(507e) Applying Dynamic Similarity Principles to a Narrow Therapeutic Index Drug Powder Blending Process Scale-up: Laboratory Case Studies and Relevant Regulatory Experience

Powder blending process scale-up is one of the critical aspects to be evaluated during scientific and regulatory assessment of oral solid dosage form manufacturing. It directly impacts content uniformity (CU), especially for potent drug applications such as narrow therapeutic index (NTI) drug applications and low dose drug applications. Theoretically, geometric, kinetic, and dynamic similarity should be collectively considered during manufacturing process scale up. However, quantitative process scale-up relationships are rarely used to support powder blending processes in new and generic drug applications. In the past few years, certain powder blend process scale-up deficiencies have been identified during the scientific and regulatory reviews of the drug applications. In this work, we report our feasibility evaluation of applying dynamic similarity principles to blending process scale-up for an NTI drug powder. Data were obtained using a laboratory-scale high-shear mixer with PAT real time process monitoring. Two types of dynamic similarity rules, i.e., maintaining either Froude number (Fr) or impeller tip speed, were applied for guiding the model formulation for blending process scale. This presentation will also cover relevant regulatory review experience on powder blending process scale up. This work provides case studies which demonstrate the utility of process engineering scale-up principles in drug development and manufacturing for rational process design space selection and better product quality.