Integrated Continuous Drug Substance Manufacturing from Biomass-Derived Building Blocks

The pharmaceutical industry aims to advance its technological capability in process development and manufacturing to improve process efficiency, safety, and product quality. Though research activities in continuous manufacturing have increased significantly in the last decade, process integration, sustainability needs, and reduction of its environmental impact pose challenges to pharmaceutical manufacturing that need to be addressed. Generally, pharmaceutical manufacturing is linked with generating significant wastes and emissions, primarily through its sole dependency on petroleum-derived resources as well as batch-focused/non-integrated manufacturing. To that end, continuous drug substance manufacturing, in which several reaction steps and their inherent purification steps can be telescoped, has the potential to reduce the environmental footprint. This can be further supported using biomass-derived building blocks and bio-based solvents to replace conventional petroleum-based resources.
As part of the 2-h symposium entitled “Drug Substance Continuous Manufacturing” hosted by Dr. Adil Mohammad, examples will be presented, including from a multi-institutional research activity for continuous manufacturing of the antibiotic drug substance Nitrofurantoin from a biomass-derived building block and the use of bio-based solvents. These proof-of-concept processes can deliver drug substances, e.g., Nitrofurantoin, as crystalline material ready for formulation applications in compliance with quality attributes outlined by the U.S. Pharmacopeia (USP). For example, the presented Nitrofurantoin process platform integrates the multi-step continuous synthesis developed by CiTOS (University of Liege) with continuous crystallization developed by CDI (University of Puerto Rico) and MIT. The integrated platform is monitored using process analytical technology for real-time quality control supported by advanced analytics. In the presented case studies, emphasis will be given to the often-neglected vital purification and solid form controlling steps in continuous drug substance manufacturing, continuous crystallization. Ultimately, the presented work contributes to the advancement of the current science by demonstrating reliable process operations with minimal human interventions while addressing the urgent need for sustainable pharmaceutical manufacturing.