The Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) applies from 28 January 2022.

Marketing authorisation holders (MAH) should use the eSubmission Gateway/Web Client for all variations requiring assessment submitted to the Agency. For more information, including links to guidance on registration with the system see the Veterinary eSubmission website.

Separate guidance is also available on variations not requiring assessment.

Guidance

Guidance on variations requiring assessment is available below. This includes information on the documents that marketing authorisation holders will need to submit for each variation type.

Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EU) 2019/6 for veterinary medicinal products and on the documentation to be submitted pursuant to those variations

AdoptedReference Number: EMA/CMDv/7381/2021 Rev.2

English (EN) (563.72 KB - PDF)

First published: Last updated:
View

Questions and answers

Variations Requiring Assessment (VRA) are described in the Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EU) 2019/6 for veterinary medicinal products and on the documentation to be submitted pursuant to those variations (the Guidance).

References

The Guidance assigns a timetable to each variation based on the complexity of the variation and the amount of assessment time needed. The timetables are indicated for each variation. These are:

  • “R” for a Reduced timetable of 30 days  
  • “S” for a Standard timetable of 60 days 
  • “E” for an Extended timetable of 90 days

Upon receipt of a technically valid application, the Agency will perform the validation of the application content. Supplementary information may be requested in order to finalise the validation and the procedure will commence at the next available start date after resolution of issues identified during validation. The Agency will inform the MAH of the outcome of the validation and timetable.

The submission deadlines and full procedural detailed timetables are published on the Agency website 
(Recommended submission dates for veterinary medicinal products). 

VRA following a reduced timetable (30 days)

DayAction
Day 1Start of evaluation
Day 16Rapporteur circulates assessment report to CVMP
Day 20Comments by other CVMP members
Day 30Adoption of the CVMP opinion [Or request for supplementary information]

VRA following a standard timetable (60 days):

DayAction
Day 1Start of evaluation
Day 30Rapporteur circulates assessment report to CVMP
Day 37Co-rapporteur circulates critique to CVMP
Day 43Comments by other CVMP members
Day 50Revised assessment report
Day 60Adoption of the CVMP opinion [Or request for supplementary information]

VRA following an extended timetable (90 days):

DayAction
Day 1Start of evaluation
Day 39Rapporteur circulates assessment report to CVMP
Day 45Co-rapporteur circulates critique to CVMP
Day 50Comments by other CVMP members
Day 53Revised assessment report
Day 60Adoption of the CVMP opinion [Or request for supplementary information]

 

For all timetables, where issues are identified which prevent the adoption of an opinion, the CVMP will adopt a request for supplementary information/list of questions and the MAH will be informed of the deadline for the submission of the requested data. The clock will be stopped until the receipt of the supplementary information. Any response to a request for supplementary information must be sent to the EMA via the eSubmission Gateway/Web Client.

The clock may be stopped once for VRA that follow reduced and standard timetables. The length of the clock stop will depend on the questions, with up to three months possible, but as a general rule, a clock stop of up to one month will apply. For extensions to the clock stop of longer than one month the MAH should send a justified request to the Agency for agreement by CVMP. Such requests should be sent after receipt of the adopted CVMP request for supplementary information but before the expected submission date for the responses. In exceptional cases (e.g. where the variation requires an inspection) a clock-stop of up to a maximum of six months may be applied. The CVMP assessment of responses to the request for supplementary information will take up to 30 days.

An oral explanation to the CVMP can be held at the request of the CVMP or of the MAH, where appropriate. This should be requested as soon as possible in the procedure.

References:

For VRA that are on a reduced timetable (30 days) no advance notice is required.

However, in order to facilitate the planning of VRA that run on longer timetables, MAHs are advised to send a notification of intent, including details of the change via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets, at least 2 months in advance of submission of a VRA following a standard (60 days) timetable and at least 4 months in advance of submission for VRA following an extended timetable (90 days). This is to coordinate the availability of the rapporteurs and, when relevant (for instance in case of application for a new indication or changes of active substance(s)), the CVMP can be informed of the future submission and agree on the co-rapporteur’s involvement and submission date.

The notification of intent to submit should provide the following information:

  • Types and scope of variations;
  • MAH target submission date;
  • MAH contact person for the VRA.

A shorter pre-submission phase is envisaged in cases where:

  • the variation concerns the implementation of urgent safety-related changes;
  • the variation concerns the implementation of changes requested by CVMP (e.g. following signal detection procedure or post-authorisation measure assessment).

Please inform the Agency via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets.

The involvement of the co-rapporteur depends on the scope of the procedure. The co-rapporteur is normally not involved in the assessment of an application for VRA concerning quality, safety and most of the clinical changes within the product information.

The involvement of the co-rapporteur is, however, deemed necessary for new indications, new target species, and changes of active substance(s), strength, pharmaceutical form, route of administration or food producing target species.

For other VRA the involvement of the co-rapporteur will be decided by the CVMP on a case-by-case basis. The Agency will inform the MAH accordingly.

References:

MAHs may choose to group the submission of several VRA for the same product into one application. It is not possible for a MAH to group VRA with variations not requiring assessment (VNRA).

Grouped VRA will be processed according to the longest timetable applicable to any of the included variations.

Where one or more VRA affects several marketing authorisations from the same holder, the MAH must submit these variations as one application for ‘worksharing’. Please also refer to the Q&A on worksharing of variations.

Due to resources required for assessing VRA, it is strongly recommended that MAHs submit grouping procedures corresponding to the following cases:

  • All variations in the group are changes to an Active Substance Master File, Vaccine Antigen Master File or vaccine Platform Technology Master File.
  • All variations in the group relate to a project intended to improve the manufacturing process and the quality of the medicinal product concerned or its active substance(s).
  • All variations in the group relate to the implementation of a given class labelling.
  • All variations in the group are consequential to a given post-authorisation study conducted under the supervision of the holder.
  • All variations in the group are safety-related changes.
  • All variations in the group are efficacy-related changes.

In addition, there are some restrictions for VRA included in Chapter I of the Guidance:

Grouping of ‘I’ variations with non-I-variations:

Grouping of I-variations concerning changes of active substance(s), strength, pharmaceutical form, route of administration or food producing target species (‘I’ category variations) with unrelated non-I-variations is discouraged due to the limited time available for the assessment of the changes. If other changes, such as updates to the Active Substance Master File (ASMF), are required the MAH is advised to submit these separately and in advance of the submission of the ‘I’ variation(s).

However, where the MAH proposes, in any case, to simultaneously submit an I-variation with a non-I-variation, particularly where all the simultaneous VRAs affect the product information, please discuss the possibility of grouping with vet.applications@ema.europa.eu in advance of the upcoming submission.

Grouping of multiple ‘I’ variations such as addition of a food-producing target species, new pharmaceutical form and new strength is permissible.

References

An application for VRA should contain the elements listed in Article 62 of Regulation (EU) 2019/6 and should be presented in accordance with the appropriate headings and numbering of the dossier format.

Add-info folder

A cover letter stating the nature of the change. For grouped VRA, include a short overview of the nature of the changes and indicate whether the proposed grouping is in accordance with question 5

  • Can I group the submission of VRA? Can they be grouped with other types of variations?, or, indicate whether the grouping has already been agreed with the Agency.
  • If the variation addresses a specific post-authorisation measure (PAM), the applicant should refer to the PAM reference number in the cover letter, application form and clinical and/or non-clinical overview, as appropriate. In case the reference number for the PAM has not been confirmed by the Agency, a description of the commitment/measure is sufficient at time of submission.

Part 1

  • The completed veterinary EU variation application form (as published on the eAF eSubmission website), including the details of the marketing authorisation concerned. Where a variation leads to or is the consequence of other variations, a description of the relationship between these variations should be provided in the appropriate section of the application form. All proposed changes should be declared in the ‘Type of changes’ section of the form and be clearly described in the “scope” section of the form. In case an alternative timetable has been agreed in advance, please indicate and provide supporting documentation.
    • For VRA under ‘I’ category, the completed MAA-Vet application form should be dated and signed by the official contact person as specified in the application form. Section 1.2 should be ticked as “Yes” and the relevant type of I Variation change(s) selected. The EMA strongly recommends the use of a single electronic application form per submission, even if the submission concerns multiple strengths/pharmaceutical forms.
    • The 'present/proposed' section in the application form should reflect all proposed changes to the English product information (SPC, Annex II, labelling and package leaflet) as current and proposed text. Alternatively, if the proposed changes are extensive, the MAH may instead provide the 'present/proposed' comparison as part of a separate annex to the application form. In this case, the MAH should include in the 'present/proposed' section of the application form a cross-reference to this annex.
    • For VRA concerning quality changes, the 'present/proposed' table (or annex) should reflect all changes applied for. Dossier section numbers should be provided to the lowest level possible and, where feasible, include the precise current and proposed wording as reflected in the relevant sections of the dossier. Where this is not feasible, a summary of the change(s) applied for should be included in the section.
  • Reference to the part of the Guidance or reference to the published recommendation on the classification of variations not already listed, if applicable, used for the relevant application. In case of groupings, the corresponding classification scopes should be indicated as many times as needed taking into account that one classification scope is to be indicated per variation.
  • Update or addenda to the critical expert reports (quality, safety, efficacy as appropriate). When safety or clinical study reports are submitted, even if only one, their relevant summaries should be included.
  • For variations submitted to implement changes requested by the Agency or for generic/hybrid medicinal products, a copy of the request should be annexed to the cover letter.

If changes to the product information are proposed, a revised full set of annexes (SPC, Annex II, labelling and package leaflet) should be provided in English. The application must include clean and highlighted versions of the annexes, clearly showing all proposed amendments in tracked changes. The clean version should be provided as a PDF document and the highlighted version as a word document as part of the 'working documents'. In addition, the proposed product information should always be included in the dossier as a PDF version with tracked changes, as a comparison of the present and proposed wording in the application form and/or as an attachment to the application form. Please see also “When do I have to submit revised product information? In all languages?”.

Parts 2, 3 and 4

  • Supporting quality, non-clinical and/or clinical data/study reports relating to the proposed variations, including literature references, should be provided.

It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and good quality documentation is crucial to the overall process.

For queries relating to the presentation of the application, please contact the Agency.

References

There are two types of submission deadlines and consequently procedure start dates: monthly and weekly ones.

Weekly starts are applicable to applications for VRA received by the Agency that follow a reduced timetable (30 days).

Applications for VRA that follow standard (60 days) or extended (90 days) timetables have monthly start dates.

Grouped VRA will be processed according to the longest timetable applicable to any of the included variations in the application.

Opinions for variations with weekly start dates may be adopted by way of written procedure and are independent of plenary Committee meetings. However, when a linguistic review is required for a reduced VRA there are specific submission dates to facilitate an opinion being adopted during the Committee plenary meeting.

Opinions for monthly start variations are adopted during the Committee plenary meetings.

Where appropriate, EMA/CVMP may decide to use other timetables, than those detailed in the Guidance, not exceeding 90 days. The Agency will inform the MAH of the applicable timetable, and consequently submission date, in the validation confirmation e-mail.

For more information see also question ‘How shall my variation requiring assessment application be handled (timetable)?’.

For both weekly start and monthly start assessment timetables, the MAH should submit their applications at the latest by the recommended submission dates published on the Agency’s website.

MAHs are reminded of their legal obligation to submit forthwith any information that becomes available which might require a variation of the MA. In particular, for any signal which has been detected, validated and assessed by the MAH as changing the benefit-risk balance or representing a new risk, following the submission in the Veterinary Signal Management module of the Union Pharmacovigilance Database, MAHs are required to also submit a VRA category G.I.19.

In addition, MAHs should submit any variation application resulting from the fulfilment of a post-authorisation measure (recommendations or specific obligations) within the requested timeframe. Please see also the Q&A on post-authorisation measures.

Where the CVMP requests the submission of a variation following the assessment of a detected signal or of a post-authorisation measure, or following adoption of class-labelling, MAHs must submit the corresponding variation application at the latest within 2 months following the adoption of the relevant assessment.

Variation applications resulting from the imposition of temporary safety restrictions shall be submitted without undue delay to the Agency.

Implementation of agreed wording changes following the above-mentioned procedures for which no additional data are submitted by the MAH will follow a variation not requiring assessment under the C.4 classification of the Commission Implementing Regulation (EU) 2021/17.

References

When two or several stand-alone applications for VRA are being submitted and/or assessed in parallel, the following general principles apply:

  • Each variation should comprise only the supporting data and product information changes proposed in the context of the specific variation;
  • The assessment of the different variations will be independent and the procedures will be kept separate regardless of the anticipated timelines of the different procedures;
  • The product information from one variation should not include the proposed product information changes from a different variation, neither as highlighted nor as clean text.

In order to simplify the handling of different versions of the product information, submissions affecting the product information should be, whenever possible, combined in a grouped variation application. It is strongly recommended that MAHs submit grouped procedures corresponding to the cases listed in the Q&A on grouping of VRA.

Once a Commission Decision has been granted for a VRA, the approved product information can be used as baseline for the product information of any subsequent variations. The consolidation can be done at the time of any procedural milestone of the subsequent variations, e.g. as part of the MAH's responses to a request for supplementary information, but in any case at the latest before the adoption of the CVMP opinion.

Once included, the already approved changes related to a previous variation should appear as clean text in both the clean and highlighted versions of the product information for subsequent variations. Only the new proposed changes related to the subsequent variation should continue to be highlighted in tracked changes during that procedure.

Upon adoption of the CVMP opinion, the Agency will inform the MAH within 15 days as to whether the opinion is favourable or unfavourable (including the grounds for an unfavourable outcome), as well as whether the Annexes to the Commission Decision granting the marketing authorisation require amendment.

Where the outcome of the procedure is favourable and the Annexes to the Commission Decision granting the marketing authorisation require amendment, the Agency will inform the Commission accordingly.

Re-examination

In accordance with Article 66(10) and (11) of Regulation (EU) 2019/6 the MAH may give written notice to the Agency that it wishes to request a re-examination within 15 days of receipt of the CVMP opinion on VRA.

A positive CVMP opinion may be subject to re-examination as long as the request for re-examination relates to aspects of the opinion for which there had been objections by the Committee, further to which the MAH opted to amend the application. In such a case, the MAH, when submitting the amended documentation (e.g. revised product information) prior to the opinion, will need to reserve

the right to re-examination in the covering letter. MAHs should refer to the EMA website for further specific Procedural advice to applicants/marketing authorisation holders on re-examination of CVMP opinions (according to Regulation (EU) 2019/6).

Linguistic review

Where the product information is affected, a linguistic review of the changes to the product information will be performed. The linguistic review will start 5 days after the CVMP plenary meeting following the adoption of the CVMP opinion on the variation. Please refer to the The linguistic review process of product information in the centralised procedure - veterinary for further information.

In the event that the only change to the product information concerns deletion of text or a change to numerical characters, e.g. shelf life of a finished product, no post-opinion linguistic review will be necessary.

In all cases, the MAH should provide the amended product information in all languages, by the date specified in the translation timetable, which is provided with the CVMP opinion.

Decision-making process

Following the adoption of a favourable CVMP opinion which requires amendment of the Annexes to the Decision granting the marketing authorisation, and upon receiving the complete translations of the product information, the Commission shall amend the marketing authorisation (Decision) to reflect the variation within 30 days.

The Agency will apply the post-opinion timeframes set out in the document on The linguistic review process of product information in the centralised procedure - veterinary. The Agency, in cooperation with the QRD members and the MAH, will aim to provide final, checked translations to the Commission by Day +27. (See also: “When do I have to submit revised product information? In all languages?”)

Where a group of variations, submitted as one application, to the terms of one marketing authorisation has been approved, the Commission will update the marketing authorisation with one single decision covering all the approved variations.

Implementation

VRAs which require amendment of the Annexes to the Decision granting the marketing authorisation may only be implemented once the Commission has amended the Decision. The time limit for the implementation of these VRAs is set by the Commission and will be included in the Commission Decision on the VRA (the default implementation time is 6 months unless otherwise stated in the Decision e.g., it is 12 months for non-grouped G.I.18 VRAs).  

VRAs which do not require any amendment of the Annexes to the Decision granting the marketing authorisation can be implemented once the MAH has been informed of the favourable outcome by the Agency.

References

For information on the fee applicable for VRA, please refer to fees payable to the European Medicines Agency.

When an inspection is required, please note that in addition an inspection fee will be requested (see also the pre-submission guidance “What is the fee for a GMP/GCP/pharmacovigilance inspection?”).

References

  1. Do I have to submit mock-ups?

Please consult the Mock-ups section of this Q&A.

References

Please consult the Mock-ups section of this Q&A.

References

Where the VRA affects the SPC, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

  • At submission
    • English language: revised complete set of product information annexes. The application must include a clean and highlighted version of the annexes, clearly showing all proposed changes in tracked changes. The clean version should be provided in Part 1b of the dossier and the highlighted version should be provided as a word document as part of the 'working documents' in the Add-info folder. The provision of a highlighted word version is mandatory as it facilitates the review of the application. The highlighted version should additionally be provided as a PDF document in Part 1b. In addition, proposed changes must be documented in the ‘present/proposed table’ of the application form or in an annex to the application form.
  • During the procedure
    • English language: The MAH should take into account the assessment feedback and provide revised versions of the highlighted product information as part of the responses to any requests for supplementary information during the procedure. The revised highlighted product information provided as part of the responses to requests for supplementary information should be submitted in line with the requirements outlined above 'at submission'.
    • In addition, during the later stages of the procedure there is often a need for fast informal exchanges between the MAH and EMA or the rapporteur in preparation of the CVMP opinion. During this process the MAH can provide any revised versions of the product information as well as comments/justifications, such revised versions may be provided in Word format via Eudralink or email. These product information versions are considered 'working documents' only and there is consequently no need to submit these updated product information proposals as part of a formal Gateway submission (unless they are part of formal responses to a CVMP list of questions or list of outstanding issues).
  • After the CVMP opinion (Day +5)
    • All EU languages (incl. Norwegian and Icelandic, and Irish for MAHs established in Ireland that have not submitted an Irish language derogation). Translations for the variations should be sent directly to the NCAs Member states contact points for translations review:
      - if a linguistic review will be performed: complete set of annexes electronically only in Word format (highlighted);
      - if a linguistic review will not be performed: complete set of annexes electronically only in Word format (highlighted) and in PDF (clean bookmarked) to be submitted to the EMA.
  • After linguistic review (Day +25)
    • All EU languages (incl. Norwegian and Icelandic, and Irish if required): complete set of annexes electronically only in Word format (highlighted) and in PDF (clean bookmarked)

According to Article 145(2) of Regulation (EU) 2019/6, Commission Decisions on VRA will be adopted, where applicable, following a Standing Committee consultation procedure. Consequently, there will be no further revision of the translations of the Annexes after Day +25.

Overview in case of linguistic review:

DayLang*Post-opinion linguistic review Timetable
At submissionENElectronically Word format (highlighted)
+5All EEAElectronically Word format (highlighted)
+25All EEAElectronically Word format (highlighted) PDF format (clean)

 

* = complete set of Annexes, i.e. Annex I, II, IIIA and IIIB, submitted as one document per language

The ‘complete set of Annexes’ includes Annex, I, II, IIIA and IIIB, i.e. SPC, labelling and package leaflet texts for all strengths and pharmaceutical forms of the product concerned, as well as Annex II. The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. As of 1 January 2022 this includes the Irish language for MAHs established in Ireland that have not provided an Irish language derogation to the Agency. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. All Annexes should be in compliance with the ‘Quality Review of Documents (QRD) convention to be followed for the European Medicines Agency QRD templates’ published on the Agency website. When submitting the full set of Annexes in PDF format, the formatting checklist and the User guide on how to generate PDF versions of the product information - veterinary should be followed.

Highlighted changes should be indicated via ‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

Icelandic and Norwegian language versions must always be included.

The Annexes provided should only reflect the changes introduced by the variations concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts, or to align the product information with the latest QRD template, this should be clearly mentioned in the cover letter and in the precise scope section of the application form. In addition, the section “present/proposed” in the application form should clearly list the minor linguistic amendments introduced for each language. Alternatively, such listing may be provided as a separate annex to the application form. Any changes not listed will not be considered as part of the variation application. In such cases, and in cases where any other ongoing procedures may affect the product information Annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedures concerned.

References

Any changes in the number of units of a veterinary medicinal product will trigger a different EU number.

Differentiation should be made between the addition of a presentation, where previous and new presentations will co-exist on the market on a long-term basis versus the replacement of a presentation where the new presentation will replace the previous one (it is expected that for a certain period of time the two presentations will co-exist on the market until the stock of the previous presentation runs out).

In principle, a replacement of one presentation by another presentation does not trigger a new EU number, unless the number of units of veterinary medicinal product is changed.

Examples of changes in presentations for replacement, not triggering a new EU number (this is not an exhaustive list):

  • Replacement of the primary or secondary packaging,
  • Change in composition (e.g. change in excipients).

In case of addition of one or more presentations, where the previous and new presentations will co-exist on the market, packs with different contents cannot be covered by the same EU number. They will be considered as different presentations that require different EU numbers.

Changes in the number of any unit (not restricted to the veterinary medicinal product) or changes in the specifications of any unit (not restricted to the veterinary medicinal product) contained in the pack will trigger a new EU number.

An example of another change that would trigger a new EU number is the introduction of an alternative immediate (primary) packaging made from a different material.

If you have any questions on any upcoming submission, please contact the Agency via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets.

At the time of adoption of a CVMP opinion for a VRA which includes additional presentations, the Agency will assign new EU numbers, which will be transmitted to the MAH together with the CVMP opinion and respective annexes.

Where applicable, the MAH should include the newly assigned numbers in all language versions and in all applicable sections of the product information, which are submitted following the CVMP opinion for linguistic review.

If the opinion for a VRA is adopted during the CVMP plenary meeting then the name of the product and the general categorisation of the VRA is included in the published CVMP meeting highlights for that meeting.

More detailed information is published for the following variations: variations concerning the addition of a new therapeutic indication or the modification of an existing one; variations concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine; variations concerning the addition of a new contraindication; variations concerning the addition of a non-food producing target species or the modification of an existing one; and variations concerning changes to the withdrawal period for a veterinary medicinal product. For these VRA the CVMP meeting highlights will include the name of the product, the indication and specific details of the change.

The CVMP meeting highlights following each CVMP meeting also give information on opinions on the ‘I’ variations which are variations concerning changes of active substance(s), strength, pharmaceutical form, route of administration or food producing target species. The published information will include the name of the MAH and the nature of the change.

For variations requiring assessment mentioned in paragraph2 above, the CVMP assessment report, with commercially confidential information deleted, will be published after the adoption of the Commission Decision.

For these variations, together with the CVMP meeting highlights, a ‘summary of opinion’ for the VRA is published by the Agency. This document summarises the variation concerned (e.g. MAH, indications, target species, pharmaceutical form).

The CVMP monthly report following each CVMP meeting provides up-to-date information related to the volume and evaluation of pre- and post-authorisation applications (including VRA) for veterinary medicinal products.

VRA’s that are adopted by written procedure outside of the plenary meeting (reduced TT) are not included on the meeting highlights and information is not published.

For information on publication principles to be followed in case of withdrawal of a VRA, please refer to the respective CVMP reflection paper on publication of withdrawals of marketing authorisation applications for veterinary medicinal products (Reflection paper on publication of withdrawals of marketing authorisation applications for veterinary medicinal products).

References

General principles

If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation. They may be included in any variation that concerns the part of the dossier in which the editorial changes are to be made. In such cases the changes should be clearly identified in the application form as editorial changes, and a declaration that the content of the concerned part of the dossier has not been changed by the editorial changes beyond the scope of the variation submitted should be provided. Changes that can be classified as a variation according to the Guidance are not considered editorial changes and should be submitted under the appropriate variation category. The Agency strongly recommends the submission of editorial changes within procedures that have an administrative validation phase (i.e. VRA). This allows for the appropriate review of proposed editorial changes during validation and any consequential amendment of the submission prior to assessment, if needed. The editorial changes proposed should affect the same part of the dossier as concerned by the variation procedure. For example, if a variation affects Part 2.C, editorial changes to Part 2.C can be submitted.

MAHs are reminded to follow this guidance and to ensure a high quality of variation applications to support timely processing of these submissions.

Since editorial changes should generally not be submitted as a separate variation, no reference to a variation category is required when they are encompassed within another variation procedure.

Within the ‘Precise scope and background…’ section of the variation application form, the MAH should provide:

  • a brief description of the proposed editorial changes and a justification as to why they are considered ‘editorial’ (i.e. why they should not trigger a specific variation);
  • a declaration confirming that the changes proposed as editorial do not change the content of the concerned part(s) of the dossier beyond the scope of the variation within which the editorial changes are being submitted;
  • confirmation that all relevant parts of the dossier have been updated accordingly and are included within the variation package.

Additionally, all the editorial changes should be listed in the present/proposed table (or provided as a separate annex that is cross-referred to from this table), identifying each related change in the dossier down the lowest section heading and page numbers where possible.

Any changes proposed by the applicants as editorial will be carefully considered by the Agency at time of submission and may be subject to further assessment at the same time as the overarching variation. Proposed editorial changes that cannot be accepted as such will be rejected. In case of doubt, applicants can contact the Agency via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets in advance of the planned submission.

Editorial changes in Part 2 (quality)

The following may be considered as examples of editorial changes to Part 2: adding headers for ease of use, reordering of existing information without changing the meaning, alignment of information among/within the sections, provided the correct reference that had been previously agreed can be demonstrated (e.g. alignment of information in flow charts to process description), punctuation changes and grammar/orthographic corrections that do not alter the meaning of the text.

Examples of changes that cannot be considered editorial: removal of specification parameters or manufacturing description, update of information to bring the dossier content in line with the current manufacturing process, etc.

Proposed changes that require confirmation by the rapporteur may only be accepted when submitted within the scope of an upcoming VRA which impacts upon the corresponding section of Part 2.

If editorial changes are required and there is no upcoming procedure, the MAH may consider submitting these changes separately as a variation not requiring assessment (VNRA, B.43).

Editorial changes in Parts 3 (safety & residues) and 4 (pre-clinical & clinical)

Editorial changes in Parts 3 and 4 are not foreseen. Please contact the Agency via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets.

Editorial changes to the product information in Part 1.B (SPC, labelling and package leaflet)

Formatting changes, correction of typographical errors and/or mistakes to the English product information or other linguistic versions of the product information are considered editorial changes provided that the meaning of the text is not altered. These changes can be included within the scope of any upcoming procedure impacting on the product information.

Changes in the scientific content or meaning cannot be accepted as an editorial change. These changes should be classified under the scope of the relevant category in accordance with the Guidance (e.g. G.I.4).

Proposed changes that may require confirmation by the rapporteur or linguistic review will only be accepted when submitted within the scope of an upcoming VRA under chapter G the Guidance which impacts upon the product information and where linguistic review is foreseen, if applicable.

Should there be no upcoming regulatory procedure in which to include the editorial changes, these could also be submitted as a stand-alone variation not requiring assessment e.g. under C.9 if they affect the English product information. If other languages are affected and in case no procedure affecting the product information is upcoming, MAHs are advised to contact the Agency via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets, to discuss how to handle these necessary changes.

The MAH should liaise with the Agency without delay if a mistake is noted that concerns incorrect or missing important information (e.g. contra-indication or adverse event), in the English or any of the other language versions, that could affect the safe and effective use of the medicinal product and/or lead to potential medication errors (e.g. wrong strength, wrong posology, wrong route of administration).

References

The following complex, related changes could be considered for submission under a single VRA scope F.II.b.1 - Addition of a new finished product (FP) manufacturing site: changes to the manufacturing process, batch size and in-process controls to adapt to the new manufacturing site settings.

Complex, related changes submitted under a single VRA should always be clearly identified in the application form as follows: a clear description of all the related changes should be provided in the precise scope. All the related changes should be listed in the present/proposed table.

Changes affecting the FP not directly related to the introduction of the new manufacturing site such as changes in excipients, specification parameters /limits for the FP, container closure system including suppliers should be submitted as additional variation scopes.

Any pre-submission queries of any intended submission of complex related changes under one single VRA scope should be addressed via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets.

The introduction of a new manufacturing site for an active substance supported by an ASMF should be submitted under a single VRA scope F.I.a.1.a). The introduction of a new manufacturer of the active substance not supported by an ASMF that requires significant updates to Part 2C of the dossier should be submitted under a single VRA scope F.I.a.1.e).

In cases where the introduction of the new manufacturer has an impact at the level of the finished product manufacturer (e.g. changes to the active substance specifications or related analytical methods) separate variations have to be submitted under the corresponding variations listed under F.I.b. They may be grouped together, if related to the introduction of the new active substance manufacturer.

Any pre-submission queries of any intended submission of complex related changes under one single VRA scope should be addressed via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets.

In principle, one change to the product information supported by one set of data constitutes one assessment and consequently one scope, i.e. one single VRA.

All data/study reports provided as part of a variation must support the same changes to the product information. If this is not the case, i.e. some data support one change (update A), and other data support another change (update B), it will be necessary to submit separate stand-alone variations or a group of variations, as appropriate; one variation for product information update A including the data supporting A, and one variation for product information update B including the data supporting B.

Only when changes are consequential to the same supporting data, can one VRA application propose changes to several different sections of the SPC, as well as corresponding changes to the package leaflet. Any additional changes to the product information that are consequential to the assessment of another set of data will have to be submitted as part of a separate variation (stand-alone or part of a grouped application, to be decided on a case-by-case basis).

Any pre-submission queries of any intended submission of complex related changes under one single VRA scope should be addressed via Service Now by selecting Veterinary Regulatory > Post-Authorisation-Vets.

How useful do you find this page?

Average: