Critical Analysis of cGMP Large-Scale Expansion Process in Bioreactors of Human Induced Pluripotent Stem Cells in the Framework of Quality by Design
Araceli Rivera-Ordaz, Valeria Peli, Paolo Manzini, Mario Barilani, Lorenza Lazzari
Abstract
Human induced pluripotent stem cells (hiPSCs) are manufactured as advanced therapy medicinal products for tissue replacement applications. With this aim, the feasibility of hiPSC large-scale expansion in existing bioreactor systems under current good manufacturing practices (cGMP) has been tested. Yet, these attempts have lacked a paradigm shift in culture settings and technologies tailored to hiPSCs, which jeopardizes their clinical translation. The best approach for industrial scale-up of high-quality hiPSCs is to design their manufacturing process by following quality-by-design (QbD) principles: a scientific, risk-based framework for process design based on relating product and process attributes to product quality. In this review, we analyzed the hiPSC expansion manufacturing process implementing the QbD approach in the use of bioreactors, stressing the decisive role played by the cell quantity, quality and costs, drawing key QbD concepts directly from the guidelines of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.