Automated and cost-effective production of mRNA vaccines as well as cell and gene therapeutics

The development of drugs for advanced therapies such as gene and cell therapeutics as well as mRNA vaccines is booming. Driven not least by the COVID-19 pandemic, the market for advanced therapy medicinal products (ATMPs) is growing steadily. These drugs for novel therapies are a groundbreaking milestone in the treatment of complex, previously incurable diseases. These include many cancers, for example. However, ATMPs are still only rarely administered.

The limiting factor is the labour-intensive and cost-intensive manufacturing process, which has often been carried out manually to date. Digitalised, automated production processes are required in order to be able to offer customised, personalised therapies to as many patients as possible. In the lead project RNAuto (see box), seven Fraunhofer Institutes are therefore pooling their expertise from the fields of medicine, biology and engineering to produce mRNA vaccines and gene and cell therapeutics that use mRNA as a starting material automatically, quickly and cost-effectively in large quantities.

One focus of the research work is the development of a screening system that is scalable up to industrial scale with digital process control and data-driven quality control, with which mRNA (messenger RNA) can be encapsulated in nanotransporters made of lipids. The project team is initially aiming for mRNA drug production on a laboratory scale of up to 20 ml. In cooperation with the Fraunhofer Institutes for Microsystems and Microtechnology IMM, for Production Technology IPT and for Cell Therapy and Immunology IZI, the Fraunhofer Institute for Experimental Software Engineering IESE is coordinating the design and construction of the automated, component-based screening system.

Exchangeable and combinable components

The system with a size of 1.20 m x 0.90 m x 0.90 m consists of scalable, flexible and manufacturer-independent production modules that can be exchanged via plug and play in the event of a defect.

In order to produce a reliable mRNA drug, consistent product quality must be guaranteed, including quantification of the amount of encapsulated mRNA in the nanotransporters. The uneven ratio of encapsulated mRNA at the start of the mixing process and high flow rates in the production process pose challenges for continuous quality control. The technique of packaging mRNA in lipid capsules or gels is complex. Numerous parameters such as the length and structure of the mRNA, the size, viscosity and charge of the lipids or machine settings such as pressure, flow rates and temperature influence the packaging properties," says Rolf Hendrik van Lengen, Programme Manager Digital Healthcare at Fraunhofer IESE. Due to the resulting fluctuations in the viscosities of the mixture, refractive indices, conductivities, temperatures and pH values and the corresponding influence on product quality, not only process optimisation but also comprehensive quality control of the fractions is crucial.

System with integrated online analytics for digital quality assurance and documentation

Quality assurance and process control, i.e. the control of pumps, mixers and the like, are completely digitalised – üvia digital twins and AI-supported software tools – a novelty in the production of mRNA active ingredients. The researchers are utilising their experience from Industry 4.0 and using software such as the Industry 4.0 middleware Eclipse BaSyx from Fraunhofer IESE and the process control software COPE from Fraunhofer IPT. The required digital information is supplied and documented to the digital twins via dynamic light scattering (DLS) - a measurement technology for characterising particle sizes in emulsions - as well as additional temperature and pressure sensors, with each component represented by its own digital twin.

The screening system enables the project partners to determine the optimum combination of mRNA and lipids and the best degree of packaging. Each individual test with modified parameters can be digitally recorded using the digital twin of product quality. Any errors, such as temperatures that are too low, are documented in this way and the associated information is made available digitally. In the final expansion stage of the system, the digital twin will be able to initiate appropriate corrective measures in such a situation.

»With our integrated online analytics, we can automatically measure the quality during the manufacturing process and thus determine the optimum composition of the active ingredient. In many manufacturing processes in the pharmaceutical industry, samples are usually taken during the ongoing process and analysed externally. In the worst case, complete batches have to be disposed of. We avoid this with our online analytics«, explains the computer scientist. »The system will enable automated, component-based, flexible and validatable production.« Upon completion of the system, the research team will be able to produce 20 ml of mRNA active ingredient with assured quality within a few seconds.

Once the plant has been set up, the mRNA active ingredient will be produced automatically in the RNAuto project for prophylaxis against the viral disease West Nile fever and tested for its effectiveness at the Fraunhofer IZI in Leipzig. At the end of 2025, the plant is to be completed at the Fraunhofer IMM in Mainz and also made available to industrial partners.

The heart of the system demonstrator - the pumps, the mixer and the digital components - will be presented from 13 to 16 November at COMPAMED in Düsseldorf at the joint Fraunhofer stand in Hall 8a, Stand G10.

Source: Press release Fraunhofer-Gesellschaft from 02.11.2023