The broad theme of the research training addresses the most rapidly developing parts of the bio-centred pharmaceutical and healthcare biotech industry. It meets specific training needs defined by the industry-led bioProcessUK and the Association of British Pharmaceutical Industry. The Centre proposal aligns with the EPSRC Delivery Plan 2008/9 to 2010/11, which notes pharmaceuticals as one of the UK's most dynamic industries. The EPSRC Next-Generation Healthcare theme is to link appropriate engineering and physical science research to the work of healthcare partners for improved translation of research output into clinical products and services. We address this directly. The bio-centred pharmaceutical sector is composed of three parts which the Centre will address:- More selective small molecule drugs produced using biocatalysis integrated with chemistry;- Biopharmaceutical therapeutic proteins and vaccines;- Human cell-based therapies.In each case new bioprocessing challenges are now being posed by the use of extensive molecular engineering to enhance the clinical outcome and the training proposed addresses the new challenges. Though one of the UK's most research intensive industries, pharmaceuticals is under intense strain due to:- Increasing global competition from lower cost countries;- The greater difficulty of bringing through increasingly complex medicines, for many of which the process of production is more difficult; - Pressure by governments to reduce the price paid by easing entry of generic copies and reducing drug reimbursement levels. These developments demand constant innovation and the Industrial Doctorate Training Centre will address the intellectual development and rigorous training of those who will lead on bioprocessing aspects. The activity will be conducted alongside the EPSRC Innovative Manufacturing Research Centre for Bioprocessing which an international review concluded leads the world in its approach to an increasingly important area .

Molecular robotics represents the ultimate in the miniaturisation of machinery. We shall design and make the smallest machines possible and use them to perform tasks. Applications of molecular robotics systems could help reduce demand for materials, accelerate and improve drug discovery, reduce power requirements, facilitate recycling, reduce life-cycle costs and increase miniaturisation. In doing so it will help address the needs of society and contribute to competitiveness and sustainable development objectives, public health, employment, energy, transport and security. Perhaps the best way to appreciate the technological potential of molecular robotics is to recognise that molecular machines lie at the heart of every significant biological process. Over billions of years of evolution Nature has not repeatedly chosen this solution for achieving complex task performance without good reason. When we learn how to build artificial structures that can control and exploit molecular level motion, and interface their effects directly with other molecular-level substructures and the outside world, it will potentially impact on every aspect of functional molecule and materials design. An improved understanding of physics and biology will surely follow.

We are currently living in an obesity epidemic which has huge health consequences for individuals and for the whole of society. Therefore, it is imperative that we investigate how our body regulates fat mass under normal and obese conditions, so that we might provide new avenues to educate or treat people suffering with excess body weight. Most treatments for obesity involve decreasing the amount of food we eat, either through dieting, pharmaceutical drugs or surgery. An alternative would be to increase the amount of energy we expend either by increasing exercise or by changing the balance between the fat we "store away" and the amount we "burn off." Our laboratories have had a long-standing interest in how the brain controls body weight. In particular, we have shown previously that brain cells, which produce a class of messenger called RFamides, can affect body weight quite dramatically. Some RFamides reduce food intake, while others increase energy expenditure, or do both. Recently, we have discovered that selective drugs which act on the receptors for RFamides can reduce body weight in obese mice, when the drugs are administered into the body, rather than into the brain. Very importantly, the drugs do not affect the amount of food the mice eat. Instead, they appear to affect the way fat is handled in the body. This is exciting because currently there are no safe treatments which have this effect. However, we do not know whether this is because the mice make less fat or burn more off. Nor do we know if the drugs have to get into the brain to have their effect, or whether they act directly on other organs, such as the liver or fat depots. To answer these questions, we will examine drugs which have different affinities for different RFamide receptors and measure their action on fat balance. We will breed mice which express special genes in specific cells of the brain. These mice are normally healthy, but we predict that they will become very fat if given a high-fat diet, similar with what is happening to people in the UK today. By using these mice, we will be able to pinpoint exactly where the drugs are having their action. In the future, this will allow us and our collaborators within the pharmaceutical industry to devise new treatments for obesity.

The bioprocess industry manufactures novel macromolecular drugs, proteins, to address a broad range of chronic and debilitating human diseases. The complexity of these protein-based drugs brings them significant potential in terms of potency against disease, but they are also much more labile and challenging to manufacture than traditional chemical drugs. This challenge is continuing to increase rapidly as novel technologies emerge and make their way into new therapies, such as proteins conjugated to chemical drug entities, DNA, RNA or lipids, or fusions of multiple proteins, which increase their potency and targeted delivery in patients. The UK holds a leading position in developing and manufacturing new therapies by virtue of its science base and has unique university capabilities underpinning the sector. Whilst revenues are large, ~£110bn in 2009 on a worldwide basis, there are huge pressures on the industry for change if demands for healthcare cost reduction and waste minimisation are to be met, and populations are to benefit from the most potent drugs becoming available. A sea change in manufacturing will be needed over the next decade if the potential of modern drugs are to make their way through to widespread distribution. Moreover there is a widely accepted skills shortage of individuals with fundamental "blue-skies" thinking capability, yet also with the manufacturing research training needed for the sector. The proposed EPSRC CDT will deliver a national capability for training the next generation of highly skilled future leaders and bioprocess manufacturing researchers for the UK biopharmaceutical sector. They will be capable of translating new scientific advances both in manufacturing technologies and new classes of macromolecular products into safely produced, more selective, therapies for currently intractable conditions at affordable costs. This is seen as essential where the rapid evolution of biopharmaceuticals and their manufacturing will have major implications for future medicine. The CDT will be a national resource linked to the EPSRC Centre for Innovative Manufacturing (CIM) in Emergent Macromolecular Therapies (EP/I033270/1), which aims to tackle new process engineering, product stability, and product analysis challenges that arise when manufacturing complex therapies based on radically new chemistry and molecular biology. The CDT will embed PhD students into the vibrant research community of the top UK Institutions, with collaborations overseen by the EPSRC CIM, to enable exploration of new process engineering, modelling, analysis, formulation and drug delivery techniques, and novel therapies (e.g. fusion proteins, and chemical drugs conjugated to antibodies), as they emerge from the international science and engineering community. Alignment to the EPSRC CIM will ensure projects strategically address key bioprocess manufacturing challenges identified by the industrial user group, while providing a cohort-based training environment that draws on the research excellence of the ESPRC CIM to maximise impact and knowledge transfer from collaborative partners to research led companies.

It is now widely accepted that up to ten years are needed to take a drug from discovery to availability for general healthcare treatment. This means that only a limited time is available where a company is able to recover its very high investment costs in making a drug available via exclusivity in the market and via patents. The next generation drugs will be even more complex and difficult to manufacture. If these are going to be available at affordable costs via commercially viable processes then the speed of drug development has to be increased while ensuring robustness and safety in manufacture. The research in this proposal addresses the challenging transition from bench to large scale where the considerable changes in the way materials are handled can severely affect the properties and ways of manufacture of the drug. The research will combine novel approaches to scale down with automated robotic methods to acquire data at a very early stage of new drug development. Such data will be relatable to production at scale, a major deliverable of this programme. Computer-based bioprocess modelling methods will bring together this data with process design methods to explore rapidly the best options for the manufacture of a new biopharmaceutical. By this means those involved in new drug development will, even at the early discovery stage, be able to define the scale up challenges. The relatively small amounts of precious discovery material needed for such studies means they must be of low cost and that automation of the studies means they will be applicable rapidly to a wide range of drug candidates. Hence even though a substantial number of these candidates may ultimately fail clinical trials it will still be feasible to explore process scale up challenges as safety and efficency studies are proceeding. For those drugs which prove to be effective healthcare treatments it will be possible then to go much faster to full scale operation and hence recoup the high investment costs.As society moves towards posing even greater demands for effective long-term healthcare, such as personalised medicines, these radical solutions are needed to make it possible to provide the new treatments which are going to be increasingly demanding to manufature.