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The broad theme of the research training addresses the most rapidly developing parts of the bio-centred pharmaceutical and healthcare biotech industry. It meets specific training needs defined by the industry-led bioProcessUK and the Association of British Pharmaceutical Industry. The Centre proposal aligns with the EPSRC Delivery Plan 2008/9 to 2010/11, which notes pharmaceuticals as one of the UK's most dynamic industries. The EPSRC Next-Generation Healthcare theme is to link appropriate engineering and physical science research to the work of healthcare partners for improved translation of research output into clinical products and services. We address this directly. The bio-centred pharmaceutical sector is composed of three parts which the Centre will address:- More selective small molecule drugs produced using biocatalysis integrated with chemistry;- Biopharmaceutical therapeutic proteins and vaccines;- Human cell-based therapies.In each case new bioprocessing challenges are now being posed by the use of extensive molecular engineering to enhance the clinical outcome and the training proposed addresses the new challenges. Though one of the UK's most research intensive industries, pharmaceuticals is under intense strain due to:- Increasing global competition from lower cost countries;- The greater difficulty of bringing through increasingly complex medicines, for many of which the process of production is more difficult; - Pressure by governments to reduce the price paid by easing entry of generic copies and reducing drug reimbursement levels. These developments demand constant innovation and the Industrial Doctorate Training Centre will address the intellectual development and rigorous training of those who will lead on bioprocessing aspects. The activity will be conducted alongside the EPSRC Innovative Manufacturing Research Centre for Bioprocessing which an international review concluded leads the world in its approach to an increasingly important area .

In 2002 the UK Government established that a Bank of human embryonic cell lines should be established to oversee the use of these cells to ensure that any cells of this type, used in the UK were obtained ethically and only used in research for the benefit of treatment of serious human disease. In addition the Bank should provide access to quality-controlled stocks of these cell lines to provide a high quality international resource in support of the UK s stem cell community and to further the use of these cells in regenerative medicine. Such a role for the Bank in supporting the move of stem cell therapies from the laboratory to the bedside was confirmed to be a key element in the UK Stem Cell Initiative Report prepepared by Sir John Pattison and accepted by the Government. In the next phase of funding (Phase III) the Bank aims to sustain and develop its position as the foremost repository of ethically-sourced and well characterised stocks of human stem cell lines banked to international quality standards. Whilst in Phase II the primary focus of the Bank was on academic research, Phase III will see the Bank coordinating more closely with scientific programmes translating research developments into therapeutic applications, the regenerative medicine clinical community and those developing human cell culture models to improve the efficiency of development of new drugs to reduce costs and increase patient safety. The Bank will continue to develop its international role in supporting the development of stem cell therapy through: ? the provision of quality-assured and safety tested cell lines and other products supporting researchers and clinical applications; ? its continued lead on best practice and the setting of international consensus standards for the delivery of high quality and safe stem cells; ? its developing training programme for stem cell scientists, technical staff and quality assurance personnel in support of the UK s developing regenerative medicine industry; ? its scientific collaborations and internal research programme to establish robust methodologies for cell expansion, differentiation, preservation and characterisation which will improve the qulity of materials supplied for research and provide improved methodological approaches for clincial application. It is intended that the Bank will now implement its position as a national resource and international centre of expertise in support of the development of regenerative medicines and product safety in the UK.

The proposal is for capital funding to provide equipment and facilities for improving the banking and characterisation of pluripotent stem cells provided by the UK Stem Cell Bank as seed stocks for research and clinical applications. The automation of key processes in the banking, characterisation and quality control of stem cell lines, intended as starting materials for research and development of cellular therapies, will generate significant improvements in the speed and quality of cell banking and testing. These increased efficiencies will be focused mainly in the area of staff "contact time" where automation of some banking functions and reduction in sample preparation time for QC and research will free up significant staff time for enhanced characterisation of clinical seed stocks. This streamlining will result in improved quality and consistency of cell products: minimising process variability and enhancing robustness and reliability. It will also enhance the Bank's ability to conduct underpinning development work on key safety characteristics which will define the suitability of cell lines used for therapy, such as studies of genetic stability and maintenance of phenotype and function after banking and extended in vitro culture. This information will be essential for the utility of these cells for cell-based medicines. It will also enable the Bank to provide further support to the clinical and manufacturing communities in the development of both clinical hESC and hiPSC lines. The equipment will also be used in the numerous current and proposed collaborations with academic, regulatory, SME and pharmaceutical partners, in which the UKSCB is providing support to facilitate regulatory approval of commercial products.

Investigators: Paul Dalby (Biochemical Engineering, UCL), Paul Matejtschuk (NIBSC, HPA) We aim to establish an automated microscale platform to assess therapeutic protein, vaccine and cell formulations, and identify any correlations (or lack of) between physical property measurements, forced degradation studies, and the long-term shelf life of liquid and freeze-dried formulations Significance: To minimise the chemical and physical degradation of biologics, excipients can be added in complex formulations. The optimisation of freeze-dried or liquid formulations is currently empirical, and requires many time and sample-consuming experiments. To save time and materials, initial formulation screens often measure properties such as melting temperatures (biologic thermostability - Tm & glass transitions - Tg), aggregation propensity (B22 values), or aggregate formed by forced degradation at elevated temperatures (light scattering, SEC). The validity of using such measurements as indicators for long term (1-2 yr) storage stability is still debated as degradation mechanisms can be complex. We recently established accurate microscale methods to subject small quantities of biologics to bioprocess stresses such as protein refolding, agitation and freeze-drying [1,2] (EPSRC studentship with NIBSC), and rapidly evaluate their thermostability [3,4], activity [1,2,5] and propensity to aggregate [1,6]. Recent BBSRC/BRIC and follow-on (BB/FOF/272) projects established microfluidic techniques to measure the thermostability of 85000-fold less protein [7]. We aim to integrate the microscale techniques to simultaneously evaluate multiple bioprocess stresses and molecular properties, obtain a body of data for a range of biologics and formulations, then identify or disprove potential correlations between initial (Tm, Tg, B22 by DLS, activity), medium-term (forced degradation) and long-term (shelf life) properties. Workplan: Year 1 - training in analytical and bioprocess skills at NIBSC. Formulate and freeze dry a range of biologics [8,9] in process vials. Evaluate their biological activity and aggregation. Learn existing microscale and DoE techniques at UCL and NISBC, and validate them in process scale vials. Integrate microscale techniques to allow parallel evaluations of the impact of formulations on liquid and freeze dried sample stability, and sample properties. Year 2 - combine microscale techniques and Design of Experiments (DoE) to derive parallel surface response models for the impact of formulations on product Tm, Tg, B22, aggregation, tolerances to freeze-drying and forced degradation (liquid and freeze-dried), for a wide range of proteins, vaccines and cells. Year 3 - evaluate long-term storage (0-12 months at 70 to 45oC) of optimal and selected sub-optimal liquid and freeze-dried formulations in 10 ml vials. Measure biological activity, aggregates and misfolded forms, oxidation and deamidation by standard HPLC, DLS and LCMS techniques at UCL and NIBSC. Compare data to equivalent short-term property measurements, and medium term forced degradation studies from yr2, to identify or disprove correlations between them. Determine the best microscale DoE, measurement and bioprocess stress strategy for predicting 10 ml vial formulations with long-term stability. 1. Mannall GJ, Myers JP, Liddell J, Titchener-Hooker NJ, Dalby PA 2009 Biotech Bioeng 103:329 2. Grant Y, Matejtschuk P, Dalby PA 2009 Biotech Bioeng 104:957 3. Aucamp JP, Cosme AM, Lye GJ, Dalby PA 2005 Biotech Bioeng 89: 599 4. Aucamp JP, Martinez-Torres RJ, Hibbert EG, Dalby PA 2008 Biotech Bioeng 99:1303 5. Miller OJ, Hibbert EG, Ingram CU, Lye GJ, Dalby PA 2007 Biotech Letts 29:1759 6. Ahmad SS, Dalby PA 2010 Biotech Bioeng 108:322 7. Gaudet M, Remtulla N, Jackson SE, Main ERG, Bracewell DG, Aeppli G, Dalby PA 2010 Protein Science 19:1544 8. Hubbard A, Bevan S, Matejtschuk P 2007 Anal Bioanal Chem 387:2503 9. Matejtschuk P et al 2009 Biologicals 37:1-7