Predictive chemometrics modelling for enhanced robustness of integrated continuous biomanufacturing processes

The proposed PhD project will address the challenge of developing robust continuous manufacturing processes for new modalities of biopharmaceutical proteins such as bispecific antibodies. Continuous bioprocessing is experiencing a resurgence within the sector. It has the potential to enhance product quality and radically reduce capacity and facility footprint requirements for manufacture. Furthermore, continuous processing is considered by some to be better able to address market demand uncertainties and minimise technology transfer risks. A rigorous approach to assessing the impact of introducing products adopting continuous bioprocessing on product quality, process robustness and portfolio management is required to determine the best route to commercialisation of new modalities. The department of Biochemical Engineering at UCL is well-placed to address this challenge as it has pioneered the development of decisional tools comprising bioprocess optimisation and chemometrics. These tools will enable ultrascale-down studies of integrated unit operations to better mimic large scale continuous bioprocesses, the enhanced understanding of which will address effective bioprocess design, portfolio management and capacity planning decisions.
This project aims to create experimental and predictive modelling tools to assess and optimise novel ideas for end-to-end continuous bioprocessing of biopharmaceuticals. The potential of continuous processing to maintain and control product quality of biologics will be evaluated.
MedImmune is evaluating the potential of integrated continuous bioprocessing at bench scale with ATF perfusion culture linked to multi-column continuous chromatography systems. The development of an integrated scale-down platform of perfusion culture linked to continuous capture chromatography will enable higher throughput experiments to be performed to explore the impact of critical process parameters in the continuous upstream and downstream processing steps on quality and performance.
Initially, analysis of the capabilities and limitations of existing perfusion culture mimics (e.g. with high throughput mini-bioreactors (eg ambr, Sartorius) and spin tubes) and continuous chromatography mimics (e.g. 1ml columns) will be carried out. This will form the basis of novel designs of scale-down mimics that overcome limitations with existing methodologies and have sufficient sensors integrated into the devices for e.g. pH and dissolved oxygen for cell culture. The performance of the integrated scale-down platform will be validated with bench scale (5L) perfusion runs linked to continuous chromatography at MedImmune.
Experimental data generation for integrated continuous bioprocesses
The scale down perfusion mimics will be linked to continuous capture chromatography mimics for experimental data generation linking cell culture performance with downstream performance. Key process parameters in perfusion culture (e.g. feed flowrates) and continuous chromatography (e.g. residence time, flowrates) will be identified using risk analysis. Key performance outputs (e.g. productivities) and quality attributes (e.g. glycosylation, charge isoforms, product-related impurities) to measure in each experiment will be identified. These inputs and outputs will form the basis for DoE experimentation using industrially relevant cell lines from MedImmune expressing novel modalities eg bispecific antibodies.
Chemometrics for bioprocess modelling and control of continuous processes
Experimental data will be used to build predictive cause-and-effect models that link critical process parameters (e.g. perfusion feed flowrates) to critical quality attributes (e.g. aggregates) and performance metrics (e.g. perfusion culture productivity, chromatography yield) using advanced chemometrics / multivariate data analysis techniques. The temporal impacts of continuous operation will be explored; m