Closing The Loop: Closing Cell Therapy Manufacturing Processes

This article examines the evolution of cell therapy manufacturing technologies, including the transition from open, manual workflows to closed, automated systems. We discuss the operational and financial benefits of process closure, including improved contamination control, reduced capital and operational costs, and enhanced sustainability through lower cleanroom requirements.

Integrated platforms and modular technologies have advanced reproducibility and scalability, yet limitations persist, especially in handling critical reagents and maintaining fully closed workflows. Innovative solutions—such as SMART bioreactors, robotics-driven platforms, and improved supply formats for cytokines and gene-editing materials—are progressing the industry toward automated solutions and end-to-end process integration. The adoption of these innovations is essential for enabling efficient, affordable, and accessible cell therapies. This article provides a comprehensive overview of current best practices, challenges, and future technologies for streamlined, sustainable manufacturing capable of meeting global patient needs.

Background

Cell therapies and ex vivo gene therapies represent a groundbreaking approach to disease treatment. This is because they offer targeted solutions that address conditions at a cellular or genetic level. These innovative therapies hold the potential to cure diseases once considered untreatable, transforming patients’ lives and providing hope where none previously existed.

Autologous Cell Therapy

In autologous cell therapy, a patient’s own cells are collected, typically genetically modified, and then reinfused into the same individual. Because these therapies are patient-specific, manufacturing requires multiple parallel production lines, each dedicated to a single patient. Each patient corresponds to a single batch, and increasing patient access requires scaling out production.

The risk of an immune response against the product is minimal, as the therapy is derived from the patient’s own cells. Most currently approved cell therapy products fall into this category, including US Food and Drug Administration (FDA)-approved chimeric antigen receptor T cell (CAR T) therapies such as YESCARTA, CARVYKTI, and Kymriah.

Allogeneic Cell Therapy

In contrast, allogeneic cell therapy uses cells from a donor (who may or may not be related to the patient) to manufacture the cell product that is infused into patients. These therapies offer potential for greater scalability through process scale-up and the generation of larger product batches capable of treating multiple patients, potentially resulting in economies of scale, standardized processes, and lower manufacturing costs. Additionally, they enable “off-the-shelf” treatments from a donor cell source that is ready for immediate use, eliminating the “wait time” associated with autologous cell manufacturing.

Although they offer these benefits, allogeneic cell therapies may face challenges related to immune responses, including graft-versus-host disease and host-versus-graft (HvG) rejection, necessitating strategies to mitigate these risks. There are a limited number of allogeneic cell therapies approved for commercial use, and several are being evaluated in advanced clinical trials.

Manufacturing Challenges

Even with clinical validation and a growing number of successful applications, manufacturing remains one of the biggest barriers to making cell therapies widely accessible. As our understanding of both processes and products deepens, new manufacturing technologies and solutions continue to emerge. These gradually address existing production challenges. Full adoption of these innovations is essential to ensure these therapies can be scaled efficiently and affordably, ultimately reaching more patients.

A major contributor to the high cost of manufacturing (whether for autologous or allogeneic cell therapies) is the complexity of unit operations, many of which are not fully integrated. Each step often requires separate equipment, multiple manual interventions, and, in many cases, open processing. The latter is particularly challenging in cell therapy manufacturing, because unlike traditional biologics, cells cannot be sterilized using 0.22 µm filtration. As a result, aseptic control must be maintained throughout the entire process and open steps are traditionally performed within a biosafety cabinet (Grade A) in Grade B clean-rooms, further increasing production complexity and cost. Although larger-scale allogeneic production offers better opportunities for process control due to its similarities to traditional biologics, the low-volume handling required in autologous therapies makes it even more challenging to achieve a fully closed and automated manufacturing workflow.

In this article, we explore the challenges and opportunities of closing cell therapy manufacturing processes, emphasizing the technical and operational advantages of closed systems. We also examine the financial impact of process closure, particularly its potential to enhance scalability and cost-effectiveness. Finally, we discuss future innovations that could further advance process closure. Ultimately, we aim to provide insights into the evolving landscape of cell therapy manufacturing and its trajectory toward greater accessibility and sustainability.

Overview of Cell Therapy Manufacturing Technologies

Early cell therapy manufacturing processes for clinical supply often relied on repurposed equipment from research laboratories and hospital settings. This included standard lab tools such as laminar flow hoods, biosafety cabinets, centrifuges, and culture flasks, as well as consumables and devices commonly used in blood transfusion procedures, such as blood bags, pumps and tubing sets, apheresis machines, plasma separators, and cell washers. Prominent examples included the COBE 2991 cell processor, initially developed for separating blood components, and manual plasma extractors, which were employed to isolate plasma from whole blood. Although these tools were instrumental in enabling early clinical development, they were not designed to meet the stringent requirements of GMP manufacturing. Their use often involved manual, open operations that increased the risk of contamination, introduced process variability, and limited scalability. This reliance on non-specialized equipment reflects the field’s early ingenuity but also underscores the pressing need for purpose-built, closed, and automated systems to support consistent, scalable, and cost-effective cell therapy production.

To address the limitations of early cell therapy manufacturing approaches, a new generation of purpose-built technologies were developed to meet the specific demands of these processes, emphasizing GMP compliance, closed-system operation, and automation or semi-automation of key unit operations. These innovations have played a critical role in enabling both clinical and commercial production of first-generation cell therapy products, including CAR T therapies for oncology and hematopoietic stem cell (HSC)-based therapies for rare genetic disorders. Notable examples include the CliniMACS Plus system (Miltenyi Biotec), designed for clinical-grade magnetic cell enrichment in a closed, automated format, and cell processing platforms such as the Sepax C-Pro (Cytiva), CTS Rotea (Thermo Fisher Scientific), and Lovo (Fresenius Kabi). These streamline cell labeling, cell washing, concentration, and formulation with minimal manual intervention.

For autologous cell expansion, G-Rex flasks and single-use culture bags provide gas-permeable, scalable environments that support high-density cell growth while maintaining sterility. In cases requiring higher cell doses—such as T cell receptor T cell (TCR T) therapies or allogeneic applications—systems like the Quantum Flex Cell Expansion System (Terumo BCT), which uses a hollow-fiber bioreactor, and the Xuri rocking bioreactor system (Cytiva) have been incorporated into manufacturing workflows. Additionally, for non-viral gene delivery, electroporation platforms such as the MaxCyte ExPERT GTx, Lonza 4D-Nucleofector, and CTS Xenon Electroporation System (Thermo Fisher) have been widely adopted, offering scalable, GMP-compatible transfection solutions.

Even with these advancements, a significant challenge persists: the lack of integration among the various purpose-built systems, many of which are developed by different manufacturers. Most cell therapy manufacturing workflows still rely on a collection of standalone devices, each tailored to a specific unit operation but rarely designed for seamless interoperability. This fragmentation adds complexity to process orchestration, increases the risk of operator error, and limits the potential for full automation and end-to-end workflow closure. To address this gap, integrated manufacturing platforms have emerged, offering more cohesive and streamlined solutions.

The CliniMACS Prodigy (Miltenyi Biotec) was among the first to provide end-to-end automation within a single closed system, enabling cell selection, activation, transduction, expansion, and formulation in a GMP-compliant environment. Its compact footprint supports the installation of multiple units in an open-plan ballroom setting, facilitating parallel manufacturing of multiple batches while significantly reducing space requirements compared to traditional setups using discrete equipment. Similarly, the Cocoon Platform (Lonza) provides integrated, automated control of multiple process steps within a closed, single-use, self-contained processing chamber. Its modular design also allows for vertical stacking, further optimizing facility layout and manufacturing throughput. These integrated manufacturing platforms represent a significant leap forward in simplifying cell therapy manufacturing, improving reproducibility, and accelerating clinical translation. Their adoption across global GMP facilities has helped standardize workflows and reduce the operational burden associated with coordinating multiple devices.

Although integrated platforms like the CliniMACS Prodigy and Cocoon have advanced cell therapy manufacturing, they still present limitations that highlight the need for continued innovation. For example, the CliniMACS Prodigy features a fixed-volume, single-use cell culture chamber that, though effective for many applications, may be insufficient for therapies requiring larger cell doses, such as certain TCR T therapies for solid tumors or allogeneic cell therapies.

In addition, although the CliniMACS Prodigy is designed as a closed, automated system capable of operating in lower-classified environments, in practice, most implementations still place it in Grade B cleanrooms. This is due to the persistence of manual interventions and open processing steps, such as cytokine supplementation and lentiviral vector preparation for transduction, which must be performed in a Grade A environment. These workflow realities limit the system’s ability to fully realize the vision of closed, automated manufacturing in Grade C ballrooms, which is essential to successfully scale out autologous therapy production at the commercial level.

Additionally, the emergence of non-viral gene delivery and gene-editing technologies has introduced new process requirements (such as electroporation and complex gene modification steps) that these platforms were not originally designed to accommodate. This requires the integration of supplemental modules or entirely new systems. Finally, the all-in-one design of platforms can lead to inefficiencies in facility utilization. This is because the extended duration of the expansion phase ties up the entire device, preventing concurrent use of other modules for different products. These limitations underscore the need for more modular, flexible, and fully closed manufacturing platforms for cell therapy manufacturing that can adapt to the increasing complexity and diversity of cell therapy workflows.

Innovative solutions are continually evolving to address these emerging challenges, driving the field toward more scalable, efficient, and adaptable manufacturing paradigms. In addition, a comprehensive assessment of the recent advancements in cell therapy technology can be found in the ISPE Good Practice Guide: ATMPs – Equipment Design and Qualification for Cellular Products.1

Approaches to Closing Cell Therapy Manufacturing Processes

Before discussing the progress and improvements that have been made to date with cell therapy manufacturing technologies, it is important to understand the concepts of open and closed processing technologies as well as the technical and operational benefits of closed manufacturing systems. Open operations are operations where the product is exposed or in contact with the surrounding cleanroom environment, even if that exposure is brief. Closed operations, in contrast, provide a fully segregated means of production with no contact between the product and the surrounding environment. Even though cleanroom environments are maintained to protect the product, the presence of operators in the cleanroom environment is the greatest source of contamination in cleanrooms,2 and inevitably, open operations and manipulations are a source of risk to the product.

Process closure can be accomplished through multiple means. This includes utilizing an end-to-end equipment solution, utilizing aseptic transfer solutions between equipment devices, or enclosing open equipment platforms within a controlled environment such as an isolator. The first method of process closure is to utilize an integrated platform as described in previous sections, including systems like the CliniMACS Prodigy or Lonza Cocoon for the cell manufacturing process from start to finish. Although these equipment platforms are an option for some manufacturing processes, they inevitably have limitations. These include limitations in scale, in the process manipulations that are required, or in the cost of occupying the end-to-end platform for the duration of the cell therapy manufacturing process.

The second option is to utilize a collection of standalone devices but to transfer the product from one system to another in a closed manner. This can be accomplished using aseptic connection devices or using sterile tubing welds and seals. Aseptic connection devices are more robust than tubing welds and seals, but they are costly and there are limited suppliers that are compatible with the scale of cell therapy operations, leading to supply chain concerns. Tubing welds and seals are less costly; however, they are time consuming and are prone to leaks.

A third method is to enclose the open processing steps within a Grade A isolator. For this option, equipment that is “open” is housed within a Grade A isolator, thus allowing the room background to be reduced to a Grade C or in some cases even a Grade D background. Because the product and the processing are segregated from both the cleanroom and the environment, even with open operations, the risk to the product becomes negligible if proper procedures are followed within the isolator. As a limitation, isolators can be expensive and timely to procure. Also, the use of glove ports can make it difficult to perform some of the intricate manipulations required for cell therapy manufacturing.

No matter the methodology, there are many benefits of closing the process or using barrier technology. These benefits include greater contamination control and a reduction in mix-ups. This approach can also significantly decrease capital cost due to reductions in manufacturing space and area segregation and operating costs through reduction in cleanroom background. These savings in spatial requirements and energy consumption also result in more sustainable facilities.

The Impact of Closed Systems in Cell Therapy Manufacturing

One of the largest attractors for moving to a closed process in cell therapy production is the ability to downgrade the room background from a Grade B environment to a Grade C (or Grade D) environment. Historically, this has precedent in the bio-pharmaceutical industry as bulk biologics (e.g., monoclonal antibodies, cell culture-based vaccines) have successfully downgraded room classifications over the last 20 years. This includes through robust process closure, implementation of single-use systems, and risk assessments. It is not uncommon for the upstream cell culture operations for a biologics facility to be manufactured in a Grade D or even controlled not classified (CNC) environment due to the implementation of process closure solutions.

Figure 1: Comparison of support spaces for Grade B vs. Grade C cleanrooms

Moving from a highly classified environment to a lower classified environment has numerous benefits. These include reduced capital costs and operating costs. Operating cost savings stem mainly from lower energy consumption, reduced environmental monitoring and cleaning requirements, and fewer gowning requirements. These also lead to waste reduction and create a more comfortable working environment for operators.

Reduced Capital Costs

Downgrading cleanrooms results in multiple opportunities for reduction in capital expenditure. In Figure 1, the cost savings in terms of heating, ventilation, and air conditioning (HVAC) reduction are quantified for a theoretical 500-square-foot cell therapy cleanroom. Notice that as the cell therapy suite is downgraded from a Grade B to a Grade C. There is a corresponding reduction in airlock HVAC classifications and corridor classifications. With the transition to a Grade C cleanroom, utilizing a CNC corridor system is also a possibility, one that translates into savings from both an HVAC and environmental monitoring perspective.

Reduced Operational Costs

Downgrading cleanroom classifications is also associated with a reduction in operating costs. This comes from a decrease in the number of air changes required per hour, the environmental monitoring frequency, and the gowning required. Table 1 compares the requirements for air changes per hour and associated energy consumption costs for cleanrooms per classification. 3 Note that cleanroom energy consumption will vary depending on the facility location, heat load generation, personnel present in the space, and other factors. However, we can expect three times the savings in energy costs if we move from a Grade B to Grade C environment.

There is a significant reduction in environmental monitoring frequency, cost, and expectations as operations are moved from a Grade A/B environment to a Grade C environment. Per the EudraLex, Volume 4, Annex 1,4 continuous viable air moni-toring must be performed for the duration of critical processes performed in a Grade A environment. Based on risk, the Grade B cleanroom may also be subject to these requirements. Grade C cleanrooms are to be monitored according to risk as assessed in the contamination control strategy (CCS).

Table 2 compares the requirements for Grade A, B, and C monitoring of total and viable particulates. Note the reduction in frequency of monitoring as cleanrooms transition to a less critical background. Additionally, cleanrooms must be requalified on an ongoing basis. When moving from a Grade B to a Grade C background, the requalification interval is extended from a minimum of 6 months to 12 months.

Cleaning requirements also differ between Grade B and Grade C environments. With Grade B being the background for sterile operations, cleaning is stringent and often on a daily or per shift basis. In addition, cleaning chemicals used in a Grade B cleanroom should be sterile. With a Grade C cleanroom, cleaning chemicals are not required to be sterile, and the cleaning frequency can be less frequent as validated through the manufacturer and defined in the CCS.

Gowning requirements also decrease when moving from a Grade B to a Grade C requirement. Figure 2 shows an example of typical gowning requirements for different cleanroom classifications. Although specific gowning requirements will vary by manufacturer and risk tolerance, it is important to note that there is a significant jump in cleanroom gowning between a Grade B and a Grade C background. Additionally, gowning materials in a Grade B room are required to be sterile, a requirement that does not exist for Grade C and higher classifications. In addition to the cost of goods (CoGs) of the increased gowning, there is also the less quantifiable factor of operator comfort with decreased classification levels leading to an improved working environment for operators.

Decreased gowning in turn leads to a reduction in waste materials. Cell therapy manufacturing processes are labor intensive with high headcounts compared to traditional biologics facilities. A reduction in gowning materials, though it may seem small, is significant when multiplied by the number of operators in the facility as well as the number of gowning changes per day. It is also important to note the cell therapy facilities are BSL-2 due to the manipulation and handling of human cells; thus all waste materials need to undergo proper decontamination prior to disposal. This is a cost that should not be neglected.

Limitations and Challenges in Fully Closing the Cell Therapy Manufacturing Process

Manual human interventions involving open manipulations represent one of the greatest contamination risks in cell therapy manufacturing. The following section highlights several common examples of labor-intensive, manual, open operations within cell therapy workflows that pose the highest contamination risk and require practical strategies to close. Ultimately, addressing these material handling and delivery challenges, from cytokines and viral vectors to gene-editing materials and reagents, is critical to achieving truly closed, scalable, and GMP-compliant manufacturing processes for next-generation cell therapies.

Cell Expansion Phase

Among all unit operations, the cell expansion phase (and any open manipulation during that stage) poses the greatest contamination risk because microbial contaminants can proliferate rapidly in culture media. In standard CAR T manufacturing, this step typically lasts 7–14 days, creating an extended window for potential contamination. Accelerated platforms, such as Gra-cell/AstraZeneca’s FasTCAR or Novartis’s T-Charge, reduce this period to three days or less, significantly lowering risk and improving process robustness. Regardless of duration, strict control over raw materials, consumables, and product-contacting equipment, coupled with rigorous aseptic practices throughout the process, is essential to ensure final product sterility.

Figure 2: Gowning strategy by cleanroom grade.

Cytokine Handling

One major obstacle to closing the cell expansion workflow is the handling of cytokines. These supplements are added to the culture media to stimulate cell growth and/or maintain a desired cell phenotype during cell culture and expansion. They are often supplied in lyophilized form and must be reconstituted shortly before or during manufacturing, introducing open steps into the process. A practical solution is the use of liquid-stable cytokine formulations that can be added directly to culture media via sterile welding, or ideally, incorporated into ready‑to‑use media prepared prior to cell therapy manufacturing.

This approach eliminates the requirement for manual cytokine reconstitution in Grade A environments and enables a streamlined, closed system. For example, AKRON Biotech’s Closed System Solutions (CSS) liquid cytokines (IL‑2, IL‑7, IL‑15, IL‑21) are packaged in weldable bags for aseptic integration and have been incorporated into platform protocols for CAR T and TCR T manufacturing.5 This enables closed-system automation, minimizing operator error and improving aseptic processing. Similarly, Bio‑Techne’s ProPak GMP Cytokines (IL‑7, IL‑15) are available in liquid formats optimized for G‑Rex bioreactor systems to support closed-system CAR T manufacturing.6

Genetic Modification Reagents

Another major challenge to fully closing the manufacturing process involves the handling of genetic modification reagents, particularly viral vectors used for cell transduction (typically lentiviral vectors, retroviral vectors, or adeno associated viruses [AAVs]). For example, lentiviral vectors used in CAR T cell manufacturing are commonly supplied as liquids in frozen vials with variable titers. This requires onsite thawing and dilution to achieve a target multiplicity of infection (MOI) that ensures a defined vector copy number (VCN).

The US FDA guidance document “Considerations for the Development of CAR T Cell Products,” states that developers should control transduction conditions (including the MOI) to achieve a defined VCN, generally ≤ 5 copies per cell, as part of product characterization and to minimize insertional mutagenesis risk.7 These viral vector preparation steps are typically manual and open, performed in biosafety Grade A cabinets using pipettes and tubes. This is especially true when the vector is not supplied in weldable, closed system–compatible bags that can be aseptically connected to the cell culture vessel or a dilution bag to achieve the required dilution before addition. This step ensures transduction at a fixed target MOI. Instead, vectors are commonly supplied in low-volume vials at variable titers, which significantly complicates closing cell transduction steps.

Gene-Editing Reagents

Gene-editing workflows face similar challenges as genetic modification reagents. Editing components such as nucleases (mRNA or protein), guide ribonucleic acids (RNAs), and transfection reagents often require rehydration, complexing, and/or sterile filtration in a Grade A cabinet before use. For instance, CRISPR gene-editing components delivered as ribonucleoprotein (RNP) complexes (Cas9 protein pre-complexed with guide RNA) are typically supplied to cell therapy GMP facilities as lyophilized Cas proteins and guide RNAs. These must be reconstituted, complexed, and sterile‑filtered prior to use, adding complexity and contamination risk. Providing these materials in sterile, ready‑to‑use liquid formats and weldable small‑bag configurations that can be aseptically connected would eliminate such open operations. However, challenges include maintaining gene-editing component stability in liquid forms and handling very small volumes (1–2 mL) to achieve a fixed target RNP concentration for gene editing.

One practical solution is to manufacture RNP complexes in advance and supply them to the cell therapy GMP facility as sterile frozen solutions in vials, similar to AAV or lentiviral vectors. This reduces GMP cell therapy manufacturing complexity. Moreover, if a fixed volume of RNP reagent can be added to the cells (either at a fixed RNP concentration or a range of RNP concentrations showing no impact to product quality), a small weldable bag could enable closed‑system addition of gene‑editing components. Finally, electroporation, commonly used to deliver gene‑editing components, often entails multiple cycles of manual interventions required to process the entire cell population, making automation and closed‑system integration difficult. Chemical or lipid‑based delivery approaches, such as lipid nanoparticles (LNPs ) carrying gene‑editing components, may offer promising alternatives, as they can be more readily incorporated into closed systems, particularly if supplied in sterile liquid formats compatible with sterile welding to cell culture bags.

Future Directions and Innovation Potential

Innovations in closed and automated cell therapy manufacturing are reshaping the field by improving scalability, reducing costs, enhancing consistency, and lowering contamination risks through reduced (or even fully eliminated) human intervention during product manufacturing.

SMART bioreactors represent a transformative innovation in cell therapy manufacturing, combining process closure with real-time adaptive control. Unlike traditional systems that follow fixed schedules for feeding, harvesting, and other steps, these platforms integrate automation, advanced sensors, AI-driven decision support, and digital connectivity to respond dynamically to actual cell behavior. Continuous feedback loops and predictive analytics enable real-time adjustments of critical parameters, preventing process drift and improving batch-to-batch reproducibility. This approach streamlines manufacturing and supports decentralized production through self-contained, cGMP-compliant ecosystems with minimal facility requirements. By basing decisions on live cell data rather than static protocols, SMART bioreactors deliver more robust, scalable, and cost-efficient processes, paving the way for consistent, high-quality cell therapies.

Several emerging platforms illustrate the potential of SMART bioreactor-driven approaches. Ori Biotech’s IRO platform is designed as a fully automated, closed system intended to address cost and scalability challenges through features such as automated tube welding and digitally integrated workflows, aiming to reduce manual steps and improve sterility control. Cytiva’s Se-fia system incorporates two functionally closed units to automate key workflow operations and integrate digital controls, with the goal of enabling higher throughput and reducing operator-induced variability.

Similarly, the ADVA X3 platform seeks to embed cell processing within a tightly regulated, single-use environment. Its CAMP technology is designed to maintain precise control of oxygen, media, and waste removal using AI, sensors, and smart bioreactor–like control loops to sustain optimal conditions for cell expansion. These platforms also aim to leverage real-time analytics and predictive control to anticipate shifts in metabolism or proliferation and adjust nutrients or stimulation parameters before deviations occur. Collectively, these emerging solutions have the potential to improve consistency, support decentralized manufacturing, and provide scalable, self-contained ecosystems that minimize facility requirements while maintaining compliance with cGMP standards.

Robotics-driven platforms are emerging as powerful enablers of process closure and automation in cell therapy manufacturing. These systems aim to reduce human intervention, minimize contamination risks, and deliver true walk-away automation. Cellares’ Cell Shuttle exemplifies a “factory-in-a-box” concept. This means the entire manufacturing process, from starting material to final product, occurs within a sealed, single-use cassette that robotic arms transfer between stations inside the shuttle. This design has the potential to produce more than ten batches in parallel while eliminating nearly all manual interaction. As AI-driven orchestration matures, the platform is expected to coordinate multiple unit operations, optimize scheduling, and autonomously troubleshoot deviations.

Cellular Origins offers a different approach with its Con-stellation ecosystem, a mobile robotic system designed to perform manual operations traditionally carried out by operators within a cleanroom setting. These robots connect separate instruments into a closed process by performing sterile fluid transfers between bioreactors, centrifuges, and other devices, physically and digitally linking workflows without requiring redesign. The company projects that this approach could reduce labor up to sixteen-fold and cut production costs by more than 50%.8

Multiply Labs focuses on automating long-standing manual steps using robotic arms trained through imitation learning within fully enclosed cleanrooms. Designed to replicate human precision while maintaining validated protocols, these systems aim to remove contamination risks and improve efficiency. With real-time sensors and AI-driven control, robotic platforms are evolving from mimicking human actions to actively optimizing processes, reducing unnecessary steps, improving timing, and preventing errors before they occur. If successful, these innovations could significantly increase throughput, reduce variability, and improve cleanroom productivity while lowering costs.

Across all these advances, the common theme is integrating and closing processes end-to-end while embedding intelligence, smart bioreactors, robotics, real-time analytics, and AI-driven control systems to remove manual interventions and proactively steer process performance. These advancements deepen automation and process control, making cell therapy manufacturing more predictive, more consistent, and increasingly autonomous. Collectively, they move industry toward a future where cell therapies can be produced reliably, affordably, and at scale. Ultimately, this expands patient access to life-saving treatments.

Although these innovations offer tremendous promise for the future of closed, automated cell therapy manufacturing, widespread adoption will take time. Some companies may choose to leverage existing platforms and equipment to avoid the cost and complexity of transitioning to new technologies. Others, particularly those with programs nearing Phase 3 clinical trials, may seek to minimize commercialization delays and comparability risks associated with late-stage process changes. Despite these challenges, regulatory support is emerging and is expected to accelerate adoption. For example, Ori Biotech’s IRO platform recently received US FDA Advanced Manufacturing Technology (AMT) designation, enabling earlier and more frequent engagement with the agency throughout investigational new drug, new drug application, and biologics license application processes.9 This designation provides faster feedback, reduces regulatory uncertainty, and creates a clearer path from early development to commercial launch, an encouraging sign for the future of these technologies.

Conclusion

Since the approval of Kymriah in 2017, cell therapy manufacturing has progressed from artisanal, open workflows toward increasingly closed, automated, and integrated platforms. The next major differentiator will be energy‑ and time‑efficient manufacturing that preserves product quality while materially reducing cost per dose. Fully closing unit operations extends beyond contamination control: it enables downgrading from Grade B to Grade C, or even Grade D environments, reducing air change rates, environmental monitoring, gowning requirements, and HVAC demand. Collectively, these shifts can deliver an approximately three-fold reduction in energy intensity relative to Grade B operations. This translates into lower operating costs, smaller facility footprints, and improved sustainability.

In parallel, accelerating cell expansion and incubation from conventional roughly 7- to 14‑day paradigms to less than 3-day processes reduces incubator occupancy, utility consumption, and work in process while increasing throughput and enabling faster product release. These operational gains compound economically through fewer manual interventions, lower batch failure rates, and reduced reliance on high‑grade cleanroom space. In addition to reducing time in the manufacturing suite, manufacturing strategies that default to closed reagent additions decouple extended expansion from all‑in‑one platforms to improve asset utilization. They also integrate SMART bioreactor control with in‑line analytics to enable earlier, data‑driven harvests that are poised to define next‑generation processes.

As regulatory frameworks continue to support advanced manufacturing paradigms, adoption of fully closed and robotic workflows is expected to accelerate. This will provide a clear pathway toward scalable, cost‑effective, and sustainable cell therapy manufacturing that expands global patient access.