A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process

This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1. This includes the development of a novel mechanistic model for the heterogeneous Barbier-type Grignard reaction. After the model was characterized with laboratory-scale batch experiments, its performance was compared with experimental data collected under continuous operating conditions. Under nominal operating conditions, the experimentally measured conversion of morpholine amide varied from 94.3% to 96.7%, a range that was encompassed by the model. With a mechanistic model validated under continuous operating conditions, relationships between the magnesium charging interval and the variability in conversion of morpholine amide 1 to enone 2 were determined to further explore the experimental design space. The remaining unit operations were subsequently characterized, and the models developed for the individual operations were integrated into a flowsheet-level dynamic process model implemented in the gPROMS FormulatedProducts software. The impact of various process disturbances and model uncertainties on the critical quality attributes were then investigated, and critical process parameters, failure modes, and control strategies to address these disturbances were identified. The process was found to be most sensitive to operational disturbances in the supplied reactants: morpholine amide 1 and 2-bromopropene (2-BP). As 1 is manufactured upstream by the process described in Part 1 of this series, in silico analysis of potential process control strategies focused on manipulation of the 2-BP concentration and flow rate into the primary reactor. Overall, this work highlights the benefits of using mathematical modeling to deepen the understanding of pharmaceutical manufacturing processes and enable integrated unit operations in a continuous manufacturing setting.