Marketing authorisation holders (MAHs) must keep their marketing authorisations up to date throughout the product lifecycle. Changes to approved dossiers are managed through variation procedures in accordance with EU variation regulations. Variations are classified into different types (IA, IAIN, IB and II), each with specific requirements, timetables and implementation times.
Below we answer some of the most common questions about EU variation procedures for human medicines, covering both general regulatory principles and more specific practical cases.
What are marketing authorisation variations?
Variations are changes made to an approved marketing authorisation. They are submitted to authorities when updates affect elements such as manufacturing processes, labelling or manufacturing sites. Variations are a key part of maintaining an up-to-date marketing authorisation dossier.
Do all changes require a variation submission?
No, but every change requires a regulatory assessment. MAHs must evaluate whether a change requires a variation submission, falls under another regulatory category, or can be managed internally. Incorrect change classification is one of the most common MA maintenance compliance risks.
How long does an EU variation procedure take?
The assessment timeline depends on the variation type. Type IA and IAIN variation procedures take 30 days. Type IB variation assessment time is also 30 days but if additional documentation is requested from the MAH, another 30 days assessment will follow.
Type II variation assessment takes usually 60 days, but it depends on the nature of the change. The assessment time for safety type II variation can be 30 days and for extension of the therapeutic indication the assessment time can be 90 days. National procedure will follow in a Mutual Recognition Procedure (MRP), Decentralised procedure (DCP) and Centralised Procedure (CP) and that lasts 30 days.
When must the changes be implemented?
For variations type IA and IAIN, the change is implemented before the variation submission. The implementation date is the date when the change is officially implemented in the MAH’s quality system.
Variation type IA must be submitted within 12 months after the implementation date and variation type IAIN must be submitted immediately after implementation.
For variations type IB and II, the change is implemented after the variation is approved. MAH is responsible for implementing the changes to production in accordance with their own quality system. However, this should happen as soon as possible, usually from the next possible production run.
Can editorial changes in the package leaflet be included in a variation application?
Editorial changes refer to formatting changes, correction of typographical errors and minor linguistic edits. Such editorial changes in product information do not need to be submitted as a separate variation, but they can be included in a variation impacting the product information. It is recommended to check whether the relevant national authority has separate guidance for different variation types.
These editorial changes should be clearly stated in the cover letter and in the application form under the precise scope and present/proposed table, and marked with tracked changes in the product information.
Why does a change require a type IA variation even if it has no impact on product quality?
If the proposed state of the item to be changed differs from what is currently described in the approved marketing authorisation documentation, the change must be notified to the authorities to keep the marketing authorisation dossier up to date. Typically, administrative or minor changes may be submitted as type IA variations.
When can a change be classified as a type IA variation instead of type IB?
Type IA variations are defined in the EU Variations Regulation (EC) No 1234/2008 and its associated guideline. Only those changes that are listed in the type IA classification tables can be submitted as type IA variation. If the change does not fall under any of the type IA categories in the guideline, it cannot be classified as type IA and must follow the next applicable category, usually type IB.
A recommendation on the classification of an unforeseen variation, issued in accordance with Article 5 of Commission Regulation (EC) No 1234/2008, can be also be checked on the Heads of Medicines Agencies (HMA) website: Art 5 recommendations
It is also possible to request a classification recommendation prior to submission of the variation. Such a request may be submitted to the EMA for CPs, to the Reference Member State (RMS) for MRPs or DCPs, or to a national competent authority (NCA) for purely national marketing authorisations. Guidance on how to apply for an Article 5 recommendation is available on the EMA website: Article 5 procedure: Regulatory and procedural guidance
Which variation type is used to apply for an active pharmaceutical ingredient (API) re-test period when the European Pharmacopoeial Certificate of Suitability (CEP) does not specify one?
Changes to marketing authorisations to human medicinal products are classified in accordance with Guidelines on the details of various categories of variations. Type IB Q.I.d.1.a.2 can be used to apply for a re-test period for the API, if the CEP does not specify one.
If a new or updated CEP is submitted at the same time as grouped variation, condition 5 of the Q.III.1 variation has to be ticked, as the re-test period is approved only after the approval of the type IB Q.I.d.1.a.2 variation.
Medfiles experts support pharmaceutical companies with variations across EU procedures. We take care of the whole process: reviewing your proposed change, confirming the correct variation classification, and identifying the most efficient submission route – whether a single variation, a grouped application or a worksharing procedure.
With over 30 years of experience, we provide tailored regulatory support for projects of all sizes, from initial marketing authorisation applications (DCP/MRP/CP/NP) and CMC documentation to lifecycle maintenance.
Author: Elina Karp, Regulatory Affairs Expert
Elina works as a Regulatory Affairs Expert at Medfiles and has been with the company for over four years. She has more than 10 years of experience in marketing authorisation work, having worked with regulatory tasks already before joining Medfiles.
She holds a Master of Science in Technology (Biotechnology) and has solid expertise in the maintenance of marketing authorisations, particularly in managing variations and updating product information. Her work includes the compilation, submission and management of variations and renewals, as well as handling authority questions during regulatory procedures.
In addition, Elina works extensively with SmPC, package leaflet and labelling updates and translations. She also supports clients through proofreading and regulatory review of packaging materials and pharmaceutical marketing materials, ensuring compliance with current regulatory requirements.
Author: Ulla Orava, Head of Operations, CMC
Ulla Orava has worked at Medfiles since 2007. She has more than 25 years of experience from pharmaceutical development, product maintenance, marketing authorisation dossiers and post-approval variations. Before joining Medfiles, Ulla worked with assessment and coordination of variations at the Finnish Medicines Agency, as well as with drug product development and product maintenance in the pharmaceutical industry.
She has experience from planning pharmaceutical and chemical studies needed for global marketing authorisation applications as well as the guidelines steering these studies. In addition, Ulla has considerable competence in changes needed for drug products, problem solving, planning and classification of variations and writing variation documentation, not to forget a good grasp of how the authorities interpret variation guidelines. At Medfiles, Ulla’s roles as Head of CMC Operations, leading an extremely experienced team of CMC experts, and before that, as a CMC Expert, have allowed her to fully utilise her wide range of expertise in various drug development projects and in managing the quality dossiers for human and veterinary products and post-approval variation applications.
