The Pyrogenicity Manufacturing Challenge
Pyrogens constitute a heterogeneous group of fever causing substances which comprise both microbial and non-microbial substances. The most potent and most widely known are the endotoxins or lipopolysaccharides (LPS), which are cell wall components of gram-negative bacteria. Gram-positive bacteria are also sources of pyrogens, in particular lipoteichoic acid (LTA), as are particles from yeasts and viruses. Non-microbial pyrogens often emanate from production environments. Small particles of packaging materials are a typical example.
Because pyrogen contaminations in pharmaceutical products, biotherapeutics, cosmetics and on medial devices can induce life threatening fever, it is mandatory for manufacturers to ensure that the pyrogen concentrations do not exceed certain limits. Sterility tests cannot address this requirement appropriately as many of the pyrogenic structures persist after elimination of living pathogens.
The pyrogenicity hazzard was discovered more than a century ago, and tests to determine whether a parenteral or medical device is safe for human use have been in place for 70 years. Currently, there are three test methods available: the rabbit pyrogen test (RPT), the Limulus Amoebocyte Lysate (LAL) assay (a bacterial endotoxin test), and a method based on human whole blood or human monocytes called Monocyte Activation Test (MAT).