Abstract

ANALYTICAL QUALITY BY DESIGN VERSUS QUALITY BY DESIGN IN CELL AND GENE THERAPIES: REGULATORY IMPLICATIONS ACROSS MAJOR AGENCIES

Robert Falcone*, Nkiruka Umaru, Bozena Michniak-Kohn, Ash Pradhan, Sam Salek

ABSTRACT

Cell and gene therapies (CGTs) raise CMC questions that are not readily addressed by conventional development models. Biological variability is high, manufacturing experience is often limited, potency concepts may change, and process modifications are common. As a result, process knowledge and analytical capability frequently mature together. This narrative review considers the related, but distinct, roles of Quality by Design (QbD) and Analytical Quality by Design (AQbD) in regulatory decisions across the CGT lifecycle. QbD concerns how quality is designed into the product and manufacturing process through the quality target product profile, critical quality attributes, critical process parameters, risk management, and lifecycle controls. AQbD concerns the performance of the procedures used to measure that quality. It includes the analytical target profile, critical method attributes, knowledge of method performance, and management of the analyticalprocedure over time. The distinction matters in CGT development because uncertainty associated with potency, comparability, specifications, and release testing may be as important as, or greater than, uncertainty in the process. Drawing on ICH guidance, peer-reviewed literature, and regulatory perspectives from FDA, EMA, MHRA, Health Canada, and NMPA, this review proposes an integrated framework that separates process uncertainty from measurement uncertainty before bringing both into the regulatory decision. In this context, AQbD is not simply the analytical portion of QbD. It is the basis for deciding whether conclusions drawn from QbD can be supported and maintained as the product, process, and methods evolve.

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