Chimeric Antigen Receptor (CAR) T cell products hold the promise of curing various cancers previously considered incurable. Since each lot of these products is specific to one patient, however, chain of custody, chain of identity, and other logistic/quality requirements are critical to ensure the correct patient receives the correct dose.

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CAR-T cell therapy is a kind of cancer treatment in which white blood cells (T cells) are taken from a patient and modified such that they can target a specific type of cancer. T cells are a type of white blood cell that play a key role in helping the immune system fight off diseases like cancer. The altered cells are then injected back into the patient’s body.

At the 2020 PDA/FDA Joint Regulatory Conference held virtually in mid-September, Gilead-Kite Global Quality Compliance Senior Director Brian Silvey provided an in-depth look at the numerous quality challenges his company faced in the commercialization of its CAR-T cell therapy, YESCARTA®.

“There are many quality challenges that need to be overcome in the development, manufacturing, and administration of cell therapy products that we have learned during the development and commercialization of Kite’s YESCARTA®,” Silvey said. YESCARTA® is an autologous CAR-T therapy approved in the United States in 2017 and in Europe in 2018 for adult patients with certain types of relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

Autologous products use cells that are taken from a patient, treated in some way, and then returned to the patient they came from to treat their disease.

7 Quality Challenges of CAR-T Products

“Several of the quality challenges I want to speak about are notable,” Silvey said. Each is listed below along with Silvey’s comments.

1) Each lot is an individual batch
“Each patient is one lot. One lot is one dose. And so, as you can appreciate, versus traditional biologics, where one lot may be 10,000, 20,000 units of prefilled syringes, we are making potentially thousands of lots a year. That has a unique challenge in terms of all the quality systems that go around that.”

2) The product requires a chain of identity and chain of custody throughout the process
Since the platform is autologous, it is a critical safety concern to make sure the patient gets back their dose from their cells. “One of the unique aspects of our process is the necessity of maintaining the cells at a certain temperature from needle out to the beginning of the manufacturing process.”

3) Cryo configuration is also critical
This requires well-developed packaging and shipping validation regarding the cryopreserved cells that are going back to the patient. “These present unique challenges in terms of packaging and shipping validation,” Silvey emphasized. With a global market, the company needs to consider temperature variations during the four seasons—for example, shipping cells to Europe or Australia and back and the temperature variations that occur during transit. All the various shipping routes need to be taken into consideration, and a very robust shipping validation package needs to be assembled.

4) Apheresis
This is a medical technology in which the blood of a person is passed through an apparatus that separates out one specific constituent and returns the remainder to the circulation. This technology is used with YESCARTA®. After the patient’s cells are received, they go through an apheresis process. After that, it is a continuous process from apheresis to final product.

“That presents several quality challenges to make sure that the manufacturing process is not only consistent but that it has the right controls to assure that process is reliable,” Silver pointed out. “Remember, there is no inventory to this biologic. Each patient has one dose, and one shot at this. So, the actual inability to produce a dose due to manufacturing issues or delays can be just as much a safety issue as a patient not getting the product or any type of quality issue within the product.”

5) Continuous process verification (CPV)
Another important quality system aspect is continuous process verification, CPV. “In this case, with so many lots being produced weekly, monthly, yearly, this really requires a new approach to robust data management and the associated analytics.”

6) A global manufacturing network
With a global manufacturing network, “the product must be made exactly the same way at every site and by our partners and in our joint ventures. This creates a whole new set of challenges in terms of the oversight of the process,” Silvey noted. “Commercialization requires robust capabilities and teamwork between key technical operations and the commercial organization. Think about the cycle time and the coordination, and handoffs to getting a patient registered all the way to getting the dose back to the patient. This all requires significant timing.”

7) Global quality systems and controls
Of particular importance is ensuring that the global quality systems and controls assure the product and its manufacturing processes align across the networks and partnerships. This includes the establishment of global procedures within the company—for example, for deviations, corrective and preventive actions (CAPA), and change control.

For partnerships and joint ventures, quality technical agreements are needed. “These go beyond traditional supplier quality agreements that we are used to in the industry. Where we have to make sure that these arrangements with these partners in these joint ventures are aligned—for example, regarding change control—to make sure that any changes are completely understood and completely tested before introducing them to the manufacturing process.”

Connecting Product, Provider, and Patient

“Manufacturing and administering autologous cell therapies requires quality aspects not seen in the supply chain of typical biologics,” Silvey said.

He explained that Kite introduced “a process where we make sure that we are helping physicians and patients get their dose and get it on time. This system we call ‘Kite Connect’ is enabled and validated to make sure that we have chain of custody and chain of identity.”

Part of the supply chain involves tracking shipments that are transported by couriers. “When you think about the wintertime and flight delays, and even the COVID situation that interrupted the supply chain, this type of system is critical to make sure that communication between patient and physician facility and the manufacturing site are all coordinated to make sure that the patient gets the dose back on time and as planned.”

The hospital has access through a portal such that it can track the progress of the dose. All these aspects come together within a validated system—part of the quality system—to make sure that there is a reliable supply chain for the patient.

Site Qualification is Vital

The nature of autologous therapies makes the hospital where the product is administered a symbiotic partner in the care of the patient receiving treatment. To ensure hospitals can take on this role they must be qualified (Figure 1).

**FIGURE 1 | Site Qualification for Apheresis Centers**

“Unlike any other biologic or drug, the hospital site is uniquely linked to the product and uniquely linked to the company to make sure that the prescribed treatment is successful,” Silvey stressed.

To begin with, he said, the company needed to assess a hospital’s ability to perform apheresis and infusion while maintaining full traceability of the patient material and the final product. It also needs to assess the adequacy of the hospital’s cold chain processes and the ability to handle fragile product.

Another unique aspect is the risk management plan (RMP), which is part of the approval process by regulatory authorities and includes traceability and cold chain aspects of product handling. This includes creating and delivering training to the involved hospital personnel on the RMP and documenting delivery of the training.

The quality portion of the site qualification process consists of three elements: gap assessment, training, and risk management, which are conducted by Kite quality staff.

The gap assessment evaluates whether a hospital can incorporate not only the cold chain aspects but also the ability to handle both the shipping of the apheresis material and the containment and dosing of the final drug product.

The training element covers the specific requirements and SOPs that govern apheresis material labeling and packaging. In addition, when the product comes back to the hospital there are specific requirements about handling the cryopreserved cells until the dosing of the patient.

Lastly, is the completion of the risk management program requirements that are linked to the training and documentation of delivery of the training.

After those systems are in place, the company does a “dry run” to ensure that all the systems are in place and the hospital can be authorized to order and dose the product.

Lack of Standard Requirements Creates Challenges

Silvey explained that one important quality challenge of initial site qualification “is that there are no standard requirements in the United States, Europe, or globally.” He said, however, it is important to apply a consistent approach for global product distribution.

“What we have learned from this endeavor is that we have to fit within the hospital’s framework while ensuring company and product requirements.” Coupled with that the company needs to understand the regional landscape, including the Joint Accreditation Committee ISCT-Europe & EBMT (JACIE)—Europe’s only official accreditation body in the field of hematopoietic stem cell transplantation (HSCT) and cellular therapy—and cell establishment licenses in Europe, as well as unique aspects in Canada and Australia.

“All of this has to come together and be well understood by the company and the quality compliance leaders that are involved with the qualification process to be able to make sure we qualify these sites according to the product requirements.”

Resources that are available to help the qualification process include the hospital point of contact and their governing SOPs and training.

Unlike any other biologic or drug, the hospital site is uniquely linked to the product

The hospital’s point of contact facilitates communication between the company and the hospital departments, to ensure that aspects of the Kite quality system are in place and trained personnel are in place to oversee the apheresis and the final dosing.

It is important to ensure that the SOPs required for these products are in the local language and that the hospital has multiple training sessions to cover all the involved staff. “As you can imagine, a hospital is 24/7, several shifts, several healthcare providers are involved. So, the training aspects should not be underestimated,” Silvey pointed out.

Company requirements need to be aligned with hospital standards. “This really is a collaboration,” Silvey emphasized. “We work within the governing hospital SOPs and the hospital has specific SOPs in the apheresis unit, the cell therapy lab, and also at the bedside infusion of the dose.”

While this is a collaborative process, there is a separation of responsibilities, he explained. “The apheresis process and the dosing of the patient is the practice of medicine. Kite cannot give directions in the practice of medicine. However, we do make recommendations on equipment or brands to use, and work with the healthcare providers at the hospital to collaborate to solve any identified gaps.”

Patient Needs Drive Cycle Times

The serious conditions being treated by CAR-T cell therapies and the patient’s need for the product drive a minimal lot release cycle time. Each patient lot release is targeted within days of manufacture.

“That is really important because there are some preconditioning and preparation of the patient prior to administration of the therapy that is on the product label that has to happen (Figure 2). Also, the hospital needs to schedule the patient and ensure he or she is ready for administration of the dose.”

**FIGURE 2 | Patient Experience with a CAR T Product**

To help enable minimal lot release times, the company has licensed rapid test methods that are well known in the industry now—such as sterility test and PCR methods—such that the required testing can be completed in a timely manner.

Critical for products with such short cycle times are robust deviation management and disposition processes. “They have to be streamlined, they have to be adapted to cycle times,” Silvey emphasized. “We certainly do not compromise on any of the GMP requirements in terms of deviation, product impact, root cause analysis and CAPA, but that all has to be resourced and timed appropriately to get these products back to the patient.”

To learn more about cell and gene therapies, read the rest of our series: