EDQM revises 5.1.10. Guidelines for using the Test for Bacterial Endotoxins

In September, the European Directorate for the Quality of Medicines & HealthCare (EDQM) published in Pharmeuropa online the information about their  new policy for bacterial Endotoxins, which was approved by the Ph. Eur. Commission at its 149th Session in June 2014. Amongst others they announced for existing monographs:

"BET specifications are kept in individual monographs for substances for pharmaceutical use. Existing limits remain in individual monographs to maintain the use of well-established limits.

In order for the policy to be applied, the following changes are proposed to existing Ph. Eur. texts:

  • General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits.
  • General monograph Substances for pharmaceutical use"

In consequence it is up to the users of these EP chapters to determine whether compliance to BET is needed or not for a given substance. Where a test is included in the monograph with no specific limit, it is up to the user to set the limit for the substance, based on the following considerations: use of the substance (route of administration, patient population); calculation according to the formula given in general chapter 5.1.10; process capability; or any other considerations raised by the competent authority.

Recently, on 26 September, a revision of Chapter "5.1.10. Guidelines for Using the Test for Bacterial Endotoxins" was issued and open for comments until 31 December 2014. The revision now includes possible alternative methods to the Limulus amoebocyte lysate (LAL) test, like testing with recombinant factor C.

Following a short overview of the additions and changes:

  • "The monocyte-activation test (2.6.30) is a suitable method to be used to rule out the presence of non-endotoxin pyrogens in substances or products."
  • "Hence, the analyst who wishes to implement a test for bacterial endotoxins or to replace the pyrogen test by a test for bacterial endotoxins has to demonstrate that a valid test can be carried out on the substance or product concerned; this may entail a procedure for removing interference"
  • "Replacement of the rabbit pyrogen test required in a pharmacopoeial monograph by an amoebocyte lysate test, or by other methods such as the monocyte-activation test or a test using recombinant factor C as a replacement for the amoebocyte lysate, constitutes the use of an alternative method of analysis and hence requires demonstration that the method is appropriate for the given substance or product and gives a result consistent with that obtained with the prescribed method as described in the General Notices"
  • The additions under paragraph 13. "Replacement of Methods prescribed in Monographs" are of particular importance. In section 2, you can find information about the replacement by methods not described in the PH.EUR:
  • "The use of alternative reagents such as recombinant factor C as a replacement to the amoebocyte lysate eliminates the use of live animals. Replacement of a rabbit pyrogen test or a bacterial endotoxin test prescribed in a monograph by a test using recombinant factor C or any other reagent as a replacement of the amoebocyte lysate is to be regarded as the use of an alternative method in the replacement of a pharmacopoeial test, as described in the General Notices: “The test and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative.”

The complete revision can be found in Pharmeuropa, Issue 26.4. The online version can be accessed at the website of EDQM. Access to the online version requires registration, but this is a free service.

Representatives of the European Authorities as well as of the FDA will present the current developments at the Endotoxin and Pyrogen Testing Conference on 19 and 20 November in Düsseldorf/Neuss, Germany.

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