Quality by Design for Bilayer Tablets: Integrating Formulation, Manufacturing, and Process Analytical Technology.

Abstract

Bilayer fixed-dose combination tablets are increasingly used to improve adherence and tailor drug-release profiles, but their development remains challenging because multiple interacting formulation and process variables strongly affect product performance. Quality by Design (QbD) offers a systematic framework to address these challenges, yet its implementation for bilayer tablets and associated analytical methods remains fragmented. In this review we map and critically analyze published applications of QbD to the formulation design, manufacturing process, and testing of bilayer tablets. Using the available literature and regulatory guidance, we summarize the rationale for bilayer formulations, the experimental designs employed, the RA tools used, and the main critical material attributes (CMAs), critical process parameters (CPPs), and critical quality attributes (CQAs) identified. Particular emphasis is placed on the use of design of experiments, process analytical technology, and multivariate data analysis to understand and control mechanical properties, interfacial adhesion, and drug-release behavior, as well as on the current status of analytical QbD for bilayer products. Overall, the evidence shows that QbD has improved control of drug release and interfacial strength and supported the scale-up of bilayer manufacturing, but prior risk analysis, robust control strategies, and Analytical Quality by Design (AQbD)-based dissolution and stability methods are still inconsistently implemented. The concepts and design principles summarized here are expected to support more rational, regulatory-aligned development of bilayer tablets and to guide future QbD applications in this field.