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EL- Endotoxin Limit

Endotoxin is highly potent and ubiquitous in nature, and perhaps it is


impossible to render some materials completely endotoxin free. Therefore it is
necessary to assign an allowable EL (safe amount of endotoxin) for a health
care product that is below the threshold dose of endotoxin pyrogenicity.

The K/M formula was presented in the FDA LAL-Test guideline (1987) as a
way to calculate the endotoxin limit as shown below:

K(tolerance limit)
Endotoxin Limit (EL) =
M (maximum dose/kg/hour)

The EL represents the maximum safe amount of endotoxin that is allowed in a


dose of a specific drug. The tolerance limit varies with the type of parenteral
product and route of their administration as summarised in the table below.
Product specific endotoxin limits can be found in individual pharmacopoeial
monographs.

Endotoxin Tolerance or Allowable Limit by Parenteral Products


Parenteral Type Endotoxin Tolerance Limit (K)
Human, or Veterinary drugs and biologics 5 EU/kg
Parenterals by intrathecal injection 0.2 EU/kg
Radiopharmaceuticals 175 EU/V*
Intrathecal radiopharmaceuticals 14 EU/V*
Large Volume Parenterals 0.5 EU/mL
Water for injection (WFI) 0.25 EU/mL
Medical devices by extraction 0.5 EU/mL **(up to 20 EU/device)
Medical devices by intrathecal spaces 0.06 EU/mL (up to 2.15 EU/device)
*Maximum dose in volume, by mL.
** Limit when a 40 mL extract per device is utilised

EXAMPLE

To calculate the endotoxin limit (EL) of a parenteral drug with a dosage (M) of
1.40 mL per kg per hour.

For a Parenteral drug K = 5 EU/kg


Average weight per person = 70 Kg

K 5 EU/kg 350 EU
EL (Endotoxin Limit) = = or
M M dosage
Product: A (injection)
Maximum Dose/kg (M): 1.40 mL/kg

K 5 EU/kg
EL (Endotoxin Limit) = = = 3.57 EU/mL
M 1.40 mL/kg

Or

K 350 EU
EL (Endotoxin Limit) = = = 3.57 EU/mL
M 98.0 mL

Minimum Valid Concentration (MVC)

The MVC is used to determine the lowest concentration of sample that can be
tested while still being able to detect the required endotoxin limit. It is used
when the EL is listed in units, other than mL.

(λ )(M) λ
MVC = or MVC = EL
K

• Example 1

(a) Drug administered on a weight-per-kilogram basis with no published EL.

Product: A (injection)
Potency: 20 mg/mL
Maximum Dose/kg (M): 30 mg/kg
Lysate sensitivity (λ ): 0.0625 EU/mL

(λ )(M) 0.0625 EU/mL X 30 mg/kg


MVC = = = 0.375 mg/mL
K 5.0 EU/kg

• Example 2

(b) Drug administered on a weight-per-kilogram basis with published EL.

Product: B (injection)
Endotoxin Limit: 0.20 EU/mg
Lysate sensitivity (λ ): 0.05 EU/mL

(λ ) 0.05 EU/mL
MVC = = = 0.25 mg/mL
EL 0.20 EU/mg
Maximum Valid Dilution (MVD)

The MVD calculation is used to determine how much a parenteral product or


test material can be diluted while still being able to detect the required
endotoxin limit. It is used when the EL is listed in EU/mL

Two methods of calculating the MVD can be used (all examples given are for
a non-intrathecal parenteral drug and appropriate values have been utilised).

Method 1

This method is used when an official Pharmacopoeia endotoxin limit is used.

For drugs administered on a weight-per-kilogram basis, the potency is expressed as mg or

units/mL and for drugs administered on a volume-per-kilogram basis, the potency is equal to

1.0 mL/mL.

(EL)(product potency)
MVD =
λ

Method 1 Examples

(a) Endotoxin Limit Expressed by mg or units/mL

Product: A (Injection)
Potency: 20 mg/mL
Lysate Sensitivity (λ ): 0.0625 EU/mL
Endotoxin limit: 0.17 EU/mg

0.17 EU/mg X 20 mg/mL 3.4


MVD = = = 1:54.4 or 1:54
0.0625 EU/mL 0.0625

(b) Endotoxin Limit Expressed by Volume

Product: B (5% by Injection)


Lysate Sensitivity (λ ): 0.05 EU/mL
Endotoxin limit: 0.5 EU/mL

0.5 EU/mL X 1 mL/mL 0.5


MVD = = = 1:10
0.05 EU/mL 0.05
Method 2

This method is used when no official endotoxin limit provided. It has two
steps.

Step 1: Calculate MVC

(λ )(M) λ
MVC = or MVC = EL
K

Step 2: Use calculated MVC and apply in following formula below;

Product potency
MVD =
MVC

Method 2 Examples

(c) Drug administered on a weight-per-kilogram basis.

Product: A (injectable)
Potency: 20 mg/ml
Maximum Dose/kg (M): 30 mg/kg
Lysate sensitivity (λ ): 0.0625 EU/ml

Step 1

(λ )(M) 0.0625 EU/mL X 30 mg/kg


MVC = = = 0.375 mg/mL
K 5.0 EU/kg

Step 2

Product potency 20mg/mL


MVD = = = 1:53.3 or 1:53
MVC 0.375 mg/mL

(d) Drug Administered on a volume-per-kilogram basis

Product: B (5% by Injection)


Maximum dose/kg (M): 10.0 mL/kg
Lysate Sensitivity (λ ): 0.05 EU/mL
Step 1

(λ )(M) 0.05 EU/mL X 10.0 mL/kg


MVC = = = 0.10 mL/mL
K 5.0 EU/kg

Step 2

Product potency 1.0 mL/mL


MVD = = = 1:10
MVC 0.1 mL/mL