Summary
Cellular therapies are regulated differently from conventional drugs and biologics. Since a May 31, 2021, deadline, manufacturers must comply with section 351 of the Public Health Service (PHS) Act unless excluded by 21 CFR Part 1271 — and the FDA has already issued Form 483s and warning letters to products that fell outside those exclusions. This article walks through the core regulatory framework, the manufacturing challenges unique to cell-based products (reproducibility, sterility, potency, and impurities), and the validated quality management and control approach these therapies demand.
Manufacturing of cellular therapies has garnered a lot of attention at the U.S. Food and Drug Administration (FDA) since a May 31, 2021, deadline required compliance with section 351 of the Public Health Service (PHS) Act for products (i.e., drugs or biologics) unless excluded by 21 CFR Part 1271.
Several manufacturers have been issued FDA Form 483s, and worse, warning letters because their products did not meet all the requirements of 21 CFR Part 1271, meaning their products were intended for homologous use or were more than minimally manipulated.
What Counts as a Somatic Cell Therapy?
Somatic cell therapies are a growing segment and are defined as any autologous, allogeneic, or xenogeneic cells that have been propagated, expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics ex vivo,1 to be administered to humans and applicable to the prevention, treatment, cure, diagnosis, or mitigation of disease. If your product meets any of these criteria, the FDA regulation applies to you; clinical development requires an Investigational New Drug (IND) application and premarket approval is required.
The Regulatory Framework for Cellular Therapy Products
Cellular therapy products are regulated under 21 CFR Part 1271, 21 CFR Part 600, and 21 CFR Part 610. Drug manufacturing requirements in 21 CFR Part 211 and 212 also apply. Because of this, cellular products have unique concerns.
Because cellular therapy products live at the intersection of multiple regulations — 21 CFR Parts 1271, 600, 610, 211, and 212 — the same record-keeping, electronic-system, and data-management expectations that govern conventional GMP manufacturing apply. The integrity of your batch records and test results underpins every claim you make to the FDA. See how to protect it with data integrity in life sciences.
Reproducibility of Product Lots
One challenge is the reproducibility of product lots. Because your starting material for manufacture is coming from a different patient or donor, there is inherent variability that may lend to processing variation during manufacturing. The FDA understands this issue, but it is imperative that you allow for these variations in your manufacturing processes and they are accounted for in your batch records.
Sterility and Aseptic Processing
Another challenge is sterility. Since these products cannot be terminally sterilized, the FDA recommends aseptic processing, preferably in a closed system.
Since cellular products cannot be terminally sterilized, the FDA recommends aseptic processing, preferably in a closed system — making validated, well-controlled processes the foundation of product safety.
Quality Control for Cellular Products
What about quality control for these products? Have you defined your critical quality attributes? Do you have processes to control incoming cells or tissues? What about ancillary materials? You need to exercise controls throughout your processes to ensure product quality, including in-process testing, final product testing, stability testing, and endotoxin testing. Potency testing is also a requirement. Since this type of testing for cellular products can be a challenge, the FDA has been flexible in manufacturers’ approaches. Direct assays and matrix approaches have been accepted. Viability testing alone is not acceptable.
Quality Testing Checkpoints for Cellular Therapies
- In-process testing — verify quality attributes during manufacturing, not just at the end.
- Final product testing — confirm the finished therapy meets release specifications.
- Stability testing — demonstrate the product holds its quality over its claimed shelf life.
- Endotoxin testing — control pyrogenic contamination that aseptic processing cannot fully eliminate.
- Potency testing — required; direct assays and matrix approaches are accepted, but viability testing alone is not.
FDA Concerns Around Impurities
There are FDA concerns surrounding impurities. Outside of endotoxins, impurities may include residual solvents, antibiotics, or animal products that may have been used in the tissue culture media. You must validate your processes surrounding the removal of these impurities or establish final product testing to show that the residuals are at acceptable levels. Contaminating cell types that may affect safety and efficacy could be considered impurities.
Validating the processes that remove these impurities — and keeping that validation current as your manufacturing evolves — is exactly where a disciplined approach to validation lifecycle management pays off. A risk-based methodology such as computer software assurance (CSA) can help you focus validation effort where product quality and patient safety are most at stake.
Conclusion
In conclusion, cellular therapy manufacturing is unique and requires a different good manufacturing practices (GMP) approach that includes quality management and control (depending on the specifics of the therapy) compared to conventional drugs and biologics.
How USDM Can Help
USDM can help you identify your quality management and control needs and help to ensure that your manufacturing processes are adequately defined, flexible, and validated to meet regulatory requirements and keep you continuously compliant. To sustain that compliant state as your processes and systems change over time, explore USDM Cloud Assurance.
FAQ: Cellular Therapy Regulations
Which FDA regulations apply to cellular therapy products?
Cellular therapy products are regulated under 21 CFR Part 1271, 21 CFR Part 600, and 21 CFR Part 610. Drug manufacturing requirements in 21 CFR Part 211 and 212 also apply, which is why these products carry concerns that span multiple parts of the regulations.
When does an IND and premarket approval become required for a somatic cell therapy?
If your product is an autologous, allogeneic, or xenogeneic cell therapy that has been propagated, expanded, selected, pharmacologically treated, or otherwise altered ex vivo and is administered to humans for the prevention, treatment, cure, diagnosis, or mitigation of disease, the regulation applies. Clinical development requires an Investigational New Drug (IND) application, and premarket approval is required.
Why can't cellular therapy products simply be terminally sterilized?
Living cell-based products cannot withstand terminal sterilization without destroying the therapy itself. Because of this, the FDA recommends aseptic processing, preferably in a closed system, to control sterility throughout manufacturing.
Is viability testing enough to demonstrate potency?
No. Potency testing is a requirement, and viability testing alone is not acceptable. The FDA has been flexible on approach — direct assays and matrix approaches have been accepted — but you must demonstrate potency, not just cell viability.
What impurities should cellular therapy manufacturers control for?
Beyond endotoxins, impurities may include residual solvents, antibiotics, or animal products used in the tissue culture media. Contaminating cell types that may affect safety and efficacy could also be considered impurities. You must validate the processes that remove these impurities or establish final product testing to show residuals are at acceptable levels.
1 Guidance for Industry: FDA Guidance for Human Somatic Cell Therapy and Gene Therapy