Last updated: 3 February 2026
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The worksharing procedure for the assessment of Active Substance Master File (ASMF)
The document with the above title has been updated. Here, you can view the track changed (May 2024) and clean (Dec 2025) versions of the document.
The update concerns the removal of ASMF summary and update to align with the new EC guidelines on the details of the various categories of variations and operation of the
procedures coming into effect from 15 January 2026.
Source: HMA
EMA/CMDh Explanatory notes on Variation Application Form – Human medicinal products only
Here, you can view the track changed (November 2024) and clean (December 2025) versions of the form.
Q&A – List for the submission of variations for human medicinal products according to Commission Regulation (EC) 1234/2008 as amended
The Q&A with the title above has been amended. Here, you can view the track changed (October 2025) and clean (December 2025) versions of the document. Note that the document has been substantially updated.
Source: HMA
Report and minutes from the CMDh meeting held on 9 – 11 December 2025
The reports from the CMDh meetings (also called press releases) reflect highlights/important outcomes of each meeting and are usually published in the week following the CMDh meeting. The reports therefore only contain a subsection of the complete CMDh agenda and are used for a more timely communication of the most important outcomes.
The CMDh minutes are a full record of the CMDh meetings (minus redaction of confidential content). They are adopted at the following CMDh meeting and subsequently published.
Acronyms and abbreviations used in the report and minutes are available here.
The report and minutes from the above meeting include (but are not restricted to) the following items):
1. Nitrosamines call for review
MAHs are reminded of their responsibilities to ensure the quality, safety and efficacy of their medicines and to adhere to the Nitrosamines guidance outlined by the EMA and the CMDh. This includes the obligation to monitor and mitigate nitrosamine risks throughout the lifecycle of their products.
Conduct confirmatory testing
- MAHs are expected to conduct confirmatory testing for all products at risk for which an AI is published in Appendix I, unless it can be justified that the N-nitrosamine cannot be formed in their product.
- This should be thoroughly discussed according to appropriate scientific principles. For example, where an AI is recently published it is expected that the MAH who has products containing that active substance performs confirmatory testing to determine the level of nitrosamine in their product.
- The outcome of the risk assessment should be notified to the relevant competent authorities as a matter of priority, by using the dedicated response templates.
- If N-nitrosamines are detected above the AI a quality defect report should be submitted as well.
Implementation of CAPAs and step 3 responses
- The implementation of CAPAs and submission of step 3 responses should be done at the earliest opportunity, but no later than 3 years from the date of publication of the initial AI.
- This deadline has elapsed or is approaching for a large number of N-nitrosamines included in Appendix I.
- MAHs are requested to actively inform NCAs about the status of CAPA implementation.
- If it is expected that products cannot be brought in compliance within this 3-year period, this should be discussed with the concerned authorities without delay.
Compliance of MAHs with the above-mentioned requirements is subject to regular controls by
competent authorities, including during GMP inspections.
2. CMDh Best Practice Guide on Variation Worksharing
The CMDh agreed an update of the CMDh Best Practice Guide on Variation Worksharing (Chapter 7) to specify how products should be listed in the eAF section “Products concerned by this application”.
The updated document has now been published on the CMDh website under “Procedural Guidance > Variations”.
Here, you can view the track changed (October 2024) and clean (December 2025) versions of the document.
3. National recommendations for requests to act as RMS
The CMDh agreed an update of the compilation of links to NCA’s webpages where their national recommendations for requests to act as RMS are published.
The updated document has been published on the CMDh website under “Procedural Guidance > Application for MA > DCP”. You can view it here.
4. Working Party on Variation Regulation
i) Acceptance or rejection of Type IA/IAIN notifications
Following a request related to PLM, it was clarified that the RMS should communicate to the
MAH in his country whether Type IA/IAIN notifications are accepted or rejected within 30
days following receipt.
- However, if this communication is not received, the variation will be considered automatically accepted.
- No need to update the guidance was identified. This approach was supported by the CMDh.
ii) Partial approvals in Worksharing procedures
Regarding the issues with partial approvals in worksharing procedures issued by some RMSs,
it was acknowledged that the CMDh agreed that the outcome of the procedures applies to all
MAs and MSs concerned, except in cases where partial approval relates to specific changes.
- Some MSs noted that their automated approval letters can only include MAs approved in their country.
- In such cases, it should be clearly stated that the assessment covered all authorisations listed in the eAF, even though, for technical reasons, not all are reflected in the approval letter.
iii) Proposal to waive the requirement for submitting a worksharing procedure after a previous assessment
Following the CMDh meetings with Interested parties in June and November, the Working Party on Variation Regulation (VRWP) discussed a proposal to waive the requirement for submitting a worksharing procedure after a previous EU assessment (e.g. following signals or to adapt to the RefMP), when only national translations need to be assessed.
- It is not foreseen in the Regulation that any changes be excluded from mandatory worksharing.
- The VRWP does not consider alternative procedures feasible in such cases; submissions should continue to be made through worksharing (type IB variations).
- This approach was supported by the CMDh.
iv) MSs should continue to work to improve the handling of requests to act as Reference Authority for mandatory worksharing
It was emphasised that MSs should continue to work to improve the handling of requests to
act as Reference Authority for mandatory worksharing and the adherence to CMDh guidance.
Additional proposals are welcome until the next VRWP.
v) Requirement for listing MSs in alphabetical order in section 2 of the eAF
The VRWP discussed whether the requirement for listing MSs in alphabetical order in section
2 of the eAF should be maintained for worksharing procedures.
- The CMDh agreed that a nonalphabetical order is not a validation issue and that purely NAPs should be handled separately from MRP.
- It was proposed to update the CMDh Best Practice Guide on Variation Worksharing
- (Chapter 7) to specify how products should be listed in the eAF section “Products concerned by this application”. Chapter 7 has been updated and links are provided above.
vi) Can changes to the container and excipients of the original MA be considered a line extension?
The VRWP discussed a case where a line extension was submitted only including
changes to the container and excipients of the original MA.
- The MAH wants to keep the old formulation and to add a new MA for the new formulation.
- It was agreed that the changes applied for do not constitute a change of the pharmaceutical form nor a switch from single dose to multidose; therefore, the application cannot be considered a line extension.
- However, it was agreed that a new speciality MA can be applied for under the same MRP number.
5 Electronic submission
The CMDh was informed and consulted about proposed changes to the PLM Portal eAF.
- A change was proposed to enable non-CAP users to specify which are the packages relevant for an application.
- The CMDh considered that this change would not be needed.
- It only seems applicable for a limited number of MSs that issue MAs at package level, but for EU procedures all packages will have to be included in a variation.
- The CMDh agreed to loosen the rules for when super-grouping can be applied in the PLM Portal eAF (although the term “super-grouping” is not correct in all applied situations, the principle of grouping is possible in such cases as per legislation).
New variation classification in eAF – reminder for cut-off date 15 January 2026
The updated Variation Regulation Classification Guideline has been made available in the interactive pdf eAF v1.28.0.0 and in the PLM Portal web-based variation form January 2026 version.
- Applicants are reminded that applications using the v1.28.0.0 or the January 2026 version of the form must not be submitted to the EMA prior to 15th January 2025 CET 00:00.
- Applications received before the 15th January 2025 will be rejected, and the application must be resubmitted on or after the 15th January 2026.
For any exceptions to these rules and applicability for different scope types must be reviewed on the following EMA dedicated page: Guidance on the application of the revised variations framework | European Medicines Agency (EMA)
New variation classification in eAF – Q&A session – 8 January 2026 10:00 – 11:00 CET
The updated Variation Regulation Classification Guideline has been made available in the interactive pdf eAF v1.28.0.0 and in the PLM Portal web-based variation form January 2026 version.
To support this change, the EMA eAF team will host a Q&A Clinic on 8 January 2026 10:00 – 11:00 CET dedicated to addressing your questions about the eAF form functionalities related to the new variation classification. To register, please use the following link: Q&A eAF registration – 8 January 2026.
PLM Portal eAF – reminder for FHIR XML attachment
Applicants are reminded that eAFs generated in the PLM Portal need to have the FHIR XML attached when submitted to health authorities. The applicants need to check that all PLM Portal eAFs contain the FHIR XML before adding them to the eCTD package. For more information, please consult the eAF – Guidance Documents
Source: eSubmission
Go-live announcement for EU eCTD v4.0 optional use for CAP new MAA
The EMA is pleased to announce that from 22 December 2025, applicants may optionally submit new Marketing Authorisation Applications (MAAs) for Centrally Authorised Products (CAPs) in eCTD v4.0.
- Given the need to ensure that enhanced support is provided and that the assessment team is informed, applicants must contact the EMA eCTD v4.0 team (eCTD4consultation@ema.europa.eu) prior to any eCTD v4.0 submission.
- Note that the Agency is closed from the 23rd of December 2025 until the 2nd of January 2026 included.
- The eCTD v3.2.2 remains accepted during the optional-use period. Additional updates will be provided in 2026.
- Applicants intending to use eCTD v4.0 should ensure that their systems, processes, and tools support the EU technical requirements, including the published validation criteria and controlled vocabularies.
- These documents and related guidance are available on the EMA eSubmission website.
- An additional practical guidance for EU eCTD v4.0 (for CAPs MAA) is now published on the same page.
- EMA will provide updates on further steps in the eCTD v4.0 implementation roadmap.
The introduction of eCTD v4.0 represents a significant step towards a more harmonised and efficient electronic submission environment, offering:
- enhanced metadata structures,
- improved lifecycle management, and
- greater interoperability with global regulatory authorities.
Source: eSubmission
Updated PLM Portal eAF Release notes now available
An updated version of the PLM Portal eAF Release notes reflecting bug fixes and updates to web eAF made in the version 1.2.1.2 released to production on 11 December 2025 is now available on the eSubmission PLM Portal
Checklist for the submission of day 215 translations for post-opinion linguistic review – human
You can view the document with the above title, here.
For initial marketing authorisations and line extension applications the applicant/MAH submits the day 215 translations for a post-opinion linguistic review in one Eudralink message to the European Medicines Agency qrd@ema.europa.eu with a copy to the Product Shared Mailbox.
Source: European Medicines Agency
PLM Portal eAF – updated Q&A document
The PLM Portal eAF Q&A has been revised to incorporate questions gathered during the 2025 webinars and Q&A sessions.
- The newly added questions are clearly marked with the label “Nov ’25” for ease of identification.
- It is highly recommended to review this document before initiating the creation of a PLM Portal eAF for a human variation, as well as during or after completion, should you have any inquiries or encounter difficulties.
- Doing so ensures compliance with the latest guidance and supports the efficient resolution of potential issues.
Source: eSubmission
EU eCTD v4.0 – Forward compatibility pilot for CAPs to be announced in 2026
EMA is planning to start the Pilot Phase 3 on Forward Compatibility for the Centrally Authorised Products in 2026.
All eCTD v4.0 tool vendors are strongly encouraged to ensure that their tools are ready to support Forward Compatibility in early 2026.
Further information and details how to participate will be published on the eSubmission website in Q1 2026.
AND
EU eCTD v4.0 – Validation criteria v1.1 – open for comments
The eCTD v4.0 EU Validation Criteria is under review. The draft updated validation criteria v1.1 is now available for your comments. Please send your feedback via email to eCTD4consultation@ema.europa.eu by 31st December 2025.
Source: eSubmission
PLM Portal eAF – January 2026 final version now available
The final “January 2026” version containing the new human variation classification, entering into force on 15 January 2026, is now available on the PLM Portal eAF.
- A single cut-off date for the entry into application (i.e., 15 January 2026) is set out in the final version of the Variations Guidelines.
- Until 15 January 2026, marketing authorisation holders should continue to rely on the current Variations Guidelines and on the specific procedural guidance.
- Please review this page for further details: Guidance on the application of the revised variations framework
- Findings related to the functionality of the form must be consolidated and submitted via an EMA eAF ticket.
- Findings related to the classification scopes (Section 3 of the eAF) must be raised through an RMS change request.
Note: The z-scopes are not visible yet in the new variation classification, they will be added soon.
Source: eSubmission