Seeding and Continuous Biopharmaceutical Crystallisation (SCoBiC)

Biotechnology has made significant advancements in the understanding of human genomics and proteomics revolutionising medical diagnosis, prevention and treatment. Advances and breakthroughs in target-oriented biotechnology research have been used to enhance the synthesis of a number of commercially significant products. It has been reported that there are over 6000 biopharmaceuticals currently in development, potentially worth in excess of $100's bn (£145bn in 2012). Despite the increasing successes in discovering protein-based medicines, their manufacture in a cost effective and reliable fashion remains a major industrial challenge, which currently limits the ability of the biopharmaceutical industry to deliver solutions to patients. The vision here is to develop a programme for process intensification and de-bottleneck of downstream bioprocessing (DSB), by implementation of Seeding and Continuous Biopharmaceutical Crystallisation (SCoBiC), for the separation and purification of biopharmaceuticals. The ambition of this proposed project to develop strategies for a continuous biocrystallisation process, including selective crystallisation directly from multicomponent fermentation broths by seeding, for whole antibodies and antibody fragments. The goal is to reduce manufacturing costs, provide for simpler processes while achieving the high purity of material achievable from multi step chromatography. This ambition is driven by the awareness that separation and purification processes represent one of the most time and cost-intense downstream operations in the manufacture of commercial biopharmaceutical products. This proposal will develop a continuous biocrystallisation platform as an alternative to conventional DSB, offering improvements to manufacturability, enabling higher throughput, lowering the product costs, an increase in product quality and stability, including opportunities for novel formulations and technologies.

This research work will have a direct impact on the academic community and the commercial sector (biopharmaceutical manufacturing community, equipment manufacturers and computation modelling companies).

Findings from this research work may lead to an improved understanding of macromolecular nucleation and crystallisation. Scientists involve in work relating to structural determination will benefit directly, in the availability of new strategies to improve the likelihood and probability of crystallisation of complex macromolecules. This will have an impact on the wider community involved in protein structural studies, from the understanding of how proteins work to drug discovery. Work on preparation and characterisation of next generation nanotemplates will benefit material scientists. Whilst the scaling-up and development of a continuous platform, including modelling work, will directly benefit engineers.

It is likely that the research will also have a direct impact commercially. Biopharmaceutical manufacturing companies will have access to a new approach for the isolation and purification of proteins; which will lead to a reduction in manufacturing costs, improved stability of products and potentially ease of formulation. There will be opportunities developed from this research for instrumentation and equipment companies to provide solutions to the biopharmaceutical companies. I also expect that companies providing modelling software to benefit from the fundamental science developed in this research to improve their models, and further apply the approaches to biopharmaceuticals.

The improvements to downstream separation of biopharmaceuticals will inevitably reduce manufacturing costs, which currently can account up to 80% of production cost. This reduction in manufacturing cost should lead to reduced product costs, and possibly more accessible medicines for the patients.

The development of biopharmaceutical products has seen a significant acceleration in the pharmaceutical industry with a relatively high success rate. Over 20% of drugs in the market are discovered and developed in the UK. Many companies, including AZ, FDB, GSK, etc in the UK, have set-up dedicated business units in the area. The compounds considered range from monoclonal and domain antibodies to "smaller" antisense or doubled stranded siRNA oligonucleotides. The UK currently has a world-class pharmaceutical industry with trade exports of over £20b since 2009 (till date) and investing over 23% in R&D (highest in Europe). The global pharmaceutical and biologics market is expected to grow between 3-6% annually this decade. The UK is well placed to take a world-leading role in this exciting field, recognised by the inward investment, high level of R&D spend, and strong commitment from the government as reported in the Bioscience 2015 government report. Nevertheless, this aim is an aspiration objective with the USA maintaining a clear lead in biotechnology currently. This proposal has the potential to delivery innovative technology resulting in efficient manufacturing, producing high value products that are underpinned by scientific understanding and for which there is potential for global demand.

It is anticipated that the impact and benefit of the research, will start to be realised within the first couple of years of the programme. A prototype if planned for the later stage of the programme and will be tested at our industrial partner's site (FDB). If successful, the goal is to deliver biocrystallisation as an industrial bioseparation step within the next 10 years.