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?
这ICH 6QB guidelinesdefine potency as “the quantitative measure of biological activity based on the attribute of the product which is linked to the relevant biological properties”.1This 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
- 具有验证的性能参数，即准确性，灵敏度，再现性和特异性。定义的性能限制是必不可少的。
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 foundhere。3.
优化ATMPS的效力测定开发
在效力测定de有着很多独特的挑战velopment 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 foundhere。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
早期发展期间对早期发展的广泛和聚焦产品表征不能过分强调。由于测量效力的能力与产品表征根本相关，因此监管机构建议您应在临床前和早期临床调查期间通过产品表征启动效力试验，以获得尽可能多的产品信息。yaboapp体育官网效力测定开发需要时间，特别是对于复杂的ATMP。如果开始太晚，它可以延迟商业化和最终监管批准和批量释放。
使用效力测定矩阵方法来解决多个或未确定的MOAS
建立效能分析之间的联系d 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
需要验证矩阵中的每个效力测定，并限定了接受标准和限制，以获得生物学许可，这可能改变依赖于测定的类型。分析验收标准应设置为数值范围，基于数据，并在整个产品开发阶段进行调整，因为获得更多信息。这种渐进性效力测试的方法很重要，因为早期临床研究中使用的产品批次的效力测定更可能具有比后后相位试验所用的产品较宽的验收范围。在临床研究的所有阶段都需要确定ATMP的身份，纯度，强度和稳定性，其临床研究中具有透明的测定和在第II期（枢轴）临床试验的临床试验之前建立的验收限制，其中III阶段批量释放需要。
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
验证您的效力测定对于证明您的产品符合某些效力要求 - 获得生物制剂许可的必要性。目前正在修订的ICH Q2（R1）中概述的验证过程识别潜在的错误来源，并在测定方法中量化它们。此外，ICH Q14及其专注于设计（QBD）方法，在2021年生效，并改变了分析验证的总体方法。您应该对所有相关的测定参数进行分析和验证，包括准确性，灵敏度，精度和特异性。因此，必须根据CGMP法规设计测定，可以产生将允许人们评估其预期用途的性能和适用性的数据。这涉及几种实际考虑因素，例如限制测定变异性并具有适当的控制。
Consider the Practical Execution of Potency Assays to Help Facilitate Product Commercialization
这re 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?
廉价且简单的测定。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.
Conclusion
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 foundhere。2
References
- 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: //www.wfliji.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
