(249a) End-to-End Reconfigurable Process Development for the Cancer Drug Lomustine

Anti-cancer therapeutics represent a specialized portion of the pharmaceutical market. The recipients of these medications are often facing substantial health challenges, but supply chain issues may negatively impact patient access. Our research team at Purdue University a small-scale integrated, modular, reconfigurable platform was designed and constructed as a proof-of-concept platform that can can be used to meet the market demand for Lomustine, an anti-cancer drug first produced in 1976 that is a first line treatment for glioblastoma and a second line agent for Hodgkin’s lymphoma¹. In 2014, a change in manufacturing rights caused the Lomustine price to increase from $50 to $768 per capsule² in subsequent years, which helped to garner attention from the worldwide community. This work details the successful integration of a small-scale end-to-end process for continuous and hybrid (combined continuous-batch) manufacturing process alternatives for Lomustine.

In this work, enhanced Quality by Design (QbD) techniques – including multivariate experiments and process analytical technology (PAT) tools – were used to determine the impact of various process parameters on design space and drug substance critical quality attributes (CQAs)³. Additionally, we eliminated a reagent used in the novel flow synthesis pathway for Lomustine to improve process safety,⁴and carried out the synthesis in low-cost, tubular fluorinated propylene ethylene (FEP) reactors. The work also highlights our upscaled Lomustine synthesis and process intensification with an integrated continuous solvent switch distillation (CSSD) module and flow crystallization module. After discovering that crystallization was not achieved directly from the reaction mixture, we designed the CSSD to operate under vacuum, enabling the continuous evaporation of the reaction solvent, while continuously feeding in the crystallization solvent. Nitrogen-segmented flow crystallization was implemented in a low-cost PTFE, tubular crystallizer to provide for final drug substance isolation. The fully continuous process alternative was of particular interest because it provides enhanced manufacturing safety of this DNA alkylating agent by reducing the handling of Lomustine, as well as its intermediate and associated reagents, prior to the crystallization step. Experimental validation of other selected process alternatives demonstrate the ability of PharmaPy to capture platform dynamics⁵ and the reconfigurability of the manufacturing platform. Both batch and continuous unit operation modes were considered to find an “end-to-end optimal” configuration that does not require fully continuous operation.

Additionally, integration of PAT for process monitoring is incorporated within this study and provides key insight into this rarely studied, Lomustine manufacturing process. Reaction monitoring with Mettler Toledo’s React IR and automated sampling through EasySampler allowed for reaction component monitoring with compounds that are active at the same UV wavelength range. Batch crystallization monitoring was achieved with the use of various PAT tools including: focused beam reflectance measurement (FBRM), UV-Vis spectroscopy, and particle vision and measurement (PVM). The use of various PAT tools helped to define the operating space and determine key parameters for model development⁶.

In summary, this presentation depicts the experimental validation of various manufacturing process alternatives for the anti-cancer drug Lomustine. This work showcases novel approaches in engineering to manufacture a high value compound with low-cost process materials. Enhanced QbD approaches were used to determine operating conditions that result in desired CQAs for isolated Lomustine product. Finally, manufacturing process design and intensification with small-scale modules integrated with PAT tools provided valuable insight into process dynamics and find an “end-to-end optimal” configuration.

References

1. Lee, F. Y.; Workman, P.; Roberts, J. T.; Bleehen, N. M., Clinical pharmacokinetics of oral CCNU (lomustine). Cancer Chemother. and Pharmacol. 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-generi... (accessed Mar 15, 2019).
3. U.S. Food and Drug Administration, Guidance for Industry Q8(R2) Pharmaceutical Development. 2009. https://www.fda.gov/regulatory-information/search-fda-guidance-documents... (accessed Mar 29, 2021).
4. 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. Org. Process Res. & Dev. 2019, 23 (3), 334-341.
5. Casas-Orozco, D.; Laky, D.; Hur, I.; Mackey, J.; Mufti, A.; Wang, V.; Abdi, M.; Feng, X.; Wood, E.; Reklaitis, G. V.; Nagy, Z. In Use of PharmaPy for digital twin construction of a process for the manufacturing of Lomustine, AICHE, 2021.
6. Casas-Orozco, D.; Laky, D.; Mackey, J.; Mufti, A.; Reklaitis, G. V.; Nagy, Z. In Chemometric techniques for the combined calibration/parameter estimation of pharmaceutical drug substance manufacture, AICHE Annual Meeting, 2021.