Although the cell and gene therapies (CGTs) industry continues to advance the approvability, accessibility, and affordability of this new generation of treatments, it remains a constant challenge to create not only safe and effective products but also commercially viable ones. Escalating development costs and complex supply chains have manufacturers increasingly exploring new production models to streamline logistics, increase throughput, and enhance patient access.
Centralized production of CGTs—where therapies are manufactured at a few large-scale facilities serving multiple geographically dispersed treatment centers—works well for the small molecule and biologics manufacturing processes they were built for. However, for living and often personalized medicines such as CGTs, this approach is falling far short.
Unlike chemically synthesized small molecules, CGTs are large, complex molecules derived from a patient’s cells, which are genetically modified and (usually) personalized for an individual patient. This level of personalization and biological complexity requires unique handling, storage, and administration protocols that differ vastly from the manufacturing and distribution models suited for more traditional therapies. Applying a centralized manufacturing approach to CGT production, therefore, has resulted in high costs of goods (COGs), limited throughput, and variable quality (eg, high out-of-spec rates).
The resulting logistical and economic challenges have created significant access challenges for patients. Less than 20% of patients in the United States who could benefit from genome-targeted or cell-based therapies are actually able to access them.1,2 For the lucky few who do get access, vein-to-vein times often exceed 4 to 5 weeks, which can prove fatal for patients with aggressive, advanced cancers. Doctors at large treatment centers, such as The University of Texas MD Anderson Cancer Center, Mayo Clinic, and Dana-Farber Cancer Institute, see as many as 20% of their patients die while waiting for therapy.3
Vein-to-vein times are not just extended by manufacturing logistics; geographical distance between the manufacturer and treatment facility can also increase the time it takes for a treatment to reach a patient. A patient is often left with no other option than to stay close to a treatment center because cell therapies are not available at community cancer centers, increasing logistical complexities and costs (eg, gasoline, airline tickets, temporary housing, lost wages, etc). Even then, the complexities of multistep supply chains, international logistics, and manufacturing itself can leave patients in limbo.
An increasing number of manufacturers recognize that adopting different manufacturing approaches to meet the unique requirements of CGTs is one of the best ways to potentially lower COGs, improve scalability, and ultimately get these therapies to more patients faster. Given the limitations of the centralized model to deliver affordable, accessible treatments, alternative regional or point-of-care (together called “decentralized”) manufacturing models are evolving. For example, chimeric antigen receptor T-cell developer Galapagos, among the pioneers in decentralized manufacturing, announced a partnership with the Blood Centers of America in 2024 to create a multisite, decentralized clinical manufacturing network.4
Decentralized manufacturing is an emerging alternative manufacturing model with the potential to bring significant benefits to both manufacturers and patients. In this model, manufacturing sites can be located closer to local community treatment centers, increasing accessibility to a wider range of patients and dramatically reducing vein-to-vein times. Additionally, decentralized manufacturing reduces the need for complex and costly transportation logistics, both for the cell therapies and the patients. By manufacturing therapies near the point of care (ie, by colocating manufacturing facilities near major academic medical centers or hospitals), providers can minimize costs and delays associated with shipping cells by car or plane over long distances, enabling faster access to treatment and likely better outcomes. More time closer to home, reduced travel costs, and fewer disruptions to daily life for patients and caregivers will also enhance the overall patient experience by reducing costs and logistics, as well as emotional and physical stress.
These advancements could pave the way for decentralized manufacturing to meet the demands of CGTs while maintaining regulatory compliance, operational efficiency, and commercial viability... After all, what is the point of having cures for cancer and potentially many other conditions if patients cannot get access to them?
Despite the promise of decentralized manufacturing models, where production occurs closer to the point of care, widespread adoption has been slow to gain traction. Although a few organizations, such as Galapagos and Caring Cross,5 are pioneering decentralized approaches for CGTs, most manufacturers remain reliant on historical manufacturing models utilizing centralized facilities. Many hesitate to adopt a decentralized approach because process variability between sites may hinder their ability to maintain Good Manufacturing Practices (GMP) standards across sites and could compromise the quality and consistency of their product.6 Adhering to stringent regulatory requirements also becomes more complex with multiple sites, as each location must demonstrate compliance with health authority standards, often adding time and cost to ensure consistent oversight and quality control.7
Reliance on manual manufacturing processes and paper-based tracking systems, or “paper on glass”—which most manufacturers rely heavily on—are other significant barriers to the adoption of decentralized manufacturing models. These approaches make it almost impossible to manage multiple sites effectively. Paper-based systems also contribute to an unclear understanding of process biology, process inefficiencies, unpredictable yields, manufacturing slots, high cost of manufacture, and high failure rates.8 This is an even more prevalent issue for individualized product manufacturing—the approach necessarily used for autologous CGTs—which often suffers from low-capacity utilization and corresponding financial inefficiencies.
It is evident that to make decentralized manufacturing a viable model, regulatory innovation and the adoption of digitally enabled manufacturing automation platforms is essential. The FDA and the Medicines and Healthcare products Regulatory Agency have taken proactive steps, such as issuing draft guidance9,10 and hosting workshops, to understand and support decentralized manufacturing in a way that balances regulatory requirements and feasibility.
Key Takeaways
- Decentralized manufacturing can help reduce vein-to-vein times, improving access and outcomes for patients with aggressive conditions requiring timely cell and gene therapies.
- Advanced digital platforms and automation in cell and gene therapy manufacturing can enhance quality, consistency, and scalability, enabling clinicians to trust product reliability across decentralized facilities.
- Regulatory innovations that support decentralized models may help expand local access to cutting-edge treatments, allowing clinicians to deliver life-saving therapies closer to patients' communities.
Standardized, digital infrastructure could also be a game changer for decentralized manufacturing. Not only will the use of digital tools enable centralized quality control personnel to more effectively oversee decentralized operations, but digital capabilities will also enable manufacturers to adopt a Design for Manufacturing9 framework that supports reproducible and robust manufacturing platforms, processes, and analytical methods. Such frameworks can be standardized, with identical implementations across sites, supporting the quality, consistency, and traceability required for GMP compliance.
Digitally enabled platforms go hand in hand with automation technology, such as Ori Biotech’s IRO system11 or Lonza’s Cocoon platform,12 which help reduce process variability across sites and tech transfer times associated with more manual, paper-based processes. Closed manufacturing systems with in-line sensing capabilities can further enhance efficiency by allowing multiple products or patient samples to be processed in the same clean room, facilitating both remote quality monitoring for regulators and manufacturers and higher capacity utilization to improve the financial profile of a decentralized model.
Together, these advancements could pave the way for decentralized manufacturing to meet the demands of CGTs while maintaining regulatory compliance, operational efficiency, and commercial viability. Importantly, their implementation will enable decentralized manufacturing to offer significant competitive advantages to CGT manufacturers seeking to produce therapies that aren’t just approvable but that are also accessible and affordable. After all, what is the point of having cures for cancer and potentially many other conditions if patients cannot get access to them?
REFERENCES
1. Patient access analytics. Ori Biotech. Updated August 2024. Accessed November 5, 2024. https://oribiotech.com/insight/patient-access-analytics
2. Haslam A, Kim MS, Prasad V. Updated estimates of eligibility for and response to genome-targeted oncology drugs among US cancer patients, 2006-2020. J Ann Oncol. 2021;32(7):926-932 doi:10.1016/j.annonc.2021.04.003
3. Chen A. ‘How do you decide?’: cancer treatment’s CAR-T crisis has patients dying on a waitlist. STAT. June 2, 2022. Accessed November 5, 2024. https://www.statnews.com/2022/06/02/car-t-crisis-cancer-patients-die-waiting/
4. Galapagos and Blood Centers of America announce strategic collaboration to accelerate Galapagos’ decentralized CAR-T manufacturing network in the U.S. Galapagos. May 15, 2024. Accessed November 5, 2024. https://www.glpg.com/press-releases/galapagos-and-blood-centers-of-america-announce-strategic-collaboration-to-accelerate-galapagos-decentralized-car-t-manufacturing-network-in-the-u-s/
5. Germfree and Caring Cross partner to transform access to cellular gene therapies. Caring Cross. August 21, 2024. Accessed November 5, 2024. https://caringcross.org/press/germfree-and-caring-cross-partner-to-transform-access-to-cellular-gene-therapies-2/
6. Markarian J. Considering the promises of point-of-care manufacturing. BioPharm International. November 1, 2023. Accessed November 5, 2024. https://www.biopharminternational.com/view/considering-the-promises-of-point-of-care-manufacturing
7. Harrison RP, Ruck S, Medcalf N, et al. Decentralized manufacturing of cell and gene therapies: Overcoming challenges and identifying opportunities. Cytotherapy. 2017;19(10): 1140-1151. doi:10.1016/j.jcyt.2017.07.005
8. Foster JC, Shah G, Srivastava S. New economics of cell and gene therapy – part II. Cell & Gene. October 1, 2024. Accessed November 5, 2024. https://www.cellandgene.com/doc/new-economics-of-cell-and-gene-therapy-part-ii-0001
9. Conducting Clinical Trials With Decentralized Elements. Guidance for Industry, Investigators, and Other Interested Parties. FDA. September 2024. Accessed November 5, 2024. https://www.fda.gov/media/167696/download
10. Consultation on point of care manufacturing. Medicines and Healthcare products Regulatory Agency. Updated January 25, 2023. Accessed November 5, 2024. https://www.gov.uk/government/consultations/point-of-care-consultation/consultation-on-point-of-care-manufacturing
11. Scale your impact: introducing IRO. Ori Biotech. Accessed November 5, 2024. https://oribiotech.com/iro-2
12. The Cocoon cell therapy manufacturing platform. Lonza. Accessed November 5, 2024. https://www.lonza.com/cell-and-gene/cocoon-platform
