Endotoxin Limits
Technical Services Department
Calendar
pfiJLAL
UPDATE®
Volume 13, No.2 June 1995
o 1995, Associates of Cape Cod, Inc., Woods Hole, Massachusetts All rights reserved
once, which is a common occurrence. issue of the LAL UPDATE® first divide it by 70 kg to give the dose
Fortunately, most drug products and Generally, the aim of testing is to per kg. Then divide K (5 EU/kg, 0.2
solutions contain considerably less insure that the sample under test EU/kg, 194 EU/m 2 or 175 EU) by M
endotoxin than the allowable limit. could not deliver more than 5 (or 0.2) (or V) to give the endotoxin limit per
Many manufacturers set specifica- EU/kg/hr of endotoxin to a patient. unit weight/volumelinternational
tions that are tighter than the required Thus, the endotoxin limit for a unit, etc.
limit. specific product depends on the
The calculation of endotoxin maximum dose of product that a Examples:
limits for injectable drugs adminis- patient might receive. The smaller
the dose of the product per kg, the Calculation of the endotoxin limit
tered per square meter is based on the for a non-intrathecal, injectable
assumption that a typical adult has a higher the endotoxin limit per unit drug product:
surface area of 1.8 square meters. dose of the product.
For drugs with a dose expressed per This discussion of limits only Product A has a maximum human
kg, the whole body limit is 350 ED. applies to release testing of finished (whole body) dose of 1.0 g
Thus, the endotoxin limit per square products. However, endotoxin limits
may be set for raw materials and in- Dose per kg =
meter is 350 EU/1.8 m 2= 194EU/m2 .Ls, = 0.0143 g/kg = 14.3 mg/kg
This is an absolute and is equivalent process samples. 70 kg
to a value of 5 EU/kg for K for
products administered per kg. To Determining the Endotoxin Limit
Endotoxin limit =
calculate the endotoxin limit of a ofa Product K = 5 ED/kg = 0.35 ED/mg
product with a dose expressed per M 14.3 mg/kg
square meter, divide 194 EU/ m? by The first step is to look up the
the dose to give an endotoxin limit per product in the FDA Guideline to see Use the concentration of the product
unit of product. if an endotoxin limit is listed in the (potency in final product) to convert
Endotoxin limits for radio- Appendix E. (The most recent the endotoxin limit into EU/m!.
pharmaceuticals are addressed in a revision to Appendix E at this time is Thus, using the example above, if
footnote at the end of Appendix E to dated July, 1994). If the product is the concentration of product in the
the FDA Guideline on the LAL Test listed, check that the maximum dose (presentation) container is 100 mg/
(3). For these productsK = 175 (EU)/ of the product is correct for your ml, or if bulk product is dissolved to
V (or 14(EU)N for intrathecals), product. If the dose is greater than give 100 mg/m!:
where V is the maximum (whole that given in the table, calculate the
limit as described below. It is a good Endotoxin limit =
body) dose in ml at expiration of the
0.35 EU/mg x 100 mg/ml = 35 ED/ml
product. The units (the EU given in idea to calculate the limit as described
parentheses) are not specified in the below anyway. There have been
Convert the limit to EU/ml
Guideline but must be included if the mistakes in the Appendix in the past.
because these are the units of the
units are to be expressed in EU/m!. The 1987 Guideline states that the
endotoxin standards in the LAL test
The USP limit for large volume dose used should be the rabbit dose
(as well as the limits for the sensitivity
parenterals (LVPs) is 0.5 EU/ml and (as used in the USP Pyrogen Test) or
of an LAL gel-clot reagent). This
is derived from a rabbit dose of 10 ml/ the maximum human dose, which- gives an endotoxin limit for the
kg for Pyrogen tests. A typical LVP ever is greater. Since 1987, the USP product so that it can be determined
administered at 700 ml/hr also gives a has used only human doses to whether the product passes or fails at
limit of 0.5 EU/m!. The USP calculate endotoxin limits and the that limit. It is important to note that
endotoxin limit for WFI and SWFI is FD A has incorporated this into their the limit in EU/ml only applies to the
0.25 EU/m!. For medical devices, more recent revisions of Appendix E. stated concentration ofproduct. Ifthe
the USP limit is 20 EU/device, and The term M is used for the maximum concentration changes, the limit
2.15 EU/device for devices that dose. changes.
contact the cerebrospinal fluid. The When calculating the limit for The limits calculated above are
endotoxin limits for devices were drug products, if the dose is the maximum allowed. It may be
discussed in the September 1994 expressed for whole (adult) body, decided that tighter limits are
References: