(407d) Regulatory Case Studies on in-Process Controls and Scale up of Pharmaceutical Powder Blending

Powder blending is a critical unit operation in the manufacture of solid dosage forms. The uniformity of final blend has a direct impact on the unit dose uniformity of the finished drug product. Since blending is a complex operation that involves a large parametric space including processing parameters (i.e., blender RPM, fill level, loading order, and blending duration), equipment design, and material attributes, assessing powder blending uniformity (BU) is critical to ensure delivering the intended dose of the drug to the patient consistently. In-process testing of powder blends to demonstrate “adequacy of mixing” is a CGMP requirement (21 CFR 211.110). Since the withdrawal of FDA’s draft guidance document for industry “Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment” in 2013, various approaches have been developed to assess blend and/or dosage unit uniformity and submitted to the FDA in NDAs and ANDAs by applicants.

In this presentation, we will provide case studies on in-process controls (IPCs) of blending uniformity and content uniformity (BU/CU) as well as FDA’s assessment on the IPCs as an integral part of the overall control strategy of the drug product manufacturing process. Our focus will be on how our assessment the proposed IPCs is linked to the critical quality attributes (CQAs) of the finished drug product. Additionally, considering the recent publication of ICH Q12, we will also discuss how ICH Q12 will affect our assessment of process parameters and IPC testing, especially with regards to applicant’s overall control strategies on scale-up for commercial production. By analyzing these cases, we wish to shed some light on FDA assessors’ current thinking on these important topics.