GMP News
22/10/2014

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

EDQM修订5.1.10“细菌内毒素测试方法使用指南”

In September, the European Directorate for the Quality of Medicines & HealthCare (EDQM) published in Pharmeuropa online the information about their  

Ph_Eur_policy_for_Pharmeuropa_E.pdf

在9月份，EDQM 在欧洲药典在线上公布了其细菌内毒素新政，该修订已被欧洲药典委员会2014年6月第149次会议通过。其中，他们宣布了对以下已有各论的修订：

"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.

“BET质量标准保留在原料药的单个各论中。现有限度保留在各论中以维持使用已建立的限度。”

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

为了应用该政策，对现有欧洲药典正文提议修订如下：

• General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits.
• 凡例5.1.10内容延伸包括对限度的设定考虑
• General monograph Substances for pharmaceutical use"
• 通论“药用物质”
  

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.

鉴于此，EP使用者可自行决定其原料药是否需要符合BET。如果在各论中已包括了该测试，但没有指定限度，则使用者自行决定根据以下考虑来制订原料药的限度：原料药的用途（给药途径、患者人群）、根据凡例5.1.10中给定的公式进行计算、工艺能力，或其它由相关药监机构提出的考虑要求。

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: 以下是对变更和增补内容的概览：

• "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."
• “单核细胞活化试验2.6.30适用于排除原料药或制剂中非内毒素热原的排除”
• "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"
• “因此，希望实施细菌内毒素试验，或希望采用细菌内毒素试验来代替热原试验的化验员必须要证明采用被测试的原料药或制剂可以进行有效的试验，这可能牵涉到去除干扰的步骤”
• "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"
• “采用变形细胞溶解物试验，或其它方法如单核细胞活化试验或使用重组因子C替代药典各论中所要求的家兔热原试验，建立替代方法的使用，从而要求证明该方法适用指定的物质或制剂，所给出的结果与凡例中要求的方法所获得的结果一致”
• 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:
• 在第13段下面增加了“替代各论中所述的方法”尤其重要。在第2部分，你可以找到关于采用非欧洲药典方法替代的信息。
• "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.”
• “使用替代性的试剂，例如，重组因子C替代变形细胞避免了使用活体动物。使用重组因子C试验代替各论中要求的家兔热原试验或细菌内毒素试验，或使用其它试验代替变形细胞试验将会被认为是凡例所述的采用可替代方法替代药典方法：药典中所述描述的方法是药典建立的标准正式方法。在药监当局同意的前提下，如果所用的方法可以得到明确的结论，证明如果采用官方方法时所测对象是否符合各论标准，则该方法可以用来替代药典方法达到控制目的”
  

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.

完整版本可以在欧洲药典论坛26.4中找到，在线版本可以通过EDQM官网获得。在线版本需要注册，但是免费的。

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.

欧洲药监机构的代表，以及FDA代表会在11月19-20日德国内毒素和热原测试会议上呈交各自的研究进展。