2006-12-31-世界卫生组织-Proposed_Requirements_for_Rift_Valley_Fever_Vaccine_Inactivated_for_Human_use,_Annex_4,_TRS_No_673_40页_1mb

Summary of Proposed Requirements for Rift Valley Fever (Inactivated) Vaccine for Human Use

Core Content

This document outlines the proposed requirements for the manufacturing, production control, and testing of inactivated Rift Valley Fever (RVF) vaccines for human use. These requirements are based on the Requirements for Biological Substances No. 32 and are structured into several parts, each addressing specific aspects of vaccine production and quality assurance.

Main Requirements and Key Points

1. Definitions

• International name: "Vaccinum febris Rift Valley inactivatum (ad usum humanum)".
• Proper name: Equivalent of the international name in the language of the country of origin.
• Virus seed lot: A quantity of virus processed together, with a maximum of 10 subcultures from the original seed lot.
• Cell seed: Frozen cells from normal tissue used to establish a manufacturer's working cell bank (MWCB).
• Single harvest: Virus suspension harvested from a single batch of cells.
• Single pool: Virus suspension processed at the same time.
• Purified and concentrated pool: Virus suspension or vaccine that has been purified and concentrated.
• Final bulk: The finished biological preparation in the container before filling.
• Filling lot (final lot): A collection of sealed final containers filled in one session from a single final bulk.

2. General Manufacturing Requirements

• Production areas: Must be decontaminated before use for RVF vaccine production.
• Staff requirements: Only healthy personnel, free from infectious diseases and immune to RVF, should handle the vaccine.
• Cell culture restrictions: Only approved cell cultures may be used in production.
• Quarantine for monkeys: Monkeys used for tissue collection must be quarantined for at least 6 weeks and monitored for health issues.
• Cell source: Monkeys used for tissue collection must not have been previously used for experimental purposes.
• Cell culture medium: Must be free from bacteria, fungi, and mycoplasma. Penicillin is prohibited, while other suitable antibiotics may be used at minimum concentrations.
• Serum concentration: If animal serum is used, its concentration in the final vaccine must not exceed 1 µl/l.

3. Production Control

3.1 Control of Source Materials

• Virus strains: Must be approved by the national control authority.
• Cell cultures: If using monkey cells, they must be from healthy, quarantined monkeys and tested for extraneous agents.
• Karyology: May be required in some countries.
• Tumorigenicity testing: If diploid cells are used, they must be tested for tumorigenicity.

3.2 Control Cells for Monkey Cell-Based Vaccines

• Control cell cultures: At least 1% of the cell suspension is used to prepare control cells.
• Testing for haemadsorbing viruses: 25% of control cells are tested using guinea-pig red cells. Additional red cell types may be used in some countries.
• Testing for simian herpesvirus (B virus): Using rabbit kidney cell cultures, with a control group.
• Testing for SV40 virus: Using Cercopithecus kidney cell cultures, with a control group.
• B virus detection: If detected, production must be halted and the national control authority must be informed.

3.3 Production Precautions

• Animal serum restrictions: If used, serum concentration must be minimized to not exceed 1 µl/l.
• Residual serum testing: Required in some countries to ensure no animal serum remains in the final product.

3.4 Control at the Single Harvests

• SV40 and extraneous agent testing: Each single pool is tested in Cercopithecus cell cultures.
• Rabbit testing: Each single pool is tested in 3 healthy rabbits (1.5–2.5 kg), with intradermal and subcutaneous inoculation.
• Inactivation preparation: Each pool must be filtered before inactivation, using a final 0.22 µm filter.
• Inactivation timing: Should be initiated within 72 hours of filtration, preferably within 24 hours.
• Inactivation method: Must be approved by the national control authority and shown to be effective.
• Inactivation verification: Two samples are tested for residual infectivity: one at the end of inactivation and one at 75% of the inactivation period.
• Inactivation record: Consistency must be demonstrated through 5 consecutive lots; if broken, 5 more lots must be tested.

3.5 Control of Bulk Products

• Final product testing: Includes identity, sterility, innocuity, potency, and protein nitrogen content.
• Storage and expiry: Must be stored under conditions approved by the national control authority and have an expiry date determined by such authority.

Additional Requirements

• Labeling and distribution: Must comply with national regulations.
• Record-keeping: All steps and test results must be documented.
• Sample testing: Samples must be taken at various stages of production for testing.
• Reporting protocol: A standardized protocol for reporting test results is included (see Appendix).

National Control Authority Role

• The national control authority is responsible for approving virus seed lots, cell cultures, and inactivation methods.
• If countries wish to adopt these requirements, they must allow modifications only if they ensure the same level of safety and potency.
• The World Health Organization must be informed of any national changes.

Key Information

• The vaccine is intended for use in humans, particularly in areas with high human-animal interaction.
• The use of monkey-derived cells is common but requires strict health and safety protocols.
• Human diploid cells and continuous cell lines (e.g., VERO cells) are also acceptable, provided they meet specific criteria.
• Sterility, innocuity, and potency are critical quality attributes.
• Filtration is a key step in the inactivation process, with specific filter requirements.
• Control cell cultures and virus testing are essential for ensuring the absence of extraneous agents.
• Monitoring and record-keeping are mandatory for compliance and traceability.

Conclusion

The document provides comprehensive guidelines for the safe and effective production of inactivated Rift Valley Fever vaccines for human use. It emphasizes the importance of using approved materials, maintaining strict hygiene and safety protocols, and conducting thorough testing to ensure vaccine quality. These requirements are adaptable but must be modified only with approval from the national control authority to maintain safety and efficacy standards.