What Is Pyrogen Testing?

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  • Written By: Marlene Garcia
  • Edited By: Daniel Lindley
  • Last Modified Date: 24 March 2020
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Pyrogen testing defines a process used by drug manufacturers to determine if bacterial toxins are present in vaccines and drugs that might cause fever when used on humans. It determines if microbes or their metabolites are present in intravenous solutions during the manufacturing process. The most common and oldest form of pyrogen testing consists of injecting drugs into rabbits to determine if a fever develops. A newer test uses blood from the horseshoe crab to test for toxins.

The rabbit pyrogen testing method surfaced in the 1940s after some patients became ill from intravenous drugs. Hypodermic devices at the time proved useful for administering drugs directly into the bloodstream for patients who were unable to tolerate oral medications. Even though hypodermics devices were sterile, the drugs were not always safe.

Patients sometimes developed high fevers, chills, and body aches, and some people suffered shock. Doctors didn’t know why this occurred, frequently calling the condition injection fever, saline fever, or distilled water fever. Researchers later discovered some drugs and vaccines were contaminated in production labs with pyrogen endotoxins, potent bacteria that withstand sterilization.

The human body fights exposure to bacterial toxins in the environment through the skin. When contaminated drugs are injected into the bloodstream, toxins bypass normal defense mechanisms. White blood cells begin releasing another form of pyrogen that causes high fever, which might lead to shock and death.


Pyrogen testing in drug labs involves heating equipment used to ensure sterilization. The drug is injected into ear veins of rabbits to see if a fever develops. Rectal temperatures of test animals are analyzed after 30 minutes and again one to three hours later. If the animals remain fever-free, the solution is free from toxins.

The process of pyrogen testing on animals typically involves injecting several rabbits at a time within a 10-minute time frame. The dosage for each rabbit depends on body weight, age, and gender. The same group of rabbits might be tested repeatedly every few days until they develop a tolerance to the drugs.

A newer pyrogen testing technique is called the limulus amoebocyte lysate (LAL) test. Blood from horseshoe crabs contains high levels of toxins naturally found in marine life. Scientists discovered a way to use the blood to test for bacterial toxin in drugs and the raw materials used to manufacture medicine. The LAL pyrogen testing procedure might be 100 times more sensitive than the rabbit testing methods. Medical devices that are implanted into humans go through LAL testing, along with radioactive drugs and anesthesia.


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Post 1

Horseshoe crabs are really very interesting. This limulus amoebocyte lysate test only emphasizes the amount of wonder these creatures induce.

Horseshoe crabs look almost alien, but are in fact related to the arachnid family along with spiders and scorpions.

There are fossils of this creature that are 450 million years old. Many scientists label them a living fossil.

Sadly, their numbers are dwindling. The natural habitat they live in is in great decline. This combined with their overharvesting is causing them to disappear rapidly.

There is a lot we can still learn from this ancient species.

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