EPSRC-SFI: Cutting Edge Analytical Solutions for Smart, Integrated, Efficient Biopharmaceutical Production

There was a time when small molecules dominated the pharmaceutical market for the treatment of diseases like cancer as well as bacterial, fungal and viral infections. However, over the last decade biopharmaceuticals have revolutionised the treatment of chronic diseases, as well as a number of orphan diseases. Advances in biopharmaceutical research have contributed to reduction in mortality from major diseases and also contributed towards increased life expectancy.

Around 40% of the thousands of pharmaceuticals in the current Research and Development pipeline are biopharmaceuticals. These protein molecules have the potential to offer life-changing targeted personalised treatments to millions of patients and address the challenges associated with ageing populations.

While mammalian cell culture for biopharmaceutical production is well established, the product must have the correct fidelity in terms of the structure of the protein and the way in which it is glycosylated (the patterns of sugars attached to these proteins). Therefore, product quality needs to be monitored during the fermentation process to confirm the safety and efficacy of the final product.

However, the development and optimisation of these cell factories is limited by the performance of currently available analytical technology.

Currently biopharmaceutical process development is performed in a rather empirical manner, based on the ability to measure limited features such as cell growth, cell viability and product expression using ELISA (an antibody-antigen detection system). In addition, technologies that enable product quality and safety characteristics to be determined are not employed until late in the product development cycle due to the low throughput of currently employed analytical platforms, as well as the lack of ability to couple these within the fermentation system.

In order to address this unmet need we have assembled a unique team with complementary skills in biologics and proteomics, on-line analysis of fermentations with Raman spectroscopy and mass spectrometry-based metabolite and secreted protein analyses, as well as data processing using multivariate chemometrics and machine learning. This grouping puts us in a rare position to exploit work at the cutting-edge trisection of biopharmaceuticals, analytical chemistry and informatics.

Finally, and most importantly, we have access to a state-of-the-art automation system for the production of biologics at NIBRT (National Institute for Bioprocessing Research and Training) and we shall focus on antibody production by Chinese hamster ovary (CHO) cells as this production system dominates the pharmaceutical market. We shall develop an integrated technology platform based on: (i) MS for measuring proteins secreted into the culture media; (ii) at-line LC-MS for measuring small molecules in culture media that are either secreted or taken up by the cells; and (iii) Raman spectroscopy for on-line monitoring of the protein structure and glycosylation pattern.

In addition, we shall use computational approaches to control the fermentation based on feed-back from the analytics as well as using computer software for designing optimal growth media and feeding regimes during fermentation to enhance protein production and maintaining cellular health.