Developing Efficient Models to Define Economic and Low Risk High Value Manufacture of Cell Based Products

New treatments for disease are increasingly made from biological materials rather than the chemicals in conventional drugs. The most advanced of these treatments use humans cells as treatments for serious and incurable diseases. Recent successes include dramatic long term remission of previously untreatable blood cancers. However, the manufacturing of such products is highly complex compared to a conventional drug. Products have to be 'grown', sometime over weeks or months, rather than quickly synthesised in a chemical reactor. This creates many challenges for manufacture. In particular there are many opportunities for the manufacturing environment to move outside an acceptable range. This can mean the product grows into the wrong number or type of cells. Further, cells talk to each other through the release of small signalling agents and deplete things from the environment around them. This creates a complex system that evolves over time, and a potentially very expensive system to handle for a manufacturer. Many current manufacturing processes for these new treatments are exceedingly inefficient and high risk due to a poor understanding of these issues.
We propose to create mathematical models of these relationships so that manufacturers can create their products at lower cost and with lower risk of process failure. We propose to use different types of modelling for optimum efficiency. The first will efficiently screen for things that affect the cells being grown. The second is a specific type of modelling that describes a system in terms of the rate of change of its components and is therefore good for modelling systems that evolve with time. These models will help us understand how to control manufacture for maximum efficiency and acceptable risk.
Avoiding process failure is very important because some of these products could be dangerous if the wrong cells are produced. Furthermore if a patient's own cells are being grown to treat them there is no replacement product available if manufacture fails. If we succeed it will help the UK see more ground breaking therapies at market as well as supporting a high value manufacturing industry contributing to UK economic growth.

Cell therapies are poised to revolutionise serious and previously incurable medical conditions (e.g. cancers, macular degeneration, and Parkinson's disease). As such research that enables manufacturing and hence clinical delivery of products at a scale and economy suitable for market demand stands to benefit the clinical community and patient groups that currently have no alternative treatment options. In the case of just one immunopharmacology company (of many) this is projected to translate to 4000 terminally ill patients per year. Yet manufacturing control and variability issues are still cited as one of the main threats to clinical realisation; manufacturing efficiency and control solutions will be critical to enabling successful commercialisation and hence clinical impact.
The proposed research will impact the clinical and patient end users through providing cell therapy product developers and manufacturers with methodologies for optimal and robust manufacturing process design including determination of operationally targeted process models, key process variables, and improved input material specifications. Our proof of principle data indicates a fuller model based understanding of manufacture operation, in particular medium component delivery, could deliver order of magnitude improvements in key process metrics such as volumetric productivity, cell output to input yield, and cell phenotype control. This level of change in productivity is likely to make the difference between commercial viability and therefore clinical reality of some cell based products. It would also generate commensurate value in the novel manufacturing input materials and methods. The impact plan will ensure that these innovations are exploited through careful IP planning, partnering and licencing to ensure the UK economy retains the added value to manufacturing processes. The proposed research will further support product developers/manufactures, and therefore patients/clinic, through facilitating regulatory approval of new products. Medicinal product regulators (i.e. MHRA, EMA, FDA) are essentially looking for evidence that risk of issues with product safety or efficacy have been rigorously defined. An appropriately defined and tested modelling approach could provide a new gold standard for regulatory submission.
A project that is successful in enabling more efficient and robust manufacturing options for new cell based therapeutics this will have direct societal and economic impacts through two routes: via improved population health through increased product availability and from capturing (in the UK) the intellectual property associated with the methodological expertise and novel design of physical process inputs associated with delivering improved manufacturing processes. Further academic impacts will arise through increased control of cell culture based experimental systems and framing of new hypotheses.