By John Tomtishen
Cell therapies are in the process of revolutionizing the medical field. Last February, a pioneer of cell therapy, Carl June, reported that the second patient to ever receive a chimeric antigen receptor (CAR) T-cell therapy—dosed in 2010—has been cancer-free for over a decade. The engineered cells, expected to last for months, have persisted instead for years. The results have been so promising, in fact, that when referring to CAR T-cell therapy, oncologists have tentatively begun using the c-word—“cure.”
But the expensive, time-consuming manufacturing processes used today have failed to make the life-saving treatments available to all who could benefit. And the path they’re on is unsustainable.
Since 2017, the U.S. Food and Drug Administration (FDA) has approved six autologous CAR T-cell therapies, several of which the agency has since approved for additional indications. But despite the billions of dollars biotechnology companies and contract development and manufacturing organizations have sunk into expanding manufacturing capacity, production has not, and cannot, keep pace with demand.
Thanks to the success of these therapies, the FDA has been expanding the Center for Biologics Evaluation and Research to prepare for an onslaught of cell and gene therapy submissions. In 2021, the agency approved two new cell and gene therapy products, and last year saw the approval of Carvykti, a BCMA-targeted CAR T cell co-developed by Janssen Biotech and Legend Biotech, and four new gene therapies. By 2025, however, the agency expects to approve 10 to 20 therapies per year.
But despite cell therapy’s promise, the scientific advances to develop new therapies have outpaced innovations in manufacturing. To get these life-saving treatments into more patients and allow our field to reach its full potential, broad implementation of streamlined, automated manufacturing workflows is necessary.
On top of being lengthy and costly, current methods of cell therapy manufacturing are prone to human error. Plus, companies have a limited pool of talent for manufacturing staff with very high turnover rates.
These manufacturing shortcomings have prompted some companies to tout aspects of their manufacturing processes as a benefit of their therapeutics, but this obscures what should really differentiate treatments—efficacy and safety. Creating a chemistry, manufacturing, and controls (CMC) standard for an automated manufacturing workflow will push companies to compete on efficacy and safety, not a manufacturing “secret sauce.”
Manufacturing falls short on several fronts
It’s clear that manufacturing is one of the major bottlenecks in the field.
Current processes require teams of highly trained professionals spending weeks in expensive cleanrooms, executing some 50 manual processing steps on a plethora of benchtop instruments—all to produce one therapy for one patient at a time. With these processes, cell therapy companies cannot meet market demand for their products. About a half million patients are eligible for CAR T-cell therapies, but in 2020, only about 3,000 commercial doses were produced across all of the FDA-approved CAR T-cell therapies. Due to these manufacturing constraints, STAT News estimates that 20% of patients who are eligible for CAR T-cell therapies die on the waitlist before they can receive CAR T-cell therapy.
This problem will only be exacerbated as these therapies are approved for additional indications and are deployed as earlier line treatments. Until recently, the class was reserved exclusively as a last resort for patients who had exhausted all other treatment options.
Gilead Sciences and Kite Pharma’s CAR T-cell therapy, Yescarta, was approved in early April 2022 as a second-line treatment for large B-cell lymphoma. About two weeks later, Gilead announced that its new manufacturing site in Maryland had started operating. While the facility will boost Gilead’s manufacturing capacity by 50%, the company will still be unlikely to produce enough of its therapy to meet demand. In the United States alone, more than 18,000 people are diagnosed with large B-cell lymphoma each year, and about 40% fail first-line treatment.
For context, as of March 2021, about 4,600 doses of Yescarta have been administered in total, including clinical trials and patients prescribed the treatment.
Gilead spent three years and millions of dollars building the new facility, but at the end of the day, traditional approaches seem doomed to fail by an order of magnitude—current manufacturing methods are not able to scale up to produce the hundreds of thousands of doses that will soon be needed.
What’s more, these methods vary between companies and rely on numerous open manual manipulations. The more times a cell therapy batch is touched, the more chances for human error. Some developers have reported process failure rates of up to 18%.
On top of being cumbersome and error-prone, current processes are also resource-intensive. Most cell therapies are manufactured inside ISO 7 cleanrooms within expensive 200,000-square-foot facilities. Plus, manual manufacturing requires lots of manpower, with companies often hiring thousands of employees in manufacturing alone.
And the working conditions inside cleanrooms—which typically require a full bodysuit for 12-hour shifts and limited breaks—aren’t appealing for long-term work, or scalable in an industry already experiencing a pointed battle for talent. With an onboarding process as lengthy as nine months, companies are sinking resources to train staff that often don’t stay longer than a year and a half. Manufacturers are experiencing turnover rates as high as 70%.
How automation can plug the holes and push cell therapy to new heights
The general benefits of automated manufacturing are no secret. In our space, it enables commercial-scale production, lowering costs and accelerating timelines. Automation lowers costs by eliminating some cleanroom requirements and reducing workforce demand by 70%. A closed workflow limits the potential for human-introduced errors and contamination, thus reducing process failure rates.
But two trickle-down outcomes of automation could also herald more innovation in the field. Right now, companies often tout distinct manufacturing processes as a benefit of their cell therapies—“the process is the product,” as they say. But manufacturing should be boring and repeatable, not a differentiating factor between treatments.
Implementing a CMC standard for automated cell therapy manufacturing workflows will reduce variability between processes, freeing companies to compete on more important standards—safety and efficacy.
A standardized process will also help ensure that manufacturing isn’t holding a treatment back or promoting one treatment over another. And patients will benefit because only the most effective therapies will succeed in the market.
Automation could also promote further advances in cell therapy development, thanks to changes in the workforce. Companies will be positioned to shift personnel to projects that are better suited to their skillsets. Instead of burning out scientists in cleanrooms, companies could instead hire them within R&D, in roles focused on innovation instead of process execution.
As impressive as the field has been to date, automation is likely to inspire even more innovation, ultimately providing patients with more treatment options that are effective and affordable—and available to all who are in need.
John Tomtishen, is vice president of operations at Cellares.