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How many EU of endotoxin can this injectable contain?

Endotoxin limit calculator (K/M)

Divides the endotoxin threshold the body tolerates for the route of administration (K) by the maximum dose given per kg of body weight per hour (M) to give the product's endotoxin limit.

When to use itUse it when setting a specification for an injectable, or to check whether an endotoxin test result (LAL or similar) is within what the product allows.

Prefilled with an example: an intravenous product (K = 5) given at up to 1 mL per kg of body weight per hour. Change any value and the result updates.

EU/kg/h

5 for injections (intravenous and similar) and 0.2 for intrathecal administration around the spinal cord. Some routes, such as radiopharmaceuticals, use other values.

product unit/kg/h

The most product given per kg of body weight in one hour. Enter mL/kg/h to get the limit in EU/mL, or mg/kg/h to get EU/mg. By USP convention, adult body weight is taken as 70 kg.

Endotoxin limit5 EU/(product unit)

This product may contain up to 5 EU per unit of product (the unit you used for M, such as 1 mL). If the endotoxin test result is at or below this value, it is within the limit.

How to read it

  • Result at or below the limitWithin the limitAt or below what the product allows. Still, judge pass or fail together with the route, the product concentration and the maximum dose (the basic approach of our related article).
  • Result above the limitOver the limitReview the formulation, the process and how endotoxin got in. Always judge the result against the limit, not on its own.
  • Checking the routeK is not a single valueK changes with the route: 5 EU/kg/h for injections, 0.2 for intrathecal use, and so on. Some routes, such as radiopharmaceuticals and intraocular products, have separate criteria. Confirm K in the pharmacopoeia you follow and in the product specification.
  • Spike recovery outside 50 to 200%Suspect interference or LERIf recovery of spiked endotoxin falls outside the 50 to 200% guide, or drops over time, suspect test interference or low endotoxin recovery (LER), where endotoxin reads lower than it is. Confirm the test is valid before judging against the limit.

How it is calculated

The per kg per hour in K cancels the per kg per hour in M, leaving EU per unit of product. Enter M in mL and the limit is per mL; enter it in mg and the limit is per mg.

endotoxin limit = K ÷ M (K = tolerated EU/kg/h, M = maximum dose/kg/h)

Source: The endotoxin limit is K ÷ M, where K is the threshold the body tolerates and M is the maximum dose. The approach is shared by USP <85> Bacterial Endotoxins Test, Ph. Eur. 2.6.14 and FDA guidance.

With your numbers

  1. limit = K (tolerated) ÷ M (maximum dose) = 5 ÷ 1 = 5 EU/(product unit)

Limits of this calculation

  • The limit is a guide from the standard K/M equation. Actual pass or fail follows the pharmacopoeia you use (USP <85>, the Japanese Pharmacopoeia and others) and the product specification.
  • K varies with the route and has no single value (5 for injections, 0.2 EU/kg/h for intrathecal use, and so on). Some routes, such as radiopharmaceuticals and intraocular administration, have their own criteria, so confirm K for your product's route.
  • The unit of M (mL/kg/h or mg/kg/h) decides the unit of the limit (EU/mL or EU/mg). Keep track of which input unit gives which result unit.
  • M is assumed to be per kg of body weight per hour. Body weight (70 kg by convention) and how the maximum dose is set depend on the product information and the dosing design.
  • Test results are affected by interference from dilution, pH, salt concentration, surfactants, chelators and the like, and by LER (endotoxin reading lower than it is). Confirm the test is valid with interfering-factor and hold-time studies before comparing with the limit.
  • The related article explains K and M and gives typical K values. Body weight, specific values of M and the unit conversions here are examples and must be set for each product.

Primary sources

Every calculator gives an estimate for learning, built on published information and primary sources. Real decisions follow the applicable guidance and expert judgment.