An Integrated Process Analytical Technology (PAT) Approach for Process Dynamics-Related Measurement Error Evaluation and Process Design Space Development of a Pharmaceutical Powder Blending Bed
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2014 American Chemical Society. In this work, a model pharmaceutical powder blending system consisting of ibuprofen (drug), MCC, and lactose anhydrous was monitored in real-time via inline near-infrared (NIR) spectroscopy for dual purposes: (1) to examine the effects of formulation variables (drug and MCC contents) and a process variable (impeller rotation speed) on powder blending process kinetics via a 33 full factorial design, and (2) to examine the measurement errors associated with the real-time NIR monitoring environment. The NIR probe was in direct contact with the powder bed for process monitoring. Selected powder blend samples were collected at certain prespecified time points for UV analysis. Three consecutive spectra were used to calculate the standard deviation (stdev) of NIR absorbance at each wavelength. A moving window average was applied to establish the evolution of stdev over the course of powder blending. Two distinct process segments were found: an initial period during which the stdev rapidly decreases and a following fluctuation period during which both the mean and the stdev vary with the formulation and process parameters. Analysis of the process thermodynamics indicated that the initial period of rapid decrease was due to rapid decrease of the thermodynamic driving force, i.e., the powder component concentration gradient. Analysis of the moving powder bed dynamics suggested that the subsequent period of relative stability punctuated by minor fluctuation corresponds to the powder beds microstructure fluctuation, i.e., dynamics in compactness, density, and porosity, due to mechanic rotation of the impeller. The analysis was confirmed by ANOVA results. ANOVA shows that the formulation compositions are primary factors dictating how fast the powder system could achieve the macro-homogeneity (often within 1-2 min); both the impeller rotation speed and the formulation composition are the primary factors dictating both the powder blending homogeneity at microlevel and the measurement error associated with real-time dynamic PAT monitoring environment. General Linear Models (GLM) were used to link the critical formulation and process parameters (CPPs) with the derived response variables and to construct a powder blending process design space. For the model powder blending system, it was shown that selection of appropriate impeller rotation speed range is critical to ensure optimal powder blending performance with practically acceptable dynamic noise. Therefore, this work provided an integrated PAT approach and methodology to address practical powder blending challenges from both process engineering and regulatory science perspectives.
