Common Variation Application Invalidation Reasons

In the highly regulated pharmaceutical industry, securing and maintaining marketing authorisation (MA) is a critical step for bringing medicinal products to market. However, the journey doesn’t end there. Variations to the original marketing authorisation, such as changes to manufacturing processes, formulations, or packaging, often require additional regulatory approval to ensure ongoing compliance and product safety. National Competent Authorities (NCA) are responsible for reviewing these variation applications. Unfortunately, many applications are invalidated due to common pitfalls and non-compliance with specific regulatory criteria. Understanding these common reasons for invalidation is crucial for pharmaceutical companies aiming to streamline their processes, avoid costly delays, and ensure continued market access for their products. In this blog, we will explore the key factors that lead to the invalidation of variation applications and provide insights on how to mitigate these risks effectively.

Marketing authorisation variation application invalidation occurs when regulatory authorities reject or invalidate a submitted application for changes to an already approved medicinal product. This can happen if the application does not meet the required standards or if there are discrepancies in the submitted information. In this blog article we will delve into common reasons for invalidation of marketing authorisation variation applications.

eCTD technical invalidation

Regardless of the type of variation submitted all variations go through rigorous validation by NCA on receipt and the procedure cannot be started until a compliant validation is achieved. Firstly, the NCA 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 could be used as a guide to help prevent validation issues and improve right first time submissions.

Incomplete or incorrect documentation

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. Also, all editorial changes should be listed and described sufficiently.
• For grouped variations, each scope listed must be identified by its classification number and detailed.
• Only the presentations impacted should be listed under section 2 of eAF.
• Editorial changes are not listed or not described sufficiently.
• Incorrect Implementation date for variations. The type of variation change determines the implementation date and therefore the date will vary depending on type of the change.
• Incorrect classification of the variation including:
  • non-compliance with regulatory guidelines – failure to adhere to the specific regulatory guidelines for variation submissions, including format, content, and procedural requirements;
  • inadequate justification for variation – failure to provide a strong scientific or technical justification for the proposed 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
• Annexes are incorrectly selected throughout the form
• Incorrect or missing Letters of Authorisation
• The final sign off on the form should be by the person authorised by the MAH

In conclusion, ensuring thorough and accurate documentation is essential for successful variation submissions. By utilizing a detailed checklist to verify that all necessary documents are included and properly completed, MAHs can significantly reduce the risk of delays or rejections. Regular reviews of submission guidelines, updates in legislation, documentation templates and continuous staff training on documentation standards further enhance compliance and operational efficiency, helping to simplify the regulatory process and maintain positive engagement with regulatory authorities.

Procedure management issues

To ensure compliance and timely submissions, the MAH must diligently track variation submissions and post-authorisation commitments, facilitating the timely submission of all variations. Failing to submit Type IA/IA_IN variations on time could lead to rejection, with the NCA potentially requesting an upgrade of the late submission to a Type IB variation. Furthermore, insufficient proactive communication and engagement with regulatory authorities during the variation process may result in submission invalidation or outright rejection. It is crucial for the MAH to maintain regular dialogue with regulatory authorities, and in cases where there is uncertainty regarding certain changes, it is strongly recommended to seek advice or clarification from the NCA prior to submission. Alternatively, submitting a request for scientific advice can provide valuable guidance thought development of regulatory dossier and submission package.

National specific requirements

When submitting variation applications, MAHs must carefully adhere to local requirements to ensure successful outcomes. This begins with submitting the variation package through national systems/portals, eg. AIFA (Italy) and OGEYI (Hungary), MHRA (UK) etc. requires local variation package submission. Many authorities also require physical submissions of certain documents, like URPL (Poland), BDA (Bulgaria).

Compliance with National Competent Authorities (NCA) fee guidelines is crucial, ensuring correct payment with all necessary references. Some agencies even require to include payment in submission package. Non-compliance with these requirements always causes invalidation and delay of procedure.

Also, there are numerous local specific documents that are required to support variation applications. Failure to meet these standards often leads to delays or invalidation of the procedure. Lastly, product information should be prepared with precision, in the correct format and quality as specified by the relevant authorities.

Conclusion

Marketing authorisation variation application invalidation can lead to significant delays and increased costs for pharmaceutical companies. By understanding the common reasons for invalidation and implementing robust strategies to address these issues, companies can improve their chances of securing regulatory approval for variations. Ensuring comprehensive and accurate documentation, adhering to regulatory guidelines, and maintaining high standards of data quality and GMP compliance are critical steps in achieving successful variation applications. Regular communication with regulatory authorities and thorough risk management planning can further enhance the likelihood of approval.

We understand how critical it is to ensure that variation applications meet regulatory requirements, minimizing the risk of invalidation or rejection. To support your submission process, we’ve prepared a comprehensive Checklist for Self-Assessment, which highlights the key steps to take before submitting a variation application.

To receive your copy of the checklist and optimize your variation submission process, simply enter your contact detail below.