Scale Dependency Considerations for Process Parameter Range Definition

A key activity for pharmaceutical development is the identification and investigation of scale dependent parameters and operations. Scale dependency can limit the utility of laboratory studies intended to define long-term process parameter targets and ranges, increasing the risk of process failure. The determination of parameter ranges, of great interest to both regulatory agencies and commercial manufacturing organizations, must be done on a scale that is appropriate to the operation being studied so as to minimize the residual risk associated with variable demand during the lifecycle of the product. This presentation shows how robust process parameter ranges for two operations were determined using statistical design of experiments (DoE), but with divergent strategies that reflected the risk of scale to each operation. In the first example, a reaction with low scale up risk was characterized with small-scale DoE, followed by pilot scale confirmation of the resulting predictive model and parameter ranges. In the second example, a highly scale-dependent crystallization and wet-milling operation was characterized by on-scale DoE to provide robust parameter ranges and guidance for migration of the procedure to commercial manufacturing. This presentation will show how technological and experimental approaches are different for the two strategies, but will focus on how scale risk was assessed and the logic behind the characterization decisions.