Endotoxin testing – European Pharmacopeia changes

A proposal has been made to amend the European Pharmacopeia chapter on guidance for the bacterial endotoxin test – chapter 5.1.10.

The proposed changes are:

In the context of the new bacterial endotoxins Ph. Eur. policy, a new section (2-4) includes aspects to be considered when establishing an endotoxin limit for a specific substance or product; also, reference is made to the fact that an endotoxin limit is not always provided in a specific monograph.

– Reference is made to general chapter 2.6.30. Monocyte-activation test as an alternative to the rabbit pyrogen test, and a recommendation is given to perform a risk assessment when using the bacterial endotoxin test as a pyrogenicity test, due to the potential for contamination by non-endotoxin pyrogens. In this respect, the previous section 11 concerning the replacement of the rabbit pyrogen test by a test for bacterial endotoxins is substituted with a new text in agreement with a strategy to be applied for testing of bacterial endotoxins or non-endotoxin pyrogens. A distinction is made between replacement methods already described in the Ph. Eur. and other alternative methods.

– In the context of the 3R’s, a test for bacterial endotoxins or a monocyte-activation test is preferred to the rabbit pyrogen test. Therefore, implementation of the rabbit pyrogen test has to be justified and authorised and is appropriate only when the bacterial endotoxin test or the monocyte-activation test cannot be validated.

– Reference is made to the use of alternative reagents to the Limulus amoebocyte lysate, such as recombinant factor C: this practice avoids the use of endangered animal species and can be considered in the context of the use of an alternative method as described in the General Notices.

A number of additional specific revisions have been made.

– In line with current knowledge, Method A is no longer declared as the reference method, and all methods A to F of general chapter 2.6.14. Bacterial endotoxins can be used. Where the method is stated in the monograph, the use of another method must be supported by evidence of validation.

–The expression ‘threshold endotoxin concentration’ has been replaced by the more appropriate expression ‘endotoxin limit concentration’ to harmonise with general chapter 2.6.30. Monocyte-activation test.

– A new entry has been included in Table 5.1.10.-1 for formulations administered per square metre of body surface.

Finally, the structure of the general chapter has been modified to improve its clarity.

The proposal has been added to Pharmeuropa 26.4.

Posted by Tim Sandle