(410d) Design of a Pilot Plant for Integrated Continuous Manufacturing of a Steroid API

Continuous manufacturing (CM) offers advantages in improving process safety and quality control, reducing costs and lead time, and providing access to additional design space compared to batch processes. Unlike batch process development, where development work can be accomplished with a small set of equipment at a given scale (i.e. one jacketed reactor for reaction, extraction, distillation, and crystallization during lab development), CM process development usually requires unique equipment for each unit operation. During scale-up, this set of equipment needs to be redesigned to accommodate the increased throughput.

At CONTINUUS Pharmaceuticals, we developed individual unit operations for a CM process in small scale lab equipment. In order to demonstrate scale-up performance and integrated process performance, we piloted the process with a throughput between lab and anticipated commercial scale. To accommodate the project timeline, design and construction of the new pilot plant needed to occur in parallel with lab development, so that the pilot plant would be operational immediately when lab development was complete. This posed many unique challenges, namely that the equipment had to be designed early with limited process knowledge to accommodate the project timelines given the supply chain shortages and long lead times. We developed an uncertainty-based calculation for process parameters that informed the pilot plant design which evolved with improved process understanding acquired from lab development. The equipment was designed to cover 95% confidence interval on the process variability.

The detailed engineering design of the pilot plant retrospectively influenced the concurrent lab development activities by dictating scale-up constraints. This led to substantial process changes but provided sufficient time to de-bottleneck the process to integrate different unit operations into an end-to-end process. Ultimately, performing lab development and pilot plant design concurrently resulted in an unexpected synergistic benefit.

In conclusion, we designed and constructed a pilot plant for an integrated CM process. We quantified uncertainties during equipment design and made data-driven decisions to drive the project timeline. Executing lab development and pilot plant design concurrently ensured a smooth transition during scale-up, process integration, and tech transfer.