Experimental and CFD physical characterization of animal cell bioreactors: From micro- to production scale

Transfer of mammalian cell culture processes across stirred and aerated bioreactor scales is a delicate task, frequently leading to different conditions across scales. To provide a more rational reasoning behind scale-up of mammalian cell cultures, physical characterization of bioreactors with working volumes of 15 mL, 3 L, 270 L, 5'000 L and 15'000 L was carried out using a combination of computational and experimental methods. Maximum hydrodynamic stress, mixing time and oxygen mass transfer coefficients were experimentally determined for all bioreactor scales. Computational fluid dynamic (CFD) simulations based on Reynolds-averaged Navier-Stokes equation coupled with bubble size population balance equations were used to determine local as well as average hydrodynamic stresses and mass transfer coefficients. Furthermore, mixing times were determined by simulated tracer experiments. All calculations are well in agreement with experimentally measured values, thereby providing a validation of the CFD simulations. This integrated experimental and modeling methodology represents a valuable tool for a Quality-by-Design approach enabling the transfer of mammalian cell cultures in-between reactor scales, even for geometrically different reactors. Additionally, this study provides a rational framework to transfer an operating space developed at small scale to larger scales. (C) 2017 Elsevier B.V. All rights reserved.