Closed-Loop Manufacturing Is The Cell Therapy Revolution We Need

By Shubhranshu Gupta, Ph.D., cell therapy expert

The cell therapy industry stands at a critical juncture where revolutionary treatments for cancer and rare diseases are within reach, yet manufacturing bottlenecks threaten to limit patient access to these lifesaving therapies.^1,2,3 Current access limitations are severe. Only two out of 10 patients in the U.S. who need CAR-T therapy are able to receive it, while globally this drops to one in 10 patients.¹

The manufacturing capacity shortage is substantial, with estimates indicating a 500% shortage of cell and gene therapy manufacturing capacity, meaning five times the current capacity would likely be used if available.² Closed-loop systems in cell therapy manufacturing represent a paradigm-shifting integration of real-time monitoring, automated process adjustments, and advanced control strategies that aim to overcome the limitations of traditional batch processing.^4,5,6

Automated closed systems with integrated software controls offer numerous benefits over traditional open systems, including process standardization, lower manufacturing costs, increased batch-to-batch consistency, and reduced risk of contamination.⁴ Real-time monitoring and feedback control for cell and gene therapy manufacturing enable real-time decision-making, reduce processing bottlenecks, and enhance process reproducibility and batch-to-batch comparability.⁵

These systems leverage sensors, process analytical technologies, and computational models to continuously monitor and adjust critical parameters during cell expansion and processing.^5,7 Smart bioreactor systems with fully integrated wireless multiple-membrane sensors and electronics enable long-term, continuous, in-situ monitoring of stem cell culture.⁷ The ability to perform manufacturing in a closed system with minimal labor input allows for an economical process that reproducibly generates products meeting quality expectations.

Current manufacturing approaches face significant challenges with consistency, contamination risks, and scalability.⁸ One of the primary concerns is the risk of contamination during the handling and processing of patient cells, where any deviation from strict aseptic techniques can compromise the safety and efficacy of the final therapy.

These limitations result in the lack of fulfillment to meet the projected manufacturing demand, with an estimated 2 million CAR-T eligible patients expected by 2029, compared to the current treatment capacity that has only served 30,000 to 40,000 patients over seven years across eight approved products.^1,9

Without fundamental changes to manufacturing approaches, countless patients will be denied potentially curative treatments, as evidenced by the hundreds of thousands of patients who currently cannot access these therapies despite being eligible.

Limitations Of Traditional Labor-Intensive Batch Manufacturing

Advancements in cancer and rare disease fields have highlighted challenges faced while manufacturing cell and gene therapy products, with potential problems and obstacles that must be addressed to ease clinical translation.¹⁰

Cost of development

Despite substantial progress in the field, manufacturing of cell-based therapies presents multiple challenges that need to be addressed to assure the development of safe, efficacious, and cost-effective cell therapies.¹¹ Current manufacturing capabilities present significant challenges in bringing these therapies to patients, with the cost of development and manufacturing remaining extremely high (~$550 million) due to complexity of the manufacturing process.¹²

For instance, recent estimates for autologous cell therapies like CAR-T treatments suggest that manufacturing costs alone can range between $100,000 and $300,000 per dose,¹³ with labor alone contributing to more than 50% of the manufacturing costs.¹⁴ All in, the final cost to payers may be upward of $400,000 per dose.^15,16 Cost alone stonewalls broader adaptation of cell therapy products. Reducing the manufacturing costs would substantially increase the accessibility of cell therapy products to the patients who need them.   

Frequent clinical holds

Beyond the substantial financial barriers posed by conventional cell therapy manufacturing, these traditional manual processes create equally formidable regulatory obstacles that compound accessibility issues through chemistry, manufacturing, and controls (CMC) deficiencies and resulting clinical holds. The complex, labor-intensive nature of conventional manufacturing approaches directly contributes to regulatory compliance failures, with CMC issues being the second most common reason for FDA-mandated clinical holds.¹⁷

Analysis of clinical holds from 2020-22 revealed that typical CMC deficiencies leading to clinical holds include compatibility with administration devices and containers, stability during transport, development of adequate potency assays, comparability bridging studies, substantive manufacturing changes, and release specifications.¹⁷ The manufacturing processes for cell and gene therapy products are generally more complex than other product types, possessing higher risk for contamination due to the number of manual steps involved.¹⁸

These manual interventions not only increase the probability of human error and contamination events but also create inconsistencies that regulatory agencies scrutinize heavily during IND-enabling activities and throughout the product life cycle. The regulatory burden intensifies as products progress from clinical development to commercial manufacturing, with FDA requirements becoming progressively more stringent as development advances toward marketing.^1,9

Approximately 80% of clinical holds in cell and gene therapy require an average of 6.2 months to resolve,¹⁷ when no new patients can be recruited and existing patients must be taken off therapy involving the investigational drug unless specifically permitted by FDA.²⁰ This regulatory-induced production halt further reduces the number of therapeutic doses available to patients (in addition to the affordability factor discussed above).

Recent examples include clinical holds placed on multiple trials due to CMC concerns following manufacturing facility inspections,²¹ demonstrating how conventional manufacturing inadequacies can simultaneously halt multiple product pipelines and eliminate hundreds of potential patient doses. The cumulative effect of these regulatory disruptions, driven by the inherent variability and contamination risks of manual manufacturing processes, creates a cascade of dose shortages that extends far beyond the direct manufacturing capacity limitations, ultimately denying access to potentially lifesaving therapies for countless patients who depend on consistent, compliant production systems.

Closed-Loop Manufacturing Offers A Solution To High Costs And Frequent Compliance Issues

As it goes: “there is always a solution to every problem, it’s just a matter of looking in the right direction.” This saying applies to the above suite of problems as well. Automated closed-loop systems represent a transformative solution to the dual challenges of manufacturing costs and regulatory compliance that currently plague the cell therapy industry.

Automation fundamentally addresses the cost structure by reducing hands-on operator time from over 24 hours with modular manufacturing processes to around six hours, while increasing manufacturing throughput and reducing the complexity of technology transfer.²²

The average manufacturing operator turnover rate of 70% within 18 months, driven by difficult working conditions in cleanrooms and high-pressure environments, creates additional cost burdens that automation can mitigate by reducing operator contribution by up to 70% per batch.²³ Closed automated systems with integrated incubation capabilities enable parallel processing with minimal labor, though equipment utilization challenges remain due to lengthy incubation periods that lock machines for one to two weeks per patient, especially with autologous therapies.²⁴

The economic impact extends beyond labor savings, as increased automation improves quality and reproducibility while reducing costs through minimizing hands-on operator time, allowing parallel manufacture of multiple products.^25,26

From a regulatory compliance perspective, automated closed-loop systems directly address the CMC deficiencies that represent one of the leading causes of FDA clinical holds in cell and gene therapy development. The closed nature of automated platforms forms a critical component of contamination control strategies, enabling manufacturing processes to be performed in lower-classification cleanrooms while minimizing the risk of microbial, particulate, or cross-product contamination.²²

Furthermore, automated systems allow precise control of process parameters to demonstrate reproducibility and repeatability of the manufacturing process, including across multiple sites, which is essential for regulatory compliance.^22,26 The ability to perform manufacturing in a closed system with minimal labor input allows for an economical process that reproducibly generates products meeting quality expectations, directly addressing the FDA's requirements for consistent product quality and manufacturing control.²⁴

By eliminating many of the manual interventions that introduce variability and contamination risks inherent in traditional manufacturing approaches, closed-loop automation provides a pathway to cost reduction and enhanced regulatory compliance that could significantly reduce the clinical hold rates that currently delay patient access to these lifesaving therapies.

As someone who has witnessed the industry's struggles with consistency, contamination risks, and scalability, I believe closed-loop automation offers the most promising pathway to democratize access to cell therapies. The manufacturing process of cell-based therapies generally requires tissue collection, cell isolation, culture and expansion (upstream processing), cell harvest, separation and purification (downstream processing), and, finally, product formulation and storage, with each stage presenting significant challenges.

Progress So Far

In the second part of this discussion, I’ll dig into the latest specific technology applications and break down the biggest obstacles for closed-loop automated systems.

References:

1. https://www.pharmexec.com/view/bottlenecks-blocking-cell-gene-therapy
2. https://www.forbes.com/sites/joshuacohen/2023/07/06/cell-and-gene-therapies-face-persistent-manufacturing-capacity-constraints/
3. https://www.ajmc.com/view/the-role-of-automation-in-meeting-the-growing-demand-for-car-t-cell-therapies
4. https://www.thermofisher.com/blog/behindthebench/closed-system-automation-cell-therapy/
5. https://www.biopharminternational.com/view/process-analytical-technologies-for-manufacturing-cell-and-gene-therapies
6. https://www.insights.bio/cell-and-gene-therapy-insights/journal/article/2547/possibilities-for-continuous-closedsystem-processing-of-cell-therapies
7. https://pmc.ncbi.nlm.nih.gov/articles/PMC10866562/
8. https://www.thermofisher.com/blog/behindthebench/manufacturing-car-t-cell-therapies-challenges-insights-and-solutions/
9. https://www.ajmc.com/view/the-role-of-automation-in-meeting-the-growing-demand-for-car-t-cell-therapies
10. https://pubmed.ncbi.nlm.nih.gov/38361427/
11. https://pubmed.ncbi.nlm.nih.gov/31844924/
12. https://pmc.ncbi.nlm.nih.gov/articles/PMC10544074/
13. https://www.genengnews.com/topics/bioprocessing/cell-gene-therapy-costs-drive-deals/
14. https://www.bioprocessintl.com/cell-therapies/cost-analysis-of-cell-therapy-manufacture-autologous-cell-therapies-part-1
15. https://www.onclive.com/view/novartis-sets-a-price-of-475000-for-car-tcell-therapy
16. https://www.drugs.com/medical-answers/cost-yescarta-3342568/
17. https://pmc.ncbi.nlm.nih.gov/articles/PMC10597781/
18. https://www.cardinalhealth.com/en/services/manufacturer/biopharmaceutical/drug-development-and-regulatory/resources-for-regulatory-consulting/cmc/cmc-perspectives.html
19. https://seed.nih.gov/sites/default/files/2024-04/Regulatory-Knowledge-Guide-for-Cell-and-Gene-Therapies.pdf
20. https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-procedures-clinical-hold
21. https://www.targetedonc.com/view/fda-lifts-clinical-holds-placed-on-3-car-t-cell-therapy-trials
22. https://pmc.ncbi.nlm.nih.gov/articles/PMC10544074/
23. https://pmc.ncbi.nlm.nih.gov/articles/PMC12054169/
24. https://pmc.ncbi.nlm.nih.gov/articles/PMC8076909/
25. https://pubmed.ncbi.nlm.nih.gov/39993639/
26. https://pubmed.ncbi.nlm.nih.gov/37790245/

About The Author:

Shubhranshu Gupta, Ph.D., is a scientist and entrepreneur specializing in cellular immunotherapy, with a focus on CAR-T and CAR-NK cell therapies for hematological and solid tumors. He is the CEO and CSO at a stealth mode biotech startup that he cofounded in 2024 and serves as a scientific advisor for multiple expert insight networks. Dr. Gupta has held research positions at Caribou Biosciences, Fate Therapeutics, and Baylor College of Medicine. His work includes early discovery pipelines, gene editing, and developing cell-based assays, with several publications in peer-reviewed journals. He earned his Ph.D. in the area of immunological memory in cell therapy at Baylor College of Medicine. Contact him on LinkedIn.