Material-mediated pyrogens in medical devices: Myth or reality?

Abstract

Annex G of ISO 10993-11:2017 lists 24 substances that are allegedly material-mediated pyrogens (MMPs) in medical devices and recommends using the rabbit pyrogen test (RPT) for MMP evaluation. We aimed to establish whether medical devices contain MMPs; determine if MMPs are pyrogens or uncouplers of oxidative phosphorylation (UOPs); complete a survey of RPT failures; and develop a UOP screening list. A literature search was conducted to identify MMPs associated with medical devices. Concurrently, data mining was conducted to search for MMPs in medical device extractables databases and collect RPT data from industry and contract research labs. The literature search produced the conclusions: (1) Annex G's endogenous biological compounds are pyrogenic; (2) Annex G's drugs and UOP substances are not pyrogenic but thermogenic; (3) numerous other UOPs were identified; and (4) nearly all UOPs are poorly soluble in saline (the RPT's injection solvent). The data mining found two Annex G MMPs in medical device extracts that were not pyrogenic and confirmed that the RPT failure rate was low, with investigated failures caused by endotoxin or test incompatibilities, not by Annex G MMPs. Since no pyrogenic Annex G MMPs or saline soluble UOPs were found in medical device extracts, the RPT is unnecessary. If UOPs are detected during chemical characterization studies, an ISO 10993-17:2023 toxicological risk assessment can be used to determine their hazard potential. Residual biological contamination can be evaluated with the human monocyte activation test, which detects all biological pyrogens. The term "MMP" is inaccurate and obsolete.