By Diana M. Colleluori, Ph.D., MBA, principal CMC consultant, Biologics Consulting Group Inc.
The development of potency assays for cell and gene therapy products (CGTs) may be the most difficult assay strategy to navigate throughout product development, from both a technical and a regulatory perspective. As such, the FDA released the draft guidance for industry for Potency Assurance for Cellular and Gene Therapy Products in December 2023. The draft guidance is structured to provide the drug development industry with insight on the regulatory expectations for potency assurance of CGT products.
The drug development industry has recently expressed confusion with the interpretation of the draft guidance. This article intends to review the draft guidance to clarify the regulatory and technical requirements and to propose considerations for assuring the potency of CGT products throughout the product life cycle that align with regulatory expectations.
Required By FDA, But Guidance So Far Has Been Confusing
Potency tests must be developed that indicate the specific ability or capacity of a drug product to affect a given result. The assessment of product potency is required to essentially prove that a drug product should be clinically potent. Potency testing is required for assessing a wide variety of samples, including in-process, drug substance(s), drug product, stability, and comparability, all with predefined acceptance criteria. Potency must be specific to the product and measure all of the active ingredients. Potency assays are required to be qualified or validated and must be quantitative in nature. They should include all the necessary and appropriate reference materials, standards, and/or controls.
The 2011 FDA guidance on potency focused specifically on the potency test method alone and was published before the current influx of CGT products in development. Guidance on overall CGT potency assurance has been needed for the drug development industry for several reasons. The assessment of some CGT products for potency may be challenging due to the intricacies of the products themselves, such as complex or even unknown mechanisms of action. In addition, multiple significant and unforeseen challenges are likely to be encountered during potency assay development throughout the product life cycle. Since the assessment of drug product potency can change over time, it is imperative to consider the development of multiple potency assays incrementally and in parallel with clinical development activities.
The purpose of the new draft guidance is to advise sponsors on using a science- and risk-based, multifaceted approach to assure CGT product potency throughout the entirety of drug development. While potency assays may change over time, sponsors are required to ensure product potency at all phases of development. Potency assurance should be progressively implemented, even for products under rapid clinical development. The FDA has recently acknowledged that the potency assay(s) is one of the most common CMC issues in late-stage product development. Thus, this guidance is intended to inform sponsors of the FDA’s expectations for potency assurance as early as the IND stage. Potency assurance must keep pace with accelerated products, even those with Breakthrough Therapy or RMAT designations. In essence, the implementation of potency assays, and a potency assurance strategy, must be considered before an IND is submitted. Potency assurance must be implemented at the initial IND for lot release and stability, at a minimum. Sponsors are encouraged to take a phase-appropriate approach to potency assurance with a progressive increase during clinical development. But as many CGT products have accelerated development pathways, it is also important to be aware that Phase 2 and Phase 3 must yield data capable of marketing approval.
The overall potency assurance strategy should consider and include the following elements:
- Quality risk management
- Prior knowledge and experience
- Continued process and product understanding
- Risk assessments that specifically assess potency
- Design of manufacturing process to generate potent lots
- The control strategy – which is where the potency assay itself lies
- Progressive implementation
- FDA feedback on strategy
For the selection of a potency assay(s), the guidance provides some common examples to consider, including potency assays for cellular products, products with short shelf lives, viral gene therapies, vector-transduced autologous cellular products, and tissue-engineered products.
Common Challenges To Selecting And Developing Potency Assays
Some common challenges to the technical development and selection of CGT potency assays include the complexity of the product, complexity of the assays, critical reagents, and limited product materials. For example, a cell therapy drug product with a complex and unknown mechanism of action brings the challenge of selecting appropriate assays that represent the product’s ability to affect the desired clinical result. The assays must be appropriate for the hypothesized product mechanism(s) of action while also playing a vital role in the overall product control strategy. In this case, the development of multiple assays that contribute to overall potency assurance is key. For an oncology product, at least two quantitative cytokine expression assays may be warranted, along with a cell-based bioassay to measure cell killing.
The challenge of having limited product materials does not preclude the sponsor from developing appropriate potency assay(s) and ensuring overall potency assurance. In such cases, additional manufacturing lots may be necessary to complete appropriate assay development work without salvaging precious clinical drug product. This challenge should be assessed and appropriately planned.
Another challenge may be that the initial development of an assay by the analytical development team is not conducive to method validation or is an assay that uses a single-source, specialized critical reagent. These technical challenges illustrate the need for assays to be developed with QC in mind. This challenge may be addressed by QC team review of the assays developed early in product development and well in advance of becoming a late phase or commercial critical issue.
For products that enter a pivotal clinical program after the initial Phase 1 study, it is essential that potency assays are designed prior to or during Phase 1 such that they can be implemented for the pivotal study. This abbreviated CMC timeline often poses the most difficult challenges and strengthens the need to have potency assays at the development forefront prior to IND. In cases where the assay(s) is not ready for the pivotal study, it is absolutely essential that product retains can be saved for retrospective analyses. The potential for this occurring should be assessed and appropriately planned.
In the case of short shelf-life drug products, data from one or more potency assays may not be available at the time of drug product administration. This caveat does not preclude the sponsor from the potency requirement. The regulatory expectation remains the same: appropriate assays that contribute to potency assurance must be used. Logistically, this means that at least one potency result must be used for initial release prior to drug product administration, and one or more potency assay results may be generated after product administration. Again, this approach must be a science- and risk-based approach that assures product potency, and this approach must be pre-approved by the regulators.
Lessons learned to consider in CGT potency development include the following:
- Always have multiple potency assays in development.
- Develop and implement potency assays incrementally.
- Design potency assays with an eye toward commercial use.
- Store and control product retains early.
- Engage in open, frequent, and timely discussions with the regulatory agency.
About The Author:
Diana Colleluori, Ph.D., MBA, is a principal CMC consultant at Biologics Consulting Group, Inc. She received her Ph.D. in biochemistry from Temple University School of Medicine and MBA from the University of the Sciences in Philadelphia. She has over 20 years of industry experience in CMC and quality control. Her experience includes technical and executive roles in biologics product development, from pre-IND to commercial stages. She has direct global experience developing numerous biological products, including monoclonal antibodies, vaccines, and cell and gene therapies.
