Cell therapies are now one of the most-investigated therapeutic modalities, both in preclinical and clinical settings.¹ As of April 2024, there are 37 U.S. FDA-approved cell and gene therapy products, with 2023 being a record year with seven such treatments receiving FDA approval.

The potential of cell-based therapies is unlimited. Already the approved products treat a variety of indications ranging from Type 1 diabetes² to blood cancers³ and more. In 2024, the first FDA-approved engineered cell therapy for solid tumors was approved, notable given that recent oncology treatment advances focused on hematologic cancers, e.g., immunotherapy.⁴

Despite the enthusiasm for and the potential of cell-based therapies, significant barriers exist at the junction of late-stage development and expertise. Contract development and manufacturing organizations (CDMOs) with the necessary resources and expert capabilities stand poised to hasten important therapeutics to market.

However, not all CDMOs have the expertise necessary to get cell therapies across the finish line. While most CDMOs may be able to support manufacturing for late-stage development, a limited number of CDMOs actually possess the necessary expertise for Phase 3 and later commercialization.

Barriers for cell therapy development 

Lack of expertise and technology: According to a survey conducted by L.E.K. Consulting, a critical unmet need biotechnology companies are reporting to their CDMOs is advanced technical capabilities and lack of expertise in supporting cell-based therapies beyond Phase 2 clinical trials.⁵ Companies that are assessing CDMOs must take extra care to seek out a CDMO partner that not only claims to have the re-quired expertise but also has real experience taking a cell-based therapy into Phase 3 development and beyond.

The diversity of products plays a major role, as CDMOs serving cell-based treatments must be able to work with a range of different types of cells and technologies. For example, there are key differences between working with cells versus cell-derived products and autologous versus allogeneic treatments.

Autologous cells come from the patient’s own body, while allogeneic cells come from a donor. Not every CDMO has experience working with both types of cell transplants, and each of these transplants requires different knowledge sets and facility set-up.

Aside from autologous and allogeneic transplants, a wide range of other cell types are being investigated to treat a wide range of conditions. Some of these cells and products include⁶:

• Immune cells like T cells (including chimeric antigen receptor T (CAR-T) cells, dendritic cells and natural killer (NK) cells;
• Tissue-specific cells like fibroblasts, chondrocytes and keratinocytes;
• Stem cells like hematopoietic cells;
• Cells combined with an extra-cellular scaffold or matrix;
• Stem cell-derived preparations like those from various stem cell lines; and
• Encapsulated cells.

For example, PluriCDMO leverages its 3D-cell expansion service—an automated system which is flexible to scale diverse cell products—human, plant, and animal—from bench-top operation to large scale for commercial Good Manufacturing Practices (GMP) production. Simultaneously, partners benefit from capabilities like operation teams experienced in advanced clinical-stage manufacturing of both autologous and allogeneic treatments and full quality control (QC) support, including a sophisticated shipping and distribution service to support multi-center clinical trials or commercial supply worldwide.

Facility design: Part of having the necessary expertise is being able to design a facility that’s appropriate for the specific cell therapy in development. For example, manufacturing allogeneic cell therapies re-quires different facility set-up than manufacturing autologous therapies, with different numbers and sizes of bioreactors, manufacturing lots, and cold-chain support.

Allogeneic therapies are designed to be off-the-shelf treatments for multiple patients, meaning they must be produced at a much larger scale than autologous therapies with well-defined preservation guidelines. On the other hand, autologous treatments are designed for a single patient, so they are developed and manufactured on a micro scale.

Clean rooms and closed systems: Clean rooms are also critical for cell therapy development, especially for clinical trials in hu-mans. Grade A/B clean rooms are standard requirements for such clinical trials, which, for open-systems manufacturing, involve high biosafety levels working with biological or laminar flow cabinets in a grade B clean room that protects cells and employees from contamination during the process.

Clean rooms require special garments and certain conditions that tend to be expensive to maintain. For example, they require an HVAC system that continually cleans the air for the entire room through HEPA filters that are never turned off and highly specialized cleaning handling, requiring strict adherence to GMP guidelines daily, ensuring safety, and quality. The design, maintenance and validation processes are always critical for facility compliance.

For large-scale manufacturing, closed systems may be used to reduce risks, involving an isolator to separate the cell products from the external environment.

This type of system can be installed in a lower-grade clean room and reduces the risk of cell contamination, protects the product from the external environment, and benefits from quality, safety, and regulatory compliance. Closed systems are more reliable for cell-therapy production, consistent, and enhance efficiency and scalability while being affordable to operate, assuming a high level of expertise to ensure conditions inside are maintained at the correct levels.

Automation: Once a cell therapy moves into Phase 3, it’s highly recommended to transition from clean rooms involving manual operations to closed, automated processes, which once again require significant expertise for technology transfer, set-up and maintenance.

Automated processes are critical for consistency and product quality, helping to reduce human error while enabling robust processing and reproducibility. They also enable the production of cell products in the mass quantities necessary for allogeneic products.

According to regulatory guidance from the Health Sciences Authority, automated equipment may even help ease compliance with certain GMP requirements.⁷ However, automation must be implemented correctly to ensure compliance with GMPs and other regulations.

There has been some progress in rolling out automation within the cell-therapy field. Betty Woo of Thermo Fisher Scientific told Pharma Manufacturing in December 2024 that traditional CAR-T manufacturing once took at least three weeks.⁸ However, the last few years have brought greater focus on accelerated processes and process “intensification.” As a result, some manufacturing processes are being completed in days rather than weeks and at higher potencies.  

Recently, a group of researchers published a paper in November 2024 outlining their novel cell manufacturing platform called MARS Atlas, which integrates the isolation of T cells, viral trans-duction, and cell washing and formulation processes onto a single platform.⁹ The researchers demonstrated that their process could start with whole blood and then finish within 24 hours.

Storage and transport: Appropriate facility design for allogeneic cell therapies also ensures the appropriate storage capabilities for the products being developed are in place. Allogeneic cell therapies require facilities capable of storing them at ultra-low cryogenic temperatures to preserve them over longer periods.¹⁰

Best practices currently call for storing and transporting cell therapy products at temperatures below -150 Celsius.¹¹ While cold chains to distribute pharmaceuticals and biologics have been in place for decades, adequate infrastructure to support cold chains for cell therapy products have thus far not been built out.

Cell therapy products are unique because they are made up of viable cells, usually autologous or allogeneic human cells, which remain viable only within narrow ranges of time and temperature. Cells need oxygen and nutrients when metabolically active, requiring either just-in-time patient delivery or cryogenic storage temperatures that keep them viable by holding them in a metabolically inactive state.

The extremely cold temperatures required to store allogeneic products make developing cold chains for them extremely challenging and call for significant expertise.

Transport also must be equipped with the ability to move products at these ultra-low temperatures to eliminate the just-in-time delivery nature of cell therapies currently practiced.¹¹

The cost of process change: Process change is expensive and complex, especially at the later clinical phases and in a hurry. The average cost and time of transferring a late-stage cell therapy project to a new CDMO could take 12 to 24 months and may cost $2 million to $5 million, which is prohibitive for smaller biopharmaceutical companies.

What to verify with a CDMO before signing on

When assessing a CDMO, it’s critical to ensure they have the necessary expertise and technology to carry your project through late-stage clinical trials and commercialization. Here are some things to check before you sign with a CDMO partner.

1. Ensure they have successfully carried a cell-therapy product from the pre-clinical stage through Phase 3 clinical trials. Experienced CDMOs have already performed some Phase 3 projects internally, giving them the expertise needed to carry out the late stages of clinical trials. The CDMO should also understand the specific requirements for FDA/ EMEA commercialization for every project.

2. An appropriate facility that meets all regulatory and manufacturing requirements is vital. The facility requires validation, calibration, a quality management system (QMS), maintenance, a warehouse that follows Good Manufacturing Practices (GMP), and local regulatory approvals for all late-stage clinical activities.

3. The CDMO must have the required clean rooms and closed systems in place to bridge the gap between Phase 1 and Phase 3 clinical trials. They will need to utilize closed-system bioreactors or build them if they don’t already have them. CDMOs also require automated concentration wash systems, final formulation systems, and a semi or automated vial-filling machine. 

4. They must have established the appropriate automation to ensure quality control and batch consistency.

5. The correct infrastructure to support storage and transport specifically of cell-related and cell-derived products is needed, as is experience utilizing global logistics hubs versus local hubs for short-term supplies under controlled conditions. As part of this infrastructure, CDMOs should also have trained personnel, a robust shipping system capable of sending shipments within hours, and strong collaboration.

6. Ensure the CDMO selected provides synergy in terms of communication, flexibility and vision with your program and teams.

When it comes to selecting a CDMO, expertise is critical. With so few CDMOs possessing the expertise necessary to not only work with cell-based therapies but also establish the required facilities, biotechnology companies are advised to choose their partner(s) carefully.

References

1. Wang LL, Janes ME, Kumbhojkar N, et al. Cell therapies in the clinic. Bioeng Transl Med. 2021;6(2):e10214. Published 2021 Feb 26. doi:10.1002/btm2.10214

2. FDA Approves First Cellular Therapy to Treat Patients with Type 1 Diabetes. Press Release. U.S. Food and Drug Administration. June 28, 2023. Accessed April 7, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes

3. FDA Approves Cell Therapy for Patients with Blood Cancers to Reduce Risk of Infection Fol-lowing Stem Cell Transplantation. Press Release. U.S. Food and Drug Administration. April 17, 2023. Accessed April 7, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-cell-therapy-patients-blood-cancers-reduce-risk-infection-following-stem-cell

4. Adaptimmune Receives U.S. FDA Accelerated Approval of TECELRA (afamitresgene au-toleucel), the First Approved Engineered Cell Therapy for a Solid Tumor. Press Release. Adap-timmune. August 1, 2024. Accessed April 7, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-cell-therapy-patients-blood-cancers-reduce-risk-infection-following-stem-cell

5. Siebert, A., Holder, J. et. al. Key Trends for CDMOs Partnering With Cell Therapy Developers. L.E.K. Consulting. July 11, 2024. Accessed April 7, 2025. https://www.lek.com/insights/hea/us/ei/key-trends-cdmos-partnering-cell-therapy-developers

6. Petricciani, J., Hayakawa, T., et. al. Scientific considerations for the regulatory evaluation of cell therapy products, Biologicals, Volume 50, 2017, Pages 20-26, ISSN 1045-1056, https://doi.org/10.1016/j.biologicals.2017.08.011

7. Health Sciences Authority. Guidelines on Good Manufacturing Practice for Cell, Tissue and Gene Therapy Products. March 1, 2021. Accessed April 7, 2025. https://www.hsa.gov.sg/docs/default-source/hprg-ald/hsa_gmp_guidelines_for_ctgtp.pdf?sfvrsn=4275f463_6

8. Slabodkin, G. Cell and Gene Therapy Manufacturing Challenges to Persist in 2025. Pharma Manufacturing. December 23, 2024. Accessed April 7, 2025. https://www.pharmamanufacturing.com/all-articles/article/55251398/cell-and-gene-therapy-manufacturing-challenges-to-persist-in-2025

9. Sa, S. Yu, L. Automated Rapid CAR-T Cell Manufacturing Process, Starting from Whole Blood, on a Novel Closed Platform. Blood 2024; 144 (Supplement 1): 3479. doi: https://doi.org/10.1182/blood-2024-205825

10. Meacle, F., Salkin, J., et. al. Key Considerations of Cell and Gene Therapy Cold Chain Logis-tics. Cell & Gene Therapy Insights. 2016; 2(2), 223-236. doi: 10.18609/cgti.2016.025

11. Li, R., Johnson, R., et. al A. Preservation of cell-based immunotherapies for clinical trials. Cytotherapy. 2019;21(9):943-957. doi:10.1016/j.jcyt.2019.07.004

Nimrod Bar Zvi joined Pluri as chief commercial officer in 2022 to lead global commercialization of the company’s cell-based technology Platform. Mr. Bar Zvi brings extensive senior leadership experience in the global pharmaceutical markets and active ingredients, with over 15 years in executives roles building B2B strategies, CDMO, API & Pharma sales.