Advanced manufacturing of biopharmaceuticals
- Examining metabolic demand in high density CHO cell cultures.
- Membrane-based separations for biopharmaceutical purification
- Examining metabolic demands for continuous bioprocessing – omics data
- Development of continuous downstream processing strategies incorporating continuous chromatography
- Comparability studies of biopharmaceuticals produced by fed-batch or perfusion culture
- Cell line development for high cell density culture
High density cell culture systems offer the advantage of production of biopharmaceuticals in compact bioreactors with high volumetric production rates. However, Chinese hamster ovary (CHO) cells must be engineered to achieve maximum performance under the culture condition of choice. Cell line optimization requires a deep understanding of the cell metabolism as well as the development of bioprocess strategies to maximize cell performance. Here, our major interest is to investigate CHO cells during perfusion under different treatments to maximize its metabolic performance, stability and product yield.
Lead investigator | Dr Cristiana Dal’Molin |
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Associate investigator | Dr Esteban Marcellin |
Postdoc | Dr Veronica S Martinez |
PhD Student | Matthias Nöbel |
Industry Partner | Patheon. PI: Shave. |
Membrane-based systems have utility within a number of unit bioprocesses, and in purification offer some advantages over chromatography including overcoming solute diffusion limitations. Membrane chromatography can be used for purification of mAbs and other biomolecules. In membrane chromatography, the ligand, for example Protein A, is covalently attached to a membrane of regenerated cellulose. The pore size of the membranes is larger than those of chromatography beads enabling capture and polishing at much higher flow rates. This project will investigate integration of these technologies into biopharmaceutical manufacturing processes utilising model biopharmaceuticals.
Lead investigator | Associate Professor Linda Lua |
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Associate Investigator | Dr Christopher Howard |
Postdoc | Dr Gary Shooter |
PhD Student | Sathish Nadar |
Industry Partner | GE and Patheon joint project; PIs, O’Meara (GE), Shave (Patheon). |
The increasing demand for recombinant therapeutic proteins highlights the need to constantly improve the efficiency and yield of these biopharmaceutical products from mammalian cells, which is fully achievable only through proper understanding of cellular functioning. Towards this end, the current study exploited a combined metabolomics and in silico modelling approach to gain a deeper insight into the cellular mechanisms of Chinese hamster ovary (CHO) for high density cultures.
The Patheon process for high density cell culture (Patheon XD® Upstream Processing (USP) technology) can result in up to a 25 fold increase in bioreactor output (cell density). The proprietary Patheon XD® USP bioprocess may be further improved, if a systems biology driven understanding of the fermentation process is achieved. Understanding of the byproducts and metabolites produced, that favour high density will be used to generate an optimised bioprocesses.
Lead investigator | Dr Esteban Marcellin Saldana |
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Associate investigator | Dr Cristiana Dal’Molin |
Postdoc | Dr Veronica Martinez Salazar |
Phd Student | Craig Barry |
Industry Partner |
Patheon; PI, Crowley (Patheon)
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This project will develop and evaluate a periodic counter current (PCC) chromatography and straight-through processing (STP) continuous three-step mAb purification process. Process intensification by implementing continuous or semi-continuous downstream processes in mAb production, for example, can contribute to significant cost-savings and improved throughput. Continuous processing also offers the possibility of increased automation of the process. The project will develop these bioprocesses using model proteins, thereby developing a new, innovative bioprocess platform for the large scale production of mAbs.
Lead investigator | Associate Professor Linda Lua |
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Postdoc | Dr Gary Shooter |
PhD Student | Kristina Pleitt |
Industry Partner | Collaborative project with GE and Patheon. |
This project is focussed on upstream bioprocessing and investigates the similarity (identity) of recombinant protein biopharmaceuticals produced in batch culture compared to the same proteins produced in continuous culture. It will involve extensive physico-chemical characterisation using a variety of highly sophisticated analytical techniques. Of specific interest is the extent to which product characteristics can be manipulated using continuous process parameters (i.e. perfusion rate, bleed rate, temperature, pH, and critical media components for quality issues e.g. sugars).12, 13 The project could explore the design envelope for continuous bioprocesses and the potential for these to better meet biosimilar specifications. A successful outcome to this project will be knowledge into the effect of manufacturing process on the molecular identity of the therapeutic protein product, allowing the manufacturer to understand the potential impact of changes to the manufacturing process.
Lead investigator | Dr Christopher Howard |
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Associate Investigator | Dr Benjamin Schulz |
Associate Investigator | Prof Stephen Mahler |
Postdoc | Dr Lucia Zacchi |
PhD Student | Dinora Roche Recinos |
Industry Partner | CSL; PIs, Glover, Sandford and Lee (CSL). |
The Patheon process for high density cell culture (Patheon XD® Upstream Processing (USP) technology) can result in up to a 25 fold increase in bioreactor output (cell density). CHO cell lines can be engineered to deliver maximal performance and productivity. The proprietary Patheon XD® USP bioprocess may be improved for suitability to high density culture, by engineering CHO cell lines with acquired properties that favour high density. In this project, development of a cell line(s) optimised for high density cell culture, utilising CRISPR and other cell line engineering techniques, will be investigated.
Lead investigator | Dr Esteban Marcellin |
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Associate Investigator | Prof Peter Gray |
Associate Investigator | Dr Cristiana Dal’Molin |
Postdoc | Dr Veronica Martinez Salazar |
PhD Student | Michael MacDonald |
Industry Partner | Patheon; PI, Shave (Patheon) |