Why Better Manufacturing Is the Key to Unlocking Cell Therapy's Full Potential
By Life Science Connect Editorial Staff
Since the first CAR-T cell therapy received regulatory approval in 2017, more than 30,000 patients in the U.S. have received these transformative treatments, with many early recipients going on to experience long-lasting remission.1 While positive patient outcomes underscore the value of these medications as part of the larger oncology treatment toolbox, their comparatively limited accessibility highlights the need for manufacturing solutions that can support greater scales.
Despite advances in clinical development, the transition from laboratory-scale processes to commercial-scale production remains a critical bottleneck. Manufacturing cell therapies is especially challenging due to the personalized, sensitive, and variable nature of living cells. As such, achieving consistent process performance and product quality at scale requires overcoming significant technical and operational hurdles. The result is a fragmented manufacturing landscape that often struggles to meet demand, leading to high costs, long lead times, and limited patient access.
This complexity is also often as diverse as the products in the current development pipeline. Ultimately, the differences in autologous and allogeneic cell therapy production — alongside the unique features of a molecule, the target patient population, and stringent regulatory requirements — present potential bottlenecks in widening their availability. But new strategies and technologies are emerging to address these hurdles, driven by an industry-wide push toward democratizing advanced therapeutics.
The Great Divide: Autologous vs. Allogeneic Cell Therapy Manufacturing
Autologous cell therapies, personalized treatments derived from a patient’s own cells, offer a powerful therapeutic approach. However, their potential is constrained by profound manufacturing and logistical challenges. Unlike allogeneic therapies, autologous treatments begin and end with the same patient, creating a uniquely complex “vein-to-vein” supply chain. This involves harvesting a patient’s cells at a clinical site, transporting them under strict conditions to a central manufacturing facility, performing a multi-step production process, and returning the final product to the patient. This journey can take weeks, and often months — delays that critically affect patient outcomes.
One of the most pressing issues is the time sensitivity of autologous therapies. Many patients cannot afford prolonged waits, yet current systems are plagued by scheduling bottlenecks, manual workflows, and variability in incoming material. Manufacturing is still highly manual, often requiring upwards of 200 human hours per batch; operator variability introduces risk, inconsistency, and elevated costs, while donor-to-donor biological variability further complicates standardized processing.
Additionally, batch failure rates remain untenably high — ranging from 10% to 20% — often due to issues like insufficient dose, contamination, or material loss. Each failure represents a missed therapeutic opportunity and a personal tragedy. These challenges underscore the urgent need for robust, scalable technologies that can reduce manual dependency, standardize processing, and accelerate delivery.
In response to the inherent complexities of autologous therapies, many in the field are exploring allogeneic cell therapy as a more scalable alternative. Unlike autologous approaches, allogeneic therapies derive from donor cells and can be manufactured in large batches for use in multiple patients, enabling true scaleup rather than scale-out. This shift holds significant promise for improving manufacturing efficiency, reducing cost per dose, and increasing patient access. This is because the allogeneic model aligns more closely with traditional biomanufacturing paradigms, where a single batch can potentially serve hundreds or even thousands of patients, reducing the need for individualized production trains and lowering the operational burden of scheduling, logistics, and manual handling.
However, the transition to allogeneic therapy is not without its challenges, as scaling up biological processes does not always follow linear rules. Issues such as cell expansion limitations, viability, potency, and, crucially, the risk of immune rejection introduce significant complexity. Moreover, translating early-stage findings from preclinical or small-scale models to a robust, large-scale process demands thoughtful planning and deep process understanding.
Technical and Technological Barriers to Robust, Scalable Manufacturing
While leveraging allogeneic manufacturing for cell therapies holds significant potential for solving scalability issues and expanding commercial supply, the limitations hindering their developability have made approved allogeneic therapies a rarity. Whether developing autologous, allogeneic, or hybrid cell therapies, manufacturers face a critical mandate: achieving consistent, robust, and scalable processes that can deliver safe, efficacious treatments on time and within budget. Yet, the path to that goal is riddled with technical complexities and technological gaps.
One of the most pressing issues is the fragility of the manufacturing chain: each step, from leukapheresis collection to final product infusion, presents potential failure points. Especially in autologous and hybrid models, variability in patient-derived starting material, manual handling, and complex logistics can all compromise product consistency. Simple errors, like missing documentation, incomplete part kits, or insufficient final cell doses, can derail an entire batch, often with no second chance to treat the patient.
Automation and digital integration offer potential solutions but come with their own challenges. Implementing closed, automated systems is costly and often constrained by the lack of flexible, end-to-end platforms. Moreover, analytical testing and release processes are time consuming and frequently disconnected from manufacturing, limiting real-time decision-making.
Speed-to-clinic and speed-to-market pressures further complicate matters, as many developers race through early stages with the goal of demonstrating clinical efficacy, often deferring manufacturing considerations. However, this "sprint" mentality makes late-stage changes more expensive and disruptive. A holistic, "marathon" approach, where manufacturability and scalability are evaluated from the outset, can mitigate these downstream risks.
Enabling Technologies and Future Directions in Cell Therapy Manufacturing
In cell therapy manufacturing, innovation must be defined by its ability to deliver tangible benefit to patients. That means moving beyond conceptual or lab-scale advancements to technologies that directly solve real-world problems in manufacturing, quality, and delivery. Today, one of the most significant directions of innovation is the integration of automation, robotics, and advanced analytics into every aspect of the production lifecycle.
Automation as a catalyst for reliability and scalability: Cell therapies are still largely handcrafted, with many manual steps that introduce variability and risk, particularly in autologous and hybrid models where each batch is unique. However, automation is already transforming this landscape, with platforms that can consolidate multiple unit operations, from isolation to formulation, into a single closed system. These platforms reduce the number of operator interventions, improve standardization, and mitigate contamination risks.
As companies aim for high-throughput capabilities, automation becomes even more critical. The concept of “GMP-in-a-box” — automated manufacturing suites capable of running multiple patient batches in parallel — has moved from aspiration to reality. These systems are reshaping how facilities are designed and operated, enabling scalability without linear increases in staffing or cleanroom space.
Robotics: Two dominant models for robotics platforms are emerging within the cell therapy space: end-to-end proprietary robotic platforms, including pioneering walk-away systems that integrate multiple batch operations with minimal intervention, or retrofits of existing systems. Proprietary systems offer high reproducibility, which is critical for commercial-scale operations, and also feature robotic overlays for existing equipment. Meanwhile, some startups and innovators are retrofitting existing GMP platforms with robotic arms for material transfers, cell harvesting, and sampling, allowing manufacturers to scale up without fully replacing their infrastructure, a compelling approach for smaller companies with limited capital.
Specific pain points where robotics shows the most promise include liquid handling, cell transfer between units, mixing of viscous solutions, and sampling — areas traditionally handled manually and prone to inconsistency. The ability to automate these tasks not only boosts throughput but also reduces the variability that can derail patient delivery.
Advanced Analytics and AI: Another game-changing area is advanced analytics powered by AI and machine learning. As more data becomes available across supply chain, manufacturing, quality control, and clinical outcomes, there’s a growing opportunity to create closed-loop feedback systems. Real-time, in-process analytics allow faster deviation detection, immediate interventions, and ultimately more robust control of the product quality.
Beyond the lab, AI has the potential to unify datasets from preclinical studies to post-infusion patient data, generating predictive insights that can inform everything from raw material forecasting to individual patient response modeling. This level of visibility is crucial for transitioning from clinical to commercial scale.
Strategic Considerations for Biotechs
For emerging biotechs, the key challenge isn’t just what technology to adopt, but when and how. While full automation may be ideal, it is often impractical in early development due to high costs and evolving processes. Instead, a modular approach that starts with process closure and selective automation of high-impact steps can yield early operational wins while building toward a fully integrated future.
Importantly, any automation or robotics deployment must consider product comparability. Changes to the manufacturing process must not alter the critical quality attributes of the therapy, especially when moving between clinical and commercial phases. Planning early with a vision for the commercial process can reduce the need for costly and time-consuming changes later, smoothing the path for innovation that supports greater access to these lifesaving medicines.
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References:
- Penn Medicine. (2024, January). Secondary cancers following CAR T cell therapy are rare. https://www.pennmedicine.org/news/news-releases/2024/january/secondary-cancers-following-car-t-cell-therapy-are-rare.
- Zynda, E., & Singh, A. (2022, October 17). Overcoming the challenges of cell therapy manufacturing. BioProcess Online. https://www.bioprocessonline.com/doc/overcoming-the-challenges-of-cell-therapy-manufacturing-0001