What Are The Common Variation Validation Issues? Find Out Here

Variations are a critical part of maintaining the lifecycle of all dossiers. A variation is any change to the currently approved content of a marketing authorisation which assists in ensuring continued compliance.  We look at the main types of variations and the critical issues that you need to be aware of when completing a variation.

What Are The 5 Main Types of  Regulatory Variations?

  • Type IA are minor changes which have minimal impact on the Quality, Safety & Efficacy of the medicinal product or ‘Do and tell’ variations which do not require prior approval and can be implemented up to 12 months prior to notification.
  • Type IAIN are also minor changes; however, they require immediate notification to the competent authority on implementation.
  • Type IB variations are minor changes that are not extensions or classified in the guideline referred to in article 4 of the regulation. They require approval from the competent authority before implementation.
  • Type II variations are major changes which may have a significant impact on the Quality, Safety & Efficacy of the medicinal product. They require prior approval before implementation.
  • Extension applications. These include additional strengths, pharmaceutical forms or routes of administration.

Regardless of the type of variation submitted all variations go through rigorous validation by the competent authorities (CA) on receipt and the procedure cannot be started until a compliant validation is achieved.

Firstly, the CA verifies that the submission is technically valid, the submission must have passed eCTD technical validation criteria. The applicant must provide a copy of a Compliant validation report as part of the submission to verify technical validation.

Once the technical validation is verified a content validation is carried out. The content validation is carried out against the validation checklist, which is available on the European Medicines Agency (EMA) website and can be used as a guide to help prevent validation issues and improve right first time submissions.

Critical Areas

There are a number of key areas that have been identified as having the most issues identified on validation. These include administrative issues linked to the application form, associated annexes and documentation and the classification of the variation.

The content of the electronic application form (eAF) is one of the most common causes of invalidation of submissions. Common issues that are picked up on validation of the eAF are:

  • Incorrect Scope applied or incorrect scope classification. The scope must reflect all changes included in application. For grouped variations, each scope listed must be identified by its classification number and detailed.
  • Identification as to whether it is a single or grouped variation
  • Only the presentations impacted should be listed under section 2
  • Incorrect Implementation date for variations included. The type of change determines the implementation date and therefore the date will vary depending on the change.
  • Incorrect classification of the variation
  • Present and proposed table is not clear and concise for all changes. This table can be included as part of the eAF or as an Annex, again all changes should be reflected, including product information and editorial changes
  • ASMF number and version number not referenced
  • Annexes are incorrectly selected throughout the form
  • Incorrect Fees
  • Invalid or missing QP declarations/GMP certificates/Manufacturing Licences
  • Incorrect or missing Letters of Authorisation
  • Editorial changes are not listed or not described sufficiently
  • The final sign off on the form should be by the person authorised by the MAH

There is an example of a completed eAF on the EMA website for reference, this can be used as a guide to ensure the form is completed correctly before submission.

Other areas with common issues identified on submission validation are:

  • Classification Guideline:
  • Conditions and documentation not ticked
  • Dossier Content:
  • Documentation indicated as required on the classification guidance not present
  • Insufficient or inadequate supporting documents provided
  • Only EN versions of Product information provided, no languages provided
  • No word document versions (Clean and Tracked) of the updated product information provided in the ‘Working Documents’ folder

If deficiencies are identified a request for supplementary information may be sent to the applicant and the applicant has a specific number of days to respond to the request, the number of days is dependent on the type of variation.

The EMA has done extensive work to assist applicants in the submission of right first time variations. The website contains a number of documents which can assist applicants including the pre-notification checklists for Type IA and IB variations.

We Can Help

If you would like to speak to us about issues relating to variations or seek our advice then call us on 00353 52 61 76706, email us:  info@acornregulatory.com or complete the webform below and we will get back to you.

About the Author
Christine McGrath
Regulatory Affairs Manager
Christine McGrath is the Regulatory Affairs Manager for the Pharm Regulatory team. She is responsible for scheduling all client projects and making sure we have the right people working on each project. She works with companies around the world on issues relating to registration of new medicines to managing technical and complex hurdles affecting existing marketing authorisations. Christine has extensive experience of regulatory procedures from working on the submission of clinical trials to managing the submission of a new active substance for a CEP with the EDQM. You can read more articles by Christine by clicking the link below.
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