2011-10-22-世界卫生组织-Guidelines_on_Stability_Evaluation_of_Vaccines,_Annex_3,_TRS_No_962_28页_394kb

Annex 3: Guidelines on stability evaluation of vaccines

1. Introduction

• Vaccine stability is critical to global immunization programs.
• WHO recognizes the importance of clearly defining stability characteristics during vaccine evaluation.
• These guidelines provide a scientific basis for vaccine stability evaluation at various stages: clinical trial approval, licensing, and post-licensure monitoring.
• Vaccines are highly sensitive to environmental factors, especially temperature, which affects potency and immunogenicity.

2. Scope

• Applies to all infectious disease vaccines.
• Focuses on evaluating vaccine stability, not on stabilizing methods or genetic stability.
• Instructions for thermal stability testing relevant to lot release are limited to general stability assessments.

3. Glossary

• Defines key terms related to vaccine stability testing:
  • Accelerated stability studies: Expose vaccines to higher temperatures to determine degradation rates.
  • Adjuvants: Enhance immune response.
  • Shelf-life: The period a vaccine remains effective when stored correctly.
  • Stability-indicating parameters: Reflect vaccine potency and safety.
  • Real-time, real-condition stability studies: Monitor stability under expected storage conditions.
  • Lot release: Includes thermal stability testing in some cases (e.g. live vaccines).

4. General Considerations

• Temperature Sensitivity: Affects all vaccines. Stability data should reflect real-world conditions.
• Robust Testing: Requires biological assays (potency tests) to fully characterize vaccine changes.
• Hydrolysis, pH, and Environmental Factors: Extreme temperatures/light may influence stability, but not all factors are mandatory.
• Regulatory Alignment: Aligns with ICH guidelines for vaccines tailored to biological systems, emphasizing comparability.

5. Stability Evaluation at Different Stages of Production and Use

• Final Lot and Formulation: Covers production, presentation, and reconstitution stability; includes freeze-dried vaccines.
• Intermediates are tested for their stability in production stages, ensuring the final product maintains characteristics.
• Combined vaccines need to be assessed individually; the shortest component's shelf-life is used.
• When to Use Accelerated Testing: Used for extrapolation but real-time data is essential for regulatory approval and lot release.

6. Regulatory Considerations

• For Clinical Trial Approval: Stability data must model shelf-life and potency during trial doses.
• For Licensing: Real-time data is needed to propose expiry dates and storage conditions. Shelf-life claims must be tied to potency and safety.
• Post-Licensure Stability Monitoring: Continuous monitoring to confirm initial stability claims.
• Thermal Stability Testing: Limited to vaccines where temperature excursions have a direct impact on safety/efficacy (e.g. inactivated vaccines).

7. Design of Studies and Statistical Considerations

• Study Design:
  • Bracketing and matrixing designs can reduce testing burden.
  • Real-time study designs must align with regulatory expectations.
  • Parallel accelerated vs real-time studies are recommended where feasible.
  • Supports manufacturing process changes and comparability studies.
• Statistical Analysis:
  • Use regression analysis to estimate rates of potency loss.
  • Arrhenius analysis may help extrapolate data, though only within tested conditions.
• Sample Selection and Dosing:
  • Test multiple lots (at least 3) at defined intervals.
  • Assay variability must be anticipated and calibrated against stable reference standards.

8. Data Analysis

• Approaches:
  • Data may compare to acceptance criteria or undergo statistical validation.
  • Calculate minimum release potency to ensure immunogenicity throughout shelf-life.
  • Regression models predict expiry dates based on the rate of decline.
• Confidence Intervals:
  • Use fiducial/confidence intervals for statistical validation of stability.
  • Ensure extrapolations are limited to conditions tested; avoid overestimating shelf-life with insufficient data.

9. Stability Evaluation of Combined Vaccines

• Each component must be assessed individually.
• The combined vaccine's shelf-life depends on the component with the shortest duration.
• Cumulative age of intermediates may reduce vaccine quality; robust data required.

10. Labelling

• Includes expiry dates, recommended storage conditions, and handling instructions (e.g. avoid freezing).
• Use of VVM devices requires separate stability data validation.

Authors & References

• Guidelines developed by an international Working Group including representatives from WHO, regulatory agencies, and vaccine manufacturers.
• References include relevant ICH, WHO, and technical documents for further guidance.