(422e) Automated, Data-Rich GMP Manufacture of a Telescoped Process to Produce API at Commercial Scale with Online Analytics

Pfizer’s Flexible API Supply Technologies (FAST) group has spent the past 5 years focused on developing continuous processes, as well as bringing new facilities online to manufacture at scale, for our small molecule portfolio. A modular design approach was taken to de-risk scale-up and utilize the same modular equipment across our global manufacturing facilities. As of early 2024, our internal kilo lab manufacturing facility was approved for GMP use and was utilized to manufacture an active pharmaceutical ingredient (API) very shortly thereafter. This work will describe the development path to scale-up, implementation of new modules, incorporation of on-line and in-line process analytical technologies (PAT), and fully integrated automation through DeltaV to produce an API for our portfolio.

The first process that was transferred for internal kilo lab manufacture consisted of in-line filtration and carbon pre-treatment, two reaction steps, and two continuous extractions and separations. Both reaction steps were continuously monitored via on-line UPLC samples and in-line FTIR, providing a robust data-rich process. All process parameters were controlled and monitored using DeltaV automation software, through which any deviations could be diverted manually, via PAT, or based on process parameters (parametric control).

This process benefitted from being operated continuously for several reasons, some of which include chemically unstable intermediates, short residence times, exothermic reactions, high catalyst utilization, and direct coupling of downstream purifications steps to remove excess reagents that could lead to degradation. To show operational robustness, the campaign was broken into three separate runs to demonstrate multiple start-ups, shutdowns, and steady state periods. Throughout these three runs, 10 kg of isolated crude product were produced, after final purification steps were conducted in batch mode. Additional modules are still being designed and constructed to expand both the depth and breadth of unit operations that can be utilized to produce small molecule intermediates and APIs using continuous processing.