(653g) Model-Based Application for a Safe Scale-up and Equipment Selection on a Pressure Generating Pharmaceutical Process

Drug substance process scale-up always requires great focus from our company engineers, chemists, and safety experts. Whether under continuous or batch approach, the stream of data collected from experiments during laboratory development contains many warnings and triggers for improvement opportunities and prevention of batch failures. This case study focuses on the scale-up of an aromatic nucleophilic substitution reaction carried out under pressurized conditions while releasing a gaseous by-product. Considerable engineering constrains existed in terms of equipment fitting, process safety and a successful reaction endpoint.

Towards getting this done right first time, a model-based approach was developed using Dynochem (Scale-Up Systems) to support the safe scale-up and the quality assurance of the process. The final model integrated liquid-vapor equilibria, gas absorption equilibria, a second order reaction kinetic model and the reaction solvents thermal expansion properties. The model was then used to predict the expected pressure rise when carrying out this reaction in different vessels and batch sizes. Moreover, it was used during the hazard and operability (HazOp) exercise by enabling a sensitivity analysis on the most important operational parameters, which included deviations to material charges, process temperature, and initial system pressure (see figure 1). The in-silico simulations led to an unexpected equipment decision, namely the use of a smaller vessel, and a process temperature reduction. In return, this guaranteed that even during common maloperation scenarios the process was inherently safe.