Achieving Net Zero requires the rapid development and manufacture of medicines in the UK in ways that are both environmentally and financially sustainable. The vision of Sus-Flow, is to greatly increase the sustainability of the manufacture of active pharmaceutical ingredients (APIs) which is a major contributor to environmental footprints of small molecule pharmaceutical products. We will transform the development and manufacture of future medicines by implementing a strategy specifically designed to maximize the industrial impact of our revolutionary Vortex reactor, which has just won a prize in the 2023 RSC Enabling Technologies Competition. Sus-Flow will create a continuous, flexible reactor methodology, underpinned by computational fluid dynamics modelling, that can increase the sustainability of production for a range of APIs, by delivering single pass photochemistry, electrochemistry, and thermal chemistry and by requiring only a minimum amount of solvent for cleaning. Our methodology will largely eliminate the need to redesign processes, as API production is scaled-up along the medicine pipeline. We will: (i) Embed photochemistry and/or electrochemistry, which is currently not widely employed in manufacture to deliver more selective, higher yielding transformations, thereby reducing the number of steps needed to make an API and decreasing generation of the waste. (ii) Deliver photo- and electro-chemistry with simple reactors that can be deployed in multi-step continuous processes, scalable from milligrams to tonnes, thereby providing a single technology that can be used along the whole of development chain from initial discovery to final manufacture. We will integrate these reactors with process analytics (PAT) because successful flow processes need to be underpinned by robust PAT, which can accelerate process development and ensure the continuing quality of the product. (iii) Apply Life Cycle Assessment to quantify the financial, environmental, and resource utilisation aspects of our Vortex reactor concepts. Through a comparison with conventional batch-based production processes, this will help to identify both the commercial case for vortex reactor deployment, as well as providing a comprehensive, parameter-based understanding of the potential sustainability gains that can be achieved by deploying the technology. Our team is highly interdisciplinary comprising chemists with expertise in organic chemistry, reactor design and innovative process analytics, and engineers with skills in fluid modelling, Life Cycle Assessment and sustainability. Our recent reactor innovations are the starting point of Sus-Flow, exploiting toroidal Taylor vortices to achieve excellent mixing and mass transfer that are reflected in very high space-time yields and highly compact reactors. Using computational fluid dynamics and additive manufacture, we will take this Vortex concept to new levels. To ensure manufacturability and implementation, we are partnering with both major pharma and CROs. Aims and Objectives: To transform the Vortex reactor from a successful academic development into an attractive methodology for manufacturing medicines in an industrial context. Specific objectives will be delivered via five packages. 1. To demonstrate how the Vortex reactor concept can eliminate major bottlenecks to sustainability in manufacture of key APIs. 2. To innovate new capabilities for continuous Vortex reactors. 3. To apply effective PAT to monitor, optimise and control continuous processes in Vortex reactors, both to quantify major products and to monitor low concentrations of unwanted by-products. 4. To optimise reactor performance via Computational Fluid Dynamics. 5. To implement reliable metrics, based on Life Cycle approaches, to identify how Vortex reactors can increase the sustainability of a particular manufacturing route.

The Boeing 777 twin engine jet that entered service in 1995 was the world's first 100% digitally designed aircraft. The computer-aided design was proven to be more accurate than a human engineering team could be and all future planned physical mock-ups were cancelled. Even though this happened decades ago in the airline industry, this has not yet been replicated in the chemical industry, despite the chemicals & pharmaceuticals sector being the 3rd largest manufacturing sector in the UK economy. This is the vision that this project aspires to contribute to: design a chemical plant digitally without the need for physical prototypes. In line with the Industry 4.0 paradigm, this project aims to the development of a "digital twin" platform where in-silico surrogates of chemical processes based on reconfigurable mathematical models are used to quickly explore alternative and innovative solutions for the design of new sustainable processes, and for the robust simulation, control and optimisation of chemical processes, to achieve sustainability targets such as net-zero emissions. However, reliable digital twins, suitable for the exploration of a wide range of operating conditions, can be obtained only if the underlying models provide an accurate description of the reaction systems to be used in scale-up models. The identification of suitable digital twin models requires a significant investment in terms of experimental and analytical resources, as well as manpower to develop and rigorously validate predictive models. To make reaction modelling studies cheaper, faster and more industrially applicable, we intend to bring about a sizable step change in both pharmaceuticals and fine chemicals manufacturing by developing a digital twin platform technology, where the benefits of automation, AI and optimal design of experiments algorithms are merged for the quick identification of predictive multifidelity models, including physics-based models and surrogate machine learning (ML) models. The platform will combine a digital twin software, where virtual testing, advanced physics-informed ML and optimal experimental design algorithms are used for fast decision-making, with flexible reactors (Taylor-vortex reactors) that can guarantee efficient mass and heat transfer and adjustable hydrodynamics. The use of Taylor-vortex reactors is motivated by the fact that it is a reactor type with limited adoption in the chemical industry due to the lack of design guidelines and track record, even though it provides a realistic option for manufacturing. Thus, it provides an excellent exemplar to demonstrate the power of digital twin technology in derisking chemical process development and scale-up. Computationally cheap surrogate ML models identified by these algorithms will drive the online design of experiments and real time optimization, allowing to operate the platform without user intervention and enabling the fast generation of informative data sets and the quick identification of kinetics, mass, and heat transfer models with minimum impact on time, human and analytical resources. In order to develop this platform and ensure its direct applicability in the industrial sector, we have as direct collaborators a large pharmaceutical company, GSK, and two large chemical companies, BASF and Johnson & Matthey, to ensure transfer of knowledge and direct impact of the developed platform on chemical and pharmaceutical manufacturing. The team is complemented by Autichem (equipment provider) and Quotient Sciences (drug development and manufacturing accelerator), two SMEs who work with global pharmaceutical companies across the entire medicine development pathway to assist the development of novel manufacturing processes and approaches. Companies will contribute to directing the research and ensuring its outcomes are industrially relevant and eventually exploitable in industrial R&D and in chemical and pharmaceutical process manufacturing.

Medicines are complex products. In addition to the drug (a molecule which causes a pharmacological effect in the body), they also contain a number of other ingredients (excipients). These are added for a variety of reasons (e.g. to ensure stability or to target the drug to a particular part of the body). A very careful assessment is required to prepare a potent and safe medicine. New types of drug molecule are being devised rapidly and have the potential to transform patients' lives. However, there is a long time-lag (10 - 15 years) between the discovery of a new drug and its translation into a medicine. Most of this time is taken up by developing a suitable "formulation" (drug + excipients) and then testing this. There are very significant benefits that would be realised from accelerating the process: this was made clear by the COVID-19 pandemic, in which the rapid development of vaccines led to millions of lives being saved, and is particularly important as society ages and patients live for prolonged periods of time with multiple conditions. The UK traditionally has been a powerhouse for medicines discovery, and the medical technology and pharmaceutical sector is still a vital part of the economy. However, productivity has recently declined, and compared to peer countries the UK has a lack of high-innovation firms. If medicines development can be accelerated in the UK, there will be huge economic and societal benefits, in addition to profound improvements to the lives of individual patients. To realise this ambition, the UK pharmaceutical sector needs highly-trained, doctoral-level, scientists with the skills required to accelerate research programmes in medicines development. The Centre for Doctoral Training (CDT) in Accelerated Medicines Design & Development seeks to meet this user need, by building a cohort of innovators and future leaders. We will do this between two universities and in collaboration with a network of industrial and clinical partners from across the UK pharmaceutical, healthcare and medical technologies sector. Comprehensive science training will enable our students to develop the high-level laboratory and computational skills needed to overcome the major challenges in medicines development. Our alumni will be expert practitioners at integrating lab and digital research, recognised by industry as crucial to accelerate medicines development. Our students will receive extensive transferable skills training, ensuring that they graduate with high-level teamworking, communication, leadership and entrepreneurial skills. We will foster an open and supportive environment in which students can challenge ideas, experiment, and learn from mistakes. Equality, diversity and inclusiveness, sustainability, and responsible innovation will be at the heart of the CDT, and embedded throughout our training. By liaising closely with industry and clinical partners, we will ensure that the research undertaken in the CDT is directly relevant to the most significant current challenges in medicines development. We will further embed interactions with patients to ensure that the products are acceptable to both patients and clinicians. This will allow us to directly contribute to the acceleration of medicines development, and ultimately will deliver major benefits to patients as new products come on to the market. Our graduates will join companies across the pharmaceutical, medical technology and healthcare fields, where they will innovate and drive forward research programmes to accelerate medicines development for a broad range of diseases. They will ensure that new therapies come to market and the health and well-being of individuals across the world is improved. Others will enter academia, training the next generation. Our alumni will seed a future landscape in which medicines are designed and manufactured in a manner which protects our environment, and in which there is equality of opportunity for all.

Advanced economies are confronted with serious challenges that require us to approach problem solving in a completely different way. As the climate emergency deepens and our global population continues to rise, we must all consider several quite taxing philosophical questions, most pressingly we must address our addiction to economic growth, our expectation for longer, healthier lives and our insatiable need to collect more stuff! Societies demand for performance molecules, ranging from pharmaceuticals to fragrances or adhesives to lubricants, is growing year-on-year and the advent of competition in a globalised marketplace is generally forcing the market price downward, cutting margins and reducing the ability for some industry sectors to innovate. Feedstock to Function (F2F) is an exciting opportunity to forge a new philosophy that could underpin the next phase of sustainable growth for the chemicals manufacturing industry in the UK and further afield. An overarching driving force in the development of F2F was the desire to apply the knowledge and learning of Green and Sustainable Chemistry onto some of the biggest challenges that confront chemicals manufacture, from the smallest-scale, to the delivery of efficient and resilient processes that will future proof supply chains for the foreseeable future. Our CDT in resilient chemistry will deliver a sustainable pipeline of performance molecules, by moving towards circularity and resilience in feedstocks, and efficiency in processing and reaction chemistries . F2F will create an Integrated Approach to Sustainable Chemistry, promoting a culture of resilience in terms of materials and matter via industrially defined priorities: I. Sustainable routes to nitrogen containing molecules, avoiding Haber-Bosch fixed precursors: II. Non-petroleum routes to hydrocarbon feedstocks, particularly synthetic naphtha (C8-C30) III. Circular chemistries to manage the impact of phosphorus and other key inorganic materials; and IV. Enhanced circularity for technical materials including metals, catalysts, solvents and salts. F2F represents a multidisciplinary group of 45 academic advisors spanning 7 academic disciplines and two Universities, working together with a growing family of industrial partners who have expressed a common desire to develop Smarter products using Better chemistry to enable Faster processing and Shorter manufacturing routes. F2F will innovate by: 1 fostering a multidisciplinary, cohort-based approach to problem solving; 2 focus on challenge areas identified by our F2F partners such that sub-groups of our cohort can become immersed in research that impacts on industry; 3 embedding aspects of data-driven decision making in the day-to-day design and execution of high-quality research either on paper or indeed in the lab; 4 nurturing a vibrant and supportive community that allows PhD candidates to think 'outside of the box' in a relatively risk-free way; 5 developing 'next generation' synthesis using chemo- and bio-catalytic methods to drive efficiency, selectivity and productivity, underpinned by predictive in-silico methods and valorisation of big data; 6 streamlining the discovery process by enabling technologies: such as energy resilient photo/electrochemical methods, cleaner solvents and renewable materials 7 developing sustainable processes that deliver efficiency and transition to scale-up from g to Kg, applying state-of-the-art manufacturing including 3-D printing, fermentation, multiphase flow, in-line diagnostics to underpin rapid translation into industry; 8 applying robust reaction/process evaluation metrics such that comparative advantages can be quantified, providing evidence for real process decision making. F2F will train PhD graduates with the vision and skills to drive decarbonisation in the UK Chemicals using industries, securing innovation and future growth for this critical manufacturing sector.

Synthesis, the science of making molecules, is central to human wellbeing through its ability to produce new molecules for use as medicines and materials. Every new drug, whether an antibiotic or a cancer treatment, is based on a molecular structure designed and built using the techniques of synthesis. Synthesis is a complex activity, in which bonds between atoms are formed in a carefully choreographed way, and training to a doctoral level is needed to produce scientists with this expertise. Irrespective of the ingenuity of the synthetic chemist, the complexity of synthetic endeavours means that they are often the pinch point in the development of a new product or the advance of new molecular science. In addition, synthesis can no longer rely on intensive use of human, material, and time resources, and creative solutions to ways of making molecules faster, more efficiently, using less energy, and avoiding rare to toxic metals are urgently needed. Recent developments in digital chemistry (eg reaction technology and automation, data collection & analysis, machine learning & artificial intelligence, computation & molecular design, and the use of virtual reality) now make possible a fundamental change in the way molecular targets are identified and synthesis is carried out. The chemical and pharmaceutical discoveries which underpin a major sector of the UK's economy are almost entirely dependent on synthesis, and our industrial partners see an urgent need for a new generation of employees who combine cutting-edge chemical synthesis expertise with the state-of-the-art digital skills that are set to revolutionise the field. We therefore propose a CDT that will train students to carry out world-leading chemical synthesis at the University of Bristol, the UK's top institution for chemistry research (REF2021), with their creativity and productivity being enhanced by an initial 8-month Digital Chemistry (DC) training focus that un-derpins a subsequent 3 1/4 year PhD project. The training will be delivered in the form of a set of modules that embody key aspects of DC such automation, algorithm-driven optimisation, photochemistry, electrochemistry and flow chemistry supported by training in the techniques of machine learning and data analysis. These activities will be applied to current synthetic challenges in two short immersive 'mini-projects' in research labs and will feed into a PhD research project in an area of synthetic chemistry that is underpinned by the application of digital chemistry methods. The focus of the CDT aligns with Bristol's global reputation in chemical synthesis and computation, and in its current investment in digital chemistry as a strategic research direction. Bristol Chemistry has enviable success in spinout companies, and alongside ongoing training in professional development skills we aim to cultivate an entrepreneurial ethos by partnering with local start-up partners to provide immersive workshops, placements, network links and mentorship to nurture future spin-outs by CDT students. We will build on lessons learnt from delivering previous successful CDTs in Chemical Synthesis, and we will continue to develop our recruitment, training & research opportunities in line with best practice for Equity, Diversity & Inclusion, applying more widely lessons from the evolution that has allowed the diversity of our applicant team to be reflected in the ~50/50 M:F and ~25% minority ethnic composition of our management committee. Our evolved CDT will build on our unrivalled depth of experience to train diverse cohorts of creative and entrepreneurial experts in chemical synthesis, skilled in modern aspects of technology & data science. Our graduates will be uniquely prepared as research pioneers in the ever-changing scientific and industrial landscape of the chemical sciences that continue to underpin this country's prosperity.