2004-05-03-世界卫生组织-Discussion_on_WHO_requirements_for_Rabies_vaccine_for_human_use_14页_135kb

WHO Technical Report on Rabies Vaccine Requirements and Potency Assessment (2003)
Key Revisions:

1. Scope: Includes vaccines produced in cell lines (primary/continuous), excluding neural tissue vaccines, with updated recommendations for continuous cell line vaccines published in TRS 760 (1987).
2. Inactivation Process:
   • Inactivation must occur within 24 hours post-purification.
   • Total inactivation time validated via kinetics; must be at least double the complete inactivation period.
   • Kinetics tests to assess reproducibility.
3. Tests for Effective Inactivation:
   • Delete direct inoculation test due to inefficiency. Use only virus amplification test in cell cultures.
   • Sensitive cell lines (e.g., BHK-21, Vero) recommended for testing.
4. Potency Testing:
   • NIH mouse protection test retained as the gold standard for potency.
   • Single-dose potency test proposed for regulatory convenience.
   • In vitro assays (EIA, SRD) accepted as supplementary tools alongside NIH testing to monitor production consistency.
   • Reference materials and monoclonal antibodies standardized for cross-comparability.
5. Regulatory and Industry Alignment:
   • Harmonize requirements with EP and WHO guidelines per manufacturers' requests (e.g., harmonization of inactivation protocols).
   • Reduced reliance on accelerated stability testing (e.g., 37°C storage), with a focus on real-time stability validation.

Key Recommendations:

• Retain NIH test for efficacy but explore alternatives for regulatory efficiency.
• Incorporate EIA/SRD into quality control for batch release.
• Delete efficacy-only tests where data supports safety through inactivation validation.

Annexes:

• Annex 1: Participants include regulators (NIBSC, FDA), manufacturers (Chiron, Aventis Pasteur), and global health organizations.
• References: Includes WHO technical series (658, 760, 840), collaborative studies (Ferguson, Kumar, et al.), and journal articles on potency, antigenicity, and inactivation tests.

Major Controversies:

• Debate over NIH test irrelevance due to poor correlation with EIA results.
• Inactivation methods with diverging requirements between industry and regulators.
• Accelerated stability testing: Calls to eliminate due to redundancy, while emphasizing shelf life validation.