Vaccines that have been prequalified will have received marketing under the oversight of a national regulatory authority (NRA) that has been assessed as functional. The specifications for the vaccine will be defined in the marketing authorization (MA), including details of starting materials, manufacturing processes and quality control tests. By setting procedures, instructions and specifications, products can be consistently manufactured to the standard shown to be safe and effective in preclinical and clinical studies. However, production, safety and efficacy parameters evolve with time and the MA must be updated to reflect these changes (variations). Manufacturers are responsible for assessing the impact of planned and proposed changes on their product and regulatory approval of the changes may be needed to maintain the validity of the MA: it is recognized that not all changes affect the product to the same extent.
Some variations, such as changes to the active ingredient, significant to such an extent that the altered product is considered a new product, requiring a complete prequalification evaluation and licensing procedure. Others variations, such as the replacement of equipment by another of similar technical characteristics and functioning principles, are unlikely to affect product quality. In recognition of the varying impact on quality, safety and efficacy of the vaccines that different types of post-approval variations may have, as well as to avoid additional regulatory burden, most NRAs have developed and published a scheme to classify changes.
A manufacturer of a prequalified vaccine should submit all product variations to the responsible NRA of the country of manufacture of that vaccine. This NRA is responsible for reviewing and approving variations to the prequalified vaccine concerned before being submitted to WHO.
Classification of variations
Variations relating to prequalified vaccines that must be reported by the manufacturer of the prequalified vaccine are defined as follows:
- Minor variation, Type N (Immediate Notification): notification must be provided immediately (within one month after approval by the responsible NRA) to WHO.
- Moderate variation, Type R (Annual Reporting): Notification to be made via the annual reporting system as part of the Prequalified Vaccine Annual Report (PQVAR).
- Major variation, Type A (Approval Before Implementation): WHO approval must be received before implementation for vaccines to be made available via UN supply.
If WHO considers that a change(s) has been classified inappropriately, it will notify the manufacturer accordingly.
Note that if any of the conditions outlined for a given variation are not fulfilled, the variation is automatically classified at the next higher level of change. For example, if any of the conditions recommended for a Type N variation are not met, the change is classified as a Type A or R variation. Similarly, if any of the conditions recommended for a Type A variation are not fulfilled, the variation would warrant the filing of a new dossier (PSF or CTD) since it would be considered a new product.
Appendices 1, 2 and 3 of WHO Guidance on Variations to a Prequalified Vaccine provide detailed information on classification of variations. They complement the information regarding variations in Sections 7 and 8 of the Procedure for assessing the acceptability, in principle, of vaccines for purchase by United Nations agencies.
When a planned variation is not described in any of the above guidance, manufacturers are advised to request a consultation with the Vaccines Prequalification Team by email to firstname.lastname@example.org.