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Manufacturers face the challenge of meeting growing demand for personalized biopharmaceuticals.
As more cell and gene therapies (CGT) advance through clinical trials toward potential approval and commercialization, manufacturers are looking to automated strategies and standardized systems for scaling up production efficiently. Early process designs that came from academic labs were not focused on commercial scale-up and relied, for example, on manual handling steps and complex tubing systems for liquid transfer (1). Automated sampling has helped, but more in-line process analytical technology (PAT) and greater automation and standardization are needed (1). At the same time, the diversity of products—in the case of autologous cell therapy, a different product for each individual patient—means that any manufacturing set-up will need to be highly flexible. New systems would ideally be able to be used in a decentralized, point-of-care location, such as a hospital facility, as well as a conventional, centralized pharmaceutical manufacturing location.
Commercial production of cell therapies is currently less than 5000 doses per year, but global demand is in the millions of doses, reports Jason Arcediano, chief business officer at Multiply Labs, a robotics technology company creating systems for bio/pharmaceutical manufacturing, including an end-to-end, closed manufacturing system for CGT. Existing processes and equipment do not have the throughput needed to meet patient demand. Staffing is also a challenge. “The industry is seeing high attrition rates—over 25%—because there is a huge demand for trained teams that can run these complex processes,” says Arcediano. Complex, manual handling steps limit throughput and increase opportunities for error. “The large cell therapy manufacturers are seeking to reduce failure points, and there is general agreement that automation is the solution,” he adds.
Current manufacturing capacity is inadequate to meet patient demand, and as more new therapies are developed, the unmet need will only increase unless there is a manufacturing paradigm shift, adds John Tomtishen, vice-president of operations at Cellares, which is preparing to launch its proprietary, end-to-end automated system, the Cell Shuttle. “Automation can transform the manufacturing paradigm and help companies scale their therapies effectively to make them accessible to all patients in need,” he says.
The manual and modular approaches used in early development tend to be carried over into commercial manufacturing, but these approaches pose challenges for scalability, adds Dan Strange, CTO, Cellular Origins, a spin-out launched in January 2023 from Cambridge, UK-based technology company, TTP, with a proprietary, automated system for scalable CGT manufacturing.
Cost and drug safety are both prominent challenges for the manufacturing process, which has traditionally been highly manual and complex. “We estimate the cell therapy manufacturing process may have upwards of 40 process steps, which is not only labor intensive but creates opportunities for errors and contamination that lead to failures,” says Betty Woo, vice president of cell, gene, and advanced therapies at Thermo Fisher. “By aseptically closing and automating the manufacturing process, we’re reducing the need for the highly specialized labor required to produce these therapies, thereby eliminating touchpoints, reducing expenses, and ultimately increasing the reproducibility and predictability of the process. Automating in this way will, to some extent, also help alleviate the workforce challenges we’re seeing across the industry particularly in emerging geographies.”
The optimal workflows for CGT are still being developed and processes are not yet standardized, leading to a need for flexible instrumentation, says Woo. “As the field progresses, we expect more standardized workflows to be established, [with] improved consistency, efficiency, speed, and throughput. These improvements will likely be catalyzed by technologies that aid in further scalability—down, up, and out; in-line sensing; and autosampling,” she predicts. “Standardization reduces variability and moves us closer to a more consistent and predictable outcome, while automation provides robustness, consistency, speed, and throughput. Automation in its ideal state will drive efficiency and reduce the cost for manufacturing these life-saving therapies.”
With the current manual or semi-automated manufacturing systems, production space and the need for highly skilled operators are barriers to production capacity. Closed and automated systems address both of these bottlenecks.
“Current, manual systems require ISO 7 or 8 cleanrooms, but a fully closed system can be placed in a controlled not classified (CNC) space,” explains Tomtishen. The Cellares Cell Shuttle platform is a “factory in a box” with all unit operations inside the closed system, which is about the size of a typical cleanroom workstation. Robotics perform material transfer from one unit operation to another. The throughput of the Cell Shuttle depends on the production process, notes Tomtishen. “With a seven-day process, you could manufacture approximately 800 batches per year per Cell Shuttle. Additional Shuttles could be added to scale-out if more capacity is needed,” he explains.
All the software and hardware in the platform has been developed by Cellares over the past four years. “The software enables flexibility to develop the manufacturing workflow. The research scientist has full control over the parameters in the unit operations,” says Tomtishen. He works with users to help them develop workflows and to transfer any processes already developed on other equipment to the proprietary Cell Shuttle equipment.
Partners in Cellares’ Early Access Partnership Program include the Fred Hutchinson Cancer Research Center, PACT Pharma, and Poseida Therapeutics. The partners helped evaluate prototypes and assess product requirements, release criteria, and process workflows. Cellares is continuing to refine the technology and expects the Cell Shuttle to be market-ready in 2024, which will make it available for process development and clinical and commercial manufacturing. In the “single-platform” approach, development and all manufacturing stages take place in the same equipment, which accelerates time to market.
Multiply Labs has designed a fully automated system with robotic handling that offers a solution to the need for increasing throughput, reducing error, and allowing flexibility, Arcediano says. The system has been designed to be compatible with existing equipment through a consortium launched by Multiply Labs in 2021 to tackle the challenge of debottlenecking commercial manufacturing of CGT using robotic automation. Manufacturing development is overseen by the University of California, San Francisco (UCSF) under a sponsored research agreement. Other consortium members are contributing their expertise to bring robotic automation to their equipment within the Multiply Labs’ Robotic Cluster, including Cytiva’s bioreactors, Thermo Fisher Scientific’s incubators, and Charles River Laboratories’ rapid microbial detection platform and endotoxin testing system for automating quality control (2).
“We aim to integrate with all major equipment manufacturers, so that a CGT manufacturer can use the validated equipment and instruments they want in their process,” states Arcediano. “We’ve started with the consortium members, but we are working with other vendors already.” Using validated equipment, process, and software leads to a shorter path forward with regulatory agencies, Arcediano adds. All equipment will be integrated with the robotic handling and Multiply Labs’ in-process control system in a standardized, “plug-and-play” method of information flow that is aligned with best practices from industry organizations, such as the Alliance for Regenerative Medicine. The equipment-agnostic system can use the best currently available instruments as well as be easily updated to use next-generation instruments, Arcediano adds.
Another feature is that all data are captured digitally. Arcediano explains that the end-to-end system could be run with only one operator; the operator loads the materials and then the robots transfer material from step to step through the aseptically controlled, fully closed system. Fluid transfer is handled with a proprietary robotic click connector system that eliminates the need for tube welding.
The automated system has a much smaller footprint than traditional manual processes. Because operators do not need access to the unit operations, the modules can be stacked two to three high and five to six deep. “A ballroom facility might have 1000 to 2000 square feet, while our system requires between 200 to 300 square feet,” says Arcediano. Throughput is also higher than traditional methods. “Instead of one client [i.e., patient product] at a time, our system can prepare up to 36 products at the same time,” he adds. The system can be scaled out as needed by including more modules for greater throughput. It can also be used for product development or commercial manufacturing, eliminating tech transfer.
According to Arcediano, because the process is self-contained, it can be used in a decentralized environment, such as a hospital, which would allow application of cell therapies in other regions of the world that do not have centralized manufacturing capability.
Cellular Origins’ platform is a configurable robotic automation solution that enables scalable, cost-effective, and space-efficient cell therapy manufacture that is designed for adaptability, says Strange. The platform consists of a universal transport system for automated movement of consumables, reagents, and patient materials; a tube-management system that enables automated routing; and a sterile fluid-transfer system that welds tubes, moves fluids, and provides real-time analysis and quality control, he explains. “These tasks are carried out by a combination of autonomous mobile robots with proprietary, future-proofed end-effectors and a configurable automation console that integrates existing third-party equipment. These tasks are all integrated within a data management system to ensure full traceability of every process undertaken,” Strange explains.
“Our platform enables therapy developers to use the tools and technologies from third-party vendors and combine them into a modular factory that can quickly scale to producing 10,000 therapies per year with a fraction of the labor of existing methods. Because the platform is built upon proven familiar technologies, it can potentially be used to scale those therapies currently in late-stage development.”
Strange adds that the company is beginning to work with its first customers to develop system configurations and to deploy these systems at customer sites.
In May 2023, Cellular Origins announced a partnership with ScaleReady, which is a joint venture between Bio-Techne, Fresenius Kabi, and Wilson Wolf with a mission to simplify and standardize CGT manufacturing. The collaboration’s initial task is to standardize and automate the interconnections between ScaleReady’s manufacturing platform modules using Cellular Origins’ robotic system (3).
“Solving the liquid handling problem and proving how amenable a simple, modular, and scalable approach is to automation allows the field to see a path forward to economies of scale,” said Josh Ludwig, commercial director at ScaleReady, in a press release (3). “Through this partnership, we plan to create a viable pathway using cell therapies for larger patient indications and front-line treatments by enabling therapy developers to implement automation when it makes the most sense, and when their products require it.”
Lonza’s platform for autologous cell therapy manufacturing, the Cocoon, is a functionally closed, automated system that is currently being used to support clinical trials in Europe and North America, in both centralized and decentralized manufacturing models, says Tamara Laskowski, head of Clinical Development, Personalized Medicines at Lonza. “With a growing number of clinical-pipeline applications, we are optimistic about the future use of the Cocoon Platform in commercial applications as well,” she adds.
Several unit operations—from starting materials through to final harvest—take place inside the functionally closed, single-use cassette, in processes which are tailored for each product. The Gen2 Cocoon, introduced in April 2022, added magnetic cell separation capabilities, allowing separation of cell types of interest, such as T cells, for processes that require this additional upstream sample preparation step, says Laskowski.
Decentralized manufacturing, which is closer to the patient at the point of care, reduces logistic challenges but can present quality concerns. Automated, closed systems, however, may resolve these concerns. “Producing cell therapies in automated, closed manufacturing systems will help to reduce reliance on manual operations and variability in process performance, improve data management, and may enable the realization of a standardized level of quality across point-of-care sites,” suggests Laskowski.
Allogeneic CGTs aim to use a single source of cells to treat many patients, with manufacturing at a larger scale than autologous CGTs. Automation, however, is expected to be important for these processes as well.
“Given the large-volume productions in allogeneic processes, automated systems that support final product harvest, formulation, and fill/finish are advantageous,” says Laskowski. “Such systems can reduce risks associated with manual processing and human error, ensure proper addition of cryoprotectant, and decrease time requirements to cryopreservation and storage of the product. As additional allogeneic CGT modalities emerge, we anticipate new developments in automated platforms to support culture and expansion of adherent cells and enable multi-stage manufacturing processes involving modified culture regimens and conditions for cell differentiation.”
Jennifer Markarian is manufacturing reporter for BioPharm International.
Volume 36, No.7
When referring to this article, please cite it as Markarian, J. Automation Aids Cell and Gene Therapy Production. BioPharm International 36 (7) 2023.