(731f) Continuous Active Pharmaceutical Ingredient (API) Manufacturing from Biomass-Derived Building Blocks: An Integrated Process to Enable Sustainable Manufacturing

The pharmaceutical industry aims to advance its technological capability in process development and manufacturing to achieve improved process efficiency, manufacturing safety, product quality, and sustainability. In this regard, research activities in continuous manufacturing, process analytical technologies (PAT), and process modeling have increased significantly in the last decade. However, sustainability in pharmaceutical manufacturing and its environmental impact still poses challenges that need to be addressed. The pharmaceutical manufacturing is frequently linked with the generation of significant wastes, primarily stemming from the extensive use of petroleum-derived chemicals as well as numerous work-up, isolation, and purification processes inherent in batch manufacturing. To that end, continuous manufacturing, in which several reaction steps can be telescoped, has the potential to reduce the number of processing steps needed, thereby improving the overall environmental friendliness of the process. In addition, there is an opportunity to achieve sustainable manufacturing of APIs through the use of biomass-derived building blocks and bio-based solvents, replacing conventional petroleum-based chemicals.

In this work, the multi-institutional project aims to demonstrate the continuous manufacturing of the antibiotic API Nitrofurantoin from a biomass-derived building block and utilizing bio-based solvents, while ensuring compliance with the product quality attributes outlined by the U.S. Pharmacopeia (USP). Specifically, the process integration for the multi-step continuous synthesis developed by CiTOS (University of Liege) and the crystallization process developed by CDI (University of Puerto Rico) and MIT including continuous reactive crystallization is demonstrated on a computer-controlled continuous manufacturing platform. The integrated system is monitored by real-time quality control via PAT supported by advanced analytics where process data is captured in real-time and analyzed for process optimization and control. This work aims to advance the current science by demonstrating reliable process operation with minimal human interventions while addressing the need for sustainable pharmaceutical manufacturing.