(510a) Quality-by-Design (QbD): Integration of Design of Experiments (DOE) and Real-Time PAT Monitoring for Pharmaceutical Powder Blending Process Evaluation

Although pharmaceutical powder blending process as an important unit operation has received significant attention, our understanding to some of the critical issues such as blending homogeneity assessment and blending kinetics evaluation is limited. As highlighted in the FDA's PAT Guidance, significant opportunities exist for real-time process monitoring and control using PAT tools such as Design of Experiments (DOE), Process Analyzers, and Chemometrics. In this work, efforts were made to explore the impact of both formulation variables and process variables on powder blending performance measurement in a high-shear mixer, using Near-Infrared (NIR) real-time process monitoring and design of experiments (DOE) approach. Ibuprofen was used as a model drug. MCC was used as a model excipient. First, a full factorial design was created to examine the effects of blending process variables (high-shear impellor speed and probe insertion depth) on the NIR spectra of pure component MCC in the KG-5 high-shear mixer. Second, a full factorial design was created to examine the effects of both formulation variables (ratio of Ibuprofen and MCC) and process variables (impellor speed and probe insertion depth) on powder blending performance measured via NIR real-time process monitoring. The first DOE study demonstrated the measurement robustness of the real-time NIR process monitoring and provided evidence of the experimental errors expected in this kind of study protocol. The second DOE study demonstrated how formulation variable and process variables impact the powder blending performance evaluation via NIR real-time process monitoring. The knowledge gained through this study could provide scientific justifications for necessary powder blending process control and optimization in high-shear mixer.