A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI Promoted Amide Bond Formation

This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3. Model calibration for relevant unit operations and development of a dynamic integrated flowsheet-level model in gPROMS FormulatedProducts software allowed an investigation of the impact of process disturbances and model uncertainties on critical quality attributes (CQAs) and identification of critical process disturbances and failure modes to guide the process control strategy. The main CQA for this step was the conversion of Boc-d-leucine monohydrate (≥95%). The model was used to ensure that a state of control would be maintained in the presence of disturbances to target process parameters. The process was found to be robust against the analyzed disturbance scenarios, including worst …