Model-Aided Development for a Continuous Amide Bond Formation in a Drug Substance Manufacturing Process

Mathematical models are valuable tools in development to determine acceptable parameter ranges and control strategies for continuous manufacturing. Some of the benefits of modeling in pharmaceutical development are its ability to reduce material costs and resource needs, while simultaneously increasing process understanding and quality control.

A case study is presented here that demonstrates the use of NMR reaction monitoring (ReactNMR), to gather high-value reaction data in batch mode for kinetic parameter estimation. The model describes the amide bond formation between an aniline and a mixed anhydride. The kinetic model was then employed to describe a continuous process that includes a plug flow reactor (PFR), a delay coil, two mixed-suspension, mixed-product-removal (MSMPR) crystallizers in series, and a filter/dissolution vessel. The resulting model was used to enable risk assessment, test failure modes, and build decision trees for use in the event of a process upset at manufacturing scale.