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.

The UK holds a leading position in the global life sciences scene. In this sector, biopharmaceuticals play a dominant role with almost £81bn in annual turnover (Life Sciences Competitiveness Indicators 2020, published: February 2021). Through the Life Sciences Vision 2021, the government is highlighting manufacturing innovation and ramp up as the UK's central aims. For the first time, Transition to Net Zero s brought at the centre of Life Sciences targets. For the UK to remain at the forefront of biopharmaceutical manufacturing, the Government is also encouraging digital innovation leading to time-/cost- efficient processes (Made Smarter, Review 2017). The crucial, positive health impact of (bio-) pharmaceutical processes may outweigh the environmental footprint of the sector that works with considerably lower volumes compared to other industries. Cumulatively, however, this remains to be an imminent challenge. Making those processes environmentally and economically sustainable is a complex task, involving conflicting objectives. For example, one would need to decide on the optimal number of separation cycles that meet both the target purity of the drug and create the least possible environmental footprint. Computer modelling tools can be of great help, lending themselves to the design and solution of multifactorial problems for the identification of the most suitable process setup and operating mode. In this respect, the research question this project aims to answer is: "How can we use computer modelling tools to embed environmental and economical sustainability in bioprocesses, while meeting the purity constraints?". In essence, the goal is to employ Engineering thinking and tools for the development of a systematic framework and software platform that will assist: (a) quantification of the impurity content on the downstream separation performance, (b) identification of a feasible and optimal design space, within which process performance is deemed satisfactory with respect to the tracked key performance indicators (KPIs) and (c) design of optimisation and control policies to ensure optimal operation. The novelty of the proposed work lies in two main aspects. Firstly, environmental sustainability KPIs, such as buffer and energy consumption will be considered for the first time systematically in the design of a bioprocess. Secondly, Engineering innovation will be deployed through the development of a computer modelling framework and software platform (i-PREDICT), harnessing the power of different modelling methodologies. In the junction of Engineering, Manufacturing, Digitalisation and Bioprocessing, i-PREDICT will enable bioprocess digitalisation and integration via continuous monitoring. This is one of the first computational attempts realising "Pharma 4.0" through the development and experimental validation of Industry 4.0-aligned frameworks for upstream in-process monitoring, optimisation and control. This work will create a roadmap towards the integration of product quality in the design of the bioprocess. Endorsing process intensification, this project proposes to consider upstream/downstream interplay through the quantification of the impact that impurity propagation in downstream. This novel concept will allow the design of variability-robust separation processes, enabling seamless unit integration and downstream scale-up. The digital and mathematical tools developed here will be validated experimentally, closing the loop from in silico to in vitro. This highly ambitious, multi-disciplinary project will create a step change towards a revolutionary research area of integrated design, optimisation and control in (bio-) pharmaceutical processes.

Chemical separations are critical to almost every aspect of our daily lives, from the energy we use to the medications we take, but consume 10-15% of the total energy used in the world. It has been estimated that highly selective membranes could make these separations 10-times more energy efficient and save 100 million tonnes/year of carbon dioxide emissions and £3.5 billion in energy costs annually (US DoE). More selective separation processes are essential to "maximise the advantages for UK industry from the global shift to clean growth", and will assist the move towards "low carbon technologies and the efficient use of resources" (HM Govt Clean Growth Strategy, 2017). In the healthcare sector there is growing concern over the cost of the latest pharmaceuticals, which are often biologicals, with an unmet need for highly selective separation of product-related impurities such as active from inactive viruses (HM Govt Industrial Strategy 2017). In the water sector, the challenges lie in the removal of ions and small molecules at very low concentrations, so-called micropollutants (Cave Review, 2008). Those developing sustainable approaches to chemicals manufacture require novel separation approaches to remove small amounts of potent inhibitors during feedstock preparation. Manufacturers of high-value products would benefit from higher recovery offered by more selective membranes. In all these instances, higher selectivity separation processes will provide a step-change in productivity, a critical need for the UK economy, as highlighted in the UK Government's Industrial Strategy and by our industrial partners. SynHiSel's vision is to create the high selectivity membranes needed to enable the adoption of a novel generation of emerging high-value/high-efficiency processes. Our ambition is to change the way the global community perceives performance, with a primary focus on improved selectivity and its process benefits - while maintaining gains already made in permeance and longevity.

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.

Live viral vaccines and therapeutics are growing in popularity due to their high specific potency yet their manufacture remains hampered by poor recoveries of viral infectivity following concentration and purification. In particular, practitioners highlight two such difficulties; the poor recovery of infectious virus following sterile filtration and the search for high yielding purification techniques. These related problems derive primarily from viral inactivation by fluid shear and interfacial phenomenon in the membrane modules and chromatography equipment commonly used by industry. We seek to understand the mechanisms of viral inactivation in order to design new processing systems that provide higher recoveries and are simple to use. Experiments will be conducted to characterise the key morphological and functional characteristics of representative enveloped and non-enveloped viruses (using Ad5 and MoMULV) following exposure to well characterised fluid shear typical of of that encountered during sterile filtration and chromatography. Measurement of viral infectivity will be made (TCID50) and electron microscopy, immunogold labelling and real time PCR will be used to assess the influence of shear on the external viral proteins that mediate infectivity. All these analytical techniques are available in the academic partner's laboratory where the general approach has been previously shown valuable for the study of viral inactivation during lyophilisation. The effect of stabilising excipients and rheology modifying agents will be examined . CFD data on shear distributions in commercial filter housings will be obtained to guide these studies. Sterile filtration yields will be assessed for prototype membranes with a range of porosities, morphologies and surface properties in order to assess the influenec of membrane characteristics upon viral inactivation. The distribution of representative nanoparticles on membranes will be studied using fluorescent labelled HSA particles and confocal imaging. As a result, housing designs will be modified to reduce any maldistribution of viruses. Prototype filter assemblies will be similarly probed with fluorescent immuno-labelled viruses and confocal microscopy. From these studies improved sterile filtration equipment and procedures will result. Complete prototype disposable virus manufacturing systems will be fabricated using collections of commercially available units. Typically, cell culture in disposable bioreactors, including Wave, will be linked by adsorptive and size based membrane processing cartridges and the manufacturing performances of these systems will be characterised for the test viruses. The academic partner is familiar with such approaches, having previously adopted similar approaches for the manufacture of antibody based snake antivenoms in a BBSRC sponsored project. The industrial partner is a market leader in filtration and separations and has relevant process separation technologies for exploitation in this area. Limitations in processing capability will be identified using existing systems and new systems designed to provide improved performance. We anticipate that radical improvements will emerge from the re-designed cartridge housings that result from data obtained on the influence of fluid shear on infectivity. We expect too that the understanding of interfacial phenomena together with new materials that are emerging from the laboratories of the industrial partner will enable significantly higher viral recoveries to be achieved.