Solid dose forms are the backbone of many manufacturing industries. In pharmaceutical therapeutics, tablets, capsules, dry powder inhalers and powders for re-suspension cover the vast majority of the £5.6Bn sales by this industry in the UK. Food (sales £67Bn) is the single largest industry of the UK manufacturing sector which totalled £365Bn sales in 2014 (Office of National Statistics). In all these manufacturing processes and in final use, the physical behaviour of the powder is at least as important as the chemistry. Stability, weight and content uniformity, manufacturing difficulties and variable performance are determined by decisions made during the formulation process Manufacturing problems are ubiquitous; the Rand report (by E.W. Merrow, 1981) examined powder processes and found on average 2 year over-runs to get to full productivity, and development costs 210% of estimates, due to incompatibility between powder behaviour and process design. In the intervening years, plant engineering techniques have developed, but the rationalisation of formulation decisions has never received more than cursory, empirical study. This project proposes to develop a Virtual Formulation Laboratory (VFL), a software tool for prediction and optimisation of manufacturability and stability of advanced solids-based formulations. The team has established expertise in powder flow, mixing and compaction which will be brought together for the first time to link formulation variables with manufacturability predictions. The OVERALL AIMS of the project are (a) to develop the science base for understanding of surfaces, particulate structures and bulk behaviour to address physical, chemical and mechanical stability during processing and storage and (b) to incorporate these into a software tool (VFL) which accounts for a wide range of material types, particle structures and blend systems to enable the formulator to test the effects of formulation changes in virtual space and check for potential problems covering the majority of manufacturing difficulties experienced in production plants. The VISION for VFL is to be employed widely in the development process of every new formulated powder product in food, pharmaceuticals and fine chemicals within five years of the completion of this project. VFL will consider four processes: powder flow, mixing, compaction and storage; and will predict four manufacturability problems: poor flow/flooding, segregation/heterogeneity, powder caking and strength/breakage of compacts These account for the majority of practical problems in the processing of solid particulate materials The OVERALL OBJECTIVES of the project are: (a) to fill the gaps in formulation science to link molecule to manufacturability, which will be achieved through experimental characterisation and numerical modelling, and (b) establish methodologies to deal with new materials, so that the virtual lab could make predictions for formulations with new materials without extensive experimental characterisation or numerical modelling. This will be achieved through developing functional relationships based on the scientific outcomes of the above investigations, while identifying the limits and uncertainties of these relationships.

The formation of the chemical contaminant, acrylamide, during high-temperature cooking and processing of wheat, rye, potato and other mainly plant-derived raw materials was reported in 2002, and the presence of acrylamide in foods is now recognized as a difficult problem for the agricultural and food industries. Acrylamide causes cancer in laboratory animals and is therefore considered to be probably cancer-causing in humans. It also affects the nervous system and reproduction. Cereals, of which wheat is the most important, generate half of the acrylamide in the European diet, with biscuits, snacks and breakfast cereals being of particular concern. The FAO/WHO Expert Committee on Food Additives has recommended that dietary exposure to acrylamide should be reduced and the European Commission is expected to issue guidance values on acrylamide levels in food before the end of 2010. The current draft of the guidance values proposes levels that will not be consistently achievable for many products. The proposed guidance level for breakfast cereals, for example, is 400 parts per billion (ppb), while levels in some wheat-based breakfast cereals are over 1000 ppb. Furthermore, many Member States support these guidance values becoming regulatory limits. The food industry therefore requires both short-term solutions and a long-term programme of reduction in the acrylamide forming potential of wheat in order to comply with this regulatory situation as it evolves. Methods for reducing acrylamide formation during processing have proven to be difficult to apply to wheat products, either being ineffective or having an unacceptably adverse effect on product quality. The development of commercially viable wheat varieties that are low in acrylamide-forming potential but retain grain characteristics that are important for end product quality would help to address, at source, the problem of acrylamide formation in food manufacture, catering and home cooking, without the need for additives or potentially costly changes to processes. The high-temperature degradation of an amino acid, asparagine, in the presence of sugars (glucose, fructose and maltose) has been shown to be the major route for acrylamide formation and the limiting factor in wheat products is free asparagine. Wheat contains significantly higher levels of asparagine than most other grains. Furthermore, whole wheat grain and wheat bran, which have important health promoting properties, tend also to have higher asparagine levels than refined wheat flour. This project seeks to identify currently available varieties and genotypes of wheat that are low in asparagine and provide wheat breeders with the genetic tools to reduce the concentration of asparagine further. This application is being submitted through the BBSRC's stand-alone LINK scheme. The project will benefit from the involvement of a major European/GB wheat breeder and a consortium of wheat supply chain businesses, allowing for the identification and review of key targets by the industrial partners. The level of industry support is indicative of the importance of the acrylamide issue to wheat supply chain businesses and the potential impact of the project. A letter of support has also been provided by the Food Standards Agency. The project will use state-of-the-art techniques for analysing amino acid concentrations in wheat flour, exploit the genetic resources in wheat that have been developed at Rothamsted and the John Innes Centre, including mapping populations, wheat genetic modification (as a research tool) and high-throughput screening of mutant populations, and utilise the latest DNA sequencing techniques to study differences in gene expression between high and low asparagine genotypes. The impact of reductions in acrylamide-forming potential of grain on performance in industrial processes will be assessed by food industry partners.

This Centre for Doctoral training in Industrially Focused Mathematical Modelling will train the next generation of applied mathematicians to fill critical roles in industry and academia. Complex industrial problems can often be addressed, understood, and mitigated by applying modern quantitative methods. To effectively and efficiently apply these techniques requires talented mathematicians with well-practised problem-solving skills. They need to have a very strong grasp of the mathematical approaches that might need to be brought to bear, have a breadth of understanding of how to convert complex practical problems into relevant abstract mathematical forms, have knowledge and skills to solve the resulting mathematical problems efficiently and accurately, and have a wide experience of how to communicate and interact in a multidisciplinary environment. This CDT has been designed by academics in close collaboration with industrialists from many different sectors. Our 35 current CDT industrial partners cover the sectors of: consumer products (Sharp), defence (Selex, Thales), communications (BT, Vodafone), energy (Amec, BP, Camlin, Culham, DuPont, GE Energy, Infineum, Schlumberger x2, VerdErg), filtration (Pall Corp), finance (HSBC, Lloyds TSB), food and beverage (Nestle, Mondelez), healthcare (e-therapeutics, Lein Applied Diagnostics, Oxford Instruments, Siemens, Solitonik), manufacturing (Elkem, Saint Gobain), retail (dunnhumby), and software (Amazon, cd-adapco, IBM, NAG, NVIDIA), along with two consultancy companies (PA Consulting, Tessella) and we are in active discussion with other companies to grow our partner base. Our partners have five key roles: (i) they help guide and steer the centre by participating in an Industrial Engagement Committee, (ii) they deliver a substantial elements of the training and provide a broad exposure for the cohorts, (iii) they provide current challenges for our students to tackle for their doctoral research, iv) they give a very wide experience and perspective of possible applications and sectors thereby making the students highly flexible and extremely attractive to employers, and v) they provide significant funding for the CDT activities. Each cohort will learn how to apply appropriate mathematical techniques to a wide range of industrial problems in a highly interactive environment. In year one, the students will be trained in mathematical skills spanning continuum and discrete modelling, and scientific computing, closely integrated with practical applications and problem solving. The experience of addressing industrial problems and understanding their context will be further enhanced by periods where our partners will deliver a broad range of relevant material. Students will undertake two industrially focused mini-projects, one from an academic perspective and the other immersed in a partner organisation. Each student will then embark on their doctoral research project which will allow them to hone their skills and techniques while tackling a practical industrial challenge. The resulting doctoral students will be highly sought after; by industry for their flexible and quantitative abilities that will help them gain a competitive edge, and by universities to allow cutting-edge mathematical research to be motivated by practical problems and be readily exploitable.