RETHINKING EXTRACTABLES AND LEACHABLES RISK FOR ADVANCED THERAPEUTIC MEDICINAL PRODUCTS (ATMPS)

Extractables and leachables (E&L) science has matured over three decades around a relatively narrow product archetype: small-molecule drugs, monoclonal antibodies, and conventional vaccines formulated in stable, well-characterized matrices and assessed primarily against systemic toxicological endpoints. Advanced Therapeutic Medicinal Products (ATMPs) — CAR-T and other engineered cell therapies, in vivo and ex vivo gene therapies, CRISPR-based editing products, exosomes and other extracellular vesicles, mRNA-lipid nanoparticle (LNP) constructs, organoids, and complex cell culture media — do not fit this archetype. Their critical quality attributes are not merely chemical purity and systemic safety margins but biological function: potency, transfection or transduction efficiency, immune quiescence or activation, genome-editing fidelity, and structural integrity of nanoscale or supramolecular assemblies. This review critically examines whether the toxicological logic underpinning current E&L thresholds — the Threshold of Toxicological Concern (TTC), Permitted Daily Exposure (PDE), and Analytical Evaluation Threshold (AET) — remains scientifically defensible for living-cell and nanoparticulate products, and proposes a next-generation, function-first risk assessment framework tailored to the biology of ATMPs. Graphical Abstract: Figure