2006-12-31-世界卫生组织-Requirements_for_Rabies_Vaccine_for_Human_use,_Annex_2,_TRS_No_658_42页_1mb

Summary of Annex 2: Requirements for Rabies Vaccine for Human Use

Core Content

This document outlines the international requirements for rabies vaccines for human use, revised in 1980. It serves as a guideline for the manufacturing, control, and national regulation of rabies vaccines, with a focus on ensuring safety, potency, and consistency across different production methods.

The document is structured into three main parts:

• Part A: Manufacturing Requirements
• Part B: National Control Requirements
• Part C: Requirements for Human Diploid Cells used for Virus Vaccine Production

It also includes definitions, terminology, and a reference protocol for vaccine production and testing.

Main Requirements and Key Points

1. General Considerations

• Rabies vaccines currently used are derived from animal neural tissue, duck embryos, or cell cultures.
• Inactivated vaccines are the focus, as per the WHO Expert Committee on Rabies.
• The Pasteur strain of rabies virus, maintained in rabbits, is the preferred "fixed" strain for vaccine production.
• Duck embryo vaccines are safer than neural tissue vaccines, with a lower risk of central nervous system involvement (1 in 11,000 doses vs. 1 in 2000 doses).
• Potency testing is crucial and should be based on the virus dilution rather than tissue content, especially for purified or cell culture vaccines.
• Interferon or interferon inducers may enhance vaccine effectiveness in post-exposure treatment.
• Allergic encephalomyelitis tests are not included due to lack of reliable methods, but ongoing research is encouraged.
• Adventitious agents must be avoided, and national control authorities are responsible for ensuring vaccine safety.

2. Definitions and Terminology

• International name: Vaccinum rabiei (ad usum humanum)
• Proper name: Equivalent in the language of the country of origin
• Master seed lot: Uniform virus quantity used for vaccine or working seed lots
• Working seed lot: No more than 5 passages from the master seed lot
• Single viral harvest: Virus collected from a single source (animal, egg, or cell culture) at the same time
• Bulk material: A pool of inactivated single harvests before final preparation
• Final bulk: The finished biological preparation used for filling
• Filling lot: A group of sealed containers filled from the same final bulk
• TCID₅₀: Tissue culture infective dose 50%
• LD₅₀: Mouse lethal dose 50%

3. Manufacturing Requirements

• Facility standards: Follow the general requirements for biological substances (see WHO Requirements No. 1).
• Staff requirements: Personnel involved in vaccine production must be healthy, rabies-immunized, and have antibody titres ≥0.5 IU/ml.
• Use of approved substrates: Only approved cell cultures, embryonated eggs, and healthy animals can be used for vaccine production.
• Animal sources:
  • Rabbits (preferably suckling), sheep, goats, mice, and rats are commonly used.
  • Animals must be free from infectious agents and regularly monitored.
• Embryonated duck eggs: Must come from healthy flocks free from Salmonella, Mycobacterium avium, and other pathogens.
• Cell cultures:
  • Must be derived from healthy animals.
  • Approved cell lines include fetal bovine kidney, dog kidney, and hamster kidney.
  • Cell cultures must be free from adventitious agents and tested for safety.
• Virus seed lot system: A master seed lot is used as the basis for all vaccine production, with working seed lots not more than 5 passages away.
• Virus testing: Seed lots must be tested for:
  • Bacterial, fungal, and mycoplasmal contamination
  • Virus content (via mouse intracerebral inoculation)
  • Adventitious agents (tested in suckling and adult mice)

4. National Control Requirements

• Release and certification of vaccines must be conducted by national control authorities.
• Any modifications to manufacturing requirements must be approved by the national control authority to ensure safety and potency are not compromised.
• The WHO must be informed of any changes to national requirements.

Key Information

• International Reference Preparation (IRP): Has an activity of 10 IU per ampoule, stored in freeze-dried form.
• International Standard for Anti-Rabies Serum: Contains 86.6 IU, used for potency testing of antirabies immunoglobulin.
• Testing protocols:
  • Suckling mice are used for testing adventitious agents and virus activity.
  • Adult mice are used for more comprehensive testing.
  • Minimum requirements: At least 80% of mice must remain healthy after testing.
• Safety considerations:
  • Neural tissue vaccines are effective but carry higher risks.
  • Cell culture vaccines are safer and increasingly used for pre-exposure immunization.
  • Dilution of vaccine should not be done to the minimum potency level, as this may reduce effectiveness.

Conclusion

This document provides a comprehensive framework for the manufacturing, control, and testing of rabies vaccines for human use. It emphasizes the importance of safety, potency, and consistency, while acknowledging the evolving nature of vaccine production methods. The use of approved substrates, strict testing protocols, and national oversight are essential to ensuring the quality and efficacy of rabies vaccines.