Globally antibiotic treatable infections account for 5.7 million deaths annually where the majority of this mortality burden falls on the populations of least developed low- and middle-income countries (LMICS). This significantly outweighs the 700k deaths, worldwide, currently attributed to antibiotic-resistant infections. However, the increasing threat posed by antimicrobial resistance will further extenuate the disproportionate health burden faced by LMICS. In Africa, deaths attributed to bacterial lower respiratory infections and diarrhoeal diseases together account for nearly 20 percent of all mortality. Strikingly this outnumbers the combined mortality rate of HIV/AIDS, TB and malaria. These headline figures underline the challenge faced by the health care systems in the least developed and lower middle-income countries of Africa. Here, access to frontline antibiotics is hampered by: i) substandard administration and/or unregulated over-the-counter availability, resulting in misuse and overuse; ii) weak supply chains resulting in chronic shortages; and iii) poor quality drugs and falsified medicines from a reliance on imports from generic API drug manufacturers alongside counterfeit drugs. These factors combined lead to unnecessary loss of human life and ever increasing drug resistance. As an example, multiple studies in hospital settings of Klebisella pneumonie isolates (a common urinary tract infection) from Kenya, Tanzania and Nigeria have shown multiple drug resistance (MDR) in 40-75% of cases; worryingly, this number also included samples showing extensive drug resistance. Combined, these studies demonstrate the problem faced across the three partner countries (Kenya, Tanzania, Nigeria), spanning East to West Africa, in accessing effective antibiotic therapies within the constraints of under developed healthcare systems. These nations do not have sustainable access to effective drugs, which we in the UK and the developed world take for granted. This proposal will seek to address this unmet and urgent need partnering with Kenyan, Tanzanian and Nigerian institutes to investigate and apply innovative engineering, novel synthetic biological and chemical solutions toward improving health in Africa, by building capacity in these disciplines and providing sustainable solutions to an efficient and local well-stewarded antibiotic pipeline. This highly integrated project, links experts in industrial synthesis, industrial fermentation, engineering, synthetic biology, drug discovery and medicinal chemistry to build a sustainable antibiotic production pipeline. This will equip our African partners with the capability and capacity not only for equitable production of the most needed antibiotics (categorised by WHO as "access antibiotics") but also addressing our partners' dream for capacity building and training in the discovery of new antibiotics from their own natural resources.

This project aims to deliver the underpinning tools and design principles to support the use of water as a reaction media in High Value Chemical Manufacture. Water has long been promoted as an environmentally friendly and safe 'green' reaction media for synthetic processes which can lead to much more sustainable and cost effective manufacturing process. Nevertheless, the green credential of water has been limited due to issues related to organic contamination of the water waste stream, cost of subsequent treatment and the often required organic solvents at purification stage. Water-accelerated reactions, i.e. reactions which proceed faster in water than in organic solvents and wherein organic reactants and products form hydrophobic droplets, are potential game-changers High Value Chemical Manufacture. They benefit from accelerated rates, improved productivity and much improved green metrics through reduction in the use of organic solvents. Their current limitations are: (i) a limited pool of known reactions; (ii) lack of suitable equipment and process understanding; and (iii) insufficient understanding of acceleration effects which can guide discovery and process design. This project will address these knowledge gaps and deliver the following critical outputs, identified through discussion with our industrial partners in chemical industry sector: (i) a wider range of synthetically useful water-accelerated reactions, (ii) multi-scale batch and flow reactors to support the scale-up pathway for water-accelerated processes, (iii) standardised protocols for characterising such processes and basic process understanding for scaling up, and (iv) streamlined workup/product purification and recycling of water to truly deliver green processes. These outputs will have transformative impacts in the chemical manufacture industry, delivering lower cost and better quality controlled processes through shorter routes, reduced organic waste and facile interfacing between chemo- and biocatalytic processes.

Personalised medicine (PM) is gaining significant attention in recent years as it has the potential to transform healthcare across the globe by moving away from the "one-size-fits-all" model to utilise personal circumstances, medical history and needs to deliver individually suitable treatment. Current bulk manufacturing technologies are unable to meet most of these demands as they are slow in responding to changes, capital intensive, use unsustainable methods and are not flexible to meet PM needs. A recent white paper from the EPSRC funded Redistributed Manufacturing in Healthcare has identified that small-scale, localised, high-speed and automated manufacturing platforms are urgently needed to realise PM. They identified that such "factory-in-a-box" should be: - able to manufacture on-demand, - flexible to deliver multiple products with desired properties, - sustainable (energy efficient and using mild conditions) and - able to integrate various unit operations using data science tools. Given the future needs for PM, recent research efforts have been directed towards redefining the manufacturing of active pharmaceutical ingredient (API) and their formulations into e.g. tablets for oral dosages using advanced methods such as microfluidics, Hot Melt Extrusion or 3D printing. However, as a medicine is a carefully designed formulation of an API with non-active components such as excipients or drug delivery systems (DDS), challenges in manufacturing of the non-active components for PM are also equally important, but have not been addressed. The non-active components improve physicochemical properties and bioavailability of APIs. In its many forms silica is one of the most commonly used component of many current and future API formulations, yet their manufacturing to meet the PM requirements do not exist. Specifically, despite tremendous progress made on the use of silica in pharmaceutical formulations, currently, their on-demand, automated and flexible manufacture to produce silica of desired properties for PM is non-existent. A key reason for this is that the vast majority of promising silicas require synthesis conditions that are prohibitive for any meaningful scale-up and for implementation in a 'factory in a box' platform. Hence, this missing piece, despite the recent developments in manufacturing of API and formulations, creates a significant barrier to making PM a reality. We have shown the potential of bioinspired silica (BIS) as an alternate drug delivery system, which is scalable, economical and sustainable - an ideal candidate for on-demand and flexible manufacturing. This research will rely on a close synergy between computational modelling and experimental synthesis. Green synthesis processes and research on intensified reactors by the applicants will be used as a starting point. A range of intensified reactors and Gaussian Process-based modelling will be used to achieve process intensification of particulate manufacturing processes. Comprehensive models will be used to create digital twins of fluidic devices and recipes of green synthesis of silica particles using those devices. Machine learning approaches based on results of simulations of reactors will be developed to relate quality attributes of silica produced with key process and operating parameters. Device geometry and process parameters will be manipulated to achieve the desired Critical Quality Attributes (CQAs). The work will contribute to revolutionising PM and help deliver table top pharmaceutical manufacturing equipment in hospitals and pharmacies. Ultimately, the impact will include significant improvements in treatments and quality of life as well as the formation of new companies to build such units.

Our vision is to use continuous photochemistry and electrochemistry to transform how fine chemicals, agrochemicals and pharmaceuticals are manufactured in the UK. We aim to minimize the amount of chemicals, solvents and processing steps needed to construct complex molecules. We will achieve this by exploiting light and/or electricity to promote more specific chemical transformations and cleaner processes. By linking continuous photochemistry and electro-chemistry with thermal flow chemistry and environmentally acceptable solvents, we will create a toolkit with the power to transform all aspects of chemical synthesis from initial discovery through to chemical manufacturing of high-value molecules. The objective is to increase efficiency in terms of both atoms and energy, resulting in lower cost, low waste, low solvent footprints and shorter manufacturing routes. Historically photo- and electro-chemistry have been under-utilised in academia and industry because they are perceived to be complicated to use, difficult to scale up and engineer into viable processes despite their obvious environmental, energy and cost benefits. We will combine the strategies and the skills needed to overcome these barriers and will open up new areas of science, and deliver a step-change (i) providing routes to novel molecular architectures, hard to reach or even inaccessible by conventional methodologies, (ii) eliminating many toxic reagents by rendering them unnecessary, (iii) minimizing solvent usage, (iv) promoting new methodologies for synthetic route planning. Our proposal is supported by 21 industrial partners covering a broad range of sectors of the chemistry-using industries who are offering £1.23M in-kind support. Therefore, we will study a broad range of reactions to provide a clear understanding of the most effective areas for applying our techniques; we will evaluate strategies for altering the underlying photophysics and kinetics so as to accelerate the efficiency of promising reactions; we will transform our current designs of photochemical and electrochemical reactors, with a combination of engineering, modelling and new fabrication techniques to maximize their efficiency and to provide clear opportunities for scale-up; we will exploit on-line analytics to accelerate the optimisation of continuous photochemical and electrochemical reactions; we will design and build a new generation of reactors for new applications; we will identify the most effective strategies for linking our reactors into integrated multi-step continuous processes with minimized waste; we will demonstrate this integration on at least one synthesis of a representative pharmaceutical target molecule on a larger scale; we will apply a robust series of sustainability metrics to benchmark our approaches against current manufacturing.