Continuous manufacturing processes for mRNA-based therapeutics

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 cells. mRNA is precise as it will only express a specific antigen and induces a directed immune response (humoral and cellular) without the aid of other moelcules. 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 purification with recovery of products is facilitated. 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 using enzymes in miniaturized continuous-flow devices.

- Design, fabricate, and characterize scalable purification processes in order to obtain 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.

Research methodology
The mRNA molecules will be produced using molecular biology approaches in miniaturized continuous-flow devices. The fabrication and operation of these devices will rely on microfluidic techniques.


Impact
This project aligns with UK strategic priorities in the area of Industrial Biotechnology, in particular with the EPSRC theme of Manufacturing the future, and with the departmental EPSRC Future Biomanufacturing Research Hub, EPSRC Future Vaccine Manufacturing Research Hub and EPSRC Future Targeted Healthcare Manufacturing Hub.