This proposal will establish a national multidisciplinary centre for research into crystals and powders and the challenges presented by their industrial manufacture, properties and use. Powders, particles, crystals and the molecules they are made of are important in the chemical and pharmaceutical industries as intermediate stages and final products in the manufacture of a range of materials from drugs to inks and pigments to paints to computer screens. Crucially, the structure and properties of crystals, particles and powders control the ease of manufacture, function and performance of the final product and it is therefore important to be able to make these materials reproducibly. Firstly, by understanding the ways in which the molecules, which make up the crystal pack together. Many molecules can adopt several distinct crystal forms by packing together in different ways, which can dramatically affect physical properties despite the fact the same molecule is present. It is vital to control this during crystal formation since the wrong form could for example, affect the amount of drug released by a tablet into the body after it is swallowed. Secondly as the crystal grows its size (micrometres or millimetres), shape, or morphology (flat or round) is critical for some applications especially when many crystal particles come together in a powder and impact on the ease with which the material is subsequently manufactured into a paint or ink for example. These challenges are critical as currently manufacturers struggle with crystal formation and control of their particle and powder properties due to the traditional batch methods they employ. To tackle these problems the Centre aims to revolutionise current processes by researching exciting new continuous methods of crystal formation and particle and powder production applicable to current but importantly also future products such as nanomaterials. In addition the Centre will explore how established methods for molecule synthesis are best integrated with continuous crystallisation processes and how continuously manufactured crystals are isolated, dried and transferred into subsequent formulation and final product manufacturing stages whilst preserving their carefully optimised properties. To maximize these technology changes the Centre must also understand the impact that such a transformation will have on the way companies approach this aspect of their business. This will ensure that the maximum economic potential is effectively exploited. To achieve this the Centre consists of a multidisciplinary team of 14 outstanding researchers from 7 leading Universities covering the country from Glasgow, to Edinburgh, to Cambridge, to Bath. In addition industrial support, interest and input (2 million) will be provided from 3 major pharmaceutical companies and many small technology driven companies within the UK. This provides a combination of academic and industrial expertise ranging from chemistry and chemical engineering to pharmacy and systems management capable of powerfully attacking the issues from many angles. The Centre's aim is to deliver new continuous manufacturing technologies with improved performance in a range of areas. Control of crystal formation and particle and powder properties is critical, however a key goal will also be the development of simpler and faster technologies. Such a combination will permit quicker product development and cheaper, cleaner and greener manufacturing processes. The Centre will deliver these technologies to the UK chemical and pharmaceutical industry thus maintaining this sector at the international forefront of product development and manufacture with obvious national economic benefits in terms of jobs and income. National and international benefits will also arise through better and new medicines and improved and new consumer products, which will assist the global community.

The overall aim is to improve the management of patients with Gaucher disease - a genetic disorder with very variable manifestations, but which causes disabling disease especially in the bones of the skeleton and affects the brain. Advances in biotechnology have introduced specific treatments: there are five licensed therapies manufactured by four companies which work in two distinct ways: formerly bone marrow transplantation (with high mortality) was used. Despite introduction of these high-cost therapies, many patients have persistent symptoms and suffer a long-term risk of bone injury, bone cancer and brain diseases such as Parkinson's. The exact reasons for this are unknown, but there is a clear need for improvement. To achieve our aim, we will bring key practitioners for the treatment of Gaucher disease, who are based in highly specialized national centres, together in a comprehensive research consortium. We will also bring clinical scientists from academic institutions and commercial academic sectors together in the mission to improve the outcomes of treatment by better targeting and timing of therapy, and to build a starting point for the design of specific trials in an effort to improve health outcomes for Gaucher patients. We work closely in the consortium with major industrial partners, who will bring their unique expertise in line with our clinical and laboratory work and the entire project will be partnered with patient advocacy groups and international societies in this field. Much of the specific scientific work of this consortium will be built on a comprehensive database reflecting the disease severity and manifestations of Gaucher disease in the entire national cohort of adults and children who suffer. Medical Researchers and specialized nurses will examine individual patients who have consented ethically to the study and from whom blood and other appropriate samples will be obtained and stored centrally for analysis. The data resource will be fully computerized, which will allow sophisticated analysis of the categories of disease and its behaviour to be aligned to additional information about the genetics of the condition and other variables obtained by laboratory measurement. The patients will be re-examined and clinical information obtained retrospectively about key events in their illness will be entered so that its course before and after various treatments can be described and, ultimately characterized. We are looking to define groups of patients who respond well or less well to specific therapies and whose disease progress can be characterized as 'stormy', 'sizzlers' or 'fizzlers'. We already have a range of treatments that have been authorized for prescription (because this is a rare disease they are 'high cost') and also a range of what are referred to as 'biomarkers' which may well be able to predict responses to treatment or serve as a target for when disease is controlled by therapy and complications are unlikely to occur. In the team of Investigators working alongside the UK clinical centres, there are biologists who will explore the role of these biomarkers in relation to disease behaviour so that the targeting of therapy, the best time to use it can be improved and that disease monitoring will be refined in further trials of innovative drugs. In this way, the groups 'cohorts' of patients stratified according to disease severity and behaviour will serve as an attractive platform for investment in clinical trials by the major biopharmaceutical companies. Technology companies will also be attracted to develop diagnostic kits using the biomarkers we discover to improve prognosis. Although rare, Gaucher disease promises unique insights into little-understood conditions that commonly affect the whole population. Large corporations (eg Sanofi) have been attracted to the field, and the key discoveries of the consortium will engage them strategically for future investment and health development.

This proposal is to establish a Doctoral Training Centre embedded within the EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation. The Centre tackles a core issue in the manufacture of fine chemicals and pharmaceuticals - an important sector for the UK - and has strong support from industry including major companies from the Pharma sector (GSK, AstraZeneca, Novartis). We will enable manufacturers to shift their production processes from traditional batch methods, which can be expensive, inefficient and limited in their control, to continuous methods that offer solutions to each of these issues. The Centre can potentially make a huge impact on the UK's manufacturing efficiency in a £multi-billion sector. Although the EPSRC Centre does have a limited cohort of PhD students at the moment, there is no provision for 2012 onwards. As the largest of the current EPSRC Centres, achieving a critical mass of researchers across the core disciplines is a key goal as we establish a world class research activity. It is also important for our industry partners that the UK can meet their needs for trained people in this area and embed continuous processing in their manufacturing plants. We will establish a unique and tailored training and research programme that meets these needs. The proposed DTC will add an extra dimension to the EPSRC Centre, training 3 cohorts of PhD students with the skills, knowledge and understanding to help meet the challenges of continuous manufacturing. Recruiting 45 students over 3 intakes in 2012/13/14 the DTC will mark a step change in activity in this field. We will attract the very best PGR students and equip them to become future leaders who will be influential in implementing this transformational change. The research will contribute to opportunites for new products that can be brought more quickly to market, using more reliable, energy-efficient and profitable manufacturing routes. The Centre involves a multidisciplinary team across 7 universities who will contribute to the DTC including expertise in pharmaceutical sciences, chemical engineering, chemistry, operations management and manufacturing. Thus, the embedded DTC will provide students with a unique programme of training across disciplines, using a combination of modules and research activities. . Students will register in a host institution and will follow a 1+3 year model. Year 1 will comprise intensive formal training delivered in 10 residential courses across the universities, including transferable skills and group project work, allowing the cohort to gain identity and build team spirit and fellowship. Elective specialist elements will then develop knowledge in preparation for PhD research, along with exploratory cross-disciplinary mini-projects. Assessment of modules and projects will be by a combination of presentations and reports. Years 2-4 will focus on multidisciplinary, co-supervised PhD research projects, allowing the student to work with academics from across the Centre. Further transferable skills training and cohort building activities will include an annual two-week Summer School, and networking opportunities with other cohorts. The proposed DTC has captured the imagination of our industrial collaborators with 5 additional companies having added their support to the creation of this DTC. In addition to substantial cash contributions they are offering training, site visits, project input, mentoring and short-term industrial placements. We will create a national community of highly skilled researchers in continuous manufacturing and crystallisation, building the scale and quality of research to enhance the international reputation of our Centre and make a real difference to the manufacture of high-value products, such as pharmaceuticals. The training of 45 high quality DTC PhD students will make a major contribution towards this goal.