Potency evaluation, achieved through potency assays, is essential to transition an advanced therapy medicinal product or ATMP (also known as cell and gene therapy) through pivotal clinical stages to final market authorization. However, potency is a difficult parameter to assess for ATMPs, so it is important to start developing these assays early to minimize possible delays in ATMP commercialization. This blog provides insights into how and when to develop potency assays to help overcome regulatory and manufacturing barriers in ATMP commercialization.
What is Potency and Why are Potency Assays Important in ATMP Commercialization?
The ICH 6QB guidelines define potency as “the quantitative measure of biological activity based on the attribute of the product which is linked to the relevant biological properties”.1 This definition means that potency reflects the drug’s expected mechanism of action (MoA), providing information about the clinical effect expected from a dose of a product. Potency is unique in being the only critical quality attribute (CQA) linked directly to efficacy.
Without validated potency assays, a therapeutic product cannot be licensed, and commercial lots cannot be released. Potency assessment provides reassurance that the cGMP manufacturing process is performing reliably to produce consistent safe and effective doses. It also allows comparability assessments of manufacturing process changes, which inevitably occur during both development and post-market authorization, to ensure that relevant biological characteristics are retained.
Ideally, potency assays for ATMPs should have the following key characteristics:
- Reflect the mode of action of the ATMP
- Predict product quality by unambiguously and reliably predicting clinical efficacy
- Be stability-indicating and able to differentiate between target and degraded products
- Be quantitative, although in practice absolute quantification is often not achievable and a relative potency approach, comparing a test item to a reference standard, is required
- Have validated performance parameters, i.e. accuracy, sensitivity, reproducibility and specificity. Defined performance limits are essential.
Challenges Associated with Potency Assay Development for ATMPs
Potency is based on the specific characteristics of each individual ATMP. An adequate assessment of ATMP potency is challenging for both practical and regulatory reasons that stem from the complexity of ATMPs, as highlighted in Table 1.
More detail on the specific challenges of cell-based potency assays can be found here.3
Optimizing Potency Assay Development for ATMPs
With so many unique challenges in potency assay development for each ATMP, it can be a challenge to know where to begin. From a regulatory perspective, potency assays for ATMPs are evaluated on a case-by-case basis because regulators understand the challenge of working with unique and complex biological products. As the FDA acknowledges, “the complexity of CGT products can present significant challenge(s) to establishing potency assays.”4 In certain cases, it may be necessary to establish specific novel standards or procedures not yet covered by regulatory guidance.Therefore, the regulatory framework for the approval of ATMP potency assays is flexible, around some core requirements. A list of the regulatory guidance on potency assay development from the FDA and EMA can be found here.2
It is therefore always advisable to engage with regulators early to establish possibilities for what will be appropriate and acceptable to them in terms of your potency assay plan. There are some other key considerations that will help you optimize potency assay development to smooth the development and commercialization of your ATMP.
Avoid Late Stage Delays or Failure in Licensure and Release – Start Potency Assay Development Early
The need for extensive and focused product characterization during early phase development cannot be overemphasized. Since the ability to measure potency is fundamentally related to product characterization, the regulatory authorities recommend that you should initiate potency assay development, by way of product characterization during preclinical and early clinical investigations, to obtain as much product information as possible. Potency assay development takes time, especially for complex ATMPs. If started too late, it can delay commercialization and final regulatory approval and lot release.
Use a Potency Assay Matrix Approach to Address Multiple or Undefined MoAs
Establishing the link between the potency assay and MoA can be particularly challenging because ATMPs are multifactorial with complex MoAs and sometimes have undefined or hypothetical MoAs. A way to overcome this is to use a matrix of multiple potency assays targeting several of the hypothetical MoAs and assessing different aspects of the product’s attributes. A broad array of tests in early development can then be refined as product knowledge increases during clinical evaluation. If the MoA is hard to define, then start by measuring a characteristic linked to MoA, then adapt as necessary. Discovery-driven methods, such as multiple -omics platforms, can be used to identify potential surrogate biomarkers for potency.
Refine Your Matrix and Acceptance Criteria Using Progressive Potency Assay Implementation
Each potency assay in a matrix needs to be validated and have defined acceptance criteria and limits in order to obtain a biologics license, which may vary dependent on the type of assay. Assay acceptance criteria should be set as a numerical range, based on data and adjusted throughout the product development stages as more information is obtained. This progressive approach to potency testing is important because potency assays for product lots used in early clinical studies are more likely to have a wider acceptance range than those used in later phase trials. Data assuring the identity, purity, strength and stability of an ATMP are required during all phases of a clinical study with clear assay and acceptance limits established in advance of Phase III (pivotal) clinical trials, where they are needed for Phase III lot releases.
Figure 1 describes the changing focus and key challenges for potency assay development and validation across the clinical development process.
Figure 1. Potency assays through the clinical development process2
Robust Potency Assay Design and Validation Plan to Support a Biologics License
Validation of your potency assay is essential to demonstrate that your product meets certain requirements of potency─ a necessity for obtaining a biologics license. The validation process, outlined in ICH Q2 (R1) that is currently under revision, identifies potential sources of error and quantifies them within the assay method. Moreover, ICH Q14 and its focus on a Quality by Design (QbD) approach, will come into effect in 2021 and change the overall approach to assay validation. You should perform analysis and validation of all relevant assay parameters, including accuracy, sensitivity, precision, and specificity. Therefore, it is essential that the design of the assay, in accordance with cGMP regulations, can generate data that will allow one to evaluate its performance and suitability for its intended use. This involves several practical considerations, such as limiting assay variability and having appropriate controls in place.
Consider the Practical Execution of Potency Assays to Help Facilitate Product Commercialization
There are some practical considerations for potency assays that can help drive product commercialization.
RAPID ASSAYS. Having potency assays that can be performed rapidly is beneficial, especially when they are used for the release testing of products with a short shelf life.In vivo assays, in addition to being inherently variable, often require a lot of time to run; some can take as long as two months to complete. That makes them generally unfeasible for both manufacturing and stability programs and they are impossible to repeat quickly if the assay is invalidated for some reason. Ethical and commercial judgements are also a factor here – for example, given the high variability of outcomes, are you able to justify in vivo experiments, which are costly, time-consuming and require the use of animals?
INEXPENSIVE AND SIMPLE ASSAYS. Some analytical platforms are complex and expensive, such as high-content imaging and next-generation sequencing. It can be tempting to use these cutting-edge platforms for your potency assay; however, they may not be practical. The assay needs to be as simple as possible to minimize the chances of assay failure. Better to select platforms that are widely available to reduce the overall cost of the potency assay and increase its transferability and reproducibility.
Potency assays are critical for ATMP approval and QC release; however, their development can be complex and challenging. Inadequate potency assays can result in the delay or even failure of ATMP commercialization. Early investment in potency assay development can mitigate these problems and maximize an ATMP’s chance of commercial success. In many cases, a matrix of potency assays is the only way to ensure the full and reliable characterization of an ATMP. The potency matrix may use a wide range of analytical approaches and techniques designed for both performance and practicality. Success in potency assay development requires insight and practical expertise in the science, analytics, regulation and manufacturing relevant to ATMPs.
Further detailed tips and insights on potency assay development for ATMPs can be found here.2
- International Council for Harmonisation. ICH Harmonised Tripartite Guideline. ICH Topic Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. European Medicines Agency (EMA) (1999). Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-6-b-test-procedures-acceptance-criteria-biotechnological/biological-products-step-5_en.pdf
- Covance, White Paper. ATMP Potency Assay Strategies (2020). Available at: https://www.covance.com/content/dam/covance/assetLibrary/whitepapers/ATMP-Potency-Assay-Strategies-WPCMC003.pdf
- Dunn S and Estdale S. Cell-based potency assays for QC: Considerations for development and analytical transfer (2018). [Poster presented at BioPharmaceutical Emerging Best Practices Association (BEBPA)]. Available at: covance.com/content/dam/covance/assetLibrary/posters/DunnBEBPA18.pdf
- US Food and Drug Administration. Guidance for Industry Potency Tests for Cellular and Gene Therapy Products (2011). Available at: https://www.fda.gov/media/79856/download