Söderström, Ksheereja; (2024) Scale-down models for increased capacity in egg-based Influenza vaccines manufacturing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Influenza vaccines are required to be re formulated every year to account for antigenic drift with recommendations coordinated by the World Health Organisation, leaving only six months to be able to choose and characterise a suitable reassortant of a recommended strain and proceed to commercial manufacturing of influenza vaccines. Due to exacerbating healthcare crises in countries brought about the Covid-19 pandemic and other factors, the demand for influenza vaccines has increased, prompting a need for capacity expansion (UNICEF, 2020). This has necessitated the implementation of novel approaches to increase drug substance or drug product yields in a rapid and robust manner. In this project, the impact of disc stack centrifugation on virus yield was evaluated in different influenza strains using new analytical characterisation tools. A further scale-down approach has also been evaluated for suitability in estimating initial virus yield to screen reassortants using the KompAs® shear device and suitable analytical tools. The other major focus of this work was the successful deployment of a yield improvement, which was performed by first creating a robust pilot scale model using Quality-by-design principles, and then using the aligned pilot plant to demonstrate that the variation to the process increased yield and did not affect the label claims of the drug product. The data from this pilot model was sufficient to obtain regulatory approval without any need for process validation at manufacturing scale. A yield uplift of up to 30% for Influenza A strains was seen, resulting in cost savings and the organisation’s capability to meet future demand and expand into new markets. As the Influenza community is moving to new manufacturing platforms (e.g. cell-based, mRNA etc), they often are not accessible to public health programmes due to low yields and high manufacturing costs. This work demonstrates that the egg-based process, though mature, can benefit from such rapid screening tools for candidates and yield improvement ideas and their implementation through a creative regulatory strategy.

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