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-case combined disturbances. One case study highlights the dynamics of flow blockage for a key reagent, N,N′-carbonyldiimidazole (CDI), resulting from line clogging and the relationship between blockage duration and reaction conversion. The blockage was studied in silico, and the model demonstrated that the acceptance criteria for reaction conversion were met even with a flow rate reduction of 40%. The detrimental impact on the product concentration in the downstream process, however, required modification of the final distillation operation. The revised distillation column operation was demonstrated to address this concern and tolerated variable concentrations of morpholine amide while achieving the target water specification (<0.25 wt %). The results of this in silico analysis were verified with a production-scale demonstration of morpholine amide synthesis at a throughput of 12 kg/day to experimentally evaluate the impact of disturbances on the control strategy and overall performance of the system.

• Amgen, Inc

• API
• PAT
• Control

1. API
2. continuous pharmaceutical manufacturing
3. Control
4. flow chemistry
5. pat
6. process control
7. process modeling
8. Process systems engineering
9. Rapid process development
10. Research Article