Real time flux modelling in biopharmaceutical bioprocessing

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci


Biopharmaceuticals, such as herceptin (trastumazab) which is used in breast cancer treatment, have revolutionised the treatment of many serious diseases, such as solid tumours, leukaemias, degenerative illnesses such as Alzheimer's, and other diseases having complex contributors, such as asthma. However, in addition to being the most potent drugs humanity has ever deployed, these are also the most complex. This implies lengthy development cycles, and very high costs for therapy. A course of herceptin treatment costs around £27,000 per patient. This has led to serious concerns over access to, and availability of these potent drugs. In order to make these complex agents, specially developed (genetically altered) microbial or animal cell systems (expression systems) are cultured in fermenters or bioreactors. But our understanding of how the interaction of the genetic alterations we introduce, and the fermenter or bioreactor environment we culture the cells within, impact upon the cell metabolism is quite limited, especially in early development phase. This lack of clear knowledge about cell metabolism is one major cause of the long, costly drug development cycle of these agents. Our approach is to focus cutting edge techniques upon achieving better undertsanding of the behaviour of these expression systems early in the development phase. We plan to use non-invasive monitoring techniques (near and mid infrared spectroscopies) actually in the culture vessels together with a previously non real time metabolic analysis tool (flux balancing) to gain real time understanding of the metabolism of these specialised cells when in culture. This technology would give increased knowledge of cell metabolism early in the process cycle, helping accelerate product development, leading to reduced cost therapeutics reaching patients more speedily. This would contribute to increased health in society in general. It would also provide a competitive advantage to the UK biomanuafturing sector involved in making these drugs. In the very near future, this approach could greatly help the development and deployment of specialised cell based therapies ( e.g. stem cells). This is especially important as these agents are even more complex than biopharmaceuticals, and have tremendous potential to contribute to enhancing the health and welfare of society in the immediate future. Achieving

Technical Summary

Metabolic flux analysis has shown tremendous promise in understanding and manipulating the metabolism of cells in culture ranging from E.coli to cancer cells. However, our ability to use this powerful technique in real time is very limited. This is unfortunate as real time metabolic flux modelling offers prospects such as improved clone selection, accelerated identification of medium and processing conditions, improved scale translation and process control based on better understanding of the direct relationships between cellular characteristics(genome) , processing conditions and cellular metabolism. We wish to investigate how this increased capability for real time metabolic analysis and control can be achieved. The elements of our approach are to build upon a method of developing flux models based on the flux balancing approach, to add to this robust in- situ non-invasive sensor technologies (near and mid infrared probes), and to utilise error minimisation strategies linked to these sensor platforms to reduce error by computing true not apparent error (an approach widely used in other industries outwith biotechnology). These will be deployed to monitor metabolite fluxes in continuous cultures of a major industrial expression system for biopharmaceuticals, Pichia pastoris . Measurements made by the in situ spectroscopic methods(NIR and MIR) ) will be critically evaluated against conventional metabolic analysis in steady state cultures for this expression system. Finally, the predictive capability of the formulated real time steady state flux models will be examined in fed-batch and batch systems in terms of their ability to predict cell metabolism in a real time environment. This platform technology should be generically applicable to most biopharm expression systems, and could be of value in the development of specialised cell based therapeutics in the near future. This study will critically examine the feasibility of our approach.

Planned Impact

Increased useful real time understanding of the metabolism of expression systems early in the development cycle via a platform of sensors, should be of direct interest to the biotechnology research community, since it would represent a signficant new tool for them. This technology could be deployable in specialised aspects of medical research such as development of cell therapeutics and tissue/organ culture also. The outcomes of the work described will be of direct interest to many in industry concerned with manufacture of biopharmaceuticals and cell therapeutics(including several BRIC club members) since the technology has the capacity to shorten development timelines, with signficant economic advantages to both the UK biomanufacturing sector, and to those companies using this approach. There is clear potential for commercialisation, and we would follow BRIC guidelines here. This aspect would be dealt with by R&KES at Strathclyde who have an outstanding record of effective collaboration with industry. In the medium term, the research will contribute to improved health and well-being in the UK and elsewhere through the delivery of cheaper therapeutics reaching the market sooner. Since demand for biopharms and cell based therapies will rise sharply, the research will also contribute to enhancing the UK's competitive position in biomanufacturing thus helping ensure wealth creation and economic prosperity. The research would considerably extend the capabilities of the researcher and the project team due to the synergies arising from its cross disciplinary nature. Since the sensors at the heart of the project are non-invasive, use of chemical reagents for routine analysis should be reduced, minimising environmental impact of these manufacturing processes. We aim to publish our findings in two papers in high impact journals, and to make several conference presentations, including at least two national meetings and one international meeting. We would also seek to present our findings at local seminar series, and to seek opportunities to present at industrial seminar series. We have found the latter route is a very effective dissemination vehicle with potential industry partners such as Eli Lilly, Roche/DSM and GSK. We will also seek to present our findings to research groups and centres in the field of medicine, such as the MRC Centre for Regenerative Medicine in Edinburgh, and other equivalent units and centres, to make sure the potential utility of these techniques are widely appreciated, and this approach is taken up as widely as possible.


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Description Flux measurement in biomanufacturing processes hs been shown to be a powerful tool for reducing costs and improving effciency. But at present, it's slow and expensive and essentially offline. We whowed that using Near Infrared spectroscopy and existing flux models, we could carry out this detailed monitoring of intracellular flux in real time. This is potentially a revolutionary fiding in biomanufacturing, offering cheaper biopharmaceuticals faster.
Exploitation Route Real time flux could be or relevance in Industrial Biotechnology manufacturing chemicals, or in biomedical sector, giving enhanced understanding of physiology and pathology in systems.
Sectors Aerospace, Defence and Marine,Agriculture, Food and Drink,Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

Description Improved techniques used in industrial practice for biopharm
First Year Of Impact 2012
Sector Aerospace, Defence and Marine,Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic