The challenges of potency assay development for cell-based medicinal products in Europe

Among critical quality attributes which need to be monitored during drug development, potency is considered essential for its direct link to product effi cacy. Developing the relevant set of potency assays for cell-based medicinal products comes with numerous challenges due to the complex nature of the products. This paper highlights several approaches to consider when designing the potency assay strategy in the framework of current EU regulatory expectations. Potency is considered a critical quality attribute (CQA) for any biological product, and the implementation of relevant assays is o en at the centre of many challenges and discussions among developers and regulators throughout product development. Potency assessment is indeed important not only for manufacturing, as a tool to assess product quality and consistency, but also for clinical development to help predict product clinical e cacy and create a link to the dose. This link is di cult to establish for biologicals in general, and for cell therapy medicinal products the challenge is even more complicated. This is because these cellular products present a high level of molecular complexity, and their modes of action (MoA) may not always be fully understood and o en involve multiple pathways. The status of knowledge on the MoA supported by literature, together with the collection of development data and the use of a risk-based approach, will constitute important elements to build and defend the potency assessment strategy throughout product development and for registration. This article provides an overview of the EU regulatory expectations in terms of potency assessment for cell-based medicinal products (CBMPs). The retrospective analysis of the approach followed by both regulators and developers for some of the approved products illustrates how de ning an incremental potency strategy early on can help alleviate certain challenges and strengthen overall product development. Potency: De nition and evolving requirements Potency is de ned in the ICH Q6B guideline1 as: “The measure of the biological activity using a suitably quantitative biological assay (also called potency assay or bioassay), based on the attribute of the product which is linked to the relevant biological properties. ” Historically, the concept of potency has been applied to all types of drugs (starting with plants and chemicals) at the time when elucidation of structure was limited. Veri cation of potency was the only way to guarantee that the active substance would ful l its properties when used in patients. When establishing the rst Pharmacopoeial referential, the monographs made reference to “biological activity measurement”. Nowadays, chemically synthesised small molecules usually have a wellde ned structure and elucidated MoA, hence the measure of strength (“content”) by a dosage method is o en su cient. This “content” approach (in mass unit) could in fact be considered as the premise of the surrogate approach to potency assessment. The potency measurement requirement has been kept for the quality control of vaccines and other biologicals, which are complex structures and for which their activity is also largely dependent on the integrity of the molecular structure. This holds true for the new class of medicinal products, de ned as advanced therapy medicinal products (ATMPs) in the EU legislation. Biological products, including ATMPs, feature much more complex molecular structures while their pharmacological activities and resulting MoA may not always be totally elucidated, as they sometimes involve multiple pathways. Content (in mass units) is therefore not a su cient measure of the actual biological activity (later referred to as potency) and speci c assays capable of detecting the functional activity of the product are required as part of overall quality assessment and quality control strategy. For most biologics, the main MoA is o en at least partly de ned and will help guide the design of the potency assay strategy. Challenges tend to be much greater for CBMPs, considering the intrinsic product variability, presence of cell mixtures, and extremely complex biological activities. In the context of such complex therapies, product knowledge gathered throughout development will help re ne and build pieceby-piece the relevant potency assessment strategy that may start with a simple indicator, such as a speci c cell surface marker, and evolve towards more relevant and reliable quantitation of biological activity. Product understanding, elucidation of the MoA, analysis of development data and the drawing of a correlation between quality attributes and clinical outcome will all contribute to the design of the nal potency measurements. It is therefore expected that potency assessment evolves throughout development before reaching the nal adopted tests for any given product. In fact it took nearly 35 years to develop a suitable potency assay for the Pertussis vaccine, and more than ten years to move from animal testing to a more reliable in vitro “content assay” for insulin. Regardless of these challenges, potency testing is seen as the cornerstone to a solid product development and relevant quality control strategy. Since it is the only quality attribute for which the test should be designed based on anticipated MoA and/or anticipated physiological function(s), the potency assay is critical to many aspects of development.