In the dynamic landscape of biopharmaceuticals, ensuring the potency of cellular therapy or gene therapy (CGT) products is a paramount objective. This draft guidance serves as a compass, delineating recommendations for establishing a robust and science-driven strategy aimed squarely at potency assurance strategies.
By meticulously addressing manufacturing intricacies, process control, material management, and rigorous testing protocols, this multifaceted approach aims to mitigate risks and uphold the potency of each product batch. At its core, the goal is clear: to empower every released batch with the precise ability to achieve its intended therapeutic effect.
The potency of cell and gene therapy products serves as a critical metric, reflecting their biological activity and efficacy. Yet, achieving consistent potency across diverse production lots presents a formidable challenge owing to the inherent variability of starting materials.
Recognizing this complexity, regulatory bodies such as the U.S. FDA are spearheading efforts to provide strategic guidance tailored to the unique demands of CGT products. The draft guidance, titled “Potency Assurance for Cellular and Gene Therapy Products,” unveiled on December 28, 2023, marks a pivotal step towards ensuring the reliability and efficacy of these groundbreaking therapies.
Table of Contents

Definition: Potency testing
Potency is “the specific ability or capacity of the product, as indicated by appropriate laboratory tests or adequately controlled clinical data obtained through the administration of the product in the manner intended to effect a given result.”(U.S. Department of Health and Human Services, U.S. FDA (2011). “Guidance for Industry: Potency tests for cellular and gene therapy).
Potency Assurance Strategies: A Multifaceted Approach
Potency assurance strategies encompass various elements, including manufacturing process design, control, material management, in-process testing, and potency lot release assays. Potency measurements ensure only product lots meeting specified criteria are used throughout clinical trials and after market approval.
The overarching goal is to mitigate risks to product potency, ensuring that each released lot maintains the specific ability to achieve the intended therapeutic effect. However, achieving consistency within a target potency range can be challenging in pharmaceutical manufacturing. This difficulty is particularly pronounced in cell and gene therapy due to the intricate nature of quantifying potency.
Understanding Potency in CGT Products
Potency, defined as the capacity of a product to produce a specific biological effect, presents a significant challenge in the context of CGT products. Variability in starting materials, such as donor tissues or cell lines, and the transfer of genetic material in gene therapies contribute to batch-to-batch variability in potency.
Additionally, target gene expression and heterogeneity within cell populations further complicate potency assessment. While it’s essential to reject lots that fail to meet acceptance criteria, in cell therapy manufacturing, there might not always be an opportunity to produce a new batch. This could be due to factors such as the limited availability of starting patient materials or the patient’s critical condition.
Addressing Variability and Ensuring Consistency
The draft FDA guidance highlights weaknesses in current good manufacturing practices that can lead to potency variation. These include the need for appropriately designed manufacturing processes, rigorous material specifications and testing, and careful evaluation of container and closure systems. Furthermore, manufacturing controls and in-process testing are essential for maintaining potency throughout production.
Key Considerations for Potency Assays
Potency assays play a crucial role in quality control and lot release testing. Validated assays must accurately measure the product’s mechanism of action and demonstrate consistency in assessing potency across batches. Various assay types, including animal-based in vivo and in vitro biochemical assays, may be employed to reduce reliance on animal testing.
Implementing Quality Risk Management
Quality risk management principles underpin the development of potency assurance strategies. Manufacturers are encouraged to conduct risk assessments to identify and mitigate manufacturing processes, materials, and product attributes risks risks risks risks. A quality target product profile (QTPP) is a roadmap for defining potency-related critical quality attributes and guiding ongoing process verification efforts.
These controls include process parameters, in-process testing, material examination, lot release tests, and corresponding acceptance criteria. Identifying potency-related critical quality attributes (CQAs) is crucial for achieving the therapeutic effect, necessitating a phase-appropriate control strategy.
Manufacturers must ensure that their manufacturing processes consistently produce batches with all CQAs within predetermined limits. Critical process parameters (CPPs), which can affect CQAs, should be identified, monitored, or controlled within appropriate limitations. Additionally, conducting a comprehensive risk assessment to identify, analyze, and evaluate risks to potency-related CQAs throughout the product lifecycle is essential for adequate potency assurance strategies.
Assay Development and Time of Testing
Assays must be meticulously designed, qualified, and validated to ensure their suitability for potency assessment. Performance characteristics such as specificity, accuracy, and precision should be established under conditions that mimic real-world usage. Potency assessment typically occurs after all manufacturing steps are completed, following finishing processes such as cryopreservation.
Looking Ahead: A Forward-Thinking Approach
The FDA’s draft guidance offers a forward-thinking framework for potency assurance strategies in the dynamic landscape of CGT products. By aligning potency-related critical quality attributes with the product’s mechanism of action, manufacturers can establish a robust foundation for ensuring therapeutic efficacy and patient safety.
In conclusion, developing and implementing potency assurance strategies are integral to successfully producing cellular and gene therapy products. By embracing scientific rigor, risk management principles, and innovative assay development, manufacturers can navigate the complexities of potency assessment and contribute to advancing the field of regenerative medicine.
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