(267e) Multi-Step Continuous GMP Production of a Highly Potent Compound

Authors: 
Groh, J. M., Eli Lilly and Company
Johnson, M. D., Eli Lilly and Company
Cole, K. P., Eli Lilly and Company
Campbell, B. M., Eli Lilly and Company
Kallman, N., Eli Lilly and Company
Polster, C. S., Eli Lilly and Company
Mitchell, D., Eli Lilly and Company

The development of a GMP continuous process to synthesize a highly potent compound is disclosed.  A dedicated, inexpensive equipment set run in laboratory fume hoods was utilized on manufacturing scale with in-process monitoring.  This process included four unit operations including a continuous crystallization and filtration.  Two chemical reactions were run plug flow tube reactors.  One of these PFRs was designed to strip off a gas byproduct continuously during reaction and decouple liquid residence time from gas residence time.  Continuous anti-solvent driven crystallization was done using two MSMPRs in series.  Continuous filtration, washing, drying, and re-dissolving eliminated the isolation of a potent intermediate.  Throughput was 4 kg per day in-situ penultimate from the GMP manufacturing plant.  Finally, the robustness of the process and a comparison of lab and commercial scales highlighting the challenges that were encountered will be discussed.