(642e) Process Design and Development of a Small Scale Hybrid Manufacturing System for the Cancer Drug Lomustine

Each year, various low volume, high value medications are reported on drug shortage lists with no generic alternative. Here at Purdue University, a small-scale integrated, modular, reconfigurable platform was developed in order to meet the market demand for these drugs. The compound of interest selected for the case study was Lomustine; first produced in 1976, Lomustine is an anti-cancer drug for treating brain tumors and Hodgkin’s lymphoma[1]. In 2014, manufacturing rights changed ownership and Lomustine began to be produced under the brand name of Gleostine. Production of generics is not typically newsworthy; however, over the last few years, the price of the medication increased from $50 to $768 per capsule[2]. The current cost of the drug may prevent patient access to the medication even if it could positively impact their health, highlighting the need of an alternative process for production to lower overall costs.

This presentation details the framework for the design and development of a small-scale end-to-end process for continuous manufacturing of Lomustine at a fraction of the current dosage costs. In order to achieve the successful design and development of the Lomustine process, researchers implemented a novel flow synthesis pathway for Lomustine, which was first developed by researchers Jaman et al. at Purdue University[3] within the process. The synthesis consists of two continuous reaction steps, which eliminates the need to handle the Lomustine intermediate, 1-(2-chloroethyl)-3-cyclohexylurea; inherently improving process safety by decreasing intermediate handling and exposure. Additionally, solvent screening, solubility studies, and impurity mapping for the process are reported along with individual unit operation design and construction. Finally, flow synthesis integration with continuous liquid-liquid extraction and crystallization modules showcase an end-to-end continuous synthesis and purification platform capable of producing the anti-cancer drug Lomustine.

[1] Lee, F. Y.; Workman, P.; Roberts, J. T.; Bleehen, N. M., Clinical pharmacokinetics of oral CCNU (lomustine). Cancer chemotherapy and pharmacology. 1985, 14 (2), 125-131.

[2] Loftus, P. Cancer Drug Price Rises 1,400% With No Generic to Challenge It. The Wall Street Journal [Online], 2017 https://www.wsj.com/articles/cancer-drug-price-rises-1400-with-no-generic-to-challenge-it-1514203201 (accessed Mar 15, 2019).

[3] Jaman, Z.; Sobreira, T. J. P.; Mufti, A.; Ferreira, C. R.; Cooks, R. G.; Thompson, D. H., Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions. Organic Process Research & Development. 2019, 23 (3), 334-341.