Manufacturing medicines, medical devices and medical products in Europe is necessary to ensure that cutting-edge treatments are available to EU patients as fast as possible. However, manufacturing medical products is not straightforward – unlike in other sectors, very stringent safety considerations must be taken into account and a high level of consistent quality control is needed so that patients receive the highest level of care.
Several IHI and IMI projects are working on developing new manufacturing techniques, reducing the time that it takes to manufacture critical medical products, providing new tools to make the process more efficient and safer, as well as ensuring that Europe remains at the forefront of manufacturing techniques for innovative treatments like theranostics.
Cutting CAR-T manufacturing from 6 weeks to 24 hours
CAR-T cell therapy is a revolutionary new personalised treatment for blood cancers. This therapy represents a new lifeline for people with cancer. However, one key issue with CAR-T cell therapy is that each therapy must be manufactured individually for each patient. White blood cells are collected from a patient, and they are then sent to a centre where the cells are treated and modified to enable them to attack specific proteins found on cancer cells. All in all, the manufacturing process takes between four and six weeks, a timeframe that is too long for many patients.
The EASYGEN project aims to cut this manufacturing time from four to six weeks to 24 hours, and to enable hospitals to manufacture the individual treatments on-site. The device that EASYGEN is developing will automate all the steps between blood cell collection and administration of the modified cells.
“Only 18% of eligible EU patients currently receive CAR-T therapy,” says Sonja Steppan. “Uptake among eligible patients varies widely across Europe – from around 11% in Italy to about 30% in France, highlighting substantial under-utilisation and access disparities. We would like to reduce the manufacturing time thus increasing patient access to this treatment.”
This improvement in the manufacturing of CAR-T cell therapies will also bring the costs of the treatment down, according to Steppan. Currently, CAR-T cell therapies can cost between €250K and €350K per patient in the EU.
A number of factors cause these high prices, and EASYGEN hopes to tackle this.
“The manufacturing process is inherently complex and individualised, as each therapy is produced from a patient’s own cells in specialised facilities,” she says. “This limits economies of scale and significantly increases production costs. In addition, centralised manufacturing models require complex, tightly coordinated logistics — including time-critical transport and cold-chain handling.”
Industry analyses suggest that logistics and supply-chain activities can account for up to around 30% of total manufacturing-related costs. Decentralising CAR-T production and bringing manufacturing closer to, or directly into, hospitals could therefore meaningfully reduce costs and help make this therapy more accessible.
Thera4Care strengthens Europe's capability to manufacture theranostics
Theranostics is an innovative approach to treating cancer that combines two components – a ligand which is designed to detect cancer cells, and a radioisotope which either destroys them or makes them visible using diagnostic imaging.
Although promising, it is a relatively new field, so manufacturing times are long and efficient supply chains have not yet been established. The Thera4Care project seeks to remedy that.
“Because theranostics is so new, it takes a long time from drug discovery until it reaches the market,” says Warren John of Collaborate Project Management, which facilitates management and communication within the Thera4Care project. “This is something that Thera4Care tries to address: to create a pipeline to improve the efficiency of drug discovery to drug use.”
At the moment, the main challenge for theranostics manufacturers in Europe is the supply of isotopes – which are not always readily available in Europe. Setting up effective supply chains and pathways is crucial to the project.
“Some minerals like copper and lead are very rare in Europe and will need to be provided from outside Europe,” explains Salvatore Annunziata of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS, who is the scientific coordinator of Thera4Care.
Within Europe, Thera4Care is expanding the network of copper-producing isotope sites with good manufacturing practices and developing a hardware and software platform to share information between the sites on common methods and approaches.
Radioisotopes rapidly decay and emit radiation, and for this process to work effectively, they cannot be too far from the targeted cells as the radioactivity wears off rapidly.
Typically, particle accelerators called cyclotrons are used to produce radioisotopes, and machines called PET and SPECT imaging scanners are then used to detect the radioisotopes in the body. Both types of equipment are being provided by GE HealthCare for the project, and one focus will be on delivering novel SPECT/CT imaging scanners, which will improve the diagnosis and monitoring of cancer. A new scanner called StarGuide GX has been developed by GE HealthCare and will be tested and optimised for theranostics within Thera4Care.
“Imaging alpha‑emitting radionuclides is not straight forward and will require advanced technology to overcome current limitations. The Thera4Care collaboration enables validation and demonstration of the next generation of digital SPECT/CT capabilities, supporting improved diagnosis and monitoring of cancer by helping clinicians better understand, measure, and optimise cancer therapies,” added Ben Newton, general manager of oncology at GE HealthCare.
While isotope supply is a struggle, there are a lot of ligands available in Europe – these are pharmaceutical products that are owned by companies and protected by patents. GE HealthCare and other private partners in Thera4Care are providing ligands for the project.
“We have very large capabilities in Europe in terms of diagnostics, thanks to GE HealthCare and other providers,” says Annunziata.
Leveraging new technology to dramatically reduce vaccine manufacturing time
It takes a long time to develop a new vaccine. The road from identifying an antigen to phase one trials alone can take ten years. The Inno4Vac project aims to shorten this early stage from ten years to a few months, by harnessing the latest advances in immunology, disease modelling, and both mathematical and in silico modelling.
“Vaccines are technically challenging to manufacture,” says Dr. Nicola Viebig, Director of Research and Project Lead for Inno4Vac, European Vaccine Initiative. “Inno4Vac is building digital tools (such as mathematical models, digital twins and open-source integrative platforms) for improving vaccine manufacturing techniques. These tools allow acceleration and optimisation of the vaccine production process, and these efforts will meet the challenge of quickly producing vaccines to defend against existing and future public health threats.”
In vaccine manufacturing, the antigen is the active ingredient (usually a weakened part of the pathogen) that teaches the immune system to fight disease. Excipients are inactive substances that help to ensure that the vaccine is stable and safe while eliciting an effective response from the immune system.
Using advanced computing techniques, the Inno4Vac team has developed a model that can predict whether a new vaccine formulation will be stable and can determine the best composition of excipients to use. Vaccine manufacturers can plug the properties of any excipient into the model and receive an estimation of how effective that excipient will be.
One of the manufacturing efforts performed within Inno4Vac has been the production of a C. difficile strain for use in controlled human infection studies, which required alignment with good manufacturing practice (GMP) guidelines. Regulators have advised manufacturers of challenge agents – typically pathogens that are administered to humans to elicit an immune response, as is the case for many vaccines – to adhere to GMP guidelines so as to ensure high quality production until definitive guidelines are made available.
“Because of the nature of the challenge agent – a spore-producing bacterium – the identification of a commercial manufacturer was not possible, so the consortium produced the challenge agent internally. Commercial partners within Inno4Vac provided financial and legal support that enabled the successful production and release of the challenge agent, that is being now characterised in a clinical trial,” said Meta Roestenberg, who is in charge of Inno4Vac's work on controlled human infection models.
Inno4Vac is also contributing to the open-source software CADET for designing and optimising production processes in biotechnology. This software efficiently simulates coupled networks of chromatography, filtration, crystallization, and fermentation units, and has an active community of users and developers.
Optimising bioreactor control for faster, more stable drug production
Biopharmaceuticals are large molecules used for the treatment of a broad spectrum of diseases including cancers and inflammatory diseases. They are produced using cells in bioreactors, where temperature, pH, oxygen levels, salinity and a whole range of other factors are carefully controlled to provide the best conditions for growth. Cell cultures are complex mixtures containing dozens of components (e.g., proteins, hormones, vitamins and elements) needed for the cells to grow. These components must be carefully controlled and monitored consistently within the bioreactors to produce quality drugs efficiently.
It can often be difficult to exactly replicate the conditions found in one bioreactor, and small differences from one product to another mean that the resulting drug cannot be used. The cell cultures within the bioreactor need to be monitored on a consistent and regular basis, and sensors need to be acutely primed to detect even the tiniest of changes, as it is easy for a batch to become degraded in quality thanks to one small change.
The iConsensus project developed a series of user-friendly miniaturised tools which can more accurately detect changes in the cell cultures in bioreactors, as well as monitoring the processes within the biopharmaceutical production line. These tools ensure that quality drugs are produced, while supporting a faster, safer and more cost-effective process for the production of biopharmaceuticals.
“With the miniaturised instruments, these systems are simpler than other sophisticated instruments and that can reduce the costs of these analyses. It is easier to implement in terms of automation and the simplicity is also a positive factor. At the end of the day we want to achieve better control of the process that gives higher patient safety,” says Veronique Chotteau, project coordinator of iConsensus.
Inno4VAC and iConsensus are supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.