Integration of academic perspective into the scale-up of CHO cell bioprocessing: Manufacturing understanding

This Flexible Interchange Programme (FLIP) application will bring a senior academic (Prof Alan Dickson) from the University of Manchester into the world of Cobra Biologics, a company that manufactures biopharmaceuticals, protein medicines that have revolutionized the treatment of previously untreatable diseases. In their manufacturing processes, Cobra Biologics develop a process at small scale (cultured cells in small volumes - tea cup size) and scale this up 20,000+ times, to a scale that enables the manufacture of sufficient of the required product for commercial success. There are multiple steps of increasing scale and, although standard processes have been developed, and are followed, the nature of the biopharmaceuticals that are likely to be generated in the coming decade means that there will need to be much greater control of the processes used to increase the scale. With the need for greater control comes a need for greater basic knowledge of the processes (i.e. what works well at small-scale does not necessarily work at large-scale), information that can only be collected in limited amounts under the critical timelines of manufacturing. Whilst manufacture of tomorrows biopharmaceuticals would continue in the absence of the basic knowledge, the efficiency of processes, and the certainty of success, will be enhanced by the ability to apply greater rationality to process design and control. Such protein medicines have great potential and can be life-changing but the cost, and increasingly the economic situation, means that success (for patients and UK plc) requires the sector to work towards greater certainty in rapid manufacture. Whilst the FLIP is written in relation to Prof Dickson and Cobra Biologics, interest in certainty of production is shared across the entire industrial base and the outcome of this work will be communicated and have implications for other manufacturers of biopharmaceuticals..
To address these issues, Prof Dickson will work with Cobra Biologics to review historical data on manufacturing scale-up processes for different biopharmaceutical products and processes and define events (in read-outs from the process or the quality of the product) associated with particularly successful or more troublesome examples. From these assessments, experiments will be undertaken to test indicators of process quality in "live" manufacturing processes. The tests will be undertaken at the University of Manchester and Cobra Biologics (with the strengths of each site focused on providing a extensive, comprehensive profiling of the process quality). This technology exchange will give Cobra Biologics access to the expertise of a very strong academic group whilst Prof Dickson will have access to data, and the potential to test indicators of process quality across "real" manufacturing processes, opportunities that would not arise under other circumstances. This is a true exchange of vision across the industrial/academic interface, in which both partners will learn from each other's perspectives, learnings that will be translated to subsequent research projects and commercial activities. Overall, the long-term objective is to generate the means and techniques to ensure that scale-up to manufacturing scale is guided by detailed understanding of the system with benefit in terms of quality and amount of valuable medicines.

This application arises from development (in several BBSRC BRIC projects) of technologies applied to characterization of CHO host cell variants making recombinant proteins. Directly, the project is linked to two BBSRC project grants in which Prof Dickson is PI (13 ERA IB: Investigating NOvel VAluable bio-Therapeutics and Expression systems BB/M001164/1; Combinatorial genome editing to create enhanced biomanufacturing platforms BB/M01701X/1). Within these projects the focus is at cellular/molecular biological level but the output of many of the processes are read-outs of cell status and their ability to make and process biopharmaceuticals of different types requiring different modifications. The analytics of these projects links to the scale-up of processes (e.g. culture environment and genome stability, cellular phenotype and heterogeneity drift, ability to retain post-translational modifications) that merge with the interests of Cobra Biologics to embed appropriate analytical processes into their CMO portfolio of varied products, cell hosts, culture environment and scale-up process. Prof Dickson will work with Cobra Biologics to undertake data mining and meta analysis of historical data to define profiling events with the potential to enhance the predictability of manufacture (and the stages at which these might be most informative). This information will design of the experimental phase, undertaken on "live" processes taken at stages through the Cobra Biologics scale-up to manufacture, with analysis of multiple key parameters. The overall output will be a unique dataset that will test the predictability indicators of bioprocess development generated from historical data. Overall outputs will be identification of (a) processes associated with retention or change to bioprocess quality and (b) processes that might be controlled (e.g. culture environment) or modified (e.g. vector, host cell) to retain predictability between laboratory-scale and manufacture-scale.

Biopharmaceuticals (complex, usually, protein-based medicines) are manufactured using cells in culture as factories to turn simple components of cell metabolism into the genetically-specified biopharmaceuticals required for therapies. The UK has a strong industrial sector working along the pipeline of manufacture, from drug design/discovery to research and development scale production through to scale up for production processes (bioprocessing) that generates kgs of purified product under GMP conditions for treatment of patients.
The work to be undertaken in this FLP application integrates academic insight with the manufacturing experience of a major Contract Manufacturing Organisation (CMO). Working in close alignment with strategic priorities of the CMO, the FLIP exchanger will use historical datasets and hypothesis-driven experimental design to define means to enhance current manufacturing process. In addition, the intention is to illustrate approaches and control events that would build towards the idealized platforms and processes for future manufacture of innovator and biosimilar molecules.
The data and outputs to be derived from this FLP programme will benefit
(1) The biopharmaceuticals industrial sector, in general, and Cobra Biologics, in particular, by providing insight into the manufacturing events that determine the amount and quality of biopharmaceuticals. Consequently, these powerful medicines may be made more efficiently, rapidly and, due to predictability of success, at lower cost investment. Such outcome will strengthen the UK biopharmaceuticals sector.
(2) Whilst revolutionary in the opportunities given for diagnosis and treatment of otherwise intractable medial conditions, the industrial investment towards manufacture of a new product is huge (@£1Bn). Greater certainty and, hence, lower cost of product manufacture will pass on savings to the end user and enable greater access to such life-changing medicines due to lower costs and greater likelihood of costly products being manufactured.
(3) The information gathered from these studies will be disseminated (publications, presentations, case notes) and will enable the academic and industrial sector to build from the findings to generate further enhancement of various stages in the manufacturing process.
(4) There are general impacts for international recognition of the UK manufacturing sector (biopharmaceuticals, specifically, and Industrial Biotechnology in general). The outcome of the FLIP will add to the strong network of research leadership given by the UK sector to economic competitiveness in biopharmaceuticals, encouraging inward investment and securing existing jobs in the face of increased internationalization.
(5) Overall direct benefit to society - by potential for cheaper/better medicines and understanding the role of BBSRC support
The project will involve staff at the University of Manchester (Prof Dickson and, for 12 months of the 24 month project, a research technician) and staff at Cobra Biologics sites in the UK (Keele) and Sweden (Södertälje). The impact for Prof Dickson will be to provide access to data that would not be accessible under other circumstances, data which (within the FLIP collaboration) will allow fundamental understanding of how manufacture can be more controlled and certain. This will lead to publications and further research. The technician will gain direct interaction with commercial activity, great training and the potential to develop his/her career from the experience of working with insight into the industrial and academic worlds. Staff at Cobra Biologics will gain the input of Prof Dickson's experience into the detailed understanding of molecular and cellular events that link to certainty in their manufacture scale-up. In addition, they will gain experience of technologies held at the University of Manchester that have the potential to be incorporated into, and enhance, their standard work programmes.