(613b) Applying Feedback Control to Enhance Continuous Processing in Drug Substance Manufacturing

Flow chemistry has become a common solution towards developing and scaling up reactions that are prohibitive to operate in batch manufacturing. Flow chemistry is often the preferred mode of operation for hazardous, energetic reactions that involve unstable intermediates or product streams. Although the aspirational goal of a flow process is to operate at a fixed set of conditions that transcends scale, this is seldom achieved in practice. Variability in stock solution concentrations, drift in continuous processing equipment, and fouling along heat transfer surfaces can result in reaction performance decline from run-to-run or even from start-to-finish within a single run. While reaction performance can be maintained through a combination of frequent, manual sampling and a complex control strategy that includes an excursion plan, a more efficient method that maintains process quality is desired.

Feedback control to monitor and maintain reaction performance has been employed in other chemical industries and is readily applied in drug substance flow processes. For example, real-time reaction monitoring is achieved through Process Analytical Technology (PAT), such as in-line spectroscopy. Automation software, such as LabVIEW and Matlab, can be used to compare the measured process variable to the targeted setpoint and adjust key process parameters as needed through established process control algorithms. As will be shown using a Grignard flow reaction case study, implementing feedback control leads to enhanced process understanding during lab development with line of sight towards operational efficiency at the production scale. The associated controller tuning methodology as well as the practical considerations for implementation in both the laboratory environment and the pilot plant will be discussed and analyzed.