FDA finalizes cell and gene therapy potency guidance
In a final guidance issued on Monday, the US Food and Drug Administration (FDA) laid out its expectations for cell and gene therapy (CGT) sponsors to demonstrate that their products meet potency standards through the developer a potency assurance strategy.
“Patients who receive cellular and gene therapies are often battling serious or life-threatening conditions, such as cancers and rare diseases, and they deserve the assurance that the product administered to them will perform as intended,” said Karim Mikhail, director of the Center for Biologics Evaluation and Research (CBER).
The guidance finalizes a draft version issued in December 2023 and supersedes an earlier guidance addressing potency tests for CGT products from 2011. FDA said the final version features advice on integrating potency assurance into companies’ existing quality systems, more guidance on risk assessments, recommendations for engagement with regulators, as well as new examples and refined terminology throughout the document. (RELATED: FDA CGT draft guidance focuses on potency assurance strategy, Regulatory Focus 2 January 2024)
“The guidance provides flexible, risk-based recommendations for manufacturers on how to integrate potency considerations at every stage of development and commercialization — from early-phase investigational new drug (IND) submissions through biologics license application (BLA) approval and continued post-market verification,” FDA said.
The guidance addresses controls for raw material variability, in-process testing, and lab tests to verify that the biological activity of the products matches its intended effect in patients. Additionally, the document offers advice on products with short shelf lives, viral vector gene therapies, and individualized therapies.
“By giving manufacturers a clear, predictable roadmap, this guidance supports faster access to safe and effective therapies for patients who often have no other treatment options — many of whom receive products made individually for a single person,” FDA said.
Product lifecycle
The guidance details FDA’s expectations throughout the product lifecycle for CGT products and includes a section discussing potency requirements for licensed products, investigational products, as well as applicable current good manufacturing practice (CGMP) requirements.
FDA explains that to obtain a BLA, the application must demonstrate that the product is safe, pure, and potent, with assurance that the product will remain so throughout its shelf life. Each lot must be tested for potency with an assay performed after all manufacturing steps that could impact potency are completed, though the agency notes that alternative approaches may be allowed, if the alternative approach provides greater than or equal assurance of the product’s potency.
Additionally, manufacturing changes must be assessed and determined to have no negative impact on the potency of the product in a manner that negatively affects its safety or effectiveness.
During the premarket stage, IND sponsors should explain their strategy for potency assurance with sufficient chemistry, manufacturing, and control (CMC) information. FDA notes that the amount of information necessary will scale with the phase of development, increasing as the scope of clinical investigations expand.
Throughout the entire clinical development stage, FDA said the IND “must contain sufficient data to support the stability of the drug substance (DS) and drug product (DP),” and that stability studies for DPs should include “phase appropriate” assessments of potency.
FDA adds that it may place an investigation on hold if an IND lacks the required information about potency to assess the risk to study participants. For Phase 2 and 3 studies, FDA warns that it may place a trial on hold if it is lacking in design to meet its stated objectives.
“The product lots that the sponsor plans to administer in Phase 2 or 3 investigations should be sufficiently potent, otherwise the product lots may not have the capacity to achieve the intended therapeutic effect. In addition, an investigation conducted with product lots that have unknown or inadequately controlled potency may be unable to provide information for ensuring the continued potency of the product after licensure,” FDA wrote.
FDA also explains that various factors related to CGMP contribute to potency assurance, including the design and qualification of the manufacturing process; the materials used in manufacturing; containers, closures, delivery devices, and other equipment that comes into contact with the product; manufacturing process controls; suitability of potency assays, and having phase-appropriate assays and acceptance criteria.
Potency assurance strategy
The guidance states that a potency assurance strategy “is a comprehensive approach to help ensure that every lot of a product will have the specific ability or capability to achieve the intended therapeutic effect.”
FDA said that quality risk management principles should be applied throughout the product lifecycle, including the concepts of quality target product profile (QTPP), control strategy, critical quality attributes (CQA), critical process parameters (CPP), risk assessment, and risk reduction.
The agency encourages sponsors to leverage prior knowledge and experience, especially when gained from manufacturing and testing a similar product. FDA explains that sponsor will gain product and process understanding through understanding its mechanism of action, conducting nonclinical studies, product characterization and identification of CQAs, establishing a relationship between CQAs and potency, understanding the impact of material quality on potency, and process characterization and identifying CPPs.
The guidance also provides recommendations on risk assessments, manufacturing process design, and control strategy.
Additionally, the guidance outlines how to progressively implement a potency assurance strategy that scales with the stage of development and encourages sponsors to engage with regulators early on for feedback on their potency assurance strategy and potency assays.
