UBC Theses and Dissertations

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UBC Theses and Dissertations

Modeling of controlled-shear affinity filtration using computational fluid dynamics and a novel zonal rate model for membrane chromatography Francis, Patrick


Controlled-shear affinity filtration (CSAF) is a novel integrated bioprocessing technology that positions a rotor directly above an affinity membrane chromatography column to permit protein capture and purification directly from cell culture. The rotor provides a tunable shear stress at the membrane surface that inhibits membrane fouling and cell cake formation allowing for a uniform filtrate flux that maximizes membrane column performance. However, the fundamental hydrodynamics and mass transfer kinetics within the CSAF device are poorly understood and, as a result, the industrial applicability of the technology is limited. A computational fluid dynamic (CFD) model is developed that describes the rotor chamber hydrodynamics of the CSAF device. Once evaluated the model is used to show that a rotor of fixed angle does not provide uniform shear stress at the membrane surface. This results in the need to operate the system at unnecessarily high rotor speeds to reach a required shear stress threshold across the membrane surface, compromising the scale-up of the technology. The CFD model is then used to model design improvements that result in an in silico design of a preparative CSAF device capable of processing industrial feedstocks. To describe mass transfer in stacked-membrane chromatography a novel zonal rate model (ZRM) is presented that improves on existing hold-up volume models. The ZRM radially partitions the membrane stack and external hold-up volumes to better capture non-uniform flow distribution effects. Global fitting of model parameters is first used under non-retention conditions to build and evaluate the appropriate form of the ZRM. Through its careful accounting of transport non-idealities within and external to the membrane stack, the ZRM is then shown to provide, under protein retention conditions, a useful framework for characterizing putative protein binding models, for predicting breakthrough curves and complex elution behavior, and for simulating and scaling separations using membrane chromatography. By elucidating the intrinsic physical processes ongoing in CSAF the mathematical models presented in this thesis represent essential theoretical tools for the further development of the technology; a technology which has the potential to increase productivity and decrease costs in the downstream processing of biopharmaceuticals.

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Attribution-NonCommercial-NoDerivatives 4.0 International