(368cb) Process Intensification for End-to-End Synthesis and Purification of Lomustine

Research Interests: Process Intensification, Continuous Manufacturing

The importance of continuous manufacturing and digital modeling in pharmaceutical processes is growing, driven by their ability to reduce equipment footprint and processing time, while increasing throughput (Grover et al., 2023.; Sundarkumar et al., 2023). The degeneration of the pharmaceutical manufacturing supply chain during the COVID-19 pandemic highlighted the need for smaller-scale, domestic pharmaceutical manufacturing near raw material sources and hospitals (Sharma et al., 2020). Advancements in small-scale platform development have allowed for the integration of various unit operations like reaction, extraction, and crystallization, offering improved efficiency, safety, scalability, and adaptability to the pharmaceutical industry in the form of end-to-end manufacturing (Nagy et al., 2021). The integration of small-scale, distributed, continuous manufacturing platforms with digital simulations can further help advance pharmaceutical manufacturing while ensuring the quality and availability of essential medications (Casas-Orozco et al., 2023).

This work focuses on small-scale modular pharmaceutical manufacturing for anti-cancer drugs integrated with digital modeling. This small-scale modular setup, called mini-pharm, is useful due to its modularity, transferability, and robust operation. The individual modules can be used for the implementation of design of experiments (DoE), design space exploration, digital process design and model validation. The development and implementation of the mini-pharm end-to-end manufacturing platform were demonstrated on the high-value, low-demand oncology drug, Lomustine. Lomustine, an orphan drug affected by monopoly induced price gauging, was successfully manufactured in the mini-pharm platform, and the manufacturing process underwent process intensification in combination with digital simulations. Two-step synthesis was used for Lomustine production (Jaman et al., 2019). The reactions were followed by a continuous solvent switch distillation (CSSD) to introduce the antisolvent and evaporate the reaction solvent. Batch reaction experiments in combination with process analytical technology (PAT) tools were conducted following a systematic DoE for dynamic concentration data. Using the PAT data, reaction parameters were estimated. The effect of changing the feed ratio on separation performance was tested during CSSD experiments. Gas chromatography-mass spectrometer (GCMS) was used to analyze the distillate and bottom samples. Lomustine was purified via continuous combined cooling and antisolvent crystallization and a novel drug product formation module was utilized.

The end-to-end continuous manufacturing of Lomustine was successfully modeled using the object-oriented Python library, PharmaPy (Casas-Orozco et al., 2021). The study demonstrates the feasibility and benefits of small-scale modular pharmaceutical manufacturing for orphan drugs, such as Lomustine, showcasing end-to-end continuous manufacturing improvements applicable even for hazardous molecules like oncology drugs. Overall, this research contributes to advancing pharmaceutical manufacturing methodologies, providing insights into digital modeling's role in enhancing process efficiency, safety, and scalability.