2015-10-17-世界卫生组织-Guidelines_on_procedures_and_data_requirements_for_changes_to_approved_vaccines,_Annex_4,_TRS_No_993_86页_358kb

WHO Guidelines on Procedures and Data Requirements for Changes to Approved Vaccines - Summary

Core Content

These WHO Guidelines provide a framework for national regulatory authorities (NRAs) and marketing authorization (MA) holders to manage changes to approved vaccines. The goal is to ensure that such changes do not compromise the quality, safety, or efficacy of the vaccine. The guidelines are advisory in nature and can be adopted as national requirements if desired.

Main Sections and Key Points

1. Introduction

• Changes to approved vaccines may occur for various reasons, including routine production, quality improvement, or updates to product labelling.
• NRAs and MA holders must recognize that any change may affect the vaccine's quality, safety, and efficacy.
• WHO provides guidance to ensure comparability of vaccines after changes, particularly in terms of quality, safety, and efficacy.

2. Scope

• The guidelines apply to changes in the manufacture and use of approved human prophylactic vaccines.
• General principles may also apply to other biological products.
• The document helps NRAs establish regulatory procedures for post-approval changes.

3. General Considerations

• MA Holder Responsibility: MA holders must assess the impact of changes on vaccine quality, safety, and efficacy using appropriate studies (analytical, functional, or clinical).
• Prior Approval Supplements (PAS): Required for changes that may have a major or moderate impact.
• Routine Changes: Some changes, such as replenishment of cell banks, are considered routine and may not require formal approval.
• Regulatory Cooperation: NRAs are encouraged to collaborate with regional networks to share information and avoid redundant evaluations.

4. Terminology

• Adjuvant: A substance used to enhance immune response.
• Antigen: The active component of the vaccine that induces an immune response.
• Cell Bank: Includes master cell bank (MCB) and working cell bank (WCB).
• Change: Refers to any modification to the vaccine's composition, process, or labelling.
• Comparability Study: Evaluates whether pre- and post-change products are comparable.
• Formulated Bulk: The final formulation of antigens, adjuvants, and excipients before filling.
• Final Product: The finished dosage form of the vaccine.
• Product Labelling Information: Includes prescribing information, patient information, and packaging details.

5. Reporting Categories for Quality Changes

5.1 Major Quality Changes

• These changes have significant potential to impact vaccine quality, safety, or efficacy.
• Requirements:
  • Submission of a prior approval supplement (PAS).
  • Detailed description of the proposed change.
  • Supporting data including methods, studies, validation protocols, updated labelling, and SOP summaries.
  • May require nonclinical or clinical data.

5.2 Moderate Quality Changes

• These changes have a moderate potential to impact vaccine quality, safety, or efficacy.
• Requirements:
  • Submission of a supplement.
  • Approval from the NRA before implementation.
  • Supporting data similar to major changes, but with less stringent requirements.

5.3 Minor Quality Changes

• These changes are expected to have minimal or no impact on vaccine quality, safety, or efficacy.
• Requirements:
  • No formal supplement required.
  • Can be implemented without prior NRA approval.
  • A list of minor changes should be available upon NRA request.

6. Reporting Categories for Safety, Efficacy and/or Product Labelling Changes

• Safety and Efficacy Changes: Require PAS for major or moderate changes.
• Product Labelling Information Changes:
  • Urgent changes require immediate review.
  • Administrative changes (e.g., company name, contact details) can be submitted as general correspondence.
  • Changes affecting clinical use (e.g., new indication, dosage regimen) require detailed evaluation.

7. Procedures

• Prior Approval Supplements (PAS): Required for major and moderate changes.
• Urgent Labelling Changes: Should be reviewed and approved as quickly as possible.
• Concurrent Review: Changes to the product composition or manufacturing process should be reviewed alongside other changes to avoid delays.
• Inspections: May be required for major manufacturing changes, such as moving to a new facility.

8. Special Considerations

• Adjuvants: Changes to adjuvant composition may require new product licensing.
• Influenza Vaccines: Changes in virus composition (e.g., seasonal updates) may require new MA applications.
• Bridging Studies: May be necessary for certain changes to demonstrate comparability.

9. Authors and Acknowledgements

• The guidelines are authored by WHO and include contributions from various stakeholders and experts.

10. References

• Includes references to other WHO documents and ICH guidelines relevant to vaccine regulation.

Appendices

• Appendix 1: Suggested review timelines for different categories of changes.
• Appendix 2: Comprehensive list of major and moderate quality changes related to antigens and intermediates.
• Appendix 3: List of changes to the final product.
• Appendix 4: Examples of changes affecting clinical use and labelling.

Key Recommendations

• NRAs should establish procedures that ensure vaccine supply and public access.
• Regional cooperation and information sharing are encouraged to streamline the regulatory process.
• Manufacturers must comply with GMP, GLP, and GCP requirements.
• All changes should be evaluated based on their potential impact on vaccine quality, safety, and efficacy.
• The use of foreign approval documentation is permitted, but the final decision remains with the NRA.