(33c) Scale-Dependency Assessment Strategy to Translate Proven Acceptable Ranges from Small to Commercial Scale

Regulators have raised concerns about the applicability of proven acceptable ranges (PARs) developed on small scale to commercial manufacturing processes. These concerns are forged out of potentially detrimental impact of scale on the desired attributes of the drug substance or product. Requests have been made to verify PARs with data generated at commercial scale. It is not always feasible to manufacture large scale batches, therefore alternative strategies are needed.

In this presentation, the criteria for judging scale-(in)dependence of synthetic processes will be discussed. A decision tree will be shared for guiding the scale-dependence evaluation of each process parameter to define whether the PARs can be directly translated from small to large scale or if further work is needed. Finally, specific examples of scale-independent and scale-dependent parameters will be discussed with strategies (e.g. stressing studies, computational modeling) to alter the final categorization. These approaches address regulatory concerns around the applicability of the established PARs on commercial scale and process without compromising the quality standards for the pharmaceutical drug substance and drug product.