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Pyrogenicity

Pyrogens are substances that trigger a fever response when they make their way into our bodies. The most common pyrogens are pieces of bacterial cells, and our immune systems recognize them as foreign matter. Since pyrogens can trigger a response from our immune systems, they 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 (FDA).

Animal Test

The rabbit pyrogen test (RPT) has been used since the 1940s. In this test, rabbits are restrained and injected with a test substance while their body temperature is monitored for changes that suggest the substance might be contaminated with pyrogens.

Rabbits put through the RPT can suffer from painful reactions, including fever, breathing problems, circulatory and organ failure, and even fatal shock. Despite its long history of use, the RPT 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 differences between rabbit and human responses to pyrogens as outlined in a 2001 article in Alternatives to Laboratory Animals titled “Novel Pyrogen Tests Based on the Human Fever Reaction.”

Non-Animal Test

A pyrogen test that uses human cells—called the monocyte activation test (MAT)—has been developed as a total replacement for pyrogenicity testing in animals. The MAT detects pyrogens in a test substance by measuring the immune response of donated human blood when exposed to a test substance. The MAT is faster and better able to detect pyrogens than the RPT.

Regulators in Europe have added the MAT to the list of tests that are available for the detection of pyrogens and are encouraging companies to use it before testing on rabbits. In the U.S., the FDA still requires companies to use the RPT, but as the use of the MAT becomes more widespread and regulators become more familiar with the non-animal test, the FDA is beginning to reconsider this requirement.