(407a) Calibration-Free Approach for End-Point Determination of a Challenging Powder Blending Process: Scientific Case Study

Background: Ensure adequacy of mixing to assure uniformity and homogeneity and assure in-process testing and finished product conforming to specifications has been essential. As such, innovation on in-process monitoring and control of powder blending represents one exciting area for oral solid dosage form development and manufacturing. Over the past 18 years, quantitative calibration modeling approach using Process Analytical Technology (PAT) tools has been well documented in public literatures and regulatory submissions. In contrast, there are much less documents in the public domain regarding development of qualitative calibration-free approach for pharmaceutical applications. In this presentation, we will discuss a case study of integration of Design of Experiments (DOE) and PAT real time process monitoring for pharmaceutical blending end-point determination by calibration-free approach.

Method: Following a Quality-by-Design (QbD) and risk-based approach to illustrate key steps of in-process control strategy establishment for powder blending case study: (a) identification of most influential formulation and process variables by applying multivariate data analysis techniques (such as principal component regression (PCR) to the powder blend characterization data; (b) further narrowing down to the most critical process parameters for in-process monitoring and control development by comparing the multivariate approach and univariate approach for powder segregation tendency modeling; (c) Integration of Design of Experiments (DOE) and Near Infrared (NIR) real time process monitoring for a narrow therapeutic index (NTI) drug powder blending process for process endpoint determination via calibration-free approach, recognizing that all blend quality attributes and process performance matrix are functions of time and will approach steady state values gradually. Two calibration-free approaches, i.e., moving block standard deviation method across the entire wavelength range, and examining the dynamics of specific API characteristic peak over time, are discussed.

Results and discussions: Results from the chemometric modeling in this work suggests that moving window standard deviation (MWSD) method in conjunction with appropriate spectral data preprocessing algorithms, can be an effective means to evaluate the overall progression of the powder blending and blending process dynamics. Significant blending dynamics was observed for batches with large particle size difference between excipients. By monitoring specific NIR peak intensity of the API, it can further improve the method specificity.

Conclusions: This work illustrated the feasibility of using integrated real time PAT monitoring to establish a calibration-free approach for end-point determination of a challenging powder blending process. It covers critical parameter identification via multivariate data analysis techniques, implementation of a real time PAT monitoring for a narrow therapeutic index (NTI) drug powder blending with particle size difference as the main factor, chemo-metrical data analysis and modeling with initial MWSD method and enhanced specific NIR peak method.