The FDA’s new final guidance for cell and gene therapy potency assurance sets out a lifecycle, risk-based approach to product quality and manufacturing control.
Cell and gene therapy potency assurance now has an integrated regulatory approach, with the U.S. Food and Drug Administration (FDA) issuing final guidance asking manufacturers to consider product potency across the drug development lifecycle.
No single release assay can provide the full picture of product quality. The FDA’s new guidance specifies it needs a risk-based lifecycle approach that connects product understanding, manufacturing controls, material quality, in-process testing, and lot-release assays.
Image
What Does the FDA’s New CGT Potency Guidance Change?
On 2 November 2026, the FDA’s Center for Biologics Evaluation and Research (CBER) issued its final Potency Assurance for Cellular and Gene Therapy Products guidance.
The new guidance replaces the agency’s January 2011 version on potency tests for these products and finalises the draft published in December 2023.
It does not cover every advanced therapy category. The FDA excludes infectious disease vaccines, bacteriophage products, live biotherapeutics, faecal microbiota transplantation products, and allergenic products.
The guidance recommends a science- and risk-based Potency Assurance Strategy.
This new approach combines manufacturing process design, process controls, material controls, in-process testing, and potency assays used for lot release.
Its purpose is to give manufacturers confidence that each released batch can deliver the intended therapeutic effect.
This is a broader view of potency than a test that’s just performed at the end of production.
A result from a single assay may not capture every factor that affects a complex biological product. Manufacturing conditions, starting materials, storage, transport, and preparation for administration can all influence the final product.
The FDA also makes clear that this strategy must fit within an organisation’s existing quality system.
It does not recommend a separate potency-specific quality system or claim that the guidance creates new sponsor requirements, and of course, the document provides non-binding recommendations, while existing statutory and regulatory obligations remain in force.
Find out how Quality-by-Design improves reliability and compliance in pharma and how you can maximise innovation through quality-based pharma development systems.
Why Does Potency Assurance Matter Across the Product Lifecycle?
Potency describes a product’s ability to produce its intended biological or therapeutic effect.
For CGT products, demonstrating this can be difficult.
Their mechanisms of action may involve several biological activities, and manufacturers can face variability in starting materials, production processes, and analytical methods.
A potency assay remains important, but it should be only one part of any quality assurance framework.
The FDA recommends that sponsors understand which product characteristics contribute to the mechanism of action and identify the critical quality attributes (CQAs) that influence therapeutic activity.
Manufacturers should then identify critical process parameters (CPPs) that could affect those attributes. They can use this information to build controls into the process before a product reaches final testing.
The guidance also places greater emphasis on risk assessment throughout the lifecycle.
Sponsors should consider factors that could affect potency after a batch has passed release testing. These include container closure systems, delivery devices, storage conditions, shipping, handling, thawing, and preparation for administration.
This is particularly important for CGT products that have short shelf lives or patient-specific manufacturing requirements.
A batch may meet its release specification but still face risks during transport or preparation. The assurance strategy should account for the product’s actual route to the patient.
The agency now recommends that sponsors revisit their risk assessments as they gain manufacturing experience and product knowledge.
A process change, new material supplier, or revised analytical method can alter the risk profile.
Teams should therefore assess the potential impact on potency before implementing changes.
Image
How Should Manufacturers Build a CGT Potency Assurance Strategy?
The FDA recommends that sponsors use quality risk management to develop a strategy suited to the product and its stage of development.
The work should begin with an understanding of the product’s intended clinical use and mechanism of action.
Sponsors should consider several connected activities:
Product characterisation: Identify attributes that may influence biological activity and therapeutic effect. Use nonclinical and clinical evidence where available.
Material and supplier controls: Assess whether raw material characteristics affect potency. Apply appropriate specifications, supplier qualification, and acceptance testing.
Process design: Identify manufacturing parameters that influence potency-related CQAs. Design the process to reduce avoidable variability.
In-process monitoring: Test relevant attributes during production so teams can detect changes before final release.
Lot-release testing: Use phase-appropriate assays and quantitative acceptance criteria to support decisions about product quality.
Prior knowledge can help teams establish an initial strategy.
However, the FDA warns against assuming that experience with one product will transfer directly to another. Differences in mechanism of action, manufacturing processes, and starting materials can create unexpected risks.
The agency also recommends a progressive approach during clinical development. Sponsors should strengthen potency assurance as programmes advance and the amount of evidence required increases.
Early-stage programmes may have less extensive data, but they still need enough information to support the quality and safety of the investigational product.
By the time sponsors conduct later-stage investigations intended to support marketing approval, potency controls should provide stronger evidence that the product lots used in trials can deliver the intended effect.
Inadequate assurance may lead to a clinical hold if it creates an unreasonable and significant risk to participants or leaves the IND without information needed to assess that risk.
The Looming Threat of Geopolitical Risk in Clinical Supply Chains
Geopolitical risk is reshaping how clinical supply chains are managed, demanding resilience and foresight. Learn why building supply chain resilience is the key for clinical trial success.
Image
What Specific CGT Products Need Special Potency Consideration?
The final guidance recognises that one testing model will not suit every CGT product. It therefore discusses several situations that require tailored approaches.
For products with extremely short shelf lives, a conventional bioassay may not produce results before administration. The FDA recommends combining appropriate physicochemical testing with in-process tests that predict potency.
Sponsors should also start relevant bioassays immediately after manufacturing and review the results when available, including after release where appropriate.
For viral vector gene therapies intended for direct administration, early release testing should generally include an assay that measures transgene expression or activity in transduced cells. Manufacturers should also assess risks to the vector particles and their genetic material.
Patient-specific, vector-transduced cell therapies present another challenge.
If a batch fails for these products, patients may face a significant treatment delay while a replacement is manufactured.
The FDA therefore recommends demonstrating adequate biological activity for each vector lot before using it in production, alongside appropriate testing of the final cell therapy product.
These examples underline the importance of product-specific controls rather than a universal potency assay model.
The guidance also addresses assay performance and lifecycle management.
Sponsors should establish suitable reference materials, monitor assay performance, and define quantitative acceptance criteria.
Release assays should be qualified as soon as feasible, and no later than the start of clinical investigations intended to provide substantial evidence for a marketing application. Any licensed product release assays must be validated.
Image
What Should CGT Developers Do Next?
The final guidance gives manufacturers a clearer basis for reviewing their CMC strategies but it does not remove the scientific challenges of measuring potency.
The FDA encourages sponsors to address those challenges earlier and across more stages of the product lifecycle.
CGT developers should consider a structured review of their current programmes.
This should include the relationship between mechanism of action and potency-related CQAs, the influence of materials and process parameters, and the ability of existing assays to detect meaningful changes.
Quality, analytical development, manufacturing, regulatory affairs, and clinical teams should work from the same potency strategy.
This cross-collaboration is especially important when a programme moves between development phases, changes manufacturing sites, or introduces new suppliers and analytical methods.
Sponsors should also assess whether their quality control strategy covers the period between lot release and administration. For short-lived and patient-specific products, this may be as important as the assay itself.
The FDA has scheduled a public webinar for 10 December 2026 to discuss the final guidance. Sponsors can use this opportunity to clarify how the agency expects manufacturers to apply its recommendations.
On the commercial side, the influence of this guidance is substantial. Potency failures can affect batch release, clinical supply, comparability assessments, and regulatory submissions.
A lifecycle approach may help sponsors identify problems earlier, reduce avoidable manufacturing risk, and build a stronger evidence package for approval.
At Pharmatica, we examine the regulatory decisions and quality strategies shaping advanced therapy development and commercialisation. We connect regulatory expectations with the manufacturing, analytical, and investment decisions facing life sciences leaders.
Cell and gene therapy potency assurance is a strategy for ensuring that a product can deliver its intended therapeutic effect. It combines manufacturing controls, material controls, in-process testing, and potency assays.
What did the FDA change in its November 2026 CGT guidance?
The FDA replaced its 2011 potency testing guidance with a broader lifecycle approach. The final guidance recommends integrating potency into product development, manufacturing, quality risk management, and lot release.
Does the FDA require a separate potency assurance quality system?
No. The FDA recommends integrating potency assurance into an organisation's existing quality system. The guidance does not establish a separate potency-specific system or create additional sponsor requirements.
How does the guidance affect potency testing during clinical development?
Sponsors should progressively strengthen potency assurance as clinical development advances. Later-stage programmes need sufficient evidence that the product lots used in trials can deliver the intended therapeutic effect.
Why are potency assays difficult for cell and gene therapies?
CGT products can have complex mechanisms of action, variable biological starting materials, and product-specific characteristics. These factors make it difficult to design one assay that captures every attribute relevant to therapeutic activity.
Nicole (BSc Molecular Medicine, Honours Medical Biochemistry) has many years of pharmaceutical experience, having worked for top CROs and biopharma companies for more than a decade.
Did you enjoy the content?
1
Why not support
Nicole Dale
by giving this content a like
Precision logistics in clinical trials is transforming global study execution through real-time tracking, cold-chain management, and advanced operational visibility.
Digital Twins in Clinical Trials: Simulating Success Before Enrolment
Digital twins in clinical trials simulate patient outcomes to reduce risk and accelerate timelines. Learn how sponsors use them for predictive trial design.
Deep Learning in Clinical Trials for 2026 and Beyond
Deep learning is changing how clinical trials are designed, run, and analysed in 2026. Examine the tools, outcomes, and strategic risks shaping adoption.
How AI Is Shaping the Next Generation of Clinical Trials
In this Digital Pulse episode, Lisa Moneymaker, Chief Operating and Strategy Officer at Medidata, joins Deepankar Nayak to discuss how AI is shaping the next generation of clinical trials.
Find out how Quality-by-Design improves reliability and compliance in pharma and how you can maximise innovation through quality-based pharma development systems.
Comments (0)