Scaling strategy for cell and gene therapy bioreactors based on turbulent parameters

Abstract So far, power input has been used as the main parameter for bioreactor scale‐up/‐down in upstream process development and manufacturing. The rationale is that maintaining a consistent power input per unit volume should result in comparable mixing times at different scales. However, shear generated from turbulent flow may compromise the integrity of non‐robust cells such as those used during the production of cell and gene therapies, which may lead to low product quality and yield. Of particular interest is the Kolmogorov length parameter that characterizes the smallest turbulent eddies in a mixture. To understand its impact on scale‐up/‐down decisions, the distribution of Kolmogorov length along the trajectory flow of individual particles in bioreactors was estimated in silico with the help of computational fluid dynamics simulations. Specifically, in this study the scalability of iPSC‐derived lymphocyte production and the impact of shear stress across various differentiation stages were investigated. The study used bioreactors of volumes from 0.1 to 10 L, which correspond to the scales most used for parameter optimization. Our findings, which align with in vitro runs, help determine optimal agitation speed and shear stress adjustments for process transfer between scales and bioreactor types, using vertically‐oriented wheel and pitched‐blade impellers. In addition, empirical models specific to the bioreactors used in this study were developed. The provided computational analysis in combination with experimental data supports selection of appropriate bioreactors and operating conditions for various cell and gene therapy process steps.