A Quality-by-Design-Driven Framework for Process Variability Control and Design Space Establishment in Wet Granulation Systems

This study aimed to develop a 100 mg immediate-release (IR) tablet containing dasatinib monohydrate, a tyrosine kinase inhibitor, using a Quality by Design (QbD) framework at laboratory scale. The development strategy focused on systematic identification and control of critical process parameters (CPPs) affecting tablet quality during wet granulation. Preformulation studies were conducted to evaluate key physicochemical properties of the active pharmaceutical ingredient (API), including solubility, particle size distribution, and crystallinity, which may influence dissolution behavior. A risk assessment approach based on preliminary hazard analysis (PHA) and failure mode and effects analysis (FMEA) was applied to identify high-risk process variables. Based on the risk assessment results, chopper speed during wet granulation and compression force during tableting were identified as critical process parameters. These factors were further investigated using a Design of Experiments (DoE) approach based on Define Custom Design (DCD) and response surface methodology (RSM) to evaluate their effects on critical quality attributes (CQAs), including dissolution performance, disintegration time, and tablet friability. Response surface analysis established a design space in which chopper speed ranged from approximately 2300–2500 rpm and compression force ranged from 11 to 13 kN, ensuring consistent tablet quality within the investigated operating range. The optimized process conditions produced tablets that satisfied predefined quality targets. Comparative dissolution studies demonstrated dissolution profiles comparable to the reference product across pH 1.2, 4.0, and 6.8 media, with similarity factor (f2) values ranging from 51.18 to 85.23. The experimentally established design space demonstrated reproducible in vitro performance and physicochemical stability under accelerated storage conditions. Overall, this study demonstrates the practical application of a QbD-based development strategy integrating risk assessment and response surface optimization to improve process understanding and manufacturing robustness in wet granulation-based tablet production.