Commission proposes guidelines to flesh out the newly finalized Variations Regulation


Jun. 20, 2024

This week, the newly finalized Variations Regulation was published in the Official Journal of the E.U. This regulation provides the framework for implementing post-authorization changes, or “variations,” to a medicinal product, and the updates implement efficiencies and incorporate current regulatory practice used by the EMA and national regulators. An updated guideline implementing the changes from the new regulation is now open for public consultation until August 23, 2024.

Regulatory background: Post-authorization lifecycle management

  • Medicinal products may be authorized nationally in specific E.U. countries, in all E.U. Member States simultaneously through a centralized procedure. For products that seek approval through the “centralized marketing authorization application,” the EMA’s Committee for Medicinal Products for Human Use (CHMP) conducts a scientific evaluation and issues a positive or negative opinion on whether an authorization should be granted. After this, the European Commission makes the final authorization determination. The Commission’s centralized marketing authorization is valid in all E.U. Member States as well as Iceland, Norway and Lichtenstein. Conversely, authorization in specific E.U. countries is granted through national or decentralized procedures by the respective national competent authorities.
  • Changes to the terms of existing marketing authorizations are referred to as “ Variations.” After a product is approved, the marketing authorization holder may implement a variety of changes, including to manufacturing sites, manufacturer, strength, route of administration and adding new indications. A variation is used to implement these changes by updating the terms under which a product is authorized. Variations are divided into several categories depending on the extent of the change: 1) Minor variations are Type IA or Type IB, 2) Major variations are Type II, and 3) Extensions and urgent safety restrictions each fall into their own categories.
  • Minor Variation of Type IA: Type IA variations include changes such as a new manufacturer name and/or address, deletion of a manufacturing site, or changes to quality control testing arrangements for an active substance. Marketing authorization holders can implement minor variations of Type IA without first notifying the applicable competent authority. However, a notification to all concerned E.U. Member State authorities and/or the EMA must be made within 12 months from implementation, as appropriate.
  • Minor Variation of Type IB: Examples of type IB variations include the addition of an alternative sterilization site or a new storage site for master and/or working cell banks, or an increase or decrease of the scale for biological or immunological active substance with no change to the process. Type IB variations require a notification to the applicable competent authorities; marketing authorization holders should wait 30 days after notification before implementing the change to ensure acceptability. Several Type IB variations for the same medicinal product may be combined in one submission.
  • Major Variation of Type II: Type II variations are major changes that require approval from the relevant competent authorities. Examples of type II variations include the addition of a new manufacturer for an active substance, changes to quality control testing arrangements for a biological active substance, or a substantial change to the manufacturing process of the active substance. The review timetable for a Type II variation assessment through the centralized procedure is generally 60 days, though it may be shortened for urgent changes such as those affecting safety or increased up to 90 days in certain situations.
  • Regulation (EC) No 1234/2008 (Variations Regulation) provides the procedures for implementing the different types of variations. It applies to products with marketing authorizations according to Regulation (EC) No 726/2004 and Directive 2001/83/EC, but does not apply to the transfer of the marketing authorization from one holder to another. The European Commission has issued a guideline to facilitate compliance with the Variations Regulation; the Annex in that document provides a detailed overview of post-authorization changes and their associated variation categories. The EMA has also published additional guidance on the Variations Regulation.
  • Work-sharing option: When a marketing authorization holder elects to use work-sharing procedures, a “reference authority” evaluates a variation application on behalf of other regulatory authorities with the aim of eliminating duplication of work. The EMA serves as the reference authority if at least one product included in the variation is authorized through the centralized procedure. Otherwise, a national competent authority is chosen as reference authority.

In 2020, the European Commission identified opportunities to improve the variations regulation and adopted a revised regulation in 2024

  • The Commission identified variations as one of three main areas for potential efficiency gains. According to the document, the administrative requirements for variations “present a high workload as every type of variation requires an approval by the regulatory authority.” The report focused in on Type IA minor variations as a particularly burdensome process, offering up the solution that Type IA variations could be noted directly in the database by marketing authorization holders rather than being submitted to the EMA and/or national authorities first.
  • That same year, the Pharmaceutical Strategy for Europe called for a revision of the Variations Regulation and an evaluation of the existing legislation. That assessment, finished in 2022, found that variations increased the cost of post-authorization procedures for market authorization holders.
  • In April 2023, the Commission issued proposals to revise the current pharmaceutical Directive and Regulation. However, those proposals are at the early stages of the Ordinary Legislative Procedure, and are likely years away from full implementation. An impact assessment for this proposed pharmaceutical legislation did note that a reduction in the number of “notifiable variations” would provide an opportunity to reduce post-authorization administrative burden and costs. [See AgencyIQ’s analysis of the proposed Directive and Regulation.]
  • In September 2023, the Commission announced a new initiative to streamline variations until the revised pharmaceutical legislation will apply. According to the call for evidence, “a short-term solution under the existing legislation is needed to streamline resources for regulatory authorities and marketing authorisation holders, and speed up the authorisation of variations.” The Commission proposed multiple changes to the variations procedures, including “a re-classification of some variations into lower categories and/or the introduction of additional flexibility,” as well as “clarifying] the changes and data to be communicated to the authorities” and “simplify[ing] the single submission or notification of variations (grouping) and work-sharing procedures.” Additionally, the Commission suggested a risk-based approach for variation categorization for “certain biological medicinal products.” [ See AgencyIQ’s analysis of the call for evidence.]
  • The Commission released the draft delegated regulation, making several notable changes, for public consultation in February 2024. For example, the draft introduced the term “reference authority” as the authority which evaluates a variation application on behalf of other regulatory authorities during work-sharing procedures with the aim of eliminating duplication of work. The EMA would consult the coordination group for the classification assessment of unforeseen variations. Another new term: “Additional regulatory tools” allow the marketing authorization holder to “rely on a range of process parameters, quality attributes or summary protocols.” Additionally, the new concept of “super-grouping” would enable the “same or several minor variations of type IA” for multiple marketing authorizations to be submitted in a single application. [See AgencyIQ’s analysis of the proposed regulation.]

The finalized implementing regulation has been published in the Official Journal – and the European Commission has updated the variation guideline

  • On June 17, 2024, the final Commission Delegated Regulation (EU) 2024/1701 was published in the Official Journal of the E.U., including just one change and one clarification compared to the draft. Article 7(2a) discusses the grouping of minor variations and now specifies that minor marketing authorization holders can submit a single notification for Type IA variations to the same marketing authorization which are notified at the same time. This seems to be an expansion of which variations can be grouped, since the currently still applicable regulation and the draft only allow grouping of the “same minor variation(s).” The super-grouping provisions remain unchanged.
  • The finalized regulation clarifies how variation classification applies to medical devices and in vitro diagnostics. The draft Annex II added a subpoint for both Type IA and Type II variations discussing post-authorization changes to “medical devices and in vitro diagnostic medical devices used in combination with the medicinal product.” The final regulation specifies that these medical devices must be “an integral part of or in exclusive use with the medicinal product.” If the change has no impact on the quality, safety or efficacy of the medicine, the Type IA classification remains the same. Similarly, if the change has a significant impact, the Type II classification also remains unchanged.
  • The delegated regulation will apply beginning January 1, 2025.
  • Last week, the European Commission released an updated variations guideline implementing experience gained by regulators and the amendments included in the delegated regulation. This draft guideline is now open for public consultation. Updates to the guideline incorporate “the current practice of EMA and National Competent Authorities” and simplify sections. The guideline, available in both clean and track changes versions, is accompanied by an executive summary highlighting key changes and providing next steps. The guideline is open for public consultation until August 23, 2024.

The updated guideline provides clarification on changed provisions in the regulation and revises the classification of various post-authorization changes

  • First, the guideline clarifies that the term “ mutual recognition procedures” applies to both the mutual recognition and decentralized procedures. Chapter 4 of Directive 2001/83/EC allows Member States to recognize assessments from another E.U. regulator if the product is not authorized through the centralized procedure through mutual recognition. Alternatively, the national competent authorities can rely on the assessment of the leading Member State (reference Member State) in the decentralized procedure, which enables parallel authorization of medicines in several Member States. The updated guideline clarifies that the term “mutual recognition” applies to variations to marketing authorizations through both procedures.
  • Second, the European Commission has restructured some sections to delete duplicated information. The updated guideline extracts the submission requirements from the discussion of each variation type, placing this information before the discussion of the different variation types. Relevant translations need to be included with Type IA and Type IB variations and, for Type II and other variations, will be required at the time of authorization by the EMA or within seven days for mutual recognition procedures. Additionally, recommendations for mutual recognition and purely national authorization variations are now combined rather than discussed separately for each type of variation.
  • There are two ways that several variations can be combined in on submission: grouping and super-grouping. “Grouping” refers to the submission of several Type IA variations applicable to the same marketing authorization in a single notification. The revised guideline adds that a single notification can cover identical Type IA variations for more than one authorization for purely national authorizations in one Member State. The delegated regulation also introduces the new option of “super-grouping.” Super-grouping allows several Type IA variations affecting several marketing authorizations held by the same owner to be submitted in a single notification, provided that all variations included must be identical for all marketing authorizations.
  • The “ highest” variation type will determine how the bundled group of variations is handled. For example, some changes, such as a change of medicinal product name, require immediate notification to the regulatory agency. If a group of variations contains a change that requires immediate notification, then the assessment procedure for variations requiring immediate notification applies to the entire submission. The highest type of variation also determines the length of the assessment period. Variations that don’t require notification immediately after the implementation can be submitted as an annual update. The updated guideline explains that they also can be submitted as part of a group or super-group with other variations. A common cover letter and electronic application form should be used for grouped variations covering several marketing authorizations. Each variation needs to be supported by the appropriate documentation.
  • Sponsors must ensure that all affected marketing authorizations are included in a submission for the work-sharing procedure. The updated guideline specifies that marketing authorization holder submitting the same Type IB variations or the same group of variations for several marketing authorizations must use the work-sharing procedure for mutual recognition and purely national authorizations. The update further explains that all affected authorizations must be included in that submission. Otherwise, the marketing authorization holder will be requested to revise the application. The same is true for Type II variations.
  • The marketing authorization holder will need to inform the preferred competent authority of an upcoming work-sharing procedure if the product is not centrally authorized. According to the current guideline, the marketing authorization holder would inform the coordination group of the work-sharing procedure. However, this has been updated so that the marketing authorization holder contacts the competent authority of the Member State preferred to function as reference authority before the application is submitted. The chosen preferred authority will confirm acceptance to the marketing authorization holder and the coordination group. The coordination group will then confirm the preferred Member State as reference Member State.
  • Assessment timelines for Type II variations have been removed. The current guideline notes that the assessment for Type II variations generally involves a 60-day evaluation period, which can be shortened for urgent safety issues or extended to 90 days for certain variations. These timeframes have been deleted. Instead, the marketing authorization holder will be informed of the timelines at the beginning of the procedure. The timelines for CHMP assessment of variations depends on their complexity, and sponsors can find timetables on the EMA website. The assessment timeline for Type IB variations is still 30 days, and the variation can be implemented if the competent authority or EMA has not sent a notification within that timeframe.
  • A quick note on annual updates for influenza and coronavirus vaccine: The procedure for submission and assessment of annual human influenza vaccine updates remains the same. However, the updated guideline notes that human influenza vaccine can also be updated outside of the annual cycle; sponsors should contact the relevant authorities in advance about the application. Additionally, the application of the urgent procedure discussed in Article 21 now also applies to human vaccines addressing “a public health emergency at Union level” that is recognized by the Commission. Previously, this provision only applied to human influenza. Additionally, the EMA may decide to implement an annual update procedure for coronavirus vaccines, according to the updated guideline.
  • The Annexes providing requirements for the various types of variations include changes in how some variations are classified. For example, changes to the manufacture of the active substance involving an addition or replacement of a manufacturing site responsible for starting material manufacture are now down-graded from a Type II variation to a Type IA variation. However, some variations have been upgraded. For example, a variation introducing changes to the analytical testing of the active substance not falling in another category listed in the Annex have been upgraded from a Type IA variation to a Type IB variation. Additionally, new classifications have been added in already existing categories.
  • The updated guideline also includes new classifications in additional sections. For example, the new Section B.I.a.6 provides classifications for changes to serotype, strain, antigen or coding sequence (or a combination thereof) for vaccines against human coronavirus or addressing a public health emergency. Replacing a serotype, strain, antigen or coding sequence would be a Type II variation, while the deletion would be a Type IB variation. Another new Section (B.I.b.3) classifies various changes to in-house references standards (i.e., a reference standard made at that specific marketing authorization holder rather than a recognized reference standard) to be used for biological active substances.
  • The revised regulation introduced new “ regulatory tools,” which have now been implemented into the guideline. Generally, introducing a “ product lifecycle management document” as one of those regulatory tools is classed as a Type II variation for the active substance. Changes to the process parameters or quality attributes that ensure the quality of the medicinal product during manufacture can be classified along the spectrum of variation types. Major changes will be Type II variations. A Type IA variation would apply if the product lifecycle management document foresaw this change as a Type IA variation. The classifications are similar for the finished product.

What’s next

  • This update introduces significant revisions to the existing guideline. The guideline sections have removed duplicative text for better readability, and added new clarifications based on current EMA and national competent authority procedures. The finalized delegated regulation also required adding new provisions throughout the guideline. It also impacted the classification of some variations – AgencyIQ has provided an overview and examples, but the guideline contains more detail.
  • The guideline clarifies how grouping and super-grouping of variations works, and provides a classification scheme, with more detail than the delegated regulation itself provides. Whether variations can be super-grouped also depends on the type of authorization they address (i.e., centralized, mutual recognition or purely national).
  • The guideline emphasizes the importance of using work-sharing procedures whenever possible. Marketing authorization holders submitting the same Type IB variations or the same group of variations for several marketing authorizations must use the work-sharing procedure for mutual recognition and purely national authorizations. But sponsors also need to be careful to ensure that all affected marketing authorizations, are included to avoid a revision of the submission. Although this update could reduce duplication of effort for sponsors, the biggest impact may be for regulators, since they will review fewer submissions. Marketing authorization holders will have to take the time to ensure that all affected marketing authorizations are included. If that’s not the case, then regulators will request a revision of the submission, adding extra work.
  • Work-sharing procedures are still not expanded to regulators outside the E.U. Similar to the delegated regulation, the guideline is silent on any considerations for work-sharing or reliance opportunities with regulators outside of the E.U. Marketing authorizations holders will likely need to submit the same updates to international regulators to update their global authorizations. Some guidance on reliance procedures with regulators outside the E.U. could benefit both industry and regulators. Industry would benefit from aligned submission packages and less work to create the submissions. On the other hand, regulators could collaborate and reduce workload. The efforts at global harmonization suggested during the draft delegated regulation consultation period has not, to date, been taken into account.
  • The guideline is open for public consultation, but it isn’t applicable yet. The Commission notes that it will provide guidance “ in due course” when the new guidelines will become applicable in relation to the application of the delegated regulation. The delegated regulation becomes applicable on January 1, 2025. The draft update to the guideline is open for public consultation until August 23, 2024. Comments can be submitted through the EU Survey portal.
  • A second revision of the variation regulation will likely come after the revised pharmaceutical legislation is implemented. The ordinary legislative procedure could take several months, or even years, depending on how fast the European Parliament, the European Council and the Commission can agree. A discussion in the European Council is set for this Friday June 21, 2024. [See AgencyIQ’s analysis of the revision for more information.]

To contact the author of this item, please email Kirsten Messmer (
To contact the editor of this item, please email Kari Oakes (

Key Documents and Dates

Get an insider’s view on regulatory movements.

Sign up for AgencyIQ’s newsletters to receive exclusive regulatory updates and analysis impacting the life sciences or chemical industry.

Copy link
Powered by Social Snap