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Cell therapies made a debut in the United States and Europe with the commercial launch of autologous chimeric antigen receptor (CAR) T-cell therapies such as Kymriah and Yescarta. With more than 250 clinical trials worldwide studying CAR T-cell therapies ongoing, additional cell therapies are clearly on their way and potential indications are broadening to include solid tumors, like melanoma, pancreatic cancer, and glioblastoma. Headway is also being made for cell therapies derived from stem cells to maybe one day treat diseases like autoimmune diseases, Alzheimer’s, and Parkinson’s.
The success of cell therapies, however, hinges on not only proving that a product elicits the desired biological response but also overcoming the challenges of manufacturing and administering a complex product to any patient. To meet these supply chain challenges and deliver on the promise of cell therapies, companies need outstanding technologies and innovative strategies.
“Given the rapid timeline of clinical development, considerations for robust, scalable, industrialized manufacturing could not be incorporated during the clinical development of the Kymriah and Yescarta,” says Madhusudan Peshwa, Ph.D., chief technology officer, cell and gene therapy business, at GE Healthcare. The commercial product came first and as a result, a host of manufacturing issues exists, including lack of automation, outdated analytics, and an immature supply chain. “It is only now, post-approval, that some of the industrialization and supply chain considerations are being incorporated to facilitate commercial manufacture and delivery.”
Anything But Conventional
In a conventional manufacturing operation, the process is confined to the manufacturing facility. But with cell therapies, this process extends far beyond, creating unique logistical challenges and responsibilities, as well as requiring a paradigm shift in thinking.
Cell therapy manufacturing, in the strictest sense, begins with the collection of cells from the patient, which takes place in a clinical (or apheresis) facility, and ends with the administration of the final drug product to the patient at the bedside. Between initial collection of raw material and final administration of a product, dozens of hand-off points and processes take place. The complexity of all these moving pieces in a supply chain and the blending of the manufacturing and administration phases is new territory and what differentiates the cell therapy field from more traditional pharmaceutical manufacturing.
According to Dr. Peshwa, to achieve a successful supply chain, “one has to really map out the whole process.” A manufacturer must understand where the critical hand-off points are and understand the risks for each step in the manufacturing process. “One has to take a comprehensive view of all of these elements, and anywhere there’s an opportunity to mitigate the risk, bring in automation,” says Dr. Peshwa. Because autologous cell therapies are personalized products with a batch size of one, manufacturers must also ensure that the chain of custody and identity is maintained throughout the entire manufacturing supply chain, no matter how complex.
“The consequences of not doing that can be essentially fatal to a patient,” continues Dr. Peshwa. Failure to document and control the provenance of the samples could have dire consequences for the patient and no guarantee of consistency, robustness, or quality control for the physicians and manufacturing team.
In addition to the logistical challenges, cell therapy manufacturers must produce a consistently safe and effective product from highly variable starting material. Patients who typically provide the raw material (as is the case for autologous cell therapies) have different genetic backgrounds, stages of disease, and medical histories, all of which can introduce upstream complexity and variability into the production process.
In other words, the starting material is different every time, a situation quite different from the typical manufacturing scenario in which a well-defined cell line is used for each production run. “It comes down to the complexity of the systems that are involved: the fact that we are working with both a living starting material and a living product,” says Aaron Dulgar-Tulloch, Ph.D., director of global process sciences at GE Healthcare. “That means that you have variability coming in your front end based on the donor and the condition of those cells.”
Adding Automation to Scale Up
Most if not all cell therapies on the market are indicated for small patient populations, but if they are to become widely available across multiple indications, improvements in automation, process simplification, and supply chain management will be needed to meet demand. The goal of treating thousands (or tens of thousands) of patients on an annual basis introduces entirely different challenges than the products and the manufacturing processes that have existed until now.
To scale up, manufacturing processes have to move from being open and manual to closed and automated, providing advantages including reduced contamination and risk, greater product consistency and efficiency, and more traceability throughout the process to ensure chain of custody. With greater automation, operators can measure certain critical attributes associated with the product during critical steps and better control for the variability of the starting material. Groups in both industry and academia are already adopting new technologies that can help them have more automated, closed, and scalable systems in order to remove risk and prepare for a high production future.
Automation is particularly critical for producing single doses of autologous cell therapies because there is already so much risk of variability. “To try and create a quality management system that’s going to have appropriate, consistent training and adherence to protocols to assure low variability across a manual process is incredibly daunting,” says Dr. Dulgar-Tulloch. That is why manufacturers can reap tremendous benefits from taking the time during process development to automate key steps and remove the manual interaction. “That will pay huge dividends in variability,” he says.
Timing is another important aspect to automation–bringing it into the clinical development or research phase at the right time. If brought in too early, issues can arise further on; but introduced too late, efforts can be duplicated repeating studies for regulatory authorities to prove that introducing an automated piece of equipment does not alter the quality of the product.
“You don’t need automation to generate five batches for a clinical trial,” adds Dr. Dulgar-Tulloch, “but you do need to know that you’re going to do that in a way that is going to be automatable for your phase III clinical trial in a system that will be similar.”
Automated vs Modular
With a market in catchup mode, companies are increasingly developing disruptive technologies that can help investigators close up and automate their protocols for future success. Closed, automated systems can come either as a fully automated–executing all of the process steps inside a single device–or as a modular system, where individual steps are carried out on separate pieces of equipment. Each system has its strengths and weaknesses.
An all-in-one, fully automated solution is very attractive and has many advantages, but there can be a downside. If you try to move that process into, for example, a centralized manufacturing facility (to gain the benefits of scale), you may find the all-in-one solution is not optimized for cost, time, or space efficiency for every individual step, says Dr. Dulgar-Tulloch. That’s where you can see the advantage of a modular approach.
Because the steps in cell therapy manufacturing take different amounts of time, bottlenecks can form in a fully automated system by tying up a particular piece of equipment for days while the rest of the system sits idle, wasting time, space and resources. In a modular system, only that one piece of equipment is occupied, while the rest of the system is free to use, making the design more efficient.
Another limitation of fully automated systems is that a company or research group may be locked into a protocol, whereas a modular system may have more flexibility. A fully automated system, Dr. Dulgar-Tulloch explains, usually provides some process flexibility in the use of one box. “But you are constrained by the way that device was designed and if you decide that you want to change your process or technology, you’re stuck,” notes Dr. Duglar-Tulloch. For example, if a company has a viral-based CAR T-cell therapy process but later switches to a non-viral modification, it’s unlikely that the same system will allow for a step like this. In contrast, a modular approach would allow for swapping out the relevant module while retaining the rest of the process.
Contracting Out the Supply Chain
Building a robust supply chain with the necessary equipment and protocols to meet demand can be difficult and time-consuming for companies that are unfamiliar with the process. An outside group–such as a contract manufacturing organization (CMO) or GE Healthcare–can help bridge the gap quickly for companies that have deep expertise in the biology of their product but lack experience in understanding how to move from a small, manual production to a scaled up, automated production that can meet the needs of tens to hundreds of thousands of patients worldwide.
These organizations understand what kinds of experiments the client needs to carry out and how to run them to figure out how to move an academic- or translational-scale process into something that can be scaled commercially, and select the appropriate equipment. Outsourcing also helps manufacturers avoid investing in a large scale system and facility in preparation for the future only to have their product delayed or not pass regulatory approval.
If a company does decide to outsource, they should strive to understand the process decisions so that they can bring the process back in-house years later if they choose to do so. “You don’t want to just hand off development of your product without keeping yourself very engaged,” says Dr. Dulgar-Tulloch. “Otherwise, companies can quickly find themselves at the mercy of whatever CMO they have picked because all of the product manufacturing expertise for their product resides with the CMO.”
As for when to start thinking about the supply chain and outsourcing options, Dr. Dulgar-Tulloch’s advice is to start early on. If a company waits until the product is ready for commercialization, they will face “tremendous” delays and frustrations as they try to catch up or work within constraints that they wished they could change.