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

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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.