Innovative medicines offer hope to many patients suffering from cancer or autoimmune diseases. Unfortunately, their colossal production costs are a major obstacle to their use. The MiMédi project, supported by the Femto Engineering school, part of the Carnot TSN institute, aims to rationalise their manufacture, in order to make them more accessible.
Many diseases affecting human beings remain difficult to treat: cancers, auto-immune diseases, inflammatory syndromes, etc. In order to fight these pathologies more effectively, new treatments have been developed: advanced therapy drugs. The principle behind them is to take cells from a patient or a healthy donor, then apply selection or enhancement processes to enable them to acquire new physiological properties, and then reinject these cells – or a product derived from them – into the patient, who can then fight the disease more effectively.
For example, the French start-up MED’INN’Pharma aims to combat inflammatory diseases by exploiting a natural phenomenon: apoptosis. This process corresponds to a cell self-destruction mechanism that leads to the emission of chemical signals that reduce inflammation. The idea here is to reproduce this reaction by placing T lymphocytes in programmed death, thereby creating an innovative drug.
While the principle seems clear and the benefits obvious, advanced therapy drugs come up against a major obstacle: their production cost. “Their manufacture calls on complex technologies, requires a wide range of skills and involves a huge number of stages,” notes Olivier Lehmann, an engineer specialising in robotics at FEMTO Engineering. The environment in which this manufacturing takes place must also meet the strict criteria of a clean room, via multiple controls, in order to limit the risks of contamination as much as possible. Added to these difficulties are the new health constraints, which represent an additional burden. “At the end of the day, these drugs can cost between 300,000€ and 500,000€ per dose”, sums up the engineer. That’s a prohibitive cost if they are to be marketed to the general public.
Reducing the production costs of innovative medicines
The MiMédi (Microtechniques for Innovative Medicines) project was created with the aim of making these therapies more accessible. The project brings together biologists and engineering science specialists, as well as players from the academic and industrial worlds. The project brings together the Établissement Français du Sang, the University of Franche-Comté through two laboratories (UMR RIGHT and FEMTO-ST), the Besançon CHRU and FEMTO Engineering, part of the Carnot TSN. In addition, there are six industrial partners: iLsa, Smaltis, AUREA Technology, Diaclone, MED’INN’Pharma and Bioexigence. The aim of the project is to rationalise the manufacture of advanced therapy drugs, in order to significantly reduce their production costs.
The first step was to analyse and understand the processes used. “Biologists and engineering specialists don’t really speak the same language,” points out Olivier Lehmann. “So first we had to familiarise ourselves with each other’s vocabulary and decipher the problems to be solved. This was an essential task, which enabled us to identify the main sources of cost and to uncover relevant avenues for rationalisation. The MiMédi team then proposed two main areas for improvement, which led to the filing of several patents.
1) Efficient selection of target cells
In order to produce advanced therapy drugs, it is first necessary to isolate the cells that will subsequently be modified (T lymphocytes, for example). “Today, the most common method involves centrifugation, followed by the addition of complementary products to separate the different layers,” explains the FEMTO Engineering engineer.
Another solution developed enables cells to be separated efficiently without centrifugation. It uses the response of different biological structures to acoustic waves or electrostatic fields. In the latter case (the dielectrophoresis process), microfluidic chips are manufactured by assembling two electrodes one on top of the other. “This stage requires extreme precision,” explains Olivier Lehmann. “That’s why we use robots with nanometric resolution. We use them to position each half-chip in relation to the other, using a vision system and periodic patterns previously applied to each one. The result is measurements accurate to a hundredth or even a thousandth of a pixel”. These devices are then used to remotely control the position and speed of the cells.
2) Producing innovative medicines in a closed system
The research team has also focused on minimising the risks of contamination, by developing a closed manufacturing system. Current conventional methods generally require the culture medium to be opened up, which means that sterility tests have to be repeated as production progresses. Here, on the other hand, all the elements work in a closed system and are linked by sterile connections.
Even so, it is essential to be able to check the state of the product, without opening it or taking samples. Here again, several solutions have been developed. “Firstly, we used spectroscopy,” explains the engineer. “In concrete terms, this involves passing white light through the solution and studying the spectrum at the output. This information, compared with numerous reference samples, tells us about the concentration of the cells or any contamination by other structures.”
Another solution developed by the MiMédi teams is based on computer vision and machine learning algorithms. Using a neural network, these are able to identify the different cells present within the product circulating in the closed system, observed through microscopes. However, the artificial intelligence still needed to be trained. “There was no reference corpus, so we had to create one”, says Olivier Lehmann. “We had to identify tens of thousands of cells by hand from a large bank of images. This labelled data then served as a training set for the machine, which adapted its neural network accordingly”.
This closed-system approach could even eliminate the need for a clean room during production. “Initial tests have shown a total absence of contamination using this manufacturing process,” says the engineer. However, it is currently impossible to do without a cleanroom, as current standards require the use of one.
New methods already under study
The MiMédi project, which was completed in December 2022, has led to the creation of a start-up to exploit the results obtained. CellQuest has developed a machine for producing CAR-T cells, T lymphocytes treated to detect cancer cells more effectively by adding markers. Although the process already existed, the company wanted to make it much more affordable, by dividing the manufacturing cost by ten, thanks to its automated solution. And the initial results show that the CAR-T cells obtained in this way meet the requirements: the modified cells are present in the expected concentration and there is no trace of contamination.
Unfortunately, no patient has yet been able to benefit from the innovative medicines produced in this way. Before they can even enter clinical trials, they have to receive authorisation, which takes several years to obtain.
However, this does not discourage the MiMédi team, which intends to continue its research into optimising the production of advanced therapy drugs. “We are currently working on setting up a new project, with the same partners, which could start at the end of 2023,” says the FEMTO Engineering engineer. “In particular, we want to develop tests, at a reasonable cost, to check that patients are receptive to these drugs or to ensure the compatibility of donors. New avenues could be explored, such as measuring the impedance of a complex liquid medium, i.e. its electrical response to a low-intensity current. This could be a decisive new marker for democratising innovative drugs.