Quality by Design Strategies for Bioequivalent Generic Immediate- and Sustained-Release Tablets: A Practical Development Roadmap

Quality by Design (QbD) provides a science- and risk-based framework for developing generic immediate-release (IR) and sustained-release (SR) tablets. Its practical value, however, depends on translating formulation and process knowledge into evidence supporting bioequivalence (BE), manufacturing robustness, and regulatory decisions. This review presents a practical development roadmap integrating reference listed drug characterization, critical material attributes, critical process parameters, Design of Experiments (DoE), dissolution assessment, BE strategy, design-space justification, and scale-up verification. Its distinctive contribution is an evidence-to-decision framework combining sequential development gates with an evidence hierarchy that distinguishes experimental observations, model-derived inferences, and product-level conclusions. The review compares IR and SR development priorities, including potential Biopharmaceutics Classification System-based biowaivers for eligible IR products and polymer attributes, dissolution kinetics, food effects, and dose-dumping risks for SR formulations. Quantitative case studies illustrate formulation optimization, dissolution modelling, process analytical technology, and commercial-scale assessment, while highlighting the limitations of individual studies in establishing BE or generalized improvements in development efficiency and manufacturing robustness. Artificial intelligence, Bayesian optimization, and continuous manufacturing are critically examined, with emphasis on model validation, independent confirmation, clinically relevant dissolution testing, and representative scale-up evidence. The proposed roadmap supports systematic experimental planning, evidence interpretation, and scientifically justified development and regulatory decisions for generic IR and SR tablets.