(418a) Overcoming Challenges for Scale-up of Continuous Pharmaceutical Drug Substance Processes

Authors: 
Changi, S. M., University of Michigan
Harrold, D., Eli Lilly & Co.
Moloney, H., Eli Lilly & Co.
Johnson, M., Eli Lilly and Company
May, S. A., Eli Lilly and Company
Braden, T. M., Eli Lilly and Company
Webster, L., Eli Lilly & Co
Calvin, J., Eli Lilly & Co.
Luciani, C., Eli Lilly and Company
The area of continuous technology and reactor design applied to pharmaceutical drug substance processes has advanced significantly over the last decade. Primary drivers of flow versus batch operations are enhanced safety, greater process control, increased productivity, and better operational stability. However, several obstacles need to be overcome prior to successfully scaling-up flow processes from laboratory to manufacturing. Some examples are solid fouling, stability process hold, and mapping feasible operational space for process perturbations. This talk will focus on two case studies related to a: 1) Grignard reaction carried out in a continuous stirred tank reactor (CSTR) and, 2) hydrogenation reaction run in a pipes-in-series plug flow reactor (PFR). The investigated case studies will illustrate methodology and use of experimental tools in conjunction with mathematical models to overcome the above challenges. Specifically, the Grignard case study involved issues with instable process holds and solid fouling issues (affecting downstream performance) that were overcome by mechanistically probing the system with careful experimental design and analytical techniques. On the other hand, mathematical models were used for the hydrogenation case study to demonstrate their power in mapping out the feasible operational space. These efforts enabled scaling up these reactions to successfully run in various pivotal and validation campaigns.