Quality-by-Design (QbD) case study: Powder blending process kinetics evaluation
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abstract
The objective of this project was to develop a Quality-by-Design (QbD) case study for the evaluation of powder blending process kinetics. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipient components (HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable NIR scan of the powder mixture for obtaining the time course of the blending process for each formulation. Previous works demonstrated that NIR spectra of pharmaceutical dosage form are information rich, and may contain physical, chemical, and process information of the formulation components and unit operations. The focus of this work was to develop data analysis and modeling approaches to extract relevant process information, generate process knowledge, and evaluate powder blending process kinetics. Three quantitative approaches were used: (1) Pure component spectra linear superposition method; (2) Characteristic peak method; (3) Moving block standard deviation method. Our study revealed that the blending process experiences three distinct stages: (1) an initial rapid process to reach a quasi- end point within the first a few minutes; (2) demixing; and (3) a real blending end-point as characterized by an inflection point. ANOVA shows that the main components' compositions (Ibuprofen and MCC) are the most statistically significant variables (critical formulation/process variables) that impact the time required to reach the blending end-point. This work as a QbD case study highlighted the critical importance of integration of Design of Experiments (DOE), Near infrared (NIR) process spectroscopy, and chemometrics to extract critical process information and generate essential process knowledge to enable real-time release of the blending process.
