A regulatory gap: addressing visible particle control in cell and gene therapies through a risk-based framework.

Visible particulate matter is a critical quality attribute in injectable drug products; however, current regulatory standards provide limited guidance for addressing the specific challenges of Cell-Based Advanced Therapies (CT), where conventional inspection and rejection criteria may be incompatible with manufacturing and clinical constraints. Autologous and small-batch therapies often lack manufacturing redundancy, making the rejection of a single unit potentially equivalent to losing an opportunity to provide a life-saving treatment. To address this gap, we present a risk-based framework for evaluating and controlling particulate risk in CT, focusing on how particulate sources, process conditions, and control strategies can be characterized and improved early in development while incorporating benefit-risk considerations unique to these therapeutic modalities. Grounded in principles from international quality and regulatory publications, the proposed Visible Particulate Risk Assessment Matrix guides developers and manufacturers in assessing and managing particulate risk by integrating factors such as particle type and origin, characterization sufficiency, route and administration context, clinical urgency and therapeutic alternatives, system performance and controls, and lot replacement feasibility.