We propose a new imaging platform that combines ultra-fast confocal imaging with the the nano-fluidic functionality delivered by an integrated Fluidic Force microscope (FluidFM-UFCLSM). The proposed capability opens a new phase of exploration of biological systems by enabling characterisation of localised biochemical and physiological processes. The proposed capability provides new avenues for specific applications such as new antimicrobial agents, functional genetics and the development of sustainable crops. The unique design of FluidFM-UFCLSM enables accommodating an array of complex biological samples to perform quantitative and predictive characterisation of biofilms, tissues, whole plants, small animals, insects, mucosal membranes, food systems and tissue scaffold hydrogels. The unique feature of FluidFM-UFCLSM is it will enable study of the smallest units of biological organisation such as proteins as well as larger objects such as cells, tissues and organs. The use of FluidFM-UFCLSM cuts across many disciplines and delivers benefits to a broad range of research topics in the areas of biofilm formation, plant science, tissue engineering, food science and cell physiology. Some examples of FluidFM-UFCLSM applications are: 1) Elucidate anti-microbial resistance and the localised mechanisms underpinning quorum sensing 1) Probe interaction between immune cells with lung epithelium as one of the key pathways of Covid-19 pathogenies 2) Uncover the secrets of plant development and mechanical signalling to develop new resistant crops 3) Probe the effect of nutrition on gut microbiome and associated health outcomes 4) Explore new plant-mimetic materials for designing new food-compatible films for environmentally sustainable food production The broader areas of impact will be achieved by supporting emerging areas research that targets the major problems and challenges of food security, improved nutrition, animal and human health, combatting antimicrobial resistance, microbiome research, industrial biotechnology, waste valorisation, sustainable agricultural and synthetic biology.

3D Printing elicits tremendous excitement from a broad variety of industry - it offers flexible, personalised and on demand scalable manufacture, affording the opportunity to create new products with geometrical / compositional freedoms and advanced functions that are not possible with traditional manufacturing practices. 3D Printing progresses rapidly: for polymerics, we have seen significant advances in our ability to be able to manufacture highly functional structures with high resolution projection through developments in projection micro stereolithography, multimaterial ink jet printing and two photon polymerisation. There have also been exciting advances in volumetric 3DP with the emergence of Computational Axial Lithography and more recent work such as 'xolo'. Alongside these advances there has also been developments in materials, e.g., in the emergence of '4D printing' using responsive polymers and machine learning / AI on 3DP is beginning to be incorporated into our understanding. The impact of these advances is significant, but 3D printing technology is reaching a tipping point where the multiple streams of effort (materials, design, process, product) must be brought together to overcome the barriers that prevent mass take up by industry, i.e., materials produced can often have poor performance and it is challenging to match them to specific processes, with few options available to change this. Industry in general have not found it easy to adopt this promising technology or exploit advanced functionality of materials or design, and this is particularly true in the biotech industries who we target in this programme grant - there is the will and the aspiration to adopt 3D printing but the challenges in going from concept to realisation are currently too steep. A key challenge stymying the adoption of 3D printing is the ability to go from product idea to product realisation: each step of the workflow (e.g., materials, design, process, product) has significant inter-dependent challenges that means only an integrated approach can ultimately be successful. Industry tells us that they need to go significantly beyond current understanding and that manufacturing products embedded with advanced functionality needs the capability to quickly, predictably, and reliably 'dial up' performance, to meet sector specific needs and specific advanced functionalities. In essence, we need to take a bottom-up, scientific approach to integrate materials, design and process to enable us to produce advanced functional products. It is therefore critical we overcome the challenges associated with identifying, selecting, and processing materials with 3DP in order to facilitate wider adoption of this pivotal manufacturing approach, particularly within the key UK sectors of the economy: regenerative medicine, pharmaceutical and biocatalysis. Our project will consider four Research Challenges (RCs): PRODUCT: How can we exploit 3D printing and advanced polymers to create smart 21st Century products ready for use across multiple sectors? MATERIALS: How can we create the materials that can enable control over advanced functionality / release, that are 3D Printable? DESIGN: How can we use computational / algorithmic approaches to support materials identification / product design? PROCESS: How can we integrate synthesis, screening and manufacturing processes to shorten the development and translation pipeline so that we can 'dial up' materials / properties? By integrating these challenges, and taking a holistic, overarching view on how to realise advanced, highly functional bespoke 3D printed products that have the potential to transform UK high value biotechnology fields and beyond.

Powered by data, Industrial Digital Technologies (IDTs) such as artificial intelligence and autonomous robots, can be used to improve all aspects of manufacturing and supply of products along supply chains to the customer. Many companies are embracing these technologies but uptake within the pharmaceutical sector has not been as rapid. The Medicines Made Smarter Data Centre (MMSDC) looks to address the key challenges which are slowing digitalisation, and adoption of IDTs that can transform processes to deliver medicines tailored to patient needs. Work will be carried out across five integrated platforms designed by academic and industrial researcher teams. These are: 1) The Data Platform, 2) Autonomous MicroScale Manufacturing Platform, 3) Digital Quality Control Platform, 4) Adaptive Digital Supply Platform, and 5) The MMSDC Network & Skills Platform. Platform 1 addresses one of the sector's core digitalisation challenges - a lack of large data sets and ways to access such data. The MMSDC data platform will store and analyse data from across the MMSDC project, making it accessible, searchable and reusable for the medicines manufacturing community. New approaches for ensuring consistently high-quality data, such as good practice guides and standards, will be developed alongside data science activities which will identify what the most important data are and how best to use them with IDTs in practice. Platform 2 will accelerate development of medicine products and manufacturing processes by creating agile, small-scale production facilities that rapidly generate large data sets and drive research. Robotic technologies will be assembled to create a unique small-scale medicine manufacturing and testing system to select drug formulations and processes to produce stable products with the desired in-vitro performance. Integrating several IDTs will accelerate drug product manufacture, significantly reducing experiments and dramatically reducing development time, raw materials and associated costs. Platform 3 focusses on the digitalisation of Quality Control (QC) aspects of medicines development which is important for ensuring a medicine's compliance with regulatory standards and patient safety requirements. Currently, QC checks are carried out after a process has been completed possibly spotting problems after they have occurred. This approach is inefficient, fragmented, costly (>20% of total production costs) and time consuming. The digital QC platform will research how to transform QC by utilising rich data from IDTs to confirm in real time product and process compliance. Platform 4 will generate new understanding on future supply chain needs of medicines to support adoption of adaptive digital supply chains for patient-centric supply. IDTs make smaller scale, autonomous factory concepts viable that support more flexible and distributed manufacture and supply. Supply flexibility and agility extends to scale, product variety, and shorter lead-times (from months to days) offering a responsive patient-centric or rapid replenishment operating model. Finally, technology developments closer to the patient, such as diagnostics provide visibility on patient specific needs. Platform 5 will establish the MMSDC Network & Skills Platform. This Network will lead engagement and collaboration across key stakeholder groups involved in medicines manufacturing and investments. The Network brings together the IDT-using community and other relevant academic and industrial groups to share developments across pharmaceuticals and broader digital manufacturing sectors ensuring cross-sector diffusion of MMSDC research. Existing strategic networks will support MMSDC and act as gateways for IDT dissemination and uptake. The lack of appropriate skills in the workforce has been highlighted as a key barrier to IDT adoption. An MMSDC priority is to identify skills needs and with partners develop and deliver training to over 100 users

It may be surprising to learn, but the pharmaceutical industry is around 1000 times worse than oil refining in terms of waste generated per kg of product; the industry produces around 100kg of hazardous waste per kg of product, most of which is solvent. The proposed "SolvIT" bid will build on existing collaborations between Strathclyde and Imperial College in the area of modelling and solvent design, whilst strengthening the team with new collaborative partners, to tackle this colossal amount of waste. Our vision is to improve efficiency and reduce waste in the manufacture of new and existing medicines, lowering their cost, and making their production more sustainable and environmentally friendly. We plan to do this through three main programmes of work: 1. The identification and deployment of sustainable solvents in medicines manufacture: most medicines require multiple operations (steps) to go from bulk raw material to final active pharmaceutical ingredient (API). At each step, a different solvent is often required. These solvents may be toxic and costly to dispose of, isolation of products at each step, also incurring solvent use, adds to the cost. SolvIT will use a combination of computer modelling and experiment to evaluate alternative solvents, which are more sustainable, in the most popular chemical reactions used in the synthesis of new medicines, so that new and existing process can use these new solvents, reducing waste and cost. 2. Integrated solvent and process design: building on the outputs from the first objective, we will again combine computational modelling approaches with process design, driven by a range of key metrics, to allow multiple steps in the medicine production to be combined, or "telescoped", minimising the waste that is generated, and reducing time to production, resulting in overall cost savings from both of these improvements. 3. Stakeholder engagement: we will engage with pharmaceutical company partners, and industry regulators, to better understand from them the current barriers to solvent recycling and communicate to them new developments emerging from this work which may help to overcome these barriers. The integration of these strands of research, along with the collaborative expertise from the two partner institutions, across disciplines of synthetic chemistry, computational chemistry, and chemical engineering, will deliver findings that will be of benefit across pharmaceutical industry in particular, and the chemicals manufacturing space in general.

The pharmaceutical industry is undergoing a period of unprecedented change in terms of product development, with increased digitization, greater emphasis on continuous manufacture and the rapid advent of novel therapeutic paradigms, such as personalized medicines, becoming more and more business critical. This change is amplified by Quality by Design considerations and the now routine use of the Target Product Profile approach to the design of patient-centred dosage forms. The recent advances in the range of available therapeutic strategies, alongside the breadth of diseases that can now be successfully treated, has resulted in the need for both new dosage forms and manufacturing approaches. Crucially, there has been a shift from high volume, low cost manufacture towards a more specialized, higher value product development. Consequently, ever more sophisticated approaches, not merely to producing medicinal products, but also to controlling their quality at every stage of the manufacturing process, have become paramount. These would be greatly facilitated by the emerging technologies, based on artificial intelligence and machine learning techniques, for enhancing online process analysis as well as real-time responsive process control. These technologies are particularly important for products where the financial and practical margins for manufacturing error are low, as is the case for an increasing proportion of new therapies. In this proposal, we focus on a new way of screening, manufacturing and quality controlling drugs in the form of nanocrystals, that is, drugs prepared as nanosized crystalline particles stabilized by surface-active agents. In particular, we will combine continuous-flow processing, online advanced process analytical technology, real-time process control and quality assurance, design of experiments, advanced data analysis and artificial intelligence to deliver fully automated, self-optimizing platforms for screening and manufacturing drugs as nanocrystals via antisolvent precipitation. These dosage forms have attracted substantial interest as a means of delivering poorly water-soluble (and thus poorly bioavailable) drugs, a persistent and increasing problem for the pharmaceutical industry. While nanocrystals offer a suitable test system for our approach, our methodology and the manufacturing platform we intend to deliver can be applied to other drug delivery systems. We focus on nanocrystals because they are of considerable therapeutic and commercial significance both nationally and internationally. We intend to use continuous-flow small-scale (i.e. millifluidic) systems. These offer excellent process controllability, can generate crystals of nearly uniform size, and as the process is continuous, the product characteristics are more stable than in batch systems. Millifluidic systems are flexible (one platform can produce a larger variety of products) and agile - reacting rapidly to changes in market demands; they reduce the manufacturing time, speed up the supply chain and, being smaller, can be portable. These systems also expedite screening, curtailing the quantities of material required, benefits that design of experiments will amplify. This data-driven technique allows identifying the most informative experiments, maximizing learning while minimizing time and costs, advantages not fully exploited by the pharmaceutical industry. These technologies, coupled with online advanced process analytical methods, real-time process control, cutting-edge data analysis and machine learning methods, have the potential to disrupt the status quo, accelerate process development and deliver transformative platforms for the cost-effective and sustainable manufacturing of active pharmaceutical ingredients in solid dosage form, reducing the timeline from drug discovery to patient, and contributing to placing the UK at the forefront of innovation in the pharmaceutical sector.