Potency assurance for CGT products: an assessment of FDA’s new draft guidance

Regulatory-blog-image_100x100.jpgThis blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.


FDA published a new draft guidance on “Potency assurance for Cellular and Gene Therapy (CGT) Products” at the end of 2023, intended to replace the previous guidance published in 2011. The significant change is that it now promotes a holistic concept of a potency assurance strategy that incorporates the range of ICH Guideline Q8 – 13 considerations. Here I explore if this is an improvement over the previous guidance or if the enhanced general product development concepts inclusions dilute the specific CGT potency assay product focus. 

Assessing product potency

The development of an appropriate quantitative potency assay is a challenge for many developers of novel biotech products, exacerbated in the field of advanced therapies. Assays may only partially reflect the mechanism of action, they may not always correlate with activity in a fully quantitative, and for some products, several different functionalities may need to be reflected. To date, the FDA guidance from 2011 has been the only regulatory advice addressing the development of methodologies to assess product potency. Considering how CGT modalities have evolved and technology has advanced over the past decade, the new guidance is both essential and timely.

FDA positions potency assurance into the context of an overall pharmaceutical strategy enunciated in ICH Q8- 13 guidance. These guidelines, developed primarily with small molecule and recombinant protein drugs in mind, provide considerations for comprehensive product understanding and process control strategy – some of which are pertinent to assurance of the potency of cell therapies. 

What is in the new draft FDA guidance? 

The previous FDA guidance was focused on the assays themselves and explained what potency testing is. It also gave some helpful explanations of what should be measured, how non-biological assays could be tied to biological assays, and expectations on potency testing at various stages of clinical development. The new guidance is substantially longer at 29 pages of which the first 16 detail the overall strategic considerations for potency assurance. 

This strategic part of the guidance emphasizes that general process development and product understanding are vital in ensuring a consistent manufacturing process. This, true for all medicinal products, in turn, goes a long way to underpin the successful manufacture of batches of consistent quality and potency and thereby de-risks the manufacturing process. 

Aspects that are included in the guidance that have a potential impact on product potency that have not previously featured in potency guidance are: 

  • Emphasising that GMP is at the root of ensuring product quality. 
  • Critical raw material control, and the requirement to establish appropriate acceptance criteria. This is particularly important for autologous cell therapy products, yet its inclusion is often not fully appreciated by developers. For cellular starting material that is introduced repeatedly into the manufacturing process, understanding and characterizing the critical raw materials should also be part of product development. Unfortunately, the guidance does not discuss this process in detail.  
  • Assessment of contact materials. Contact materials can affect potency, therefore any material in contact with the product should be evaluated for effects on product quality, the most important of this being the container closure system. 
  • Identifying critical process parameters and effective in-process testing as a way of ensuring consistent potency of batches. Effective manufacturing process controls are critical to reduce the risk to product potency. FDA advises to identify potency indicating CQAs and evaluate how these are affected by critical process parameters (CPPs) and in-process controls (IPCs). While always important for consistent product quality, this is also imperative for alternative release strategies for short-shelf-life products, where potency release data may not yet be available at the time a product is administered to patients. In this situation, upstream data can confer a level of quality assurance before actual release results are obtained. 

The more technical aspects of potency assay development are covered in the remainder of the guidance, albeit after a general discussion of release assays in relation to potency-related CQAs. The guidance states that there needs to be at least one bioassay. Regarding the bioassay itself, the following points are made: 

  • A risk assessment and prior knowledge should be used to identify risk to assay performance in terms of design, reagents and parameters, which should then be mitigated. 
  • The assay itself does not need to reflect the mode of action (MoA) but should clearly mitigate risk to product potency. 
  • General ICH Q5 principles for assay attributes are re-iterated.  

The guidance then discusses how to select an appropriate assay, development and expectations over product life-cycle development, validation and reference material. This section has been substantially shortened compared to the 2011 guidance and some principles are no longer as clearly stated as in the original guidance. 

Notably, there is now a statement that advises to avoid assay redundancy, which could be at odds with the widely given, previous matrix approach to potency testing. That said, the advice elsewhere in the guidance concerning different release assays that address potency-related CQAs stands firmly with the matrix approach. The advice to focus on one key mechanistic assay where possible will certainly be welcomed, as it helps to focus resources.  

Developers are also advised to avoid animal-based assays wherever possible, advice that is not only addresses replacement, reduction and refinement (3R) principles of animal testing, but also is sensible given the fact that animal-based assay normally suffer from high variability and lack of precision.  

The shortening of the assay development section means that advice on potential surrogate release assays is not as easy to understand and advice on reference standards and materials risks being mixing up the different purposes of reference standards and reference and control materials.  

Lastly, the new guidance contains much clearer advice on how to seek FDA input on the potency assurance strategy and what information should be presented to allow for the most effective interaction with the FDA in this respect. 

In summary

Given the notion that potency is critically dependent on product and process understanding and quality assurance principles, it is beneficial that such key principles are explicitly linked back to the efficacy of a product. This may promote a more comprehensive understanding of the approaches to efficacy and safety assurance in pharmaceutical development, which many developers new to the field still struggle with.  

It seems that this has been achieved at the expense of previously clearer guidance on the actual technical expectations for potency assays. Advice has been shortened from paragraphs to more ambivalently phrased sentences that could be misconstrued or misinterpreted. For example, where the 2011 guidance on establishing a link between potency and clinical effectiveness goes over two paragraphs and clearly and firmly moderates such expectations, the corresponding advice in the new guidance is substantially shorter and at first read seems to suggest that this is a requirement for product licensing. Those with regulatory knowledge of the sector will recognize from the brief description that the new guidance is not intended to describe a situation where a fully quantitative correlation to clinical efficacy is demonstrated, but the new phrasing may contribute to substantial confusion, particularly for those new to the sector. 

As the first half of the guidance is already well covered by existing ICH Q guidelines, a much shorter recap with cross-references to existing pharmaceutical development guidelines may have been better, leaving more room to discuss the technically demanding process of bio-assay development.  

What will the CGT industry make of this guidance, which is open for public consultation until the 27th March 2024? It will be interesting to see if there are further edits in the final version. 

To discuss how your phase-appropriate potency assay development could be impacted by the new guidance, please get in touch. Parexel’s regulatory CMC experts are always available for a conversation.  

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