Atanasova, Gergana Georgieva; (2024) Fluid flow, mixing and suspension in an intermittently rotating cylinder bioreactor for CAR-T cell therapy manufacturing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This doctoral thesis presents a comprehensive investigation of the fluid dynamics within an intermittently rotating cylinder bioreactor for CAR-T cell therapy manufacturing; a personalized cell-based gene therapy, offering a singledose cure for several advanced blood cancers. The primary objective is to optimize the bioreactor's operation in terms of mixing and suspension during the expansion phase to achieve higher product yields. The cylindrical bioreactor, characterized by an intermediate aspect ratio (L/R = 0.5) and a free surface, employs intermittent rotation without conventional mixing equipment (impellers, spargers, or baffles) to facilitate homogenisation of the fluid. This unique agitation method generates transient unstable flows, prone to multiple types of instabilities, the interaction of which can lead the flow to premature transition to turbulence. These flows have not been previously addressed in the literature in the context of bioprocess engineering. The impact of different operating conditions on the fluid dynamics was studied experimentally, using Particle Image Velocimetry, Planar Laser-Induced Fluorescence, Reflective Flakes, and Stained Microcarrier experiments with the aim to optimize the rotation pattern of the bioreactor to enhance mixing and suspension efficiency while minimizing power input requirements. Each individual step of the rotation pattern (start, stop and reversal of rotation) was studied separately, and its implications for mixing and suspension were outlined. A pioneering experimental characterisation of the flow during spin-over (reversal of the rotation) is presented. This fundamental flow behaviour has not been previously documented in the literature in any discipline and analytical solutions for the flow are still not found. The knowledge generated was used to design a new rotation pattern, which demonstrated superior mixing and suspension capabilities compared to the current standard, offering the potential for higher cell culture yields and improved CAR-T cell therapy production.

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