How to calculate Endotoxin Limits for Parenteral drug Products?

The formula for calculating an endotoxin limit in parenterals is generally noted as K/M, where K = the Threshold Pyrogenic Dose and M is the dose of drug units/kg/hr.

“K”, the numerator of the endotoxin limit formula, is the Threshold Pyrogenic Dose (TPD). This is a constant, and represents a statistical assessment of the levels of endotoxin activity that it takes to induce a fever in a rabbit.

As a result of these studies, 5 EU/kg/hr is the TPD for products administered intravenously (IV) or intramuscularly (IM). If a product is administered Intrathecally (IT), meaning the material is injected into the space that holds cerebrospinal fluid, K is lowered to 0.2 EU/kg/hr. If the drug product is a radiopharmaceutical, K = 175 EU for non-intrathecal routes of administration and 14 EU for intrathecal administration.

“M”, the denominator in the endotoxin limit formula, is the maximum dose of the material per kg of patient and per hour of total administration.

Example

Calculation of the endotoxin limit for a product to be administered via intramuscular or intravenous injection at a maximum bolus dose of 2 mL/person. Maximum dose per kg (assuming a standard adult human body mass of 70 kg) = 2 mL/70 kg = 0.0286 mL/kg Endotoxin limit = K/M = 5 EU/kg / 0.0286 mL/kg = 175 EU/mL