Pyrogens are fever—and inflammation—causing agents that can pose a serious health hazard, especially in the case of intravenous drugs and pharmaceutical products. The only regulatory agency in the U.S. that routinely requires pyrogenicity studies is the Food and Drug Administration.
A rabbit pyrogen test has been in use since the 1940s. In this test, rabbits are locked in full-body restraints and a test substance is injected into their bloodstream while their body temperature is monitored.
The animals can suffer effects ranging from fever to breathing problems, circulatory and organ failure, and even fatal shock. Despite its long history of use, the rabbit pyrogen test has never been formally validated to establish its reliability or relevance to humans. In fact, there are a number of well-documented drawbacks to this test, including marked species and strain differences in sensitivity.
(T Hartung et al.,ATLA 29, 99-123, 2001)
An In Vitro Pyrogen Test has been developed and validated in Europe as a total replacement for animal-based pyrogenicity studies. As an immune reaction, pyrogenicity involves an interaction between a contaminant in a drug formulation and cells of the immune system. Using human blood donated by healthy volunteers as the test medium, this non-animal method is able to fully model the interaction between the immune system’s white blood cells and the test drug, thereby confirming the presence or absence of pyrogen contamination.
Additionally, this determination can be made in vitro with greater speed and sensitivity and at a lower cost than animal-based methods would allow. Despite these advantages, the Food and Drug Administration continues to rely on animal testing to assess the pyrogenic potential of new drugs and pharmaceuticals.