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Written by: Guillaume Wallart, CEO, CellQuest
Advanced therapy medicinal products have yet to reach their industrial golden age. This is typified by the state of chimeric antigen receptor (CAR)-T cell therapies – these drugs work, but we don't yet know how to produce them sufficiently for supply to meet demand.
Personalised cell and gene therapies (CGTs) are often discussed in the context of their novelty and some inherent unmanageability, driving up costs that hinder patient access. There are no useful analogues in the biomedical field for scaling them, the story goes. Manufacturing a drug for each patient raises expensive logistics problems, individualised production lines management, and space and personnel constraints.
By this logic, if we want to make CGTs accessible, we must make the products look more like what we are used to – older biologics like antibodies, which can be produced in batches. The production capacity problem is blamed on personalisation, and the best path forward must be to depersonalise them.
Unfortunately, making allogeneic medicines from donor cells has its own set of challenges. Additionally, while the field works through the technical hurdles, it is increasingly clear that losing personalisation sacrifices some of the remarkable efficacy that has been observed with approved autologous CAR-T therapies and other CGTs.
Among those who remain focused on autologous CGTs, some have concluded that it may never be possible to cost-effectively produce them at a scale where they can be accessible to the many patients who would benefit from them. Others think that if there are solutions, they will require importing and incorporating untried approaches from other industries.
The challenges are real, but the solutions are not as far afield as most of the industry seems to think.
Learning From in Vitro Diagnostics
One often overlooked but relevant model is the recent evolution of in vitro diagnostics for blood, urine and tissue samples. Here, the personalised medicine industrial revolution has already taken place.
For proof of this, visit a diagnostics laboratory. Thousands of tubes from thousands of different patients arrive every day. The tubes are identified, placed in gondolas and, depending on the analysis to be carried out, handled by machines.
Automation is increasingly used to improve operational efficiency in these labs. Liquid handling processes like microplate washing, sample preparation, transporting and pipetting were low-hanging fruit for incorporating robotics. Electronic labelling devices and similar technology have improved sample identification and tracking.
Notably, while automation is typically associated with improving efficiency and consistency in big labs, it is widely utilised in smaller labs too. This includes mobile analytical devices and lab-on-a-chip systems for performing certain diagnostics near or at the point of care, without need for a sterile environment. It also includes small, enclosed commercial devices that incorporate a range of different tools for interconnected processes.
Building on the Tried-and-True
Some will argue that producing a CAR-T is so much more difficult than carrying out a blood test that there is little to apply from in vitro diagnostics that will improve scalability. There are clear differences, such as the regulatory context, and a fluid or tissue sample does not need to be reinjected into the patient. But the similarities are worth a close look.
First, the complexity is comparable. In vitro analyses are not simple, and like cell therapy manufacturing, they require precise mixtures of reagents, cell counts, and measurements of physical parameters. In the case of bacteriology, there are further similarities such as long lead times and the need for traceability. As the CGT field identifies which aspects of manufacturing have the biggest impact on the end product, and moves toward standardisation, it’s likely the similarities will grow and the methodology to produce them will simplify.
Second, there are parallels between the types of workflows. Many diagnostics are performed at centralised labs, requiring transportation logistics. Commercial, regulator-approved autologous therapies still require similarly centralised facilities. Last year alone, Bristol Myers Squibb purchased such a facility for CAR-T manufacturing in Illinois and opened another in Massachusetts to support its commercial therapies. Johnson & Johnson and partner Legend Biotech also secured such space for its CAR-T as well.
At the same time, interest is growing in decentralised cell therapy manufacturing, which could help overcome barriers that have largely limited access of approved CGTs to patients at major academic medical centers so far. This follows a trend seen in diagnostics, where cutting–edge technology continues to enable the growth of mobile and point-of-care testing.
Applying Lessons for CAR-T Manufacturing
What would an approach look like for industrialising CGT production that incorporated learnings from in vitro diagnostics?
It would start by importing expertise from the diagnostics lab world, to ensure the knowhow is transferred instead of just copied. This would minimise one challenge that biopharma companies have encountered as they try to adapt processes from other industries, balancing innovation with experience. Closing the gap between these fields is much simpler than teaching an automotive engineer how to use a flask.
Further, a team with experience in the diagnostics world would understand how the broader ecosystem can work. This means they can build tools for the future, when all the hospitals who currently host diagnostics laboratories may also want their own cell therapy production capacity. At the same time, they can understand and align with the market as it is today, enabling a transition along familiar lines.
The platforms themselves would be based on the changes seen in diagnostics: smaller footprints, less manual intervention or skilled training required to operate, and accelerated end results. These are the principles that have guided CellQuest in the design of our platform, which borrows from the diagnostics space concepts like single-use cartridges for sterile liquid handling, tray feeding, automated low-volume liquid handling, and space-saving vertical architecture. The result is a scalable platform that increases CAR-T throughput 30x in a compact space.
Autologous cells should not be seen as a dead end or as a problem unto themselves, but as a challenge to the way the industry structures itself – one with a ready solution. This will be further applicable in the years to come as new industries take shape, particularly to produce custom organs. Healthcare will not progress without personalisation, which means we will have to adapt to the need, rather than the other way around.