Endotoxins

Endotoxins have molecular dimensions small enough to pass freely through bacteria-retentive filters. They are also heat stable at steam sterilization temperatures. Typically, endotoxicity is not lost with loss of viability. Treatments that are intended to achieve sterility may not guarantee freedom from pyrogenicity if the product was heavily contaminated prior to sterilization.

Pharmacopoeial limits on endotoxins in sterile parenteral products are calculated from a formula that takes account of the concentration of endotoxin in the product, the dosage regimen and the weight of the patient. The formula is expressed as K/M, where:

K = the approximate threshold pyrogenic dose for humans. With some exceptions this has been given a fixed value of five Endotoxin Units (EU) per kilogram of body weight of the patient (70 kg is used in calculations as the weight of an average human patient) M = the maximum dose of product per kilogram of body weight of the patient that would be administered in a single one-hour period.

The EU relates back to the first batch of the USP Reference Standard, which contained one EU per 2 x 10-8g of the standard endotoxin. The threshold pyrogenic dose would be in the order of10-9 g per kilogram of body weight of the patient. Since endotoxins occur in Gram-negative bacteria to the extent of about 1015 g per bacterium, this is equivalent to requiring injection or infusion of about 106 bacteria per kilogram of body weight of patient to induce a pyrogenic reaction, or 7 x 107 bacteria (living or dead) for the average 70-kg patient.

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