Pyrogenicity

Pyrogenicity is the property of a substance to induce fever when introduced into a living organism. In pharmacology and medicine, pyrogenic substances include exogenous pyrogens such as bacterial endotoxins (lipopolysaccharides) from Gram-negative bacteria, as well as other microbial toxins and, in some cases, endogenous pyrogens generated by the host during inflammation.

Fever induction typically involves recognition of endotoxins by immune receptors such as the TLR4–MD-2 complex on phagocytes, leading to the release of proinflammatory cytokines (for example IL-1, IL-6 and TNF-α) and prostaglandin E2, which reset the hypothalamic temperature set point.

Assessment of pyrogenicity is a major aspect of quality control for injectable drugs, vaccines, and some medical devices. Historically, the rabbit pyrogen test (RPT) was used; today, routine testing relies on endotoxin detection methods such as the Limulus amebocyte lysate (LAL) assay, recombinant factor C (rFC) assays, and the monocyte activation test (MAT) as alternative in vitro approaches. Regulatory guidance from pharmacopeias and authorities specifies endotoxin limits per dose or per unit body weight, with product-specific and route-specific criteria.

Endotoxins are particularly resistant to some sterilization processes, making pyrogen control essential. In vitro alternatives are increasingly adopted to reduce animal testing in line with 3Rs principles (replacement, reduction, refinement).