Pyrogenicity – Dead Bugs?

I am not a microbiologist but I play one on TV!

Pyrogens are substances that cause fever in humans. Pyrogenicity is the ability of a chemical agent or other substance to produce a febrile response. Pyrogenic responses may be material-mediated, endotoxin-mediated, or mediated by other substances, such as components of gram-positive bacteria and fungi.
Material-mediated pyrogenicity

This type of pyrogenicity originates from non-endotoxin substances. The LAL test is not suitable for determining the pyrogenicity of these substances. For detection of material-mediated pyrogenicity, the rabbit pyrogen test is generally recommended even though endotoxin could cause a pyrogenic response in the rabbits.

Endotoxin-mediated pyrogenicity

While sterilization kills bacteria, the dead cell walls (which in some gram-negative bacteria release endotoxins) remain on the products. This form of pyrogenicity is evaluated by measuring the amount of endotoxin in the devices by an endotoxin-specific LAL (Limulus Amebocyte Lysate) test without performing a rabbit test. The LAL test is highly specific for bacterial endotoxin. The biological effects of endotoxins include:

– Fever
– Augmented inflammation
– Macrophage activation
– Release of vasoactive amines
– Intravascular coagulation
– Complement activation
– Cell lysis
– Vascular necrosis
– Impaired perfusion of essential organs resulting in pathology
– Shock

According to AAMI ST72, products that have direct or indirect intravascular, intralymphatic, or intrathecal contact or have the potential for similar systemic exposure (e.g., solution administration sets, transfer sets, catheters, implants, and infusion assemblies), or ophthalmic products for intraocular use (e.g., silicone oil, viscoelastic products, intraocular lenses) shall be evaluated for the presence of endotoxin.

FDA CDRH requires devices in contact with circulating blood or cerebrospinal fluid to be nonpyrogenic. Intraocular lenses also are required to be nonpyrogenic. Requirements for other products are decided on a case-by-case basis by the FDA.

To avoid endotoxin-caused pyrogenic reactions to their devices, manufacturers must carefully control the environment in which the devices are manufactured and processed to minimize contamination with bacteria, or establish a procedure for cleaning the devices.

Published by Sam Lazzara

Sam Lazzara is a Biomedical Engineer (MS Case Western, BS Brown University) and Certified Biomedical Auditor with 30+ years medical device experience. Sam’s systems and documents have delighted dozens of regulatory auditors from the United States FDA, the California Department of Health, and a flock of European Notified Bodies. He has guided quality system implementation for over 20 firms, leading to third-party certification and government approvals. A medical device start-up specialist, Sam provides state-of-the-art solutions tailored to the needs of each client. He mentors clients on all aspects of quality assurance and regulatory affairs. Sam gets particularly excited about design control, risk management, and post-market surveillance.

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