Efficient synthesis remains a bottleneck in the drug discovery process. Access to novel biologically active molecules to treat diseases continues to be a major bottleneck in the pharmaceutical industry, costing many lives and many £millions per year in healthcare investment and loss in productivity. In 2016, the Pharmaceutical Industry's estimated annual global spend on research and development (R&D) was over $157 billion. At a national level, the pharmaceutical sector accounted for almost half of the UK's 2016 £16.5bn R&D expenditure, with £700 million invested in pre-clinical small molecule synthesis, and 995 pharmaceutical related enterprises (big pharma, SMEs, biotech & CROs) employing around 23,000 personnel in UK R&D. The impact of this sector and its output on the nation's productivity is indisputable and worthy of investment in new approaches and technologies to fuel further innovation and development. With an increasing focus on precision medicine and genetic understanding of disease there will be to a dramatic increase in the number of potent and highly selective molecular targets; identifying genetically informed targets could double success rates in clinical development (Nat. Gen. 2015, 47, 856). However, despite tremendous advances in chemical research, we still cannot prepare all the molecules of potential interest for drug development due to cost constraints and tight commercial timelines. By way of example, Merck quote that 55% of the time, a benchmarked catalytic reaction fails to deliver the desired product; this statistic will be representative across pharma and will apply to many comparable processes. If more than half of the cornerstone reactions we attempt fail, then we face considerable challenges that will demand a radical and innovative a step change in synthesis. Such a paradigm shift in synthesis logic will need to be driven by a new generation of highly skilled academic and industry researchers who can combine innovative chemical synthesis and technological advances with fluency in the current revolution in data-driven science, machine learning methods and artificial intelligence. Synthetic chemists with such a set of skills do not exist anywhere in the world, yet the worldwide demand for individuals with the ability to work across these disciplines is increasing rapidly, and will be uniquely addressed by this proposed CDT. By training the next generation of researchers to tackle problems in synthetic chemistry using digital molecular technologies, we will create a unique, highly skilled research workforce that will address these challenges and place UK academic and industrial sectors at the frontier of molecule building science. The aspiration of next-generation chemical synthesis should be to prepare any molecule of interest without being limited by the synthetic methodologies and preparation technologies we have relied on to date. Synthetic chemists with the necessary set of such skills and exposure to the new technologies, required to innovate beyond the current limitations and deliver the paradigm shift needed to meet future biomedical challenges, are lacking in both academia and industry. To meet these challenges, the University of Cambridge proposes to establish a Centre of Doctoral Training in Automated Chemical Synthesis Enabled by Digital Molecular Technologies to recruit, train and develop the next generation of researchers to innovate and lead chemical synthesis of the future.

Our Hub research is driven by the societal need to produce medicines and materials for modern living through novel manufacturing processes. The enormous value of the industries manufacturing these high value products is estimated to generate £50 billion p.a. in the UK economy. To ensure international competitiveness for this huge UK industry we must urgently create new approaches for the rapid design of these systems, controlling how molecules self-assemble into small crystals, in order to best formulate and deliver these for patient and customer. We must also develop the engineering tools, process operations and control methods to manufacture these products in a resource-efficient way, while delivering the highest quality materials. Changing the way in which these materials are made, from what is called "batch" crystallisation (using large volume tanks) to "continuous" crystallisation (a more dynamic, "flowing" process), gives many advantages, including smaller facilities, more efficient use of expensive ingredients such as solvents, reducing energy requirements, capital investment, working capital, minimising risk and variation and, crucially, improving control over the quality and performance of the particles making them more suitable for formulation into final products. The vision is to quickly and reliably design a process to manufacture a given material into the ideal particle using an efficient continuous process, and ensure its effective delivery to the consumer. This will bring precision medicines and other highly customisable projects to market more quickly. An exemplar is the hubs exciting innovation partnership with Cancer Research UK. Our research will develop robust design procedures for rapid development of new particulate products and innovative processes, integrate crystallisation and formulation to eliminate processing steps and develop reconfiguration strategies for flexible production. This will accelerate innovation towards redistributed manufacturing, more personalisation of products, and manufacturing closer to the patient/customer. We will develop a modular MicroFactory for integrated particle engineering, coupled with a fully integrated, computer-modelling approach to guide the design of processes and materials at molecule, particle and formulation levels. This will help optimise what we call the patient-centric supply chain and provide customisable products. We will make greater use of targeted experimental design, prediction and advanced computer simulation of new formulated materials, to control and optimise the processes to manufacture them. Our talented team of scientists will use the outstanding capabilities in the award winning £34m CMAC National Facility at Strathclyde and across our 6 leading university spokes (Bath, Cambridge, Imperial, Leeds, Loughborough, Sheffield). This builds on existing foundations independently recognised by global industry as 'exemplary collaboration between industry, academia and government which represents the future of pharmaceutical manufacturing and supply chain R&D framework'. Our vision will be translated from research into industry through partnership and co-investment of £31m. This includes 10 of world's largest pharmaceutical companies (eg AstraZeneca, GSK), chemicals and food companies (Syngenta, Croda, Mars) and 19 key technology companies (Siemens, 15 SMEs) Together, with innovation spokes eg Catapult (CPI) we aim to provide the UK with the most advanced, integrated capabilities to deliver continuous manufacture, leading to better materials, better value, more sustainable and flexible processes and better health and well-being for the people of the UK and worldwide. CMAC will create future competitive advantage for the UK in medicines manufacturing and chemicals sector and is strongly supported by industry / government bodies, positioning the UK as the investment location choice for future investments in research and manufacturing.