The Strategic Imperative: Why Early Potency Assay Development Makes or Breaks ATMP Success

Recent developments in the advanced therapy field highlight the critical importance of starting early and adopting a comprehensive and validated approach for potency assay development. Often, developing potency assays happens late during drug discovery. This trend does not put focus on having a suitable potency strategy with guideline-compliant validation in place at the time it is needed, which has already led to two Biologics License Application rejections due to inadequate potency assays in 2023–2024 specifically due to a lack of robust and reliable mechanism of action reflecting potency assay (Iovance and Mesoblast).

The lack of full validation and testing were showstoppers for the drug developers, according to Dr. Ulrike Herbrand, scientific director for global in vitro bioassays, Charles Rivers Laboratories. While both companies were successful in Phase III clinical trials, the BLA rejections were regulatory obstacles to overcome prior to drug product release, which created costly delays.

These rejections underscore a critical challenge facing developers of advanced therapy medicinal products (ATMPs), which is how to develop robust, reliable potency assays without breaking the bank or derailing development timelines, in order to manage potential BLA issues.

“Starting early and adopting a comprehensive, well-validated approach can significantly enhance the development and approval process for ATMPs,” explained Herbrand. Her emphasis on finding the right balance between early preparation and practical execution highlights what can make the difference between success and costly failure.

For ATMP developers, the temptation to delay potency assay development until later stages or run parallel development is strong. After all, ATMPs often undergo significant changes during development. Yet waiting can prove to be expensive and potentially catastrophic for drug developers.

Herbrand highlighted that earlier development is better not just from the regulatory point of view, but also from the perspective of ensuring that it is possible to have a

reliable measurement of the potential therapeutic effect of the individual lots during the clinical trials.

“Even if the mechanism of action of a new ATMP is not yet fully understood in the early development phase, it makes perfect sense to work on the possible assays that reflect already known mechanisms of action (MOAs). Herbrand advised. This can also include working according to the matrix approach for the early phase with methods that work at the transcriptional or translational level and then, with increasing knowledge, working on the functional mechanism of action-reflecting assay.

This early start is not just about checking regulatory boxes. It is about building a foundation for success that can save millions in development costs and prevent devastating late-stage failures. Investment in early potency assay development can pay dividends throughout the product lifecycle, from clinical trials through commercial manufacturing.

While there is no ideal potency assay, the final lot release assays, designed to determine potency critical quality attributes (CQAs), should be robust, reliable and fulfill the requirements of ICH Q2(R2) to ensure a smooth release process. However, potency assays are at risk of failure due to numerous influences on biological activity, which make it difficult for an assay to test a drug’s properties.

ATMP potency assays face unique challenges that set them apart from traditional biological products. Herbrand outlined one fundamental difference: “For the ATMPs, often you do not really have a reference, especially for the cell therapy products. If you have a reference, the shelf life is much shorter, which is the case for the majority of gene therapy products. You will never have something that remains for five years or longer.”

Consistency remains an issue for ATMPs, which are notoriously sensitive to manufacturing changes. Slight modifications in the production process can significantly impact how the product behaves in potency assays. Unsurprisingly, this sensitivity is often compounded by differences between scientific and commercial manufacturing approaches, and restrictive testing due to small lot sizes. Even the most elegant assay is ineffective if it is not reliable during commercial manufacturing.

“It doesn’t help anyone if you have the perfect mechanism of action reflecting functional assay that the regulatory authority approved, but during the release process, half of the lots fail just because the assay is so complex and so sensitive,” Herbrand stated. “Therefore, there needs to be a very good balance of early-phase methods for characterization purposes, ones that are robust reliable and stable, supporting patient safety along with assays developed later in the process, to give a reference point.”

The right timing is imperative in finding this balance. “It is really important to find the sweet spot,” Herbrand emphasized.” If there is not sufficient focus on addressing the CQAs phase-appropriately this will cause delays.”

This is largely because the CQAs are defined based on the manufacturing critical process parameters (CPP), the quality target product profile (QTPP) and the analytical target profile (ATP). In a quality by design (QbD) driven risk-based approach according to the ICH manufacturing guidelines, these are living documents that require adjustment during the lifecycle of the drug and the functional relationship between manufacturing process and CQAs needs to be taken into consideration. The key lies in strategic planning and smart resource allocation.

Developers face a critical strategic choice early in their journey: the matrix approach or the incremental approach. For products with well-understood MOAs, Herbrand advised that, “It makes sense to consider the matrix approach, combining different types of assays, looking at all relevant process steps.” Drug developers using this approach develop multiple complementary assays simultaneously. They are able to examine the transcriptional, translational and functional aspects of these assays concurrently or at different drug development stages.

This approach creates a comprehensive understanding of the product’s potency while providing a robust dataset for regulatory submissions. Herbrand highlighted that while the matrix approach is initially more resource-intensive, it is able to mitigate the risk of knowledge gaps in the future and provides a strong foundation for regulatory submissions.

For less understood MOAs, Herbrand advocated for a different strategy, which allows for continuous improvement of the assay. “If the MOA is not fully understood, it makes sense to use this approach because it involves gradual development and refinement as the developers adjust new information being gathered.”

This incremental approach gives developers the flexibility to adapt to new information, lowering the risk of investing too many resources into the development of irrelevant potency assays. Another benefit of this approach is that, unlike the matrix approach, it requires limited initial resource investment. As product development progresses, the potency assays are aligned and evolve with the product.

Both the matrix and the incremental approach have their benefits. They both work provided there is a focus on having a phase-appropriate strategy in place and there is continuous progress on improvement and refinement with a view to the next step. Herbrand emphasized, “Incremental assay development can also take place within the framework of the matrix approach. The two concepts are not mutually exclusive, it is all a question of strategy. And it is often the lack of strategy that causes problems in the end.”

Herbrand emphasized that drug developers should build a comprehensive memorandum of understanding prior to investing heavily in a potency assay. She also noted that drug developers must be flexible and accommodate changes. Additionally, drug developers must consider commercial manufacturing requirements from the beginning and adjust their testing methods for future commercialization.

The future for ATMPs is challenging. It heavily relies on the ability to develop and validate potency assays while being both time- and cost-effective. As such, it requires a delicate balance of scientific research, commercial practicality and regulatory compliance.

Herbrand stressed, “When it comes to potency assay development, the right strategy isn’t just about saving time or money–it’s about ensuring these revolutionary therapies can actually reach the patients who need them.”

Dr. Ulrike Herbrand joined Charles River Laboratories in 2007. She is Scientific Director Global in vitro Bioassays and Head of the Bioassay Research & Development team at Charles River Laboratories’ site in Erkrath, Germany. She gained a PhD in biological sciences during her time at the Max-Planck-Institute for Molecular Physiology in Dortmund (Germany) and worked five years at post-doctoral positions at medical research centers in the field of cancer research. She is an expert in mechanism of action-reflecting bioassays.