Fever responses from medical devices signal catastrophic contamination - pyrogenic reactions progress from discomfort to septic shock, yet endotoxin testing alone misses non-endotoxin pyrogens requiring comprehensive pyrogenicity assessment. Material-mediated pyrogenicity testing following ISO 10993-11 and USP <151> detects both endotoxin and non-endotoxin pyrogens through the rabbit pyrogen test, providing comprehensive fever-response evaluation required for implantable and blood-contacting devices. The protocol involves intravenous injection of saline extracts into rabbits with continuous temperature monitoring over 3 hours, detecting pyrogenic responses that LAL testing alone might miss through sensitivity to peptidoglycans, fungal components, and other fever-inducing substances. Critical device categories requiring pyrogenicity testing include all implantables per ISO 10993-1 where chronic exposure could trigger fever responses, blood-contacting devices where pyrogens directly access systemic circulation causing immediate reactions, and devices processed with materials known to contain non-endotoxin pyrogens like certain fungal-derived components. The substantial sample requirement ensures representative extraction capturing pyrogenic substances from all device components including bulk materials, adhesives, and coatings that collectively contribute to pyrogenic burden. For combination devices with biological components, pyrogenicity testing validates processing adequately removes or inactivates pyrogens from tissues, growth media, or biological additives. The test complements LAL endotoxin testing by detecting pyrogenic substances that don't trigger Limulus reactivity, providing comprehensive pyrogen control preventing febrile reactions in patients. Manufacturing validation confirms cleaning removes pyrogenic residues, sterilization doesn't generate new pyrogens through material degradation, and storage doesn't enable pyrogenic contamination through microbial growth.