This proposal bids for £4.5M to both evolve and renew the Loughborough, Nottingham and Keele EPSRC CDT in Regenerative Medicine. The proposal falls within the 'Healthcare Technologies' theme and 'Regenerative Medicine' priority of the EPSRC call. This unique CDT is fully integrated across three leading UK Universities with complementary research profiles and a long track record of successful collaboration delivering fundamental and translational research. Cohorts of students will be trained in the core scientific, transferable, and translational skills needed to work in this emerging healthcare industry. Students will be engaged in strategic and high quality research programmes designed to address the major clinical and industrial challenges in the field. The CDT will deliver the necessary people and enabling technologies for the UK to continue to lead in this emerging worldwide industry.The multidisciplinary nature of Regenerative Medicine is fully captured in our proposal combining engineering, biology and healthcare thereby spanning the remits of the BBSRC and MRC, in addition to meeting EPSRC's priority area.

By 2025 targeted biological medicines, personalised and stratified, will transform the precision of healthcare prescription, improve patient care and quality of life. Novel manufacturing solutions have to be created if this is to happen. This is the unique challenge we shall tackle. The current "one-size-fits-all" approach to drug development is being challenged by the growing ability to target therapies to only those patients most likely to respond well (stratified medicines), and to even create therapies for each individual (personalised medicines). Over the last ten years our understanding of the nature of disease has been transformed by revolutionary advances in genetics and molecular biology. Increasingly, treatment with drugs that are targeted to specific biomarkers, will be given only to patient populations identified as having those biomarkers, using companion diagnostic or genetic screening tests; thus enabling stratified medicine. For some indications, engineered cell and gene therapies are offering the promise of truly personalised medicine, where the therapy itself is derived at least partly from the individual patient. In the future the need will be to supply many more drug products, each targeted to relatively small patient populations. Presently there is a lack of existing technology and infrastructure to do this, and current methods will be unsustainable. These and other emerging advanced therapies will have a critical role in a new era of precision targeted-medicines. All will have to be made economically for healthcare systems under extreme financial pressure. The implications for health and UK society well-being are profound There are already a small number of targeted therapies on the market including Herceptin for breast cancer patients with the HER2 receptor and engineered T-cell therapies for acute lymphoblastic leukaemia. A much greater number of targeted therapies will be developed in the next decade, with some addressing diseases for which there is not currently a cure. To cope, the industry will need to create smarter systems for production and supply to increasingly fragmented markets, and to learn from other sectors. Concepts will need to address specific challenges presented by complex products, of processes and facilities capable of manufacture at smaller scales, and supply chains with the agility to cope with fluctuating demands and high levels of uncertainty. Innovative bioprocessing modes, not currently feasible for large-scale manufacturing, could potentially replace traditional manufacturing routes for stratified medicines, while simultaneously reducing process development time. Pressure to reduce development costs and time, to improve manufacturing efficiency, and to control the costs of supply, will be significant and will likely become the differentiating factor for commercialisation. We will create the technologies, skill-sets and trained personnel needed to enable UK manufacturers to deliver the promise of advanced medical precision and patient screening. The Future Targeted Healthcare Manufacturing Hub and its research and translational spokes will network with industrial users to create and apply the necessary novel methods of process development and manufacture. Hub tools will transform supply chain economics for targeted healthcare, and novel manufacturing, formulation and control technologies for stratified and personalised medicines. The Hub will herald a shift in manufacturing practice, provide the engineering infrastructure needed for sustainable healthcare. The UK economy and Society Wellbeing will gain from enhanced international competitiveness.

The UK government recognises that 'our economy is driven by high levels of skills and creativity' and has prioritised investment in skills as a means to recovery rapidly from the current economic downturn (HM Government: New Industry, New Jobs, 2009). Bioprocessing skills underpin the controlled culture of cells and microorganisms and the design of safe, environmentally friendly and cost-effective bio-manufacturing processes. Such skills are generic and are increasingly being applied in the chemical, pharmaceutical and regenerative medicine sectors. Recent reports, however, highlight specific skills shortages that constrain the UK's capacity to capitalise on opportunities for wealth and job creation in these areas. They emphasise the need for bioprocessing skills related to the application of 'mathematical skills... to biological sciences', in core bioprocess operations such as 'fermentation' and 'downstream processing' and, for many engineering graduates 'inadequate practical experience'. UK companies have reported specific problems in 'finding creative people to work in fermentation and downstream processing' (ABPI: Sustaining the Skills Pipeline, 2005 & 2008) and in finding individuals capable of addressing 'challenges that arise with scaling-up production using biological materials' (Industrial Biotechnology Innovation and Growth Team report: Maximising UK Opportunities from Industrial Biotechnology, 2009). Bioprocessing skills are also scarce internationally. Many UK companies have noted 'the difficulties experienced in recruiting post-graduates and graduates conversant with bioprocessing skills is widespread and is further exaggerated by the pull from overseas (Bioscience Innovation and Growth Team report: Bioscience 2015, 2003 & 2009 update). The EPSRC Industrial Doctorate Centre (IDC) in Bioprocess Engineering Leadership has a successful track record of equipping graduate scientists and engineers with the bioprocessing skills needed by UK industry. It will deliver a 'whole bioprocess' training theme based around fermentation and downstream processing skills which will benefit from access to a superbly equipped £25M bioprocess pilot plant. The programme is designed to accelerate graduates into doctoral research and to build a multidisciplinary research cohort. Many of the advanced bioprocessing modules will be delivered via our MBI Training Programme which benefits from input by some 70 industry experts annually (www.ucl.ac.uk/biochemeng/industry/mbi). Research projects will be carried out in collaboration with many of the leading UK chemical and pharmaceutical companies. The IDC will also play an important role supporting research activities within biotechnology-based small to medium size enterprises (SMEs). The need for the IDC is evidenced by the fact that the vast majority of EngD graduates progress to relevant bioindustry careers upon graduation. This proposal will enable the IDC to train the next generation of bioindustry leaders capable of exploiting rapid progress in the underpinning biological sciences. Advances in Synthetic Biology in particular now enable the rational design of biological systems to utilise sustainable sources of raw materials and for improved manufacturing efficiency. These will lead to benefits in the production of chemicals and biofuels, in the synthesis of chemical and biological pharmaceuticals and in the culture of cells for therapy. The next generation of IDC graduates will also possess a better understand of the global context in which UK companies must now operate. This will be achieved by providing each EngD researcher with international placement opportunities and new training pathways either in bioprocess enterprise and innovation or in manufacturing excellence. In this way we will provide the best UK science and engineering graduates with internationally leading research and training opportunities and so contribute to the future success of the UK bioprocess industries.

Vaccines are the most successful public health initiative of the 20th century. They save millions of lives annually, add billions to the global economy and extended life expectancy by an average of 30 years. Even so, the UN estimates that globally 6 million children each year die before their 5th birthday. While vaccines do exist to prevent these deaths, it is limitations in manufacturing capacity, technology, costs and logistics that prevent us for reaching the most vulnerable. The UK is a world leader in vaccine research and has played a significant leadership role in several public health emergencies, most notably the Swine Flu pandemic in 2009 and the recent Ebola outbreak in West Africa. While major investment has been made into early vaccine discovery - this has not been matched in the manufacturing sciences or capacity. Consequently, leading UK scientists are forced to turn overseas to commercialise their products. Therefore, this investment into The Future Vaccine Manufacturing Hub will enable our vision to make the UK the global centre for vaccine discovery, development and manufacture. We will create a vaccine manufacturing hub that brings together a world-class multidisciplinary team with decades of cumulative experience in all aspects of vaccine design and manufacturing research. This Hub will bring academia, industry and policy makers together to propose radical change in vaccine development and manufacturing technologies, such that the outputs are suitable for Low and Middle Income Countries. The vaccine manufacturing challenges faced by the industry are to (i) decrease time to market, (ii) guarantee long lasting supply - especially of older, legacy vaccine, (iii) reduce the risk of failure in moving between different vaccine types, scales of manufacture and locations, (iv) mitigating costs and (v) responding to threats and future epidemics or pandemics. This work is further complicated as there is no generic vaccine type or manufacturing approach suitable for all diseases and scenarios. Therefore this manufacturing Hub will research generic tools and technologies that are widely applicable to a range of existing and future vaccines. The work will focus on two main research themes (A) Tools and Technologies to de-risk scale-up and enable rapid response, and (B) Economic and Operational Tools for uninterrupted, low cost supply of vaccines. The first research theme seeks to create devices that can predict if a vaccine can be scaled-up for commercial manufacture before committing resources for development. It will include funds to study highly efficient purification systems, to drive costs down and use genetic tools to increase vaccine titres. Work in novel thermo-stable formulations will minimise vaccine wastage and ensure that vaccines survive the distribution chain. The second research theme will aim to demystify the economics of vaccine development and distribution and allow the identification of critical cost bottlenecks to drive research priorities. It will also assess the impact of the advances made in the first research theme to ensure that the final cost of the vaccine is suitable for the developing world. The Hub will be a boon for the UK, as this research into generic tools and technologies will be applicable for medical products intended for the UK and ensure that prices remain accessible for the NHS. It will establish the UK as the international centre for end-to-end vaccine research and manufacture. Additionally, vaccines should be considered a national security priority, as diseases do not respect international boundaries, thus this work into capacity building and rapid response is a significant advantage. The impact of this Hub will be felt internationally, as the UK reaffirms its leadership in Global Health and works to ensure that the outputs of this Hub reach the most vulnerable, especially children.

The UK government's support for the Life Sciences Industry Strategy (Bell Report, 2017) recognises the importance of developing new medicines to facilitate UK economic growth. Examples include new antibody therapies for the treatment of cancer, new vaccines to control the spread of infectious diseases and the emergence of cell and gene therapies to cure previously untreatable conditions such as blindness and dementia. Bioprocessing skills underpin the safe, cost-effective and environmentally friendly manufacture of this next generation of complex biological products. They facilitate the rapid translation of life science discoveries into the new medicines that will benefit the patients that need them. Recent reports, however, highlight specific skills shortages that constrain the UK's capacity to capitalise on opportunities for wealth and job creation in these areas. They emphasise the need for 'more individuals trained in advanced manufacturing' and for individuals with bioprocessing skills who can address the 'challenges with scaling-up production using biological materials'. The UCL EPSRC CDT in Bioprocess Engineering Leadership has a successful track record of equipping graduate scientists and engineers with the bioprocessing skills needed by industry. It will deliver a 'whole bioprocess' training theme based around the core fermentation and downstream processing skills underpinning medicines manufacture. The programme is designed to accelerate graduates into doctoral research and to build a multidisciplinary research cohort; this will be enhanced through a partnership with the Synthesis and Solid State Pharmaceutical Centre (SSPC) and the National Institute for Bioprocess Research and Training (NIBRT) in Ireland. Research projects will be carried out in partnership with leading UK and international companies. The continued need for the CDT is evidenced by the fact that 96% of previous graduates have progressed to relevant bioindustry careers and many are now in senior leadership positions. The next generation of molecular or cellular medicines will be increasingly complex and hence difficult to characterise. This means they will be considerably more difficult to manufacture at large scale making it harder to ensure they are not only safe but also cost-effective. This proposal will enable the CDT to train future bioindustry leaders who possess the theoretical knowledge and practical and commercial skills necessary to manufacture this next generation of complex biological medicines. This will be achieved by aligning each researcher with internationally leading research teams and developing individual training and career development programmes. In this way the CDT will contribute to the future success of the UK's bioprocess-using industries.