Continuous Manufacturing As an Enabler for Intensified Process Design and an Integrated Control Strategy in Pharmaceutical Synthesis

Development, scale-up, and implementation of a continuous multi-step route for manufacturing of an active pharmaceutical ingredient are detailed. Long recognized as essential for economical process intensification in other chemical industries, continuous manufacturing stands to offer many of the same advantages to the pharmaceutical industry. These include more inherent scalability on account of improved heat and mass transfer, access to more aggressive reaction conditions, smaller footprint equipment sets placing less material at-risk, more opportunities to leverage online measurement and automation, and established control of the process at steady-state. The integration of all of these advantages enables implementation of a control strategy that ensures quality under more cost-effective, and often safer, flow processing conditions.

For the case study herein, the transition from laboratory development to a continuous process demonstration operating at 50–100% 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) transformations—an amidation and a high-temperature deprotection—operating 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.