Endotoxin, found in Gram negative bacteria, can cause shock, tissue injury, and death. It interacts with the immune system, causing an inflammatory response. Genetically modified bacteria used in production require purification to remove endotoxins.
Endotoxin is a common contaminant of medical products that comes from bacteria. The presence of endotoxins can derive from intrinsic components of the production process or from accidental contamination of the product. Endotoxin can cause endotoxic or septic shock, tissue injury and even death. The removal of the endotoxin before the drug is approved for release is therefore necessary to avoid causing disease in the drug recipient.
Endotoxin contamination occurs when a certain group of bacteria, called Gram negative bacteria, is present or has been present in the manufacturing process. With bacteria generally divided into two groups, Gram negative and Gram positive, Gram negative bacteria are extremely common. The Gram-negative designation comes from the appearance of the bacteria after a specific staining process, called a Gram stain, has been performed. Endotoxin is present in all Gram negative bacteria, whether or not they cause disease.
The outside of a Gram negative bacterium contains lipopolysaccharides (LPS) which are used for structural stability. Endotoxin refers to this LPS part of the bacterium. For example, an E. coli cell contains about 2 million LPS molecules. LPS is not only present in the cells of live or dead bacteria, but is also continuously released into the environment. The release occurs during the growth and division of the bacterium and when the cell dies.
The LPS molecule has an indirectly deleterious effect on the body. Endotoxin interacts with the immune system by binding to blood cells called macrophages and monocytes. This binding causes an inflammatory response by releasing factors such as interleukin-6, interleukin-1 and tumor necrosis factor. This inflammatory response leads to fever and sometimes endotoxic shock and death.
These dangerous effects occur with a single high dose of endotoxin or with repeated lower exposure levels. A dose of 1 nanogram of LPS per milliliter of product may cause an endotoxic reaction in mammals when the product is injected intravenously. People with diseases such as AIDS, leukemia or diabetes are particularly at risk of endotoxic shock.
Genetically modified Gram-negative bacteria are regularly used in the production of biologically active proteins and peptides. The presence of LPS molecules in both producer cells and the surrounding culture means that the product requires purification and endotoxin removal. Lipopolysaccharide is a very stable molecule compared to proteins, resisting pH and temperature extremes, so the removal of endotoxins requires complex removal techniques. Manufacturers, therefore, use methods such as ion exchange chromatography, ultrafiltration and membrane chromatography for the removal or reduction of endotoxins to an acceptable level.
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