The U.S. Food and Drug Administration (FDA) has issued new final guidance aimed at strengthening how manufacturers assess and maintain the potency of cellular and gene therapies, including innovative cancer treatments such as CAR-T cell therapies.
Announced on November 2, 2026, the guidance introduces a comprehensive, science- and risk-based approach to ensuring that these complex biological products maintain their intended therapeutic activity throughout development, manufacturing, distribution, and clinical use.
The document, titled Potency Assurance for Cellular and Gene Therapy Products, replaces the FDA’s January 2011 guidance on potency testing, marking a significant update to the agency’s recommendations for a rapidly evolving field.
Rather than relying exclusively on testing the final product, the FDA emphasizes integrating potency assurance across the entire product lifecycle, from investigational new drug (IND) development through biologics license application (BLA) approval and post-marketing quality monitoring.
What Is Changing in the FDA’s Approach?
Potency is a fundamental quality attribute of biological therapies. Under FDA regulations, it refers to a product’s specific ability or capacity to produce its intended therapeutic effect, as demonstrated through appropriate laboratory testing or adequately controlled clinical data.
For conventional pharmaceutical products, manufacturing consistency can often be assessed through established analytical methods. Cellular and gene therapies present additional challenges because they may contain living cells, genetically modified materials, or viral vectors whose biological activity depends on multiple interacting mechanisms.
The FDA’s updated framework centers on a Potency Assurance Strategy, designed to manage risks that could compromise therapeutic activity.
This strategy integrates manufacturing process design, raw material controls, monitoring during production, potency assays, and predefined acceptance criteria for product release. Importantly, the agency recognizes that no single laboratory assay may adequately capture all the biological properties contributing to a cell or gene therapy’s activity.
Manufacturers are therefore encouraged to identify potency-related critical quality attributes and select analytical methods that meaningfully assess the product’s intended biological function. The guidance also emphasizes that potency assurance should evolve as developers acquire additional knowledge about a therapy’s mechanism of action, clinical performance, and manufacturing characteristics.
Why This Matters for Cancer Immunotherapy
The recommendations are particularly relevant to oncology, where cellular and gene therapies are becoming increasingly important components of treatment development. CAR-T cell therapies, for example, involve genetically engineering immune cells to recognize and attack malignant cells. Their manufacturing processes can include cell collection, genetic modification, expansion, quality testing, and preparation for administration.
For autologous therapies, which use a patient’s own cells, the biological properties of the starting material may vary substantially between individuals. Previous treatments, underlying disease, and differences in cell growth can influence manufacturing outcomes.
The FDA specifically identifies variability in cellular starting materials as a potential risk to potency. Consequently, developers are encouraged to evaluate how differences in starting materials affect critical product characteristics, including cell viability, phenotype, and functional activity.
For patient-specific gene-modified cell therapies manufactured using viral vectors, the guidance highlights the importance of evaluating both the vector used during manufacturing and the final cellular product.
The FDA recommends that manufacturers demonstrate adequate biological activity for each vector lot before using it to manufacture a patient-specific therapy, alongside appropriate potency testing of the final product.
This approach is intended to reduce the risk of producing sub-potent batches that could delay treatment while another batch is manufactured.
From Early Clinical Trials to Commercial Approval
Another important component of the guidance concerns how potency assurance expectations evolve during clinical development.
During early-phase investigations, developers may not yet have fully characterized every biological property relevant to a therapy’s activity. The FDA acknowledges that potency assays and manufacturing controls can be progressively refined as additional evidence becomes available.
However, developers are encouraged to establish preliminary potency-related critical quality attributes and perform risk assessments before clinical testing begins. As clinical development advances, the strategy should become more comprehensive.
For later-stage clinical investigations intended to support marketing approval, the FDA recommends quantitative potency-related testing with appropriate acceptance criteria capable of identifying and rejecting sub-potent product lots. Before submitting a BLA, manufacturers should reassess their potency assurance strategy using accumulated product-quality and clinical data. Analytical assays intended for commercial lot release must be appropriately validated.
For licensed biological products, existing regulations require potency testing of each lot, along with assessments of manufacturing changes that could affect product quality. The final guidance does not create additional legally enforceable requirements. Instead, it describes how developers can meet existing regulatory obligations through a more comprehensive risk-based framework.
Addressing Short Shelf Lives and Complex Manufacturing
One of the practical challenges discussed in the guidance involves therapies with extremely short shelf lives. Some non-cryopreserved cellular products must be administered before lengthy biological activity assays can be completed.
The FDA acknowledges that conventional pre-release bioassays may not always be feasible in these circumstances. For such products, manufacturers may use appropriate physicochemical potency assays for lot release, supported by process controls, testing during manufacturing, and additional biological assays conducted after release.
The guidance recommends initiating post-release bioassays promptly after manufacturing when appropriate, allowing developers to assess whether the manufacturing process continues to produce products with acceptable potency.
The agency also emphasizes that storage conditions, cryopreservation, thawing, shipping, handling, and preparation for administration may affect potency and should be considered during risk assessments.
These considerations are particularly important for therapies requiring complex manufacturing and distribution systems before reaching patients.
FDA Leadership Emphasizes Patient Safety
In the FDA’s official announcement, Karim Mikhail, Director of the FDA’s Center for Biologics Evaluation and Research (CBER), emphasized the importance of reliable product quality for patients facing serious and life-threatening diseases, including cancer.
According to Mikhail, patients receiving these advanced treatments face significant clinical challenges, and:
“they deserve the assurance that the product administered to them will perform as intended.”
Mikhail also emphasized the agency’s commitment to supporting therapeutic innovation while maintaining high standards of product quality and patient safety.
The updated guidance reflects an effort to provide manufacturers with greater regulatory clarity while addressing the scientific and operational complexity of modern cellular and gene therapies.
What’s Next?
The final guidance applies to cellular and gene therapy products regulated as biological products under Section 351 of the Public Health Service Act.
It covers potency assurance across development and commercialization while allowing flexibility in how manufacturers design product-specific control strategies.
The FDA recommends that developers engage with CBER early in development to discuss potency assay selection, manufacturing risks, and the scientific justification for proposed approaches.
The agency will also host a public webinar on December 10, 2026, to explain key considerations in the final guidance and support implementation.
With the release of this document, the FDA has formally replaced its 2011 potency testing guidance with a broader lifecycle approach that incorporates manufacturing consistency, quality risk management, and biological activity assessment.
For developers of CAR-T therapies and other advanced cancer treatments, the framework provides updated recommendations for demonstrating that increasingly complex biological products maintain the potency necessary for their intended therapeutic function, from initial clinical testing through routine commercial manufacturing.
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