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FindA University Ltd Featured PhD Programmes
FindA University Ltd Featured PhD Programmes

Continuous manufacturing processes for mRNA-based therapeutics


Department of Biochemical Engineering

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Dr M Marques No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

The use of vaccines prevents the death of nearly 3 million people each year. However, continuous innovations are essential to overcome persistent challenges in reaching a global vaccination programme. These challenges encompasses limitations in the manufacturing capacity, distribution and ultimately the cost of vaccines. The manufacturing of vaccines relies on the use of batch operations in large facilities requiring highly skilled operators, which concomitantly contribute significantly the total vaccine costs. The limitations in manufacturing technologies are nowadays clearly visible with our reduced ability to respond to the COVID-19 pandemic quickly and efficiently.

In particular, mRNA technology is showing potential to be an alternative to traditional vaccines and plasmid DNA-based therapies. These small molecules are ideal vaccine candidates since they are none infectious, integrative and are readily degradable by the cellular mechanism. mRNA is precise as it will only express a specific antigen and induces a directed immune response (humoral and cellular) without the aid of adjuvants. The manufacturing of these molecules is highly flexible, standardised and since the production is based on the in vitro transcription reaction is performed using a DNA template and RNA polymerase, safety concerns can be low due to the absence of cell-derived impurities or viral contaminations. However, the lack of a scalable and cost-effective manufacture process that consistently delivers a high-quality product compromises the application of mRNA-based therapies.

To achieve this aim, miniaturized continuous-flow reactors are prime candidates as a production platform. Their small dimensions allow experiments to be performed with much smaller volumes compared to traditional batch systems, offering significant cost reduction when using expensive substrates or enzymes. Within these reactors the control of reaction parameters is facilitated, and in-line purification with recovery of products has been demonstrated. Additionally, reactions can be potentially accelerated due to enhanced mass transfer with a concomitant decrease in reaction time. Therefore, miniaturized continuous-flow reactors will in the future form the basis to acquire high-quality data rapidly, allowing scalable and cost-effective manufacture platform for mRNA-based therapies to be established.

Project Objectives
• Development of a production process for 5’ capped mRNA using, for example, RNA polymerase and vaccinia capping enzyme complex immobilized in miniaturized continuous-flow devices.

• Design, fabricate, and characterize scalable purification processes (e.g. tangential flow filtration or multimodal chromatography units) to obtain 5’ capped mRNA free from reaction components and malformed mRNA.

• Assembly and validation of a continuous bioprocess sequences of the mRNA manufacture process using miniaturized continuous-flow devices.


Output & Impact
This project aligns with UK strategic priorities in the area of Industrial Biotechnology and the departmental EPSRC Future Biomanufacturing Research Hub, EPSRC Future Vaccine Manufacturing Research Hub and EPSRC Future Targeted Healthcare Manufacturing Hub. Due to the high relevance and timeliness of this research direction, we anticipate that each objective of the project will lead to a publication output. The results obtained throughout this project will be included in teaching of undergraduates or postgraduate modules.

Applications
Applicants should have a degree equivalent to a UK first class honours, or a high upper second class, in Engineering or Physical Sciences. This PhD will be multidisciplinary, straddling both biochemical and chemical engineering. The successful candidate should have strong analytical skills and aptitude for molecular biology, biocatalysis, and reactor engineering.

The starting date for this PhD will be 28 September 2020. To apply for this studentship, please send your max. two-page CV and cover letter by email to Dr Marco Marques, project supervisor to arrive no later than 12pm on Monday, 13th July 2020. In addition to this, you must submit your formal application through UCL’s Application portal for the Research Degree: Biochemical Engineering course for 20/21 entry, indicating Dr Marques as potential supervisor in the relevant section. More information about the application process is available on the department’s website: https://www.ucl.ac.uk/biochemical-engineering/study/postgraduate-research/biochemical-engineering-mphilphd

The University actively supports equality, diversity and inclusion and encourages applications from all sections of society.

Funding Notes

This research project has funding attached. It is only available to UK citizens or EU citizens. The studentship covers the full cost of UK/EU tuition fees, plus a tax free stipend for four years. Annual stipend for 20/21: £17,285.


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