Potency of Cell and Gene Medicinal Products

The FDA published a draft guideline on the potency of Cellular and Gene Therapy (CGT) in December 2023.  The draft guidance describes the FDA’s recommendations for developing a potency assurance strategy through manufacturing process design, material controls, in-process control, and release testing to ensure the product’s potency. This blog covers the key points to meet these recommendations and potential challenges. 

Potency is the quantitative measure of biological activity and is one of the critical quality attributes (CQAs) for medicinal products of biological origins. While potency testing remains essential, the new FDA draft guideline aligns with the existing principles of Quality Risk Management (ICH Q9 (R1)) and recommends developing a comprehensive potency assurance strategy for CGT products. The key points and, consequently, the impact on regulatory filings are highlighted in this article.

The deadline for comments is now closed, and the FDA is working on the document’s final version, which will eventually replace the 2011 guidance on Potency Tests for Cellular and Gene Therapy Products when finalised.

How to Develop a Potency Assurance Strategy?

The FDA recommends using the approach already described in the existing ICH Pharmaceutical Development Guideline (ICH Q8 (R2)) for potency. To develop a potency assurance strategy, it is important first to understand the product’s potency-related characteristics and then perform a Quality Risk Management (ICH Q9 (R1)) analysis to assess and minimise the risks to potency.

The following steps are therefore recommended:

• Define a Quality Target Product Profile (QTTP) based on the product’s mechanism of action (MOA), intended clinical indication and the route of administration.
• Identify the potency-related CQAs that are important for achieving the intended therapeutic effect. Understanding the MOA (s) is important when identifying the potency-related CQAs. Prior knowledge, product characterisation studies, nonclinical data, or clinical studies provide helpful information for learning about the MOA, which often results from multiple activities.
• Evaluate the impact of materials on the potency-related CQAs and identify Critical Process Parameters (CPPs) during process development and characterisation studies.
• Conduct a risk assessment for each potency-related CQA. The manufacturing process should be included in the risk assessment, as well as the steps from product release to administration.
• Mitigate risks to potency through:
  • Manufacturing process design, adapting for the variability of the materials, to consistently produce potent lots
  • Control strategy, including control of materials, process parameters, in-process and release testing and continued process verification

It is important to note that the potency assurance strategy should be reassessed and refined throughout the product development. Potency-related CQAs, risk assessment and strategy for reducing the risk to these CQAs should be in place before the start of clinical investigations. However, the product’s QTPP, CQAs, CPPs and potency assurance strategy will evolve with the increased understanding of the product and manufacturing process.

Change in Regulatory Filing

With the implementation of the guidance, the following additional information will be required in Module 2 and Module 3 of an Investigational New Drug (IND) and Biologics License Application (BLA) filing.

Risk of Clinical Hold

Inadequate potency assurance may lead the FDA to place studies on clinical hold in the following instances:

• At any stage of clinical development, if the potency of the product to be administered cannot be assured (or the information provided in the IND is not adequate for potency assurance) and therefore, the risk to subjects to illness or injury cannot be assessed.
• For late phase clinical trials intended to provide evidence of the product effectiveness for a marketing application, inconsistent potency of product lots could reduce the statistical power to detect its therapeutic effect and, therefore, be clearly deficient in design to meet its stated objectives. Additionally, if product lots used in the clinical trial have unknown or inadequately controlled potency, this will not provide sufficient data to justify the commercial product specifications.

Potency Assay

The second part of the guideline focuses on the potency assay itself. Although the potency assurance strategy provides other tools for controlling the potency of the product, potency assays are still an essential part of the strategy. Assays measuring potency-related CQAs are used for the release of the product, during stability studies to establish the product shelf-life or during in-use stability studies to ensure the product remains potent during administration.  Potency assays are also essential to demonstrate comparability of the product lots to support manufacturing changes and during manufacturing process development to identify the steps that can affect the product potency.

The following recommendations are provided for potency release assays:

• May include physicochemical assays or bioassays
• Should be precise, accurate, specific and robust
• Should quantitate a potency-related CQA that is at risk (i.e. all potency related CQAs do not necessarily need to be tested at release)
• Multiple release assays should be used with at least one bioassay which measures a relevant biologic activity of the product.

Useful examples of recommended approaches to potency design and selection for the following types of CGT products are provided:

• Cellular products
• Products with particularly short shelf-life
• Viral gene therapy vector products
• Vector-transduced patient-specific cellular products
• Tissue-engineered medicinal products

Finally, the guideline also provides some useful advice on the following:

• The assay control using sample and system suitability
• The assay qualification (necessary prior to initiation of the clinical investigation) and validation (required for licensed products)
• The use of reference materials
• The management of changes (when replacing, updating or transferring the assay to a new site)
• Setting up appropriate quantitative acceptance criteria from early development to licensing.

Summary

Potency testing is a complex yet common challenge for developers of CGT products. Moreover, the FDA often raises challenging queries related to the potency when an IND application is submitted. This draft guideline provides valuable recommendations on potency tests and for developing a complementary, broader approach to ensure potency of the product.

DLRC’s team of CMC and biologic experts can advise on current regulations on potency testing and author and/or review CMC filings.  Please get in touch with us at hello@dlrcgroup.com for further information.