New technologies, old methods- Why 99% of cell culture vessels will never scale
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.”
That’s what Scott Gottlieb, commissioner of the FDA said when the first cell therapy Kymriah® was approved in the US in 2017. Since then, only 23 cell and gene therapy products have been approved by the FDA. Why are so few of these life-changing therapies reaching the market? And when they do, why are they so hard to access? Sure, these new technologies require stringent testing through clinical trials before approval. But one of the biggest issues restricting access to approved therapies- the expensive price tag- is largely due to the inadequate manufacturing methods currently available.
So why can’t existing manufacturing methods scale-up? Let’s look at the development process.
Research typically starts with a multi-well plate. These are good because they’re cheap, don’t consume a lot of reagent and cells, and have a small footprint. But the process is largely manual, which brings in a host of issues from manual handling and makes it hard to monitor what is going on in the wells. And soon, something with a larger surface area is needed to expand the cells in. A T-flask for example.
It may seem obvious to say that a flask has a very different geometry to a multi-well plate, but this change of vessel means cells will be exposed to a different environment. Nutrients, metabolites, paracrine factors, and gasses will all diffuse differently, while seeding, agitation and harvest methods will introduce new shear stress and temperature fluctuations. All these factors will ultimately have an effect on cell density, viability, and phenotype. And now, adjusting the process to redirect cell phenotype towards their original state is going to require more space and reagents.
Once pre-clinical testing is done, it’s time to scale-up for Phase I using a stirred tank bioreactor, culture bag, or even an automated platform that genty rocks cells. All the factors in the previous jump from plates to flasks are multiplied here, so cells are going to look COMPLETELY different. Although there’s more real-time monitoring methods available with bioreactors, even more time, effort, and money will need to be spent optimizing expansion.
“We talked to over 100 cell therapy developers during our development of the Cyto Engine and on average, they will spend 1-2 years translating their process from a research scale (flask) to a manufacturing scale (stirred tank, bag or otherwise)” says Antoine Espinet, CEO & Co-Founder of MicrofluidX, “It really got us thinking – how many patients could have been treated in that time and how much money is being spent on all this?”
There is huge unmet need for truly scalable cell culture platforms that can translate cell and gene therapies from research to manufacturing scale, keeping consistency of the final product throughout. That’s why we’re developing the Cyto Engine, combining scalable bioprocessing, complete integration of online PATs, and powerful data visualization and analysis.