Virtual Formulation Laboratory for prediction and optimisation of manufacturability of advanced solids based formulations

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.

A. Industry impact for improved process efficiency
Industry impact is a top priority of this project. Our partners have an outstanding impact track record, and this proposal has found an exceptionally strong pull from industry. Keys to maximising impact are (i) to make the toolkit easy to use, highly accessible and effective, and (ii) taking it to the beneficiaries pro-actively. The plans to achieve this are articulated below.

B. Accelerating the output up the TRL scale
Accessibility requires the software package to run on a popular platform, have a user-friendly Graphic User Interface, with strong expert support maintained over the foreseeable future, and multiple access routes to suit the needs of different companies. Without these features, such advanced science would be very difficult for practicing formulators and engineers in industry to use. The starting point is the Virtual Powder Blending Laboratory (DEFRA AFM276) (Bradley and Berry), which has a functional structure, an expandable, shareable database to enter and store the properties of materials characterised, and a user friendly interface, optimised with the DEFRA project partners. It will be used as a basis to build the output of this project into a usable toolkit, moving the basic science, of TRL2, up to a position of direct impact on manufacturing, TRL4 to 5.

C. Positive engagement of the industry partners during the programme
To facilitate this, an Industrial/Academic Advisory Board will be convened including all the contributors, to meet quarterly, advised by two consultants (high level research leaders in formulation). The board will steer the programme, provide the industry context and ensure relevance. Powder producers and users will take active roles in characterisation of their powders and processes and testing the toolkit as it evolves and will help pursue compatibility with their own tools. All will involve their personnel in training in use of the techniques. The participants will thus get a head start in exploiting the output.

D. Communication with beneficiaries beyond the project participants
Around 20 open access papers in archival journals, 40 conference publications, then trade journal articles, and workshops with learned and trade bodies (IMechE, IChemE, SHAPA etc, in which many of the investigators hold positions of influence e.g. chairmen & committee members).
The toolkit will be incorporated in Wolfson Centre short courses on powder processing. Annually, about 20 courses reach 250 to 300 people involved in formulation and manufacturing of powder products, in 60 to 70 different companies. Leeds organises complementary short courses in powder science, which will also promote the toolkit and the science behind it. Britest, PSE and NFC will also lead activities in marketing and taking to users.

E. Contributing to the health of academic disciplines worldwide
The advances in modelling, surface energy characterisation etc will significantly push forwards the ability of the community to model the behaviour of powders. These will be promoted to the academic community through publications, short courses and workshops for researchers, international conferences (AAPS/AIChE, APS, PARTEC, APT, CHoPS, ICBMH), exhibitions (Powtech), learned body meetings e.g. IChemE, IMechE, EFCE, and industry bodies eg SHAPA.

F. Public communication and engagement
The PIs are active in public lectures through IOM3, schools visits, science festivals, House of Commons annual science event etc. Case studies from this project should form an excellent showcase for the direct impact of research on efficiency and competitiveness of UK manufacturing.