USFDA Guidance: Potency Assurance for Cellular and Gene Therapy Products
The US Food and Drug Administration (FDA) has issued its final guidance, Potency Assurance for Cellular and Gene Therapy Products, providing recommendations for developing a science- and risk-based strategy to ensure the potency of cellular and gene therapy (CGT) products. The guidance supersedes the January 2011 guidance on potency tests and introduces a comprehensive approach integrating manufacturing process design, material controls, in-process testing and potency assays throughout the product lifecycle.
1. Scope and Regulatory Framework
The guidance applies to human cellular and gene therapy products regulated as biological products under Section 351 of the Public Health Service Act. It covers potency assurance during product development, clinical investigations and commercial manufacturing.
It does not apply to vaccines for infectious disease indications, bacteriophage products, live biotherapeutic products, faecal microbiota transplantation products or allergenic products.
For licensed products, each lot must undergo potency testing using samples collected after all manufacturing steps that may affect potency. For investigational products, potency assurance should progressively improve according to the clinical development phase.
2. Developing a Potency Assurance Strategy
FDA recommends a comprehensive strategy based on quality risk management to ensure that every released lot can achieve its intended therapeutic effect.
Key elements include:
Product and process understanding: Understand the mechanism of action (MOA), identify potency-related critical quality attributes (CQAs) and determine critical process parameters (CPPs).
Risk assessment: Identify, analyse and evaluate factors that may affect potency during manufacturing, storage, shipping, handling and administration.
Manufacturing process design: Design processes that consistently produce potent products and address variability in starting materials.
Control strategy: Establish material specifications, process controls, in-process testing and appropriate lot-release assays.
Lifecycle improvement: Reassess risks and refine the strategy as product knowledge and manufacturing experience increase.
3. Potency Assays and Testing Requirements
Potency assays are essential components of the overall strategy, although release testing alone may not adequately assure product potency.
FDA recommends selecting assays that measure relevant potency-related CQAs and contribute to reducing identified risks. Most CGT products should include at least one phase-appropriate bioassay measuring biological activity related to the intended therapeutic effect.
Key considerations include:
Assays should demonstrate suitable accuracy, precision, specificity and robustness.
Multiple assays may be required to assess different potency-related attributes.
In-process testing should monitor relevant quality attributes, such as cell viability, growth rate and phenotype.
Stability, in-use, delivery-device compatibility and comparability studies should assess potential changes in potency.
Animal-based assays should be reduced or replaced with suitable in-vitro methods where feasible.
4. Progressive Implementation Throughout Development
The potency assurance strategy should evolve as the product advances through clinical development.
Early development: Identify preliminary potency-related CQAs, conduct risk assessments and establish an initial strategy.
Clinical development: Refine the manufacturing process, assays, acceptance criteria and control strategy using accumulated product and clinical data.
Before BLA submission: Validate assays used for lot release and in-process testing, establish suitable reference materials and justify the final potency assurance strategy.
For products undergoing rapid clinical development, FDA recommends early product and process characterisation and timely development, qualification and implementation of potency assays.
5. Assay Control and Acceptance Criteria
The guidance highlights the importance of maintaining assay reliability throughout the product lifecycle.
Establish predefined sample and system suitability criteria.
Develop and qualify appropriate reference materials and monitor their stability.
Qualify potency assays and validate them as appropriate for their intended use.
Assess the need for partial or full revalidation following assay changes.
Conduct risk-based assay transfer studies when moving assays between laboratories.
Potency specifications should include quantitative acceptance criteria. Lower limits should confirm adequate therapeutic activity, while upper limits should be considered where excessive biological activity could create safety risks. Criteria should be refined as manufacturing and product knowledge develop.
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