This two-part work applies Analytical Quality by Design (AQbD) to develop, validate, and implement a method for determining particle shape and size through image analysis using automated optical microscopy in hygroscopic pharmaceutical powder prone to agglomeration. It concludes the five-step AQbD method from Part I by using DoE to explore variable ranges and interactions (step D) and update risk assessments (step E). A two-level full factorial design includes air-dispersion powder parameters, such as injection force (bar), injection time (ms), and water content (%). Results, including particle visual analysis, are presented, establishing optimal powder-dispersion at 4.0 bar and 10 ms. Method validation is also conducted, integrating the White Analytical Chemistry (WAC) approach. Implementation results are discussed, revealing a batch group (Cluster 2) with more hard agglomerates than Cluster 1. These results were used for a retrospective QbD analysis of a legacy drug product, focusing on process yields and dissolution. This is where another novelty of this work lies: the bridging between QbD applied to the product (ICH Q8) and AQbD (ICH Q14). This approach produces comprehensive, interchangeable particle datasets that facilitate interoperability in the pharmaceutical industry. These datasets can be integrated into models to optimize drug products and manufacturing as per QbD principles. The final remarks discuss challenges from both Parts and future prospects for size and shape image analysis, particularly for agglomeration-prone powders. The emphasis is on needing clearer guidelines from pharmacopoeias, ISO, and ICH on developing and validating image analysis methods, plus more investment from academia and industry to advance powder characterization. • Development, validation, and implementation of a quantitative method for analysing agglomeration-prone powder particle size and shape within a pharmaceutical industrial manufacturing context. • Application of automated optical microscopy and image analysis following an Analytical Quality by Design approach aligning with and expanding on the gaps of the recently first-time issued United States (USP) – General Chapter − and European (pH. Eur..) - Chapter 2.9.48. - Pharmacopoeias' analytical guidance. • Establishing a link between retrospective Quality by Design of the product and the Analytical Quality by Design approach, incorporating White Analytical Chemistry principles. • Performing for the first time in the literature of a Design of Experiments to determine optimal analytical conditions for a powder image analysis method, through automated optical microscopy. • Implementing the method to industrial batches of hygroscopic powdered drug substances with agglomeration propensity, demonstrating the practical utility of this approach to further evaluate batch variability in both size and shape quantitative results, using cluster analysis.
Grangeia et al. (Sun,) studied this question.