Classification of changes
In accordance with the current European Regulation on variations to marketing applications, changes are classified into three categories:
- notifications (for changes not expected to impact quality),
- minor changes (for changes which may impact quality) and
- major changes (for changes which are likely to impact quality).
The EDQM Guideline on Requirements for Revision/Renewal of Certificates of Suitability to the European Pharmacopoeia Monographs (PA/PH/CEP (04) 2) describes in detail the classification of changes for CEPs and the conditions to be met as well as the documentation to be provided for each type of change.
Where a change is not classified in the Guideline as a notification, minor or major change, it should be classified as a minor change by default and this information should be included on the application form. Specific guidance is also given in this guideline for editorial changes.
Some key clarifications are provided:
- When a new substantially different route of synthesis is introduced (even when the impurity profile of the final substance is equivalent): an application for a separate CEP should be made. This applies to both alternative and replacement routes of synthesis. The sister file procedure may be used if the conditions are met (PA/PH/CEP (09) 141).
- Different grades (e.g. particle sizes) may be included in the same CEP application when the impurity profile is shown equivalent, and the different grades may be mentioned on the CEP when granted, with controls for each grade. Separate CEPs for the grades are needed if the impurity profiles are not equivalent or if preferred by the applicant and the sister file procedure may be used if the conditions are met (PA/PH/CEP (09) 141).
- Revised discussions on impurities in section 3.2.S.3.2 should be submitted as minor revisions. One key reason to revise this section is for the assessment on risk of nitrosamine impurities and for this, there is specific information here.
CEP holders can consult EDQM on the classification of a change on their CEP dossier prior to submission. This can be done via the EDQM Helpdesk for general queries or via email to the account mentioned in correspondence for questions about specific CEPs and the CEP dossier should be identified to ensure the most appropriate reply can be provided.
Where requests have been misclassified by CEP holders (e.g.as a minor revision instead of a major revision, or as a notification instead of a minor revision), this will lead to the rejection of all submitted changes. The CEP holder will need to resubmit the changes correctly classified, together with the settlement of the appropriate fees (i.e. there will be a need to pay twice).
Search for a list of granted CEPs, their type, the name of the substance, the full CEP number, the issue date and validity status, using the Certification Database (updated daily).
Applicants commit to provide samples of substance and/or impurities when requested by the EDQM.