(532e) Impurity Tracking in Integrated Pharmaceutical Batch Processes Subject to Raw Material Variability

In recent years, mechanistic models have been applied to a broad range of applications in pharmaceutical R&D and engineering, improving efficiency through reduced data requirements, facilitating scale-up and tech transfer, and enabling virtual design space exploration. Many pharmaceutical applications of mechanistic models focus on a single unit operation, using a component model for activities such as scale-up. However, in recent years, integrated or system models have been used to describe a series of unit operations or even the end-to-end process. These integrated models allow for a holistic assessment of the effects of upstream unit operations on product attributes and allow a combination of process parameters across multiple steps to be explored. Such system models are typically associated with continuous processes and are constructed through flowsheet modeling. However, using these same methodologies, integrated flowsheet models of batch processes can be constructed, specifying the schedule of each batch step.

In this talk, an integrated system model of a batch pharmaceutical manufacturing process will be presented, including both the drug substance and drug product manufacturing steps. This system model will be used to demonstrate impurity formation in a synthesis step, possible rejection through purification steps, tracking of the impurity through subsequent processing steps and ultimately the presence of the impurity in the drug product. Further, a sensitivity analysis is performed to identify critical process parameters (CPPs) on the critical quality attribute (CQA) of the impurity’s presence in the final product. Visualizations of the design space are presented and analyzed to identify risk mitigation strategies.