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Cellular Therapy Regulations

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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.

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.

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.

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.

Another challenge is sterility. Since these products cannot be terminally sterilized, the FDA recommends aseptic processing, preferably in a closed system.

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.

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.

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.

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.


1 Guidance for Industry: FDA Guidance for Human Somatic Cell Therapy and Gene Therapy

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