Nearly 140,000 industrial materials and chemicals are marketed worldwide. Most of them are made from fossil feedstocks with high CO2 emission embedded, and very low resources efficiency. To maintain the UK's global competitiveness, it is vital to identify sustainable alternatives for the manufacturing of these chemicals and materials. Biomanufacturing, that utilises biological systems to produce commercially important biomaterials and biomolecules plays an important role in sustainable development, and has shown successful applications in manufacturing electronic components (e.g., bio-based flexible printed circuits), fine or specialty chemicals (e.g., bio-lubricants), building and construction (e.g., biocementation), consumer products (e.g., bio-based detergents), food (e.g., vitamin and amino acid fortification) and pharmaceuticals (e.g., vaccine production). However, none of the current biomanufacturing routes has achieved zero carbon loss or emission. In fact, many bioprocesses (such as those involving fermentation) will emit large amounts of CO2. In a typical biomanufacturing, only 2/3 of the carbon resources flow ends up in final products, while the rest 1/3 are lost during the manufacturing process, in the form of CO2 emissions and residue wastes. To address this challenge, the project will create the first-of-its-kind Zero Carbon Loss biomanufacturing system that will pave the way for the UK to reach the 2050 Net Zero target. This will be achieved by developing novel sustainable biomanufacturing of aromatics, heterocyclics and other lignocellulosics products with integrated carbon capture and utilization within the manufacturing process. These bio-based products, like building blocks of Lego, then will be used in different combinations to make various product such as pharmaceuticals, plastics, textile, composite materials, etc, with overall net zero carbon loss (emission and waste) throughout the manufacturing life cycle. The technology innovation and resources optimisation of the BMCCU manufacturing route (WP1) will be guided by real-time system wide sustainability assessments (WP3), linked by an interoperable digital twin of the manufacturing process beyond the state of the art (WP2). It creates a new approach in which the lifecycle sustainability assessments will serve as an interactive decision-making tool fully embedded in the early-stage technology developments, rather than traditional retrospective assessment. The project will contribute significantly to the UK's National Industrial Biotechnology Strategy, with a potential scope of £4.5 billion GVA, 63,000 jobs, and 2.5 billion tonnes of CO2 saving per year by 2030. To achieve the vision, this proposal brings together a diverse multidisciplinary team from Loughborough University, Heriot-Watt University and Imperial College London, with world leading expertise in circular economy, intelligent manufacturing, industrial digitalisation and decarbonisation.

Nearly 140,000 industrial materials and chemicals are marketed worldwide. Most of them are made from fossil feedstocks with high CO2 emission embedded, and very low resources efficiency. To maintain the UK's global competitiveness, it is vital to identify sustainable alternatives for the manufacturing of these chemicals and materials. Biomanufacturing, that utilises biological systems to produce commercially important biomaterials and biomolecules plays an important role in sustainable development, and has shown successful applications in manufacturing electronic components (e.g., bio-based flexible printed circuits), fine or specialty chemicals (e.g., bio-lubricants), building and construction (e.g., biocementation), consumer products (e.g., bio-based detergents), food (e.g., vitamin and amino acid fortification) and pharmaceuticals (e.g., vaccine production). However, none of the current biomanufacturing routes has achieved zero carbon loss or emission. In fact, many bioprocesses (such as those involving fermentation) will emit large amounts of CO2. In a typical biomanufacturing, only 2/3 of the carbon resources flow ends up in final products, while the rest 1/3 are lost during the manufacturing process, in the form of CO2 emissions and residue wastes. To address this challenge, the project will create the first-of-its-kind Zero Carbon Loss biomanufacturing system that will pave the way for the UK to reach the 2050 Net Zero target. This will be achieved by developing novel sustainable biomanufacturing of aromatics, heterocyclics and other lignocellulosics products with integrated carbon capture and utilization within the manufacturing process. These bio-based products, like building blocks of Lego, then will be used in different combinations to make various product such as pharmaceuticals, plastics, textile, composite materials, etc, with overall net zero carbon loss (emission and waste) throughout the manufacturing life cycle. The technology innovation and resources optimisation of the BMCCU manufacturing route (WP1) will be guided by real-time system wide sustainability assessments (WP3), linked by an interoperable digital twin of the manufacturing process beyond the state of the art (WP2). It creates a new approach in which the lifecycle sustainability assessments will serve as an interactive decision-making tool fully embedded in the early-stage technology developments, rather than traditional retrospective assessment. The project will contribute significantly to the UK's National Industrial Biotechnology Strategy, with a potential scope of £4.5 billion GVA, 63,000 jobs, and 2.5 billion tonnes of CO2 saving per year by 2030. To achieve the vision, this proposal brings together a diverse multidisciplinary team from Loughborough University, Heriot-Watt University and Imperial College London, with world leading expertise in circular economy, intelligent manufacturing, industrial digitalisation and decarbonisation.

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.

Many of the small molecules essential to our every-day lives (e.g. pharmaceuticals, clothing, cosmetics, materials, etc.) are currently manufactured from diminishing fossil fuels via industrial processes that contribute significantly to global climate change. Record high atmospheric CO2 levels in 2020 and ambitious net-zero carbon emission targets by 2050 mean that urgent sustainable manufacturing solutions are now required to reduce the environmental burden of this industry on our planet for future generations. The MICROSYN project will uniquely combine cutting-edge modern biological engineering with green chemistry to create transformative solutions to the sustainable manufacture of the nylon-precursor adipic acid from abundant waste generated by the paper-mill industry (lignin) and consumer use (plastic bottles). This will eliminate carbon emissions from the current petrochemical method used to make this compound (currently >20,000,000 ton/year; 5-10% of all human-associated CO2/N2O emissions worldwide) and create circular bioprocesses that avoid the incineration of existing waste streams (releasing further CO2), whilst also addressing the global plastic waste crisis. The project recognizes low-value waste as an underutilized carbon-rich feedstock, and employs modern synthetic biology to transform these abundant and sustainable resources into a high-value chemical via novel biomanufacturing processes.

Lung diseases such as Asthma and Chronic Obstructive Pulmonary Disease affect one in five people in the UK and kill someone every 5 minutes. The number of patients with these lung diseases was increasing in the NHS even before COVID-19. We are also learning about serious long-term effects of COVID-19 that will add to the existing burden on the NHS. There have been huge advances in technologies that allow scientists to see inside the lungs and measure what we breathe out. While this information has taught us quite a lot, it is still very difficult to combine different sources of information and turn it into new or improved treatments. Getting that useful information out of large amounts of medical test results requires sophisticated physics-based mathematical and statistical models run on powerful computers - a combination of techniques called data-driven biophysical multiscale modelling. The ability to develop those kinds of models will allow us to better understand how diseases start and how they progress. Our BIOREME network will support new research that uses these techniques to mimic biological and mechanical processes that occur throughout the lung. Using the information from thousands of lung tests, the idea is then to get these models to mimic real diseased lungs. In order to improve and build trust in these models, some of our projects will be focused on comparing their outputs to results from other lung tests. Medical scientists can then use such models to test what might happen in a particular type of lung disease, and to investigate possible responses to new treatments before testing these in patients. Most importantly, this will lead to the design of new drugs and improved trials for new treatments. The first step will be to get medics, imaging experts and mathematicians together with industry and patient group representatives to decide on which specific research areas to prioritise, where this form of modelling will make the most difference. This NetworkPlus award will then allow us to organise multiple events, in different formats, designed to help researchers to collaborate, and to come up with the best initial projects to help achieve our goals. We will then help the researchers to develop these into larger projects that will attract funding from other sources and continue the research into the future. Even after this funding runs out, BIOREME will provide a lively forum for lung researchers to continue solving problems using these advanced computational tools. Finally, BIOREME will support outreach activities to engage and educate communities and young people in the role that mathematics can play in medicine and healthcare, and to inspire a new generation of respiratory scientists from diverse backgrounds.