Rethinking hemocompatibility standards: a critical appraisal of current regulatory frameworks for Advanced Therapy...

Hemocompatibility, defined as the ability of a product to interact safely with blood components, is a critical requirement for therapies intended for intravascular administration. Current evaluation frameworks, primarily based on ISO 10993-4:2017, were initially developed for inert medical devices and rely on static assays assessing hemolysis, coagulation, platelet activation, and complement activation. However, these approaches remain limited when applied to Advanced Therapy Medicinal Products (ATMPs), which are dynamic and biologically active. Unlike conventional devices, ATMPs interact continuously with immune and hemostatic systems under flow conditions. Existing methodologies do not fully capture shear-dependent and time-evolving thrombo-inflammatory processes, may show variability, and have limited translational relevance. In addition, innate immune activation, an important contributor to ATMP-related adverse events, is not sufficiently considered. Regulatory guidance from major agencies, including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), remains indirect, leading to variability in practices and uncertainty in study design and interpretation. This review critically examines current hemocompatibility assessment strategies for ATMPs and highlights the need for adapted frameworks. It proposes redefining hemocompatibility as controlled blood-interaction and supports the integration of dynamic flow-based models and mechanistic assays within a risk-based, tiered approach to improve predictivity, standardization, and safety. Such an evolution is essential to implement more biologically relevant and clinically meaningful hemocompatibility standards for ATMPs. STATEMENT OF SIGNIFICANCE: Current hemocompatibility standards were primarily designed for inert medical devices and do not adequately address the biological complexity of advanced therapy medicinal products (ATMPs), such as cell and gene therapies. This review highlights important scientific and regulatory gaps in existing testing frameworks, particularly regarding thrombo-inflammatory and immune-mediated blood interactions. By analyzing current limitations and emerging technologies, including dynamic flow-based and microphysiological models, this work proposes a shift from the traditional concept of blood inertness toward controlled blood interaction. This perspective may help improve the predictive value of preclinical safety testing and support the development of more appropriate regulatory standards for next-generation advanced therapies.