2001-06-28-世界卫生组织-Report_on_WHO_Working_Group_on_Biological_Standardization_of_Unfractionated_Heparin_Sept_1999_9页_34kb

WHO Working Group on Biological Standardization of Unfractionated Heparin (1999 Geneva)

1. Introduction

• Recap of the previous consultation held in Geneva (June 1998).
• Working Group's remit: Seek a strategy to achieve a global method for measuring unfractionated heparin biological activity, based on a single unit, to promote global harmonization.
• Three major discussion points agreed upon:
  1. Harmonization of international reference preparations considering current heparin characteristics (specific activity).
  2. Agreement on a method to measure in vitro anticoagulant activity for potency estimation.
  3. Assessing potential clinical impact on potency labeling and regulatory implications.
• Proposal to also urgently discuss the replacement of the 1st International Standard for Low Molecular Weight (LMW) Heparin, approved unanimously.
• Timeframe established (Sept-June 2000) for a collaborative study to test a proposed global anti-IIa chromogenic assay and potentially develop a new USP reference preparation.

2. Measurement of Heparin Biological Activity (Collaborative Study Findings)

• Current USP and EP standards showed discrepant results when tested against the proposed 5th International Standard (IS) for unfractionated heparin using all methods.
• When tested against previous standards/IS, method comparisons showed better agreement, particularly with the anti-IIa chromogenic assay (Thrombin Inhibition).
• The current generation of heparin products (high specific activity) showed better potency agreement when calibrated against a reference material with similar properties.
• The USP method's reliance on sheep plasma derived substrates limits its reliability and is recognized as needing update by USP. The anti-IIa method was proposed as a more robust alternative.

3. Proposals for New/Alternative Methodology (Focus on Chromogenic Assays)

• Chromogenic anti-IIa assays (based on EP LMW method) were proposed as a standard method.
• Replacing the USP biological assay with a standardized chromogenic anti-IIa method was discussed.
• ECBS consult (WHO/V&B) needed the opinion that potencies based on one agreed assay method (the anti-IIa) are acceptable.
• Concerns were raised by ECBS regarding regulatory acceptance of changing labeling based on one method.

4. Strategy for Harmonization & New Reference Material

• Agreement: Strong support for the single global assay method, likely the anti-IIa chromogenic assay.
• Need: More data on method performance (robustness tested across different product types and labs).
• Plan: Collaborative study involving:
  • Materials: Candidates for new USP reference, 5th IS, EP reference, current USP Lot K4, low-specific-activity heparin, suspected low-quality heparin.
  • Methods: Proposed global anti-IIa, EP's anti-IIa, USP's anti-Xa, in-house anti-IIa/anti-Xa methods, current USP method.
  • Timeline: Sept 1999 - listed dates for study coordination, protocol generation, recruitment, operation, analysis, reporting, and WG meeting by 2001.
• WHO Secretariat Task: Push for inclusion of the proposed new global method in the revised European Pharmacopoeia monograph for unfractionated heparin.

5. Low Molecular Weight Heparin (LMWH) Standardization

• Current 1st IS for LMWH needs replacement.
• General consensus: One single international standard is likely sufficient, given similar anticoagulant activity in commercial products (validated by EP study). Evidence: Existing LMWHs compared well without a separate standard for anti-Xa/IIa activity.
• However, a pilot collaborative study using anti-IIa/anti-Xa methods is needed to confirm comparability before selecting candidates for the main study needed to replace the LMWH IS. A slight shortage of the current LMWH IS was anticipated.

6. Dissemination

• Meetings: SSC ISTH Maastricht (June 2000), ECBS (Oct 2000, Oct 1999).
• Involvement: FDA (Dr Talarico) to be kept informed by Padilla and Murano.

### Appendix: Report Drafting Group
* Dr Trevor W. Barrowcliffe
* Dr Kristian Johansen (Chair)
* Dr E. Charton
* Dr Elaine Gray (Rapporteur)