Manual processes rely on numerous manipulations using biosafety cabinets.

Cell and gene therapies (CGTs) offer potential cures to some of the most challenging illnesses of our time. The number of such therapies approved for market is set to surge in the next 10 years (1). Yet current manufacturing approaches are not fit for purpose. Biomanufacturing must adapt to prevent the industry from unintentionally sleepwalking into causing harm to patients. Some urgently needed changes could come with learning about the mindset of the medical-devices industry.

Background and Current State
After a strong start a decade ago, the number of approved CGTs on the global market today is fewer than had been expected. The challenge of designing adequate clinical trials and manufacturing processes for living medicines has proved to be a daunting one. Meanwhile, ethical and practical considerations related to access, value, and cost also have caused delays.

Biomanufacturing processes for cell and gene therapies have evolved over the past 10 years. To help understand the industry’s progress to date, I find it beneficial to understand this progress as successive generations of manufacturing approaches. “Generation 0,” as I see it, is characterized by manual processes that have been used to demonstrate proof of concept and clinical viability, often borrowing equipment from other types of bioprocessing. “Generation 1” automates some of those early manual approaches through, for example, the introduction of closed systems. That’s where the industry is now.

“Generation 2” is being explored currently. It will bring improved automation to allow true scale-out and increased reliability. Market leaders have already demonstrated that Gen-2 is achievable, with Miltenyi’s Prodigy and Lonza’s Cocoon systems showcasing relevant qualities from this generation as part of their manufacturing processes.

Finally, the future of successful biomanufacturing for advanced therapies will involve achieving “Generation 3” processes that incorporate new technologies specifically designed for CGT processes. To achieve Gen-3, we will need to overhaul biomanufacturing as we know it, making room for more efficient designs, more reliable processes, and more user-friendly technologies.

At present, CGTs are made at small scales and often to treat rare conditions. For example, one chimeric antigen receptor (CAR) T-cell therapy has been approved to treat small patient populations affected by relapsed or refractory, diffuse, large B-cell lymphoma (R/R DLBCL), a type of blood cancer (2). However, such medicines have the potential to address more common diseases and support management of much larger patient populations, including those with solid tumors.

Novel therapies such as CAR-T cells require new and complex manufacturing processes that are unlike any the biopharmaceutical industry has seen before. Complexities arise from the source materials: Autologous therapies start and end with patients’ own cells. Thus, every batch is individual to a patient. Manufacturers have had to create effective systems for parallel production of multiple manufacturing approaches at significant scale (3). Companies also have to ensure that the end product is high enough quality for release. Every part of the manufacturing process must be sterile because cells undergoing manipulation will be reinfused into patients.

It is not only the starting materials of CGTs that differ from those of conventional medicines; the way these therapies are delivered adds complexity, too. The process requires much closer collaboration among collection, manufacturing, and treatment centers than traditional biopharmaceuticals do, given that cells need to be collected, then modified and shipped back to the same patients in a timely manner (4).

Despite those complexities, CGT manufacturing teams mostly use Gen-1 approaches to deliver advanced therapies to patients in the real world. Such approaches often involve repurposed bioprocessing equipment rather than tailor-made technologies, with few instruments designed specifically for CGT processes. One scientist has referred to the development of these manufacturing processes as “more of an art form than a science,” given the lack of controls and manual operations involved (3). Such methods have served the industry adequately until now, but as we look ahead to scale up/out existing approaches, a paradigm shift in design and technology is needed urgently.

The Scale Challenge
Demand for advanced therapies is growing. As of February 2021, the US Food and Drug Administration (FDA) had approved 19 CGT products (5). Although overall approval rates have been slow, those therapies that have progressed to regulatory submission have received rapid approval compared with the timelines for conventional drugs. A growing pipeline of investigational products makes more approvals likely in the coming years. To prepare accordingly, the industry needs to consider now how best to manufacture at a scale that can address more prevalent conditions.

Since the first cell therapies were approved in 2012 (6), a number of next-generation approaches have been developed by suppliers focusing on automating parts of the manufacturing processes to reduce errors, costs, and risks. However, many current methods are still labor-intensive, difficult to execute, and physically complex. Significant gaps remain in the standards of reliability, quality, and throughput that can be achieved with traditional cell therapy processes compared with what is expected for typical drugs and medical devices produced at scale. Approaches differ across the industry. Those differences create the potential for significant product/process failures because there are no agreed expectations about the minimum failure rate. Such variability ultimately leaves patients vulnerable to unintentional harm.

Something as seemingly insignificant as a fluidic connector is a good example of where change is needed. Connectors play a critical role in transferring cell therapy fluids from one stage of processing to another and within each stage of a biomanufacturing process. In autologous processes, one patient’s cells can pass through hundreds of individual connectors. With such therapies, often companies have just one chance to get a treatment right. So connectors play a vital role in limiting cell loss and ensuring that a delivered therapy will be highest of the quality possible.

Simple connective tubing can be purchased “off the shelf” for a few dollars/euros and is produced according to set standards, including for dimensional capacity (7). Existing options have been established for medical and biopharmaceutical product manufacturing, however, rather than for cell therapies. Such connectors have been developed carefully based on the safety and reliability considerations of other substances such as protein solutions (7). Using those connectors in cell therapy development can incur risks related to introducing contamination, damaging cell products, and leaking. Such risks get amplified when manufacturing scales up from handling hundreds of samples to thousands. Every time you double the number of connectors, you essentially double the risk.

The error margins for manufacturing CGTs at commercial scale are poorly understood in general. No broad agreement yet has been reached as to what acceptable failure rates should be. The potential consequences of not furthering our understanding and agreeing on failure rates could include

• delays to treatment approval
• revalidation costs when future process changes are made
• regulatory investigations into the suitability of single-use components used (7).

Other risks come with methods for assembling fluidic connectors, especially considering that manually applied cable ties are still in common use. When a process is scaled up to handle thousands of fluidic connectors, the risk of assembly error also is multiplied by the number of connections made.

As with any emerging industry, we need to keep asking ourselves whether we are going in the right direction. It will be easy to fall into the trap of creating highly functional solutions that are not fit for the final purpose, thus neglecting to consider appropriately the risks we face. As we move forward, we need to ensure that the industry evolves toward thoughtful simplicity rather than hopeful complexity.

Lessons from Medical Devices
The challenges facing CGT manufacturers are not unprecedented. Other industries have experienced steep learning curves as they scaled up from proof of concept to manufacturing for commercial demand. Historically, medical-device manufacturers faced high levels of product recalls based on safety and reliability concerns (8).

For example, infusion pumps are widely used devices for delivering treatments directly into a patient’s vascular system. These medical devices are estimated to deliver over a million infusions each day in the United States alone, but they have been recalled regularly since their creation (9). Patients can be seriously harmed when these devices stop working unexpectedly, deliver the wrong dose, or fail completely. The difficulty facing their manufacturers is that as their use has become more widespread, device reliability has remained at the level of the original design.

CGT manufacturers face a similar problem. If we use a manufacturing process that was designed and proven to be adequate for small-scale use (e.g., for hundreds of patients each year), then to make commercial-scale quantities serving thousands or tens of thousands of patients per year, we too will face similar risks of product recalls and worse.

Medical devices that are subject to ongoing concerns in quality and safety tend to be scrutinized by regulators — and not only for technical issues. Once a company’s reputation is damaged, it can be incredibly hard to rebuild. When regulators get involved with recalls, they rightly will continue to focus on the specific issues at hand. In the case of infusion pumps, for example, recalls have led to years of ongoing challenges and significant costs to the companies trying to overcome those events. That is a challenge we must avoid collectively for CGTs to be successful.

The medical-device industry has mitigated against such reputational damage by implementing standards for manufacturing that focus on reliability, safety, and human-centered design. It’s a mindset that CGT manufacturers can learn from. Safety, quality, ease of use, and low cost are drivers that should shape our manufacturing processes as well. We need to uphold agreed-upon minimum standards. Appropriate standards driven by the industry should reassure the regulators and thereby reduce the need for tight regulations, which ultimately can stifle progress and innovation. Together, we need to build consensus on the best processes that will help us meet our emerging objectives of manufacturing living medicines in large quantities.

Medical-device manufacturers typically enjoy a key advantage in that they normally are fully aware of the potential risks to patients that their products can pose, unlike advanced-therapy manufacturers. The complicated industry dynamic of CGT includes both manufacturing equipment providers and therapy developers — and often more than one of each at a time. Once equipment is in the hands of a user, there is little that can be done to qualify its performance in a high-volume situation. Users cannot run sufficiently extensive tests to uncover low failure rates that might become relevant only as a product grows more successful. So all parties must work closely together, and it’s important that equipment manufacturers are well versed in patient risks and how to manage those appropriately.

Cell Therapy As a Medical Device
It will be difficult to design and implement Generation-3 manufacturing approaches both rigorously and robustly. We manage this challenge at TTP through a new approach that we call “Cell Therapy as a Medical Device” (CTMD). It adapts the risk-management mindset that we use in development of medical devices using our knowledge and experience in developing cell therapies.

Medical-device manufacturers focus on meeting agreed standards of reliability, safety, and ease of use. CGT biomanufacturers also should also be careful in assessing whether designs for new equipment are adequate to meet minimum standards. But first, broad agreement on our collective response to some fundamental questions will be needed:

• What is the industry-accepted failure rate?
• How does that vary by the potential impact of different types of failure? (A loss of product should have a different acceptable failure rate to a product contamination.)
• What are we doing to reduce manual errors, and how are we predicting their rate? How far are we extrapolating our failure rate data?
• What happens when we bring our second, third, fourth facilities on line?

At TTP, we use CTMD to answer those questions and more. Based on our knowledge of the underlying biological requirements of bioprocess systems, cell handling, and maintenance, it gives us confidence that failure rates will remain low as we scale out.

Focusing Design Efforts
Cell therapy as a medical device centers on two primary design considerations: reliability and human centricity.

Designing Human-Centered Processes: As part of CTMD, it is important to view our processes through a “human lens.” Human-factors science drives safety, effectiveness, and efficiency in our approaches by improving the design of technologies, work systems, and processes we use. For healthcare products, this leads to designing systems and tools that are resilient to human error. Through this mindset, we can identify major risks that are present in current manufacturing processes and then redesign systems and approaches for sustainable improvements to safety (10).

Human-centered design also should extend to ensuring that standard operating procedures (SOPs) are easy to follow. Biomanufacturing approaches are intricate, often with complex steps written out in an SOP instead of being simplified. The responsibility of preventing errors then falls to human operators, who must make sure that they follow those steps precisely. This situation needs to be eliminated. As an industry, we must work toward simple, error-free guidance that can be understood easily. To achieve that goal, we can simplify current systems to make them suitable for scaling.

Design for Reliability: As the number of parts in a CGT system increases, we can no longer test them as we would qualify equipment in traditional biologics manufacturing. Instead, we must rely much more on predictive tools. Fortunately, such tools are well established for medical devices that are made by the thousands and even millions (e.g., inhalers). In the design of advanced therapies, we need to develop a deep understanding of the design margin for all parts in our systems. We can use that knowledge to predict failure rates for complete designs, testing only to verify the design margin. Even if we never actually experience a failure in testing (which shouldn’t be uncommon if we are designing for very low failure rates), we will have evidence that the designed failure rate is achievable.

Perhaps the most important lesson from medical devices is how valuable it can be to design for reliability early in the development process. Focusing on reliability at the end often serves only as a “postmortem” explanation for why a given device will not be suitable for manufacture. The approach taken may have been inherently wrong, with no amount of design refinement or manufacturing improvement able to yield the performance needed in scale-up. That explains the insufficient approach to a level of performance that we often find in our processes, in which greatly increased investment produces only diminishing returns. By calculating reliability factors early on, we can correct our design direction. Money will be saved, time will be saved, and (most important) lives may be saved.

What Comes Next
Advances in regulation are bringing specific guidance on CGT manufacturing. For example, one FDA guidance document sets out recommendations for what should be included in a new drug submission (11), with onus for ensuring that those recommendations are met on therapeutic developers rather than on equipment manufacturers. The industry needs to use its own experience to agree on a set approach for measuring and upholding robust safety and quality standards. That requires taking ownership of the problem and designing with reliability and human use in mind.

Regulations can be and should be relied on as a baseline for minimum standards. However, the industry is well placed to be at the forefront of determining what safe and reliable manufacturing should entail. Generation 3 manufacturing approaches that use new technologies developed specifically for CGT will have to be designed with commercial scale, reliability, and human factors in mind — while also adhering to basic good manufacturing practice (GMP) standards.

Currently, the expectation is that CGT manufacturing equipment and instrumentation do not need to be regulated as medical devices. Some experts speculate about what could be needed in the future, particularly if we move toward near-patient manufacture (12). It is critical that we do not depend on regulators to determine what is the right way to develop these systems. The industry should take the lead by focusing on patients and developing systems to ensure that risk is managed at an appropriate level.

Eyes Open to the Future
CGTs already are shaping an exciting future for medicine. As an industry, we have made good headway in developing biotechnology and manufacturing approaches to date. But to make living medicines a reality for patients, we must evolve our approaches and ensure that our eyes remain wide open to the challenges and opportunities ahead. That includes focusing on designing and building robust, reliable methods that can meet the demand of commercial volumes.

The medical-device industry offers important lessons related to accountability, reliability, and ease of use. I believe that we should prioritize those factors for our next generation of biomanufacturing processes. The CGT industry needs to devise frameworks within which we all can agree to operate, including bespoke safety measures for advanced therapies. With such processes in place, I am confident that we can play a meaningful role in a wider rollout of CGTs and improve the lives and outcomes for many more patients in the years to come.

References
1 Quinn C, et al. Estimating the Clinical Pipeline of Cell and Gene Therapies and Their Potential Economic Impact on the US Healthcare System. Value in Health 22(6) 2019: 621–626; https://doi.org/10.1016/j.jval.2019.03.014.

2 Andalo D. Cancer Patients in England “First in Europe” to Get Access to CAR-T Therapy. Pharmaceut. J. 10 October 2018; https://pharmaceutical-journal.com/article/news/cancer-patients-in-england-first-in-europe-to-get-access-to-car-t-therapy.

3 Challener CA. Mapping a Route for Cell and Gene Therapy Process Development. BioPharm Int. 33(1) 2020: 25–29, 32; https://www.biopharminternational.com/view/mapping-route-cell-and-gene-therapy-process-development.

4 Zhang C, et al. Engineering CAR-T Cells. Biomark. Res. 5(22) 2017; https://doi.org/10.1186/s40364-017-0102-y.

5 Approved Cellular and Gene Therapy Products. US Food and Drug Administration: Rockville, MD, 5 February 2021; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

6 Press Release: European Medicines Agency Recommends First Gene Therapy Approval. European Medicines Agency: London, UK, 20 July 2012; https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-first-gene-therapy-approval.

7 Pendelbury D. Cell and Gene Therapies: A Guide to Single-Use Connections. Bioprocess Online February 2018; https://www.epmmagazine.com/downloads/5806/download/Cell%26GeneTherapyWhitePaper.pdf.

8 Heneghan C, et al. Medical-Device Recalls in the UK and the Device-Regulation Process: Retrospective Review of Safety Notices and Alerts. BMJ Open 1(1) 2011: e000155; https://doi.org/10.1136/bmjopen-2011-000155.

9 Kelly S. FDA 2020 Recall Roundup: A Rough Year for Infusion Pumps. Med. Tech. Dive 23 December 2020; https://www.medtechdive.com/news/fda-2020-recall-roundup-a-rough-year-for-infusion-pumps/592602.

10 Russ AL, et al. The Science of Human Factors: Separating Fact from Fiction. BMJ Qual. Safety 22(10) 2013: 802–808; https://doi.org/10.1136/bmjqs-2012-001450.

11 CBER. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs): Guidance for Industry. US Food and Drug Administration: Rockville, MD, January 2020; https://www.fda.gov/media/113760/download.

12 Gazaille B, Scott C, Caplan V. Toward the Point of Care: Flexibility and Decentralization Are Key to Making Autologous Therapies More Readily Available. BioProcess Int. 19(6) 2021: 24–26; https://lne.e92.mwp.accessdomain.com/manufacturing/cell-therapies/toward-the-point-of-care-ompul-technoogy-flexibility-and-decentralization-are-key-to-making-autologous-therapies-more-readily-available.

Edwin Stone, PhD, is head of cell and gene at The Technology Partnership (TTP), in Melbourn, UK; edwin@ttp.com; https://www.ttp.com.