Creation of a process understanding of chromatographic performance loss during biotherapeutic manufacture: A UK-India partnership

The importance of international collaborations in research is recognised both by individual researchers and by institutions and government, with studies showing that the average impact of publications resulting from these collaborations is significantly higher than that of papers with national co-authorship. This collaborative project between leading academic groups in the UK and India addresses the purification operations used to manufacture biopharmaceuticals e.g. antibodies and hormones such as insulin. They are supported in this activity by four industrial partners selected to provide support to the analytical and manufacturing aspects (being leading companies in their respective areas) as well as to provide a route to transfer the findings of the research to practice.

Many of the latest drugs are based upon proteins rather than traditional small molecules (e.g. antibiotics). These protein drugs are produced for the treatment of diseases such as cancer. Antibodies such as Herceptin dominate this market. The research collaboration described here is focused on the study of the performance of the core purification method used for the manufacture of biopharmaceuticals - chromatography. Specifically we seek understand the mechanisms which determine the manufacturing lifetime of this operation and can lead to changes in performance. This issue presents a major hurdle to manufacturers. They must establish a robust purification process with acceptable costs for production before seeking approval for such medicines from the regulatory agencies. Clearly problems leading to delays can lengthen the times before medicines can made available to patients. This can affect both manufacturers of new products and those seeking to compete at reduced costs and widen the availability of this class of medicines (products often termed biosimilars).

In comparison to other areas of manufacturing, bioprocessing is unusual in several respects. Typical product quantities are small (~250 kg/year), but are manufactured to extremely high purity and quality specifications (impurities < 0.001%). The variability typically seen in these processes has led to extremely regulated manufacturing, whose dictum is that "the process is the product". No significant change can be made to a licensed manufacturing process without detailed and time-consuming review by the international regulatory authorities. Developing and validating a bioprocess for manufacture takes ~10 years at a cost of £800M. Development is often empirical, with little use of modelling compared to other manufacturing sectors. These unusual features emphasise the need for a more fundamental understanding of the bioprocess. This research programme is structured towards building mechanistic understanding of the events that lead to changes in chromatographic performance in the manufacturing setting. There is evidence for several mechanisms the first stage is to structure these into a series of proposed mechanisms. Following consultation and study of historical data from our industrial partners we will embark upon experimental studies. Here detailed analytical measurements are required to identify specific critical species that are associated with the root cause of the mechanism.

The project is to be led by UCL in London and IIT in Delhi in collaboration with IIT Bombay and the University of Kent. These academic groups are supported by industrial partners; ABB, Dr Reddy's Labs, GE Healthcare, Genzyme, PerkinElmer and Regeneron.

ECONOMIC IMPACT: Manufacturing is the most productive sector of most industrial economies. Manufacturing in the high-technology areas, including biotechnology and bioprocess engineering, has an especially strong impact, with each manufacturing job supporting sixteen others. Bioprocess engineering offers an unusually high return on investment to improve the state of manufacturing, with worldwide revenues of ~£110 billion in 2009. The Bioscience 2015 Report to the UK Government by the Bioscience Innovation Growth Team highlighted "the inevitable increase in the importance of bioprocessing". This programme of research described here involves close collaboration between industrial and academic partners in the UK and India led by UCL in London (with University of Kent, PerkinElmer, Regeneron, Genzyme and GE Healthcare as partners) and IIT in Delhi (with IIT Bombay, AAB and Dr Reddy's Lab's as partners). The ultimate goal is to generate new, cutting edge insights into the purification operations used in the manufacture of biopharmaceutical drugs with maximum potential for impact here in the UK, as well as mutual benefit in India.

IMPACT ON PEOPLE AND SOCIETY: This proposal would provide the opportunity to form strong and lasting connections between academic staff and postdoctoral researchers in India and the UK and provide a legacy for further collaborative research endeavours between the partners. The importance UCL attaches to such international collaborations can be seen in the recent award of the pan UCL EPSRC grant "Global Engagement for Global Impact: Strategic Interaction with China, India, Germany and USA" of which the Biochemical Engineering is one of the 10 participating Departments and Institutes. Industrial collaborators are essential in this kind of effort, and relevant industrial support will be provided by biotechnology companies (Genzyme in the UK and US, Regeneron in the US and Dr Reddy's Laboratory in India), leading chromatography resin supplier (GE Healthcare, multinational) and PerkinElmer (UK and US) as a leading in analytical technology company.

IN SUMMARY the successful prosecution of the proposed work would have substantial impact on the biotechnology industry, in several ways. First, the economic driver is clear, as discussed above, since expensive resins dominate current cost-of-goods for complex biologics. Second, this kind of success will help to demonstrate to the empirically-minded that carefully constructed and validated mathematical models have an important role to play in biotechnology. Third, this international collaboration would set the scene for more wide-ranging collaborations between India and the UK in the future. All steps facilitating the development and supply of the next generation of medicines the world so crucially needs.