Therapeutic viruses are a class of biotherapeutic which have enabled new treatments and medical advances in the areas of vaccines, cancer treatment, gene therapy, and more. In the production and purification of these products, the sterile filtration unit operation is known to have poor yields and contribute to the high cost of the final product, significantly hampering the large-scale production of some therapeutic viruses. Thus, this thesis seeks to explore various aspects of process development and fundamental understanding in the sterile filtration of therapeutic viruses. This thesis explores the mechanisms and membrane properties which govern how bacteria are retained during filtration, and applies these insights to improve the sterile filtration recovery of a therapeutic virus through proper membrane selection. To better understand the factors which cause membrane fouling and loss of virus during sterile filtration, the effect of host cell impurities on filtration performance was investigated. This revealed that small amounts of host cell protein are a major factor in both membrane fouling and reduced virus yield, and that there is a synergistic effect between the virus and the host cell protein adsorbing to the membrane surface. Recognizing that conventional polymeric membranes have many limitations, a novel ultrathin, isoporous, microfabricated silicon nitride membrane was tested for suitability as a sterile filter. Finally, the application of nanoparticles as model virus particles in filtration testing was examined, and a process was developed through which nanoparticles could be fused together to create controlled amounts of particle aggregates, similar to how viruses can be prone to aggregation. The work described here will help enable the development of next generation sterile filtration membranes and provides both insights and methodologies for improving sterile filtration performance. / Thesis / Doctor of Philosophy (PhD) / While many people are aware that viruses can be used in medicine as vaccines, there are even more new and developing ways they can be used, such as in fighting cancer or treating previously uncurable diseases. However, testing of and patient access to these new treatments is often limited due to the challenges in producing and purifying enough of the virus. Viruses are highly complex and large relative to other products, and so many of the common methods and manufacturing processes which are standard in the industry need to be significantly adapted or improved to suit the production of viruses. This study investigates one step of the purification process, sterile filtration, and considers how a variety of factors from the materials used to the properties of the virus solution can be optimized to improve performance. With a deeper understanding of the sterile filtration process, recommendations can be made to help improve the production of future virus-based therapies.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27989 |
| Date | January 2022 |
| Creators | Wright, Evan |
| Contributors | Latulippe, David, Chemical Engineering |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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