With 6 approved products currently on the market,1 autologous chimeric antigen receptor (CAR) T-cell therapies have emerged as groundbreaking treatment options for patients with hematological malignancies. Once therapies of last resort, these treatments have demonstrated remarkable efficacy and durability compared with other options, and in some cases, have even been described as curative.2 Although CAR T-cell therapies were initially approved for patients who had already undergone multiple lines of treatment, encouraging data that show cell therapies’ sustained efficacy has led to a growing desire for them to be prescribed earlier in the treatment paradigm.3 In 2022, 2 such therapies were approved as second-line treatments.4,5 Considering the thousands of ongoing cell therapy clinical trials, it is likely that this trend will continue, with these therapies potentially becoming frontline treatments in the future.6 With many cancers the eligible patient population grows dramatically as treatments are approved for earlier lines of therapy—in some cases, an order-of-magnitude increase can be observed.7,8
This increase in eligible patients runs counter to one of the biggest access challenges for these lifesaving treatments: current cell therapy manufacturing paradigms cannot meet patient demand. Patients with multiple myeloma are one of the hardest hit populations, due to viral vector shortages and limited production slots. These challenges can have deadly repercussions: data from a 2022 study showed that approximately 40% of patients with multiple myeloma had to wait a year to receive CAR T-cell therapy, and more than one-fourth of patients died while waiting for the treatment.9 It is estimated that 450,000 patients with cancer were eligible for CAR T-cell therapy treatment in 2019, and this number is only expected to rise, with an estimated 2 million eligible patients by 2029.10 In contrast, Cellares estimates that only 4,000 doses of CAR T-cell therapy were manufactured in 2021.11
Achieving the manufacturing throughput necessary to satisfy expected patient demand is dependent on several factors, including decreasing reliance on large, expensive manufacturing facilities; innovating parallel processing technologies; alleviating bottlenecks due to worker shortages and turnover; and reducing human-introduced errors. Addressing these factors holistically will allow the biopharmaceutical industry to ramp up cell therapy production while reducing the cost to manufacture these life-saving therapies. One emerging solution to tackle these roadblocks simultaneously is the implementation of automated cell therapy manufacturing technologies. Fully automated and closed, end-to-end cell therapy manufacturing solutions are poised to drastically reduce the size of manufacturing facilities, reduce the number of manufacturing operators, and enable organizations to scale up as manufacturing needs increase.
The reliance on very large cell therapy manufacturing facilities is one of the current bottlenecks restricting patient access to these life-saving therapies. Today, cell therapies are manufactured using manual processes accomplished by stringing together multiple instruments, each not originally conceived to support commercial scale manufacturing. The variety of required instruments, and the generally open nature of many of the cell therapy manufacturing processes, results in the need for massive facilities housing numerous expensive classified cleanrooms. For example, to manufacture only 4,500 doses per year, a cell therapy manufacturer will require a facility of at least 200,000 sq ft in size, with upfront build-out costs greater than $160 million for facilities and equipment.12 Beyond construction, equipment, and lease expenses, there are additional, substantial costs associated with operating the classified cleanrooms required to accommodate the manual manufacturing of these therapies.13 These massive facility footprints and costs make it impossible to scale capacity to meet demand.
Decreasing space requirements while simultaneously devising techniques for parallel manufacturing represents a major opportunity for increasing patient access to these therapies. Several emerging technologies have the potential to disrupt current cell therapy manufacturing paradigms. These solutions are fully closed, end-to-end manufacturing platforms that support the manufacture of 10 or more cell therapies in parallel and have a footprint smaller than the space currently needed to manufacture a single dose. These technologies can increase manufacturing capacity by an order of magnitude or greater.
Complex manufacturing processes are another bottleneck to manufacturing cell therapy at scale. Currently, cell therapy manufacturing requires on the order of 50 manual processing steps per dose, totaling 80 or more hours of total “touch time”.14,15 Each step represents an opportunity for operator error or contamination, either of which can result in a failed batch. For the very sick patients awaiting these therapies, every day is critical. Physicians are often fighting to keep these patients alive until the therapy arrives. A failed batch means the patient will need to undergo another blood draw, but many patients won’t live long enough for that. Implementation of a fully automated, closed manufacturing platform holds the potential for a 4-fold reduction in process failure rates by eliminating open transfer steps and limiting the number of steps requiring human intervention. This approach significantly reduces opportunities for operator error and improves the likelihood that the therapy will reach the patient in time.
Another contributing factor to the difficulty in scaling up manufacturing is an ongoing shortage of talent in the biopharmaceutical industry. It is estimated that in some regions of the United States, the demand for cell therapy manufacturing workers could grow by as much as 136% within the next decade.16 Commercial scale cell therapy manufacturing organizations are already struggling to staff the large teams of highly trained operators required for manufacturing today. Moreover, manufacturing operator roles have challenging work conditions, with operators working 12-hour shifts in full cleanroom suits. The difficult working conditions are contributing to high operator turnover rates of approximately 70% within 18 months. Restaffing these roles requires significant resource allocation toward recruiting and training, and may result in manufacturing downtime. Automation again holds the solution to help alleviate these challenges. It is estimated that by adopting a fully automated, closed cell therapy manufacturing solution, manufacturers can realize a reduction greater than 70% in required manufacturing headcount per drug product.14 An additional benefit with automation is the potential reallocation of the operator workforce to other value-added activities where their talents and skills can be better utilized. A valuable side effect of this redeployment of human resources may be the development of even more novel, life-saving treatments.
With the success of the first 6 approved cell therapies, the thousands of ongoing cell therapy clinical trials in progress, and the potential to cure intractable cancers and other diseases, it is no surprise that demand for CAR T-cell therapy has outpaced the supply of scalable manufacturing technologies.17 However, with the deployment of a fully automated, end-to-end manufacturing platform, it is likely that cell therapy manufacturing scales can be exponentially increased. The benefits of automated manufacturing also have the potential to significantly shrink the cost of production.18 By eliminating the need for cleanrooms, minimizing manufacturing footprints, decreasing the cost of wasted materials due to process errors, and reducing workforce requirements, cell therapy manufacturing costs can be reduced by more than 60%, increasing the availability of these therapeutics to patients in need.14 By shrinking the physical manufacturing footprint and eliminating manual manufacturing steps, enclosed automated systems can be distributed closer to apheresis sites, reducing the time and complexity of getting a dose to a patient, while also improving reproducibility and reducing process failure rates. This can be crucial for immunocompromised patients, who often struggle to produce enough healthy T cells as starting material for a dose.
In addition to these benefits, as automation technology continues to evolve and become an integral part of cell therapy development and manufacturing, the future potential benefits are wide reaching: improved patient outcomes, flexible manufacturing models, and adaptable technologies that can be applied to a variety of modalities are just a few examples. Automation is a net benefit to the industry, reducing the need for highly trained personnel to spend long hours on the cleanroom floor in full personal protective equipment. Instead, it enables biopharmaceutical companies to leverage their ingenuity to keep the industry innovating and moving forward, rather than struggling to scale up manufacturing to meet patient demand.
John Tomtishen is vice president of operations at Cellares.