The UK pharmaceutical industry produces 16% of the world's well-known medicines, employs more than 66,000 people (200,000 more indirectly) and contributes over £8.8 billion to the UK GVA. The current covid-19 crisis has highlighted the need for the UK and the USA to have a strong, smart pharmaceutical manufacturing base. The FDA in the USA has identified continuous pharmaceutical manufacturing as a highly promising solution to these challenges by enabling lower capital cost, smaller footprint and highly efficient facilities, which can be distributed geographically, improve national security by reducing dependency on foreign suppliers and can produce multiple products on demand with minimum risk to quality. However, the UK Government Made Smarter Review highlights that we still have a way to go to achieve a Right First Time smart manufacturing system as an enabler for the digitalization of continuous manufacturing in pharmaceutical industry. Addressing these challenges are the domain of process systems engineers. By developing right-first-time (RFT) smart manufacturing systems incorporating Industry 4.0 concepts, we intend to address these key challenges in pharmaceutical manufacturing. Our hypothesis is that the development of a systematic framework for smart continuous pharmaceutical manufacturing can deliver key benefits to the industry including: - Reduced time to market of new products; - Reduced waste and increased resilience; and - Reduced cost of manufacture. To develop this framework, we have brought together a world leading team of process systems and pharmaceutical engineers from four universities in the UK and USA. An important and unique element of this proposal is the ability to validate state of the art models, control and optimization procedures on three cutting edge continuous manufacturing experimental platforms: (1) Consigma 25 wet granulation line at University of Sheffield (UK); (2) Dry granulation line at Purdue University (USA); and (3) Continuous direct compression line, also at Purdue. The outcome of this project will be a framework and computational tools for optimal design of pharmaceutical processes with a real-time process management system and a flexible real-time release testing framework, all verified at pilot scale.

Systems Biologists, by combining cell biology with mathematical approaches, have shown that feedback loops in molecular regulatory networks tightly control cellular homeostasis and responses. The interplay between endogenous feedbacks and the extracellular environment results in complex and non-linear cellular dynamics. Mathematical models can help in tackling this complexity, aiding in characterising the links between cellular dynamics and cell-decision making. However, the validity of models relies on modelling assumptions and the quality of data used for parameter fitting: stochasticity and noise limit the power of model predictions across Systems Biology and Systems Pharmacology applications. Conversely, the forward engineering of exogenous gene expression dynamics that recapitulate native cellular behaviours, often used by Synthetic Biologists, is limited by poor robustness to physical parameter variations, diverse modular parts and choice of chassis. To tackle these challenges, this Fellowship proposes to directly and automatically program complex dynamics in mammalian cells, by combining external feedback control to ensure robustness and a microfluidics/microscopy platform to observe and perturb cells in real-time. Exploitation of this technology will allow to: i) Unravel causation in coupled processes and dissect the role that temporal patterns across scales (i.e. gene expression dynamics and cell-cycle) play in stem cell fate, ultimately exploiting such dynamics for the design of superior stem cell culture protocols. ii) Directly track from experiments non-linear biochemical dynamics, without the need of mathematical models, to quantitatively determine causes/robustness of complex native/engineered behaviours, respectively, using experimental and Control-Based Continuation. Direct industrial applications will be explored, including the characterisation of stem cell culture protocols across culture scales, and the use of feedback control to design optimal drug dosing schedules for target cancer cell responses. Our aims are underpinned by two highly synergetic research tracks at the interface of interdisciplinary disciplines. The combination of methodologies from control theory, Synthetic, Systems and Stem cell biology will provide a quantitative framework and highly novel tools to understand, steer and design mammalian cell dynamic phenotypes, with great potential for future therapeutic purposes.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Collisional and sliding contacts of two different materials are commonly associated with electric charge transfer, leading to charge accumulation. This causes an overwhelming number of handling and processing problems and explosion hazards, thereby degrading manufacturing efficiency and causing out of specification products and wastage. Examples are strong adhesion to containing walls and deposition in pipes, impairing flowability and aggravating segregation of components in a mixture, thereby upsetting formulations. It is common to experience highly active drugs filling up a spiral jet mill (thereby upsetting its functioning), components of a formulation preferentially depositing on grounded surfaces, getting concentration spikes of minor components of a formulation, poor powder spreading due to charging in additive manufacturing. In contrast, the phenomenon has been used to good effect in xerography and more recently for Tribo Electric Nano Generators (TENG). Despite being known for millennia, the triboelectrification phenomenon is not well understood and actually not predictable for non-metallic surfaces. The role of environmental humidity and temperature adds to the complexity. Considering its importance in advanced manufacturing of new materials, for which little material is initially available, a timely project with internationally leading-edge participation is proposed to tackle triboelectrification from a molecular level solid-state formation, right up to large scale manufacturing of active pharmaceutical ingredients and polymers. The project has seven industrial partners and six international collaborators from Japan, Brazil, Italy and Canada, contributing to seven work packages, each addressing a topic of scientific as well as industrial interest. The activities range from molecular solid-state level work function calculations by Density Functional Theory, to particle charge transfer characterisation by developing specialised instruments for charge distribution measurement and TENG, to unit operation level, including fast fluidisation and risers, pneumatic conveying and cyclone separation. The work is of strategic interest in manufacturing, ranging from pharmaceuticals, foods and plastics to additive manufacturing. It will have a huge impact on manufacturing sustainability, as the mitigation of triboelectrification issues will have a notable reduction in wastage and environmental footprint, and on the performance and material optimisation for the fast growing new technology of TENG. The proposed programme will tackle six challenges as addressed in the Case for Support.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.