Material-Mediated Pyrogenicity in Medical Devices

Material-Mediated Pyrogenicity in Medical Devices: Is the Rabbit Pyrogen Test Still Relevant?

Céline Furne 1, Eliott Berthelon 1, Marie Canac 1, Joseph Gorski 1, and Marie-Charlotte Notargiacomo 1

1 NAMSA SAS, Chasse-sur-Rhône, France

Medical devices must perform their intended purpose without posing unacceptable biological risks. One such risk is pyrogenicity, the ability of a substance to trigger a febrile response. Material-mediated pyrogenicity, distinct from micro-organisms-mediated pyrogenicity, is a biological endpoint outlined in “ISO 10993-1 (2018): Biological evaluation of medical devices – Part 1”, and applies to devices that come into contact with breached surfaces, tissues, bone, dentin, or blood. ISO 10993-11 “Tests for systemic toxicity” identifies the rabbit pyrogen test (RPT) as the only validated method for assessing material-mediated pyrogenicity in medical devices. However, the RPT was withdrawn from the European Pharmacopeia in July 2025, and the upcoming revision of ISO 10993-1 will allow for rationalization of this endpoint in many cases. Despite these changes, ISO 10993-11 still recommends testing for any “new chemical entities where the pyrogenic potential is unknown” and some regulatory authorities continue to request the RPT. This situation underscores a controversy: RPT remains the only validated test for medical devices, while in vitro alternatives exist for pharmaceuticals. This raises concerns about the relevance of this test, especially considering the 3Rs principle (Replace, Reduce and Refine animal testing). Furthermore, known pyrogens listed in ISO 10993-11, Annex G are largely irrelevant for medical devices. To assess the actual risk of pyrogenic response of medical devices, NAMSA’s Biological Safety & Validation Consulting Services analyzed over 1,800 RPT conducted in NAMSA Lyon laboratory between 2018 and 2025. Root causes of positive results were investigated, including device composition, endotoxin contamination, and manufacturer data. This poster presents an overview of positive RPT findings and evaluates the necessity of in vivo testing.

Key words: Pyrogenicity, medical device, risk assessment.