Bacterial Endotoxins

Q4B Annex 14 Bacterial Endotoxins Test

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Q4B Annex 14 Bacterial Endotoxins Test: General Chapter

1. Introduction: Bacterial Endotoxins Test

Bacterial Endotoxins Test: This annex is the outcome of the Q4B process, which pertains to the Bacterial Endotoxins Test General Chapter. The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG), which is a global body composed of the major pharmacopoeias from the United States (USP), European Union (Ph. Eur.), Japan (JP), and other regions. The focus of this document is to establish guidelines and standards for bacterial endotoxins testing, which is essential in ensuring the safety and quality of pharmaceutical products.

2. Q4B Outcome

2.1 Analytical Procedures

Following an evaluation by the Q4B Expert Working Group (EWG), the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Steering Committee has recommended that the analytical procedures described in the official pharmacopoeial texts for the Bacterial Endotoxins Test can be used interchangeably within the ICH regions, provided the conditions outlined in this annex are met. The relevant pharmacopoeial texts are:

  • Ph. Eur. 2.6.14. Bacterial Endotoxins Test
  • JP 4.01 Bacterial Endotoxins Test
  • USP General Chapter <85> Bacterial Endotoxins Test

The conditions for interchangeability are as follows:

2.1.1 Test Method Selection

Any of the three methodologies described in the above pharmacopoeial references can be employed for endotoxins testing. However, in cases of doubt or disputes about test results, the gel-clot limit test should be used as the final method for determining compliance. This test is often considered the gold standard when uncertainties arise with alternative techniques.

2.1.2 Interchangeability of Reference Standards

The reference standards used in the pharmacopoeias of the USP, JP, and Ph. Eur. are deemed interchangeable. These standards have been appropriately calibrated against the World Health Organization (WHO) International Standard for Endotoxin. As such, they can be used across different regions without the need for separate calibration efforts, ensuring consistency and accuracy in endotoxins testing worldwide.

2.1.3 Photometric Quantitative Techniques

For procedures utilizing photometric techniques, preparatory testing is essential. In the section on “Photometric Quantitative Techniques,” users should perform the test on at least two replicates of solutions A, B, C, and D. The testing should follow the optimal conditions recommended by the lysate manufacturer to ensure the accuracy of results. It is essential to minimize the potential for interfering factors that could distort test outcomes. This preparatory step is a critical element in guaranteeing the reliability of the endotoxins test.

2.2 Acceptance Criteria

The texts reviewed did not specify explicit acceptance criteria for endotoxin levels. Instead, the limits for endotoxins should be outlined in the application dossier for the product unless otherwise stated in an individual monograph. This means that manufacturers should ensure they adhere to the specified endotoxin limits as provided in their product dossiers, or as otherwise defined in specific monographs that apply to their product. These limits are crucial in ensuring the safety and compliance of pharmaceutical products.

3. Timing of Annex Implementation

The annex’s incorporation into the regulatory process at ICH Step 5 will trigger its official implementation in the respective regions. The timing of this implementation will vary between regions. For instance, some countries may adopt the annex sooner than others, depending on their regulatory and procedural timelines. As such, companies and regulatory bodies must stay informed about when the annex becomes applicable in their jurisdiction to ensure full compliance with the updated guidelines.

4. Considerations for Implementation

4.1 General Considerations

Manufacturers and sponsors who modify their existing testing methods to align with the Q4B-evaluated pharmacopoeial texts referenced in Section 2.1 must follow the appropriate regional regulatory processes for such changes. This includes adhering to any required notifications, variations, or prior approval procedures, depending on the regulatory framework of the region. It is essential that any changes to methods or testing procedures comply with the specific requirements set by the relevant health authorities to ensure continued product safety and regulatory compliance.

4.2 FDA Consideration

In the United States, the Food and Drug Administration (FDA) may request that companies demonstrate that the chosen testing method is acceptable and suitable for a particular product. This is true even if the method comes from a pharmacopoeia different from the USP. While the texts referenced in Section 2.1 can be considered interchangeable, the FDA may still require additional verification to ensure that the endotoxins testing method is appropriate for the material or product being tested.

4.3 EU Consideration

For the European Union, regulatory authorities can accept references in a marketing authorization application, renewal, or variation application. This is true if the application cites the use of a text from another pharmacopoeia (as referenced in Section 2.1) and fulfills the conditions set out in this annex. This approach allows companies to meet the requirements for compliance with the European Pharmacopoeia Chapter 2.6.14 on the Bacterial Endotoxins Test, based on the declaration of interchangeability provided in this document.

4.4 MHLW Consideration

In Japan, the pharmacopoeial texts referenced in Section 2.1 of this annex can also be used interchangeably, in accordance with the conditions specified in this annex. The Ministry of Health, Labour and Welfare (MHLW) will issue a notification outlining the specific implementation requirements when this annex becomes effective. Companies and manufacturers should remain attentive to these notifications to ensure that they are fully compliant with the regulatory expectations of the MHLW.

4.5 Health Canada Consideration

In Canada, the regulatory authorities will accept the use of any of the pharmacopoeial texts mentioned in Section 2.1 as interchangeable, provided that the conditions set forth in this annex are followed. This ensures that manufacturers can use either the USP, JP, or Ph. Eur. methods for endotoxins testing without the need for separate approvals, streamlining the regulatory process and enhancing global harmonization in the testing of endotoxins.

5. References Used for the Q4B Evaluation

The Q4B evaluation of the Bacterial Endotoxins Test was informed by several key references, which helped shape the conclusions and recommendations in this annex:

5.1 The PDG Stage 5B Sign-off Document

This document (Rev. 1 – Correction 1) was released by the Japanese Pharmacopoeial Forum in December 2009 (Volume 18, Number 4), and it played a crucial role in informing the Q4B evaluation. The document outlined the procedural steps taken by the Pharmacopoeial Discussion Group to assess the various methodologies used for bacterial endotoxins testing and facilitated the agreement on their interchangeability.

5.2 Pharmacopoeial References for the Bacterial Endotoxins Test

The pharmacopoeial texts referenced in this annex were used to assess the methods for bacterial endotoxins testing and to establish the criteria for their interchangeability. These references include:

  • European Pharmacopoeia (Ph. Eur.): Supplement 6.6 (official as of January 1, 2010), which includes the Bacterial Endotoxins Test (reference 01/2010:20614).
  • Japanese Pharmacopoeia (JP): General Test 4.01 Bacterial Endotoxins Test, as published in the Sixteenth Edition of the JP on March 24, 2011, under The Ministry of Health, Labour, and Welfare Ministerial Notification No. 65.
  • United States Pharmacopeia (USP): General Chapter <85> Bacterial Endotoxins Test, which outlines the procedures and criteria for conducting endotoxins testing in accordance with USP standards.

These pharmacopoeial references provided the foundational basis for the Q4B evaluation, ensuring that the recommendations made in the annex are grounded in established global standards for endotoxins testing.

In conclusion, the Q4B Annex 14 on the Bacterial Endotoxins Test provides a harmonized approach for conducting endotoxins testing across different regions. By enabling the interchangeability of the testing methods and reference standards from the USP, JP, and Ph. Eur., this annex helps simplify regulatory procedures, reduce barriers to trade, and ensure the consistent quality of pharmaceutical products worldwide. However, manufacturers must ensure that any modifications to testing methods align with regional regulatory requirements to maintain compliance with local laws and regulations.