Real-time monitoring of biopharmaceutical aggregation under flow by fluorescence

Biopharmaceutical proteins constitute a growing proportion of the drug catalogue for virtually all major pharmaceutical companies. The global market has grown from $8b in 1992, to $149b in 2010 and reached an estimated $239b in 2015. There are currently about 120 biologics in clinical use, with a further 400 currently in clinical trials. There are, however, a number of associated challenges in their manufacturing and formulation. One key bottleneck is preventing their physical degradation, which occurs primarily through irreversible aggregation pathways. Due to potential immunogenic effects, aggregation is a critical attribute strictly regulated in the final drug product. Operations such as chromatography, filtration, storage, pumping, or syringe injection, stress proteins causing aggregation through exposure of the proteins in solution to solid surfaces (i.e. solid-liquid interface) or to the air (i.e. air-liquid interface) often in the presence of flow. Because these stresses occur simultaneously, it has not yet been possible to identify the fundamental factors controlling aggregation. As part of this project, we will develop a new technology for monitoring aggregation in situ by combining our lab on a chip technology with confocal microscopy and fluorescence detection technology. This allows for monitoring at high resolution the spatial and temporal evolution of aggregation. We will combine the measurements with computational fluid dynamics to determine how the flow stresses in different geometries impact aggregation. We expect this will lead to new ways for monitoring and predicting degradation of proteins in processing-relevant flow conditions. Research Training: The project provides training in a broad range of biophysical characterization methods combined with modelling by computational fluid dynamics. The Curtis lab contains a suite of light scattering detectors, an electrophoretic light scattering detector, and a size-exclusion chromatography-multi angle laser light scattering (SEC-MALLS) set-up, all of which will be used off-line for protein physical stability indicators. Some of the work will use the analytical facilities at Manchester including temperature programmable multi-detection systems for high throughput stability screening and analytical ultracentrifugation. These methods are rapidly being integrated into biopharmaceutical research and development. The Pluen lab provides access to the confocal microscopy with fluorescence detectors to be integrated with the lab on a chip technology. Claudio Pereira da fonte will provide support for carrying out the computational fluid dynamics. The project will be part of a larger grouping of academics and students focused on research into the next generation of bioprocessing and formulation development. As part of this grouping, the student will have access to academic and industrial workshops focusing on all aspects of biopharmaceutical development including cell biosciences, downstream bioprocessing, formulation development and bioanalytical characterization. These will showcase how tools developed in academia are now being applied in an industrial environment.
Applicants should have or expect to achieve at least a 2.1 honours degree in chemical engineering, biochemical engineering, pharmacy, physics, biochemistry, chemistry, or a related discipline