CH 23 · notes
How it works
Monograph first. If the monograph specifies an endotoxin limit, that limit governs. Use K/M only when the monograph does not set a limit. USP <85> Bacterial Endotoxins, in the section Endotoxin Limit, defines the limit for a parenteral drug on the basis of dose as K/M. K is a threshold pyrogenic dose of endotoxin per kilogram of body weight. M is the maximum recommended bolus dose of product per kilogram of body weight. When the product is injected at frequent intervals or infused continuously, M is the maximum total dose administered in a single hour.
The same chapter’s footnote sets K at 5 EU/kg for any route other than intrathecal, and at 0.2 EU/kg for the intrathecal route. You can also enter a custom K. The limit is reported in the unit of the dose you enter, such as EU/mL, EU/mg, or EU/unit.
USP <85> states M per kilogram. It does not print an adult body weight. FDA’s June 2012 guidance Pyrogen and Endotoxins Testing: Questions and Answers, question 7, says the way to establish the endotoxin limit is to use the calculation methods in the USP or AAMI standards. That guidance does not state 70 kg. FDA’s questions and answers on quality-related controlled correspondence, under Microbiology (Endotoxin testing), say the USP <85> maximum endotoxin exposure is not more than 5 EU/kg, interpreted as within 1 hour, for most drugs, based on an average patient weight of 70 kg, and 0.2 EU/kg within 1 hour for intrathecal administration. This page defaults to 70 kg when you enter a dose per hour, and the weight is editable.
Maximum valid dilution is in the section Determination of Maximum Valid Dilution (MVD): MVD = (endotoxin limit × concentration of sample solution) / λ. For the gel-clot technique, λ is the labeled lysate sensitivity in EU/mL. For the turbidimetric or chromogenic technique, λ is the lowest concentration used in the standard curve. When the limit is already in EU/mL, the concentration factor is 1. When the limit is in EU/mg or EU/unit, the concentration is mg/mL or unit/mL. The dilution is shown as 1:MVD. Do not dilute past the maximum valid dilution. Reported figures use 4 significant figures, half up, in fixed point.
USP <85> does not give radiopharmaceuticals a K in EU/kg. The harmonized text calculates 175 EU/V for radiopharmaceuticals that are not given intrathecally, and 14 EU/V for intrathecal radiopharmaceuticals, where V is the maximum recommended dose in mL. Products administered per square meter of body surface use K = 100 EU/m². This page does not calculate those limits.
Other impurity and exposure limits on this site are separate calculations: Nitrosamine Limit, Residual Solvent Limit, Elemental Impurity Limit, E&L AET, and PDE / HBEL. Last checked 2026-10-31.
Not a substitute for a validated bacterial endotoxins test or for positive product control suitability. Confirm the limit against the monograph and the current USP <85> text.
Worked example
Parenteral, not intrathecal. Maximum dose 100 mg in one hour, body weight 70 kg, so M = 100/70 mg/kg in one hour. K = 5 EU/kg. Product concentration 10 mg/mL. Gel-clot λ = 0.125 EU/mL. Load example fills the same numbers. EL = 3.500 EU/mg. MVD = 280.0. Dilution = 1:280.0.
Sources
- USP <85> Bacterial Endotoxins — Endotoxin Limit K/M; Determination of Maximum Valid Dilution (MVD); λ is labeled gel-clot sensitivity or the lowest standard-curve concentration; K = 5 EU/kg except intrathecal 0.2 EU/kg; radiopharmaceuticals 175 EU/V and 14 EU/V; per m² K = 100 EU/m²
- FDA Pyrogen and Endotoxins Testing Q&A (June 2012) — Q7: use the USP or AAMI calculation methods; monograph limits may not match current dosing; the overall threshold is the one in USP <85>. Does not state 70 kg
- FDA quality-related controlled correspondence Q&A — Microbiology (Endotoxin testing): maximum dose delivered within one hour; NMT 5 EU/kg within 1 hour based on an average patient weight of 70 kg; intrathecal 0.2 EU/kg within 1 hour
FAQ
How does USP <85> calculate an endotoxin limit?
In the section Endotoxin Limit, the limit for a parenteral drug is K/M. K is 5 EU/kg for any route other than intrathecal, and 0.2 EU/kg for the intrathecal route. M is the maximum recommended bolus dose per kg of body weight. When the product is injected at frequent intervals or infused continuously, M is the maximum total dose in a single hour. A worked case: 100 mg in one hour, 70 kg, K = 5 EU/kg, concentration 10 mg/mL, gel-clot λ = 0.125 EU/mL gives 3.500 EU/mg, MVD 280.0, dilution 1:280.0. Another case: M = 10 mL/kg and a concentration factor of 1 with λ = 0.25 EU/mL gives 0.5000 EU/mL, MVD 2.000, dilution 1:2.000.
Where does the 70 kg body weight come from?
USP <85> defines M per kilogram and does not print an adult body weight. FDA’s June 2012 guidance Pyrogen and Endotoxins Testing: Questions and Answers, question 7, says to use the calculation methods in the USP or AAMI standards. That guidance does not state 70 kg. FDA’s questions and answers on quality-related controlled correspondence say the USP <85> maximum endotoxin exposure is not more than 5 EU/kg, interpreted as within 1 hour, for most drugs, based on an average patient weight of 70 kg, and 0.2 EU/kg within 1 hour for intrathecal administration. This page defaults to 70 kg and lets you change it. Radiopharmaceuticals are not given a K in EU/kg: the harmonized text uses 175 EU/V, or 14 EU/V when given intrathecally, where V is the maximum recommended dose in mL. Products given per square meter use K = 100 EU/m². This page does not calculate those limits.
How is the maximum valid dilution calculated?
USP <85>, Determination of Maximum Valid Dilution (MVD), uses MVD = (endotoxin limit × concentration of sample solution) / λ. For gel-clot, λ is the labeled lysate sensitivity in EU/mL. For a turbidimetric or chromogenic method, λ is the lowest concentration used in the standard curve. When the limit is already EU/mL, use a concentration factor of 1. Otherwise use mg/mL, µg/mL, g/mL, or unit/mL to match the dose unit. The page shows the dilution as 1:MVD. Do not dilute past the maximum valid dilution. Figures are 4 significant figures, half up.
What if the monograph already states an endotoxin limit?
If the monograph specifies an endotoxin limit, that limit governs. FDA’s June 2012 questions and answers note that monograph limits may not account for current strengths or dosage regimens and should be checked with the calculations in the standards. A calculated K/M does not replace a limit the monograph already sets.
Does this replace a bacterial endotoxins test?
No. Not a substitute for a validated bacterial endotoxins test or for positive product control suitability. Confirm the limit against the monograph and the current USP <85> text. Values were last checked 2026-10-31.