2023-07-16-世界卫生组织-WHO_BS_2023.2462_WHO_6th_International_Standard_for_FSH_LH_26页_403kb

Summary of the Proposed 6th WHO International Standard for Human Urinary Follicle-Stimulating Hormone and Luteinising Hormone (FSH/LH)

Core Content

This document outlines the proposal to establish the 6th WHO International Standard for human urinary Follicle-Stimulating Hormone (FSH) and Luteinising Hormone (LH), designated as NIBSC code 21/344. The standard is intended to replace the current 5th International Standard (IS), NIBSC code 10/286, which is nearing exhaustion.

The candidate IS, 21/344, was prepared by Instituto Massone and filled into ampoules following WHO-recommended procedures. It was evaluated in an international collaborative study involving six laboratories across six countries. The study aimed to assess the potency of the candidate IS relative to the current IS, determine its suitability as a replacement, and evaluate its long-term stability.

Main Points

1. Potency Assignment

• A total of 34 assays were performed for FSH and 32 assays for LH.
• LH data from Lab 2 were excluded due to outlier results.
• The geometric mean potency of 21/344 for FSH was 177 IU/ampoule (95% confidence limits: 163–192 IU/ampoule; GCV: 8%).
• The geometric mean potency of 21/344 for LH was 170 IU/ampoule (95% confidence limits: 163–178 IU/ampoule; GCV: 4%).
• Potency estimates were calculated using a parallel-lines model comparing $\log_{10}$ (organ weight) as assay response to log concentration, with the exception of Lab 6, which used linear data.

2. Stability Assessment

• An accelerated thermal degradation (ATD) study was conducted to predict long-term stability.
• Samples were stored at +37°C and +45°C for 7 months and then assayed for FSH and LH potency.
• No significant loss of activity was observed in samples stored at elevated temperatures.
• The data could not be fitted to the Arrhenius equation, making it impossible to predict annual potency loss.
• Based on the stability of previous ISs and the current findings, the candidate IS is expected to be stable at -20°C.

3. Collaborative Study Design

• Six laboratories from Argentina, Germany, Italy, Switzerland, the United Kingdom, and the United States participated.
• Each laboratory was asked to perform in vivo bioassays using fresh ampoules and at least two independent assays.
• The study included coded duplicate samples (A and E) for the candidate IS and ATD samples (B and C).
• The results showed very good agreement among laboratories, with inter-laboratory GCVs of 8% for FSH and 4% for LH.

Key Information

• The candidate IS was prepared from a bulk material donated by Instituto Massone with reported bioactivities of 3012 IU/mg FSH and 2855 IU/mg LH.
• The ampoules were filled with 0.2% w/v human plasma albumin and 0.5% w/v lactose.
• The preparation was lyophilized and sealed under nitrogen to ensure stability.
• The candidate IS was found to be negative for HIV, HBsAg, HCV, CMV, BKV, and HPV by PCR testing.
• The geometric mean potency of the candidate IS is 177 IU FSH and 170 IU LH per ampoule.
• The candidate IS is proposed to be established as the 6th International Standard for human urinary FSH and LH for bioassay.

Conclusion

The results of the collaborative study confirm that the candidate IS, 21/344, is suitable and stable for use as the 6th WHO International Standard for human urinary FSH and LH. It is proposed that this preparation be officially designated as the new standard to ensure the continuity of potency measurements for therapeutic FSH/LH products.

Proposal

The candidate preparation of ampoules coded 21/344 is proposed to be established as the 6th International Standard for human urinary FSH and LH, with an assigned content of:

• 177 IU FSH per ampoule
• 170 IU LH per ampoule

Acknowledgements

• Contributions from all collaborative study participants are acknowledged.
• The Biological Service Division at NIBSC performed the bioassays.
• Dr. Claudio Wolfenson from Instituto Massone donated the bulk FSH/LH material.
• The Standardisation Science Group and Standards Processing Division at NIBSC supported the preparation and dispatch of the ampouled material.

Comments from Participants

• Responses were received from Labs 1, 2, 4, and 5.
• Participants agreed with the findings of the report.
• Minor spelling corrections were implemented as requested.

References

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