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Biophysical characterisation of biopharmaceuticals under defined flow fields

Dobson, John Andrew (2017) Biophysical characterisation of biopharmaceuticals under defined flow fields. PhD thesis, University of Leeds.

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Abstract

Flow induced aggregation occurs during the manufacturing process of biopharmaceuticals. An understanding of the effects of extensional flow is required as a means of predicting the response of experimental protein molecules to flow conditions during the down-stream manufacturing operations. Adequate prediction methods allow for elimination of proteins susceptible to flow induced aggregation, reducing development costs. An experimental device is designed and implemented to subject the proteins BSA, β2-microglobulin (β2m), granulocyte colony stimulating factor (G-CSF), and three monoclonal antibodies (mAbs) to a defined and quantified flow field dominated by extensional flow. CFD analysis is used to accurately characterise the flow field throughout the geometry. Through simulation and bespoke post-processing it is possible to determine the magnitude of extensional strain which the fluid is subjected to. The device is then modified to allow for a comparison to be made between the strain and shear which is inherent in any flow device. The work shows that the device induces protein aggregation after exposure to an extensional flow field for 0.36 – 1.8 ms, at concentrations as low as 0.5 mg ml−1. Correlation is drawn between the extent of aggregation and the applied strain rate, as well as protein concentration, structural properties, and sequence of the protein. A method of equating the forces present within the flow to those experienced by a single molecule within the fluid continuum are also presented.

Item Type: Thesis (PhD)
Keywords: Biopharmaceutical, processing, manufacture, aggregation, protein, extensional flow, strain rate, MAb, monoclonal antibody
Academic Units: The University of Leeds > Faculty of Engineering (Leeds) > School of Mechanical Engineering (Leeds) > Institute of Engineering Thermofluids, Surfaces & Interfaces (iETSI) (Leeds)
Identification Number/EthosID: uk.bl.ethos.745540
Depositing User: Dr John A. Dobson
Date Deposited: 29 Jun 2018 11:41
Last Modified: 25 Jul 2018 09:57
URI: http://etheses.whiterose.ac.uk/id/eprint/20779

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