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Automation, digitalization, and supply-chain strategies help mitigate vulnerabilities in both autologous and allogeneic cell therapy manufacturing.
Cell therapies are a relatively new type of biotherapeutic in the marketplace. As such, their commercial manufacture poses unique challenges in biomanufacturing that necessitate the need for new thinking and innovative solutions. Adding to the pressure of maintaining a sterile manufacturing environment are the restrictions imposed by the current COVID-19 pandemic, which has had wide-reaching effects across all industries. Additional manufacturing practices or operating protocols may be required to ensure aseptic manufacturing in the cell therapy arena during and post the pandemic.
Speed, safety, reliability, and cost management are among the normal challenges faced by cell therapy manufacturing. But a unique challenge that cell therapies face is the variability in donated cells that form the starting material of the therapy.
For instance, autologous chimeric antigen T-cell (CAR-T) cell therapy requires a sophisticated manufacturing process and uses cells collected from an individual cancer patient, says Ryan Larson, senior director, cell therapy product and analytical development, Bristol Myers Squibb. “During the autologous process, a patient’s cells are collected through a process called leukapheresis, in which blood is drawn and white blood cells are separated out to use for manufacturing. The cells are then shipped to the manufacturing facility where they are reprogrammed to become CAR-T cells to recognize and fight cancer cells and then sent back to the patient’s certified treatment center where they receive their CAR-T cells via a one-time treatment,” Larson explains.
“One key challenge in manufacturing autologous CAR-T product is between-patient variability in starting material,” Larson continues. “In some cases, a CAR-T manufacturing run may fail due to the detrimental impact of multiple rounds of chemotherapy for prior cancer treatments on T cells that serve as the starting material for the manufacturing process. Manufacturing process robustness to handle heterogeneous autologous starting material between patients and across disease indications is an important part of process design and development.”
Further, autologous cell therapy manufacturing is much more challenging than the manufacturing process for allogeneic cell therapies. The manufacturing process for an autologous cell therapy must accommodate for the variability in the source patient’s cells in order to consistently produce final product with desired quality attributes, notes Dr. David Chang, CEO of WuXi Advanced Therapies, the cell and gene therapy contract development and manufacturing organization business unit of WuXi AppTec. Manufacturers need to have shown “proven and qualified” end-to-end manufacturing capacity to regulators for commercial production. In addition, practices such as right-first-time are essential to ensure patients can receive drug production for treatment reliably in the shortest possible turnaround time, according to Chang.
In addition, many general cell therapy manufacturing operations are conducted in “open” settings, which require aseptic processing in a biosafety cabinet (BSC) in a Grade B cleanroom, Chang says. The extensive use of sterile disposable components and complicated raw materials requires intensive supplier management effort. “There are also complicated analytical methods (e.g., flow cytometry, potency assay) for in-process control and release testing that are difficult to develop and qualify/validate,” Chang adds.
Specifically, cell-therapy manufacturing processes are most vulnerable where there is open processing under a BSC. Fortunately, significant progress has been made to date in “closing” these operations through the use of tubing welding/connections that allow the manufacturing processes to take place out from under the BSC, thus reducing vulnerabilities, notes Chang. There remain a few steps, however, such as viral transduction and cell harvesting, that are harder to “close”.
Safeguards for sterile operation include going through formal aseptic processing validation (APV) to further assure sterility throughout processing. “It is important to conduct extensive in-process and final release sterility testing to ensure final drug product sterility,” says Chang.
Allogeneic CAR-T cell products, in comparison, are produced in large batches from normal healthy donor starting material (e.g., stem cell bank or primary T cells). With allogeneic cell therapies, a single batch can be used to treat many patients, Larson explains.
“These products may be easier to produce than autologous products, because the starting materials are derived from healthy donors rather than heavily pre-treated patients. However, challenges remain with regards to gene-editing strategies that mitigate risk of graft versus host disease and engraftment,” Larson continues. “In addition, stem-cell based allogeneic T-cell therapies are being developed in which a CAR-T cell product is manufactured from a master stem cell bank, which has the benefit of lot-to-lot consistency in starting material. Allogeneic cell therapy products will reduce manufacturing costs while providing patients with quicker access to ‘off-the-shelf’ treatment and more consistent therapeutic doses.”
In both allogeneic and autologous cell therapy, Chang points out that manufacturers have to contend with requirements for maintaining chain-of-identity throughout the manufacturing and transportation processes to prevent mix-ups or cross-contamination among patients’ lots. “Highly manual operations demand a high proportion of direct labor, which results in a high cost of manufacturing and is susceptible to human error,” Chang states.
Working with what are fundamentally “living therapies” in the cell (and gene) therapy field also creates one of the most complex supply chains in medicine, says Tamie Joeckel, global business lead, cell and gene therapy, ICON. “Orchestrating the cell therapy logistics for both source materials and final doses requires detailed planning and hands-on management. The end-to-end processes of tracking and tracing the movement and handoffs of these shipments among stakeholders are rife with risk and potential points of failure,” she says.
An added dimension to this supply-chain challenge lies in the fact that, in some programs, the patient and site schedules are co-dependent and require close coordination. “Many patients must travel to specialty centers, requiring the additional coordination of concierge services for both the patients and their caretakers. Any change or disruption in schedule ripples through the entire workflow and can affect the product chain-of-custody, chain-of-condition, and chain-of-identity that are required to ensure patient and product safety,” Joeckel says. “New disruptions caused by the COVID-19 pandemic exacerbate the risks of these critical shipments.”
The challenges posed by cell therapy manufacturing have pushed forward biomanufacturing innovations already under development or in use for monoclonal antibody-based and protein-therapeutic-based production.
“In my opinion, innovations in cell therapy are actively taking place in several fields, such as disposable technologies, automation, process integration, and digital solutions,” notes Chang. The effort of automation and process integration is addressing the challenges faced with the highly manual cell therapy processing steps, such as sampling, medium exchange, in-process monitoring/testing, and cell manipulations (e.g., activation, transduction, harvest, etc.), Chang explains.
“I believe that there has been some progress made in automation, but cell therapy needs significantly more innovations in this area in order to transform the manufacturing paradigm. There are innovations in process integration that are aimed at fully integrating end-to-end manufacturing steps into a turn-key solution,” Chang says.
“Digital solutions are also evolving, such as cell-therapy-manufacturing-friendly MES [manufacturing execution system], LIMS [laboratory information management system], and ERP [enterprise resource planning] systems that are being actively developed and/or optimized,” Chang continues. “These digital solutions need to be fully integrated to be able to communicate in real time during manufacturing and release testing. It is also critical to connect manufacturers to clinics electronically to ensure the chain-of-identity is fully maintained.”
Ultimately, there is an urgent need for innovation, especially in automation, to transform cell therapy manufacturing, Chang concludes. The primary goals of innovation are to lower the cost of goods, reduce human error, and accelerate timelines with greater predictability.
“At Bristol Myers Squibb (BMS), we embrace digitization and have invested in the use of next-generation technology,” says Chris Ramsborg, vice-president, cell therapy process science and technology, Bristol Myers Squibb. BMS has invested in the development of its proprietary NEX-T manufacturing platform, for example, with which the company may be able to create a manufacturing environment that is optimized to potentially reduce turnaround time and increase product control.
“BMS currently has two active clinical trials evaluating our NEX-T technology for a CD-19-directed CAR-T cell therapy in relapsed or refractory B-cell non-Hodgkin lymphoma and an anti-BCMA CAR-T cell therapy in relapsed and/or refractory multiple myeloma. We recently dosed our first patient using this technology and look forward to seeing more progress,” Ramsborg says.
“In addition to NEX-T, we are also continuing to invest in, evaluate, and develop new manufacturing platforms to advance scientific innovation in cellular therapies, researching technologies for overcoming resistance to CAR-T cell therapies, investigating use in solid tumors, and potentially creating allogeneic CAR-T cell therapies for patients,” Ramsborg adds.
The manufacture of cell therapy product carries vulnerability and risk, which have been further pronounced during the COVID-19 epidemic.
For CAR-T cell therapies, every stage is vulnerable to scientific and technical challenges stemming from the inherent variability of the autologous starting material, states Larson. To mitigate these manufacturing vulnerabilities, BMS is creating a simple digital platform that streamlines handling, chain of identity, ordering, and scheduling to expedite delivery of CAR-T cell therapy, he says.
“We are also optimizing manufacturing through automation to make processing units more efficient while supporting product consistency,” Larson says, explaining that current CAR-T manufacturing processes require delivery of a transgene encoding the CAR, which induces T cell activation and co-stimulation in response to target antigens expressed by the tumor cells.
“Sourcing and control of the gene delivery raw materials, whether it be viral or non-viral modalities, introduce challenges to the CAR-T manufacturing process. Prioritizing this area to increase knowledge through identifying biologically relevant critical quality attributes and building a supply chain for GMP [good manufacturing practice] gene delivery, raw materials will continue to increase the technical maturity of this element of CAR-T manufacturing,” Larson continues.
The company’s investigational autologous CAR-T cell therapy, lisocabtagene maraleucel (liso-cel) for treating multiple hematologic B-cell malignancies, for example, uses a manufacturing process designed to support robustness and consistency for a diverse patient population across different B-cell malignancies. “The process employs technologies for purification, activation of the starting material, and gene delivery that aims to reduce the variability between patient populations, supporting consistent and predictable manufacturing duration and product quality,” states Larson.
Another manufacturing vulnerability lies in maintaining chain of identity, especially in autologous cell therapy manufacturing. “To address this challenge, manufacturers should establish procedures and trainings to ensure operations maintain end-to-end chain of identity throughout manufacturing process. In addition, it is strongly desired to use fully integrated digital solutions (e.g., MES, LIMS, ERP, etc.) to achieve this goal,” Chang states.
Furthermore, cell therapies are both time and temperature sensitive, leaving them at the mercy of transport logistics. “[Cell therapy] logistics is an already complex, finely tuned, orchestrated process involving numerous stakeholders—and disruptions caused by COVID-19 in site procedures, patient re-scheduling, and shipment delays can ripple through the workflow, placing both the product and the patient at risk,” indicates Joeckel.
For example, the end-to-end supply chain involves a large number of handoffs between internal departments at the sites and external service providers. “More importantly, for many patients, these therapies may be their final hope—and patients in the final stages of their disease may not be able to physically withstand an additional procedure should their cell shipments be damaged or lost. It is truly a ‘zero defect’ environment. Mapping out the detailed workflows and validating the entire process is critical,” Joeckel asserts.
Moreover, because autologous therapies involve cells from the patient—which are used to manufacture the final dose that goes back to the same patient—another element that needs to be safeguarded is that of “track and trace.” Safeguarding “track and trace” activity is important for maintaining the chain of identity of the material—from the initial collection of the patient’s cells to transportation from the apheresis center to the manufacturer—all throughout the manufacturing process of the final dose and transport back to the site of administration, Joeckel continues.
“A common delimiting factor in autologous programs is managing limited manufacturing capacity. Manufacturing schedules must be coordinated between sites, labs, patients, apheresis centers, specialty couriers, and the manufacturing center to collect the cells and ship them overnight to the manufacturing facility. These refrigerated shipments are highly time sensitive, and the manufacturer must be ready to start the process upon receipt,” says Joeckel.
In the face of the current COVID-19 pandemic, manufacturers are learning to navigate not only the complexity of cell therapy manufacturing and development, but also restrictions and necessary shifts in daily operating protocols.
“During the initial COVID-19 outbreak, the majority of clinical trials, especially in cell therapy, were put on hold,” says Chang, who goes on to say that “since some restrictions now have been eased or lifted, hospitals and clinics are once again able to receive and treat patients for clinical or commercial cell therapy applications.” WuXi Advanced Therapies (WuXi ATU) proactively increased critical inventory and is evaluating alternative suppliers for future inventory.
Autologous cell therapy clinical trials are complex in nature, and COVID-19 adds to this complexity, stresses Ramsborg. Because the cell therapy requires transportation of cells from patients to manufacturing sites and back, travel restrictions both in-country and across countries have a significant impact, he emphasizes.
“Lastly, in contrast to clinical trials of many investigational products, initial treatment with a cellular therapy product requires a lead time of several weeks. Because of the uncertainty created globally by COVID-19, healthcare professionals may be conservative about starting patients on an investigational therapy in a clinical trial, given that the trial, and thus the treatment course, may be interrupted by the uncertainties of the evolving pandemic,” notes Ramsborg.
In response to COVID-19, BMS had early on made the necessary but difficult decision to temporarily suspend screening, enrollment, and apheresis in its cellular therapy clinical trials. “That pause has since been lifted, but we are continuing to monitor the COVID-19 situation to ensure that we are supporting the safety of study subjects, staff at clinical trial sites, and our employees while also ensuring regulatory compliance and the scientific integrity of trial data,” Ramsborg states.
Disruptions varied by region, says Joeckel, but can start with the cell collection step. For example, some apheresis centers had reduced schedules or stopped operating altogether to limit the exposure of their staff and donors to COVID. Sites concerned about the transmission of the virus, especially to vulnerable patients, also had to cancel or delay appointments, and many sites reassigned personnel, which affected patient enrollment, access, and capacity. As a result of these measures, restricted access to healthcare facilities and new COVID safety and screening procedures should be included in protocols and training manuals going forward, says Joeckel.
A critical issue being faced currently is receiving shipments and supplies to and from sites, Joeckel adds, noting that border closures and reduced air traffic have disrupted the supply chain around the world. “Flight delays are more common, requiring hands-on management and monitoring of the temperatures and hold times of the cells and requiring more robust intervention procedures. Supply shortages have also caused problems—causing some service providers to shut down entirely,” she states.
“Until we have an effective vaccine for COVID-19, the threat of disruptions to the manufacture and delivery of cell and gene therapies remains. The current pandemic is far from over and the threat of new outbreaks is a possibility. Continuing to find ways to ensure business continuity, supply chain resilience, and keeping development programs on track requires ongoing innovation, flexibility, and agility. The overarching reason for urgency is quite simple—there are patients waiting for life-changing, life-saving therapies at the end of every supply chain,” asserts Joeckel.
WuXi ATU, which has made a strategic move by diversifying its suppliers, sees value in conducting extensive risk assessments of its facilities, including reviewing current manufacturing operations and the potential impact from COVID-19 on product safety. “We’ll then take that information and develop and implement mitigation efforts to ensure we can continue to conduct high quality aseptic manufacturing operations. Through our enabling platforms, technology, and security of supply chain, WuXi ATU is ready to accelerate progress and time to market in the years to come,” Chang states.
“COVID-19 has led to many uncertainties, but we have proactively taken precautions to protect and support all our clinical trial participants, trial site staff, and employees, as well as protect the integrity of our clinical trials,” adds Ramsborg.