Toward Agile, Distributed Pharmaceutical Manufacturing: Continuous End-to-End Integration of Reaction, Purification, and Formulation for Lomustine via the MiniPharm Platform

The COVID-19 pandemic exposed vulnerabilities in pharmaceutical supply chains, emphasizing the need for smaller-scale, domestic manufacturing near raw material sources and healthcare facilities. This study presents the development of modular, continuous, end-to-end manufacturing platforms integrating reaction, distillation, crystallization, and drug product formulation to improve efficiency, reduce equipment footprint, and enhance adaptability. The approach was demonstrated through a case study on a high-potency oncology drug, Lomustine, showcasing the potential of a novel miniaturized pharmaceutical manufacturing system (MiniPharm platform) for intensified, distributed pharmaceutical production. This research aimed to offer a cost-effective alternative manufacturing process to enhance patient access and demonstrated the potential of modular manufacturing platforms to deliver lower-cost, high-quality oncology drugs. Lomustine was successfully synthesized and purified through a telescoped process that included two reaction steps, a continuous solvent-switch distillation (CSSD) and a combined cooling and antisolvent crystallization. The successful integration of upstream crystallization and drop-on-demand capsule printing was achieved. The modular end-to-end manufacturing platform was shown to produce an active pharmaceutical ingredient (API) sufficient to meet the estimated annual demand for Glioblastoma patients in the United States.