Model-Guided Design Space Development for a Drug Substance Manufacturing Process

This case study outlines an application of quality by design principles to a drug substance manufacturing process. A hybrid process chemistry model consisting of mechanistic and empirical components was developed to guide the selection and verification of a design space. A multistaged experimental plan was employed to address specific goals at each stage of model development and design space selection. In addition to the multivariate evaluation of process parameters, accounting for the quality attributes of input materials was shown to be an important consideration when choosing a design space. The merits of a model-guided approach to selecting an invariant, experimentally verified design space (as opposed to a fully model-defined dynamic design space) are discussed.