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.

TRIcEPS aims at fulfilling all the requirements of the JTI-CS2-2018-CfP08-FRC-01-21, “Development of integrated engine air intake and protection systems for Tilt Rotor” by designing, manufacturing, testing and qualifying the air intakes and their integrated engine protection system for the NextGenCTR technology demonstrator, contributing to meet the goals of the CS2JU FRC WP1. The proposed engine protection system is geared on two key enabling technologies: • a removable thermoelectric ice protection system based on the heater layer technology. This is already under development on the blade of the NextGenCTR and on the wing of the regional aircraft; • a vortex tubes filter for protecting the engine from ingestion of particles in harsh environment. The air intake will be equipped with a bypass for operation in clean flow and a compressor washing system. The choice of a vortex tubes instead of a barrier filter is key in TRIcEPS. This solution, despite providing 1-to-2% lower particle separation efficiency, allows for: • full self-cleaning capabilities, thus not requiring maintenance (i.e. fit and forget approach); • stable pressure drop in brownout operation, resulting in no need of emergency bypass actuation which would expose the engine to the harsh environment; • significantly reduced icing issues; • easier flight certification path, according to FAA; resulting in the best technical compromise for the NextGenCTR considering its mission profile. Moreover, this choice does not to infringe IPRs on tilt rotor air intake (as per patenting activities by Bell Helicopters on barrier filter), thus securing the position of Leonardo with respect to the future market. TRIcEPS will deliver the air intake, its engine protection system and all the relevant sub-systems at TRL 7, supplying Leonardo with the reference technical solution for engine protection of the NextGenCTR, strengthening the competitiveness of the European rotorcraft industry.

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.

We will establish a technology platform that changes the way we diagnose and treat patients. It involves detecting and producing nano-sized biological particles that act as communication machinery in nature. These particles are called exosomes and with significant investment in the engineering required to accurately capture and profile them, it will be possible to create a new class of diagnostics that can detect disease earlier than is currently possible, based on the release and detection of specific exosomes. It will also be possible to distinguish between different stages of disease, which will help to tailor the right treatment to an individual patient. The diagnostics platform will also form the basis for manufacturing analytics that will enable cell and gene therapies to be carefully monitoring during manufacture. Cell and gene therapies currently cost in the order of £100,000 to £1,000,000 per dose and is related to the fact that bioprocesses (the manufacturing approaches used to create them) are sub-optimal. A radical advance in manufacturing analytics will help to better monitor and control manufacturing, which will lead to improved product consistency and ultimately drive down cost of manufacturing, which will catalyse the routine adoption of cell and gene therapies in the NHS. Finally, by producing exosomes using industrial bioprocesses it will be possible to create new drugs based on exosomes, exploiting their communication machinery to target therapies to sites of disease. This will involve a combination of engineering exosomes to have increased potency, or loading them with powerful drugs and targeting them directly at the diseased tissue. Ultimately, this will radically advance personalised medicine across diagnostics, analytics and drug delivery. In 30 years' time this technology platform will be widely used in healthcare to diagnose and treat disease with high fidelity using bespoke formulations. In order to advance this vision, phase 1 feasibility studies will address engineering challenges in sensor development to detect exosomes at different orders of sensitivity. It will also address the consistent production of exosomes at pilot scale in order to advance the exosome therapeutic platform.

This Centre for Doctoral training in Industrially Focused Mathematical Modelling will train the next generation of applied mathematicians to fill critical roles in industry and academia. Complex industrial problems can often be addressed, understood, and mitigated by applying modern quantitative methods. To effectively and efficiently apply these techniques requires talented mathematicians with well-practised problem-solving skills. They need to have a very strong grasp of the mathematical approaches that might need to be brought to bear, have a breadth of understanding of how to convert complex practical problems into relevant abstract mathematical forms, have knowledge and skills to solve the resulting mathematical problems efficiently and accurately, and have a wide experience of how to communicate and interact in a multidisciplinary environment. This CDT has been designed by academics in close collaboration with industrialists from many different sectors. Our 35 current CDT industrial partners cover the sectors of: consumer products (Sharp), defence (Selex, Thales), communications (BT, Vodafone), energy (Amec, BP, Camlin, Culham, DuPont, GE Energy, Infineum, Schlumberger x2, VerdErg), filtration (Pall Corp), finance (HSBC, Lloyds TSB), food and beverage (Nestle, Mondelez), healthcare (e-therapeutics, Lein Applied Diagnostics, Oxford Instruments, Siemens, Solitonik), manufacturing (Elkem, Saint Gobain), retail (dunnhumby), and software (Amazon, cd-adapco, IBM, NAG, NVIDIA), along with two consultancy companies (PA Consulting, Tessella) and we are in active discussion with other companies to grow our partner base. Our partners have five key roles: (i) they help guide and steer the centre by participating in an Industrial Engagement Committee, (ii) they deliver a substantial elements of the training and provide a broad exposure for the cohorts, (iii) they provide current challenges for our students to tackle for their doctoral research, iv) they give a very wide experience and perspective of possible applications and sectors thereby making the students highly flexible and extremely attractive to employers, and v) they provide significant funding for the CDT activities. Each cohort will learn how to apply appropriate mathematical techniques to a wide range of industrial problems in a highly interactive environment. In year one, the students will be trained in mathematical skills spanning continuum and discrete modelling, and scientific computing, closely integrated with practical applications and problem solving. The experience of addressing industrial problems and understanding their context will be further enhanced by periods where our partners will deliver a broad range of relevant material. Students will undertake two industrially focused mini-projects, one from an academic perspective and the other immersed in a partner organisation. Each student will then embark on their doctoral research project which will allow them to hone their skills and techniques while tackling a practical industrial challenge. The resulting doctoral students will be highly sought after; by industry for their flexible and quantitative abilities that will help them gain a competitive edge, and by universities to allow cutting-edge mathematical research to be motivated by practical problems and be readily exploitable.