For cell therapy to become mainstream, important issues such as management of risk and quality control need to be addressed, argues Duncan Borthwick, Global Marketing Manager at cell therapy manufacturing firm Solentim.
Research and development of cell therapies, along with other advanced medicines like gene therapies, has increased exponentially over the last few years.
According to the Alliance for Regenerative Medicine, as of June this year there were over 2,000 ongoing clinical trials of cell therapies around the world. Of these, 541 were at phase III.
“It’s absolutely boom time for cell therapy,” Borthwick told me, adding that the field has changed enormously in recent years. “It’s just unimaginably different. And not only its applications, but also the robustness of the methodologies. You speak to some of the researchers and they say ‘two years ago, we couldn’t get these cells to grow.’”
With an increased presence in medicine comes increased scrutiny. Following the appearance of adverts for cell therapies to treat or cure serious diseases in early 2020, the EMA released a statement warning patients against using unregulated cell therapies due to safety concerns.
Similar warnings have also been distributed in the US. Cell therapy developers and clinics offering such therapies were given a break by the FDA in 2017 and told to collect evidence to see if they needed to submit an investigational new drug or marketing application. That period of grace ran out in May this year and the FDA is now enforcing stricter regulations on people offering such therapies.
“Unregulated cell-based therapies are a great concern to everybody,” says Borthwick. In this context, tighter regulatory control of cell therapies can be beneficial for the industry.
“Being able to designate gene therapies and somatic cell therapies in tissue-engineered products under a category is really, really helpful. It sets a new kind of cornerstone for that regulatory framework and also a mechanism by which companies can approach the regulator in terms of clinical trials,” says Borthwick.
Although many cell therapies do go through a rigorous development process, it is still a relatively new field. Risk management and quality control can be difficult to navigate for new startups looking to take a cell therapy to market.
“One of the many challenges of cell therapy is to make robust control mechanisms by which young and old companies can build a path to develop clinical products, which are going to help people’s lives,” explains Borthwick.
A problem with any therapy based on live components is that controlling variation between different batches can be a problem.
“If you’re trying to control the risk to humans, you control the risk in production, what’s called a ‘control strategy,’” says Borthwick. “One of the key ways you can do that is to say, ‘ instead of starting with a big pool of cells that are all different, let’s take it down into individual cells, pick a good one and make that into a master cell bank.”
This has historically been a challenge, as the technology was not advanced enough, says Borthwick. Researchers reduced the volume of cells, carefully pipetted it out, and hoped that some contained single cells that could be the ‘parent’ of a new cell line.
To address this problem, Solentim’s founders created imaging processes that could take away the doubt around whether or not a single cell was present when starting a new cell line. The company now covers the whole cell line production process and has expanded into seeding and growth methods.
Solentim has been working closely with researchers and therapy developers across the industry, as well as regulators such as the EMA and FDA, on getting the different steps right.
“When you put in a proposal for human treatments, an IND submission, you don’t ‘pass’ the IND submission, you just don’t get negative comments at that time. There’s an ongoing review process,” explains Borthwick.
“It’s a very risk-averse community. Rightly so, because if you get it wrong, you’re going to get a nasty letter from the FDA. But moreover, you might be developing this for five years. If you don’t get this bit right, the regulator is going to come back and say ‘that’s too much of a risk to bring to human trials.’ So, it’s really important to get it right.”
Once a good quality cell line has been created, Borthwick says another important point to consider for cell therapy developers is the scalability and continuity of the process.
“You can’t wait until you find yourself in production before scrambling to put together a quality process. And there’s so much to be gained from starting to think early about that proportional approach to quality.”
For instance, how many other providers are involved in the process and how well do you understand their processes? “There’s a massive thing about single vendor use going on. If I can understand one vendor really well, then that’s so much easier to manage than 20.”
“The important thing is to find methods that work and then are scalable in terms of throughput. Once you’re moving from research to production, can you scale that whole story of risk analysis, paperwork, and regulation? Ultimately, it makes the whole thing so much easier.”
Borthwick encourages young startups or academic spinouts that are trying to move from an academic laboratory set up to a large-scale therapy production line to think seriously about this and to question all their initial processes. For example, some cell growth reagents are fine to use in the lab on a small scale, but won’t work when scaled up.
“There’s many which have animal products in them, which then present massive challenges as you approach clinical trials. There are others which cannot have GMP certification, and there’s others that just won’t work on high-throughput automation, for instance,” he says.
“Sometimes you need to stop and think a little bit. Put in place good practices now… That might be staff or processes, get people involved at an early stage, because it is going to give you massive time savings later on. Don’t be terrified by the world of regulation and risk. There’s a lot of good people out there.”
Having an industrial scale-up process that maintains quality and reduces therapy variation will only become more important for companies to succeed in the long run.
“We are contacted every week by some company we haven’t heard of that are moving into the space,” says Borthwick, who adds that neighbouring markets, such as cultured meat producers, are also carefully observing cell therapy developers to try and learn from their processes and methodology about how to maintain quality and reduce risks.
Both the FDA and EMA have been learning about advanced therapies and developing the best ways to regulate them over the last few years, but are now becoming more familiar with the area. Borthwick advocates good communication and discussion with the local regulatory agencies when trying to bring a product to market.
“One of our collaborators said that their greatest fear is that the regulator will never OK their products, because they won’t be able to see if they’ve managed risk appropriately. It’s up to us to communicate that approach effectively from an early stage to the regulator, because we all want this to work.”