Calculating the Endotoxin Load in Compounded Sterile Preparations

The purpose of this article is to provide a method for calculating the endotoxin load in compounded sterile preparations. Materials required include the current United States Pharmacopeia–National Formulary (USP–NF) or endotoxin limit table, and a calculator for the equations.¹ The equation to be used is:

EL = K/M
where EL = Endotoxin Limit
K = the threshold human pyrogenic dose of endotoxin per kilogram (kg) of body weight per hour, and
M = the maximum recommended human dose/kg of body weight that would be administered in a single one-hour period.

The K value is 5.0 EU/kg for parenteral drugs (except those administered intrathecally) and 0.2 EU/kg for the intrathecal route of administration. The following procedure can be followed prior to the compounding of sterile preparations.

The steps in the procedure are as follows:

1. Multiply the weight of the patient (in kgs) times the allowable endotoxin units (EU) per kg [EU/kg] to obtain the endotoxin limit per hour for nonintrathecal and intrathecal medication delivery.¹

   Examples:
   
   5.0 EU/kg × Patient Weight (kg) = Endotoxin Limit per hour (Nonintrathecal)
   
   or
   
   0.2 EU/kg × Patient Weight (kg) = Endotoxin Limit per hour (Intrathecal)

2. Obtain the required information for the calculations from the USP–NF or a current endotoxin limit table.
3. Determine the final volume of the preparation.
4. Input the information on the Endotoxin Limit Worksheet provided herein.
5. Determine the final endotoxin load.
6. Consider the route of administration and determine if the calculated value exceeds the value in Step 1.
7. If the calculated value does not exceed the value in Step 1, the compound may be prepared.
8. If the calculated value exceeds the value in Step 1, check with the prescriber.
9. If the laboratory-tested result is less than the value in Step 1, the preparation may be dispensed/administered.
10. If the laboratory-tested result is greater than the value in Step 1, the preparation should be discarded.

Let's look at an example problem.

1. A 158-lb patient is to receive an intrathecal infusion of morphine sulfate at a rate of 0.3 mg/hr. The solution will be prepared by diluting Infumorph 200 with 0.9% sodium chloride injection to produce an infusion rate of 2 mL/hr.
   1. Infumorph 200 is preservative-free morphine sulfate 10 mg/mL in 20-mL ampules. How much Infumorph 200 and 0.9% sodium chloride injection should be used to prepare a 24-hour infusion?

      0.3 mg/hr × 24 hrs = 7.2 mg morphine sulfate
      7.2 mg × 1 mL/10 mg = 0.72 mL Infumorph 200
      
      2 mL/hr × 24 hrs = 48 mL total volume
      48 mL - 0.72 mL = 47.28 mL 0.9% sodium chloride injection

   2. What is the endotoxin load for this preparation?

      The USP specifies a limit of 14.29 USP EUs per milligram of morphine sulfate in solutions for intrathecal use, and a limit of 0.5 endotoxin units per milliliter for solutions containing 0.5 to 0.9% sodium chloride.¹

      7.2 mg × 14.29 EU/mg = 102.89 EU from morphine sulfate
      47.28 mL × 0.5 EU/mL = 23.64 EU from 0.9% sodium chloride injection

      Endotoxin load = 102.89 EU + 23.64 EU = 126.53 EU

      126.53 EU/24 hrs = 5.27 EU/hr

   3. Does this limit exceed the allowable endotoxin limit for an intrathecal injection for this patient?

      The maximum amount of endotoxin in a solution for intrathecal administration is 0.2 EU/kg/hr.²

      Allowable limit: 0.2 EU/kg/hr × 1 kg/2.2 lbs × 158 lbs = 14.36 EU/hr

      The endotoxin load in the preparation does not exceed the allowable limit.

NOTE: Appreciation is extended to Shelly Stockton, PhD, for her calculation example.²

TOTAL

Total Endotoxin Contribution /Total Volume = EU/mL
____________________/_________ = ____________

EU/mL/24 hours = Endotoxin Limit/hour
______ /______ = _____________

References

1. Allen LV Jr. Quality-Control Analytical Methods: Allowable Endotoxin Levels in Sterile Preparations. IJPC 2004; 8(6): 479-485.
2. Stockton SJ. Calculations. IJPC 2004; 8(6): 468.

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