Q&A: Type II variations

The Variations Regulation defines a major variation of Type II as a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of a medicinal product.

The Variations Regulation and the Variations Guidelines set out a list of changes to be considered as Type II variations. In addition, any other change which may have a significant impact on the quality, safety or efficacy of the medicinal product must be submitted as a Type II variation. Please refer also to the Q&A on Type II variations vs extensions.

During validation of an ‘unforeseen’ variation, submitted by the MAH as a Type IB variation, the Agency may consider that the proposed variation may have a significant impact on the quality, safety or efficacy of the medicinal product. In such case, the MAH will be requested to revise and supplement its variation application so that the requirements for a Type II variation application are met (see also the Q&A on Type IB variations ”How shall my Type IB variations be handled (timetable)?”).

References

• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Variations Guidelines (2013/C 223/01)
• Q&A on Type II variations vs extensions
• Q&A on Type IB variations

In order to facilitate the planning of a Type II variation, MAHs are advised to send a notification of intent for a Type II variation by email to vet.applications@ema.europa.eu at least 2 months before submitting the application, so that the availability of the rapporteurs can be checked and, when relevant (for instance in case of application for a new indication), the CVMP can be informed of the future submission and agree on the co-rapporteur’s involvement and timetable.

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 type II variation.

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 PSUR or PAM assessment).

Please inform vet.applications@ema.europa.eu as soon as possible in advance of such submissions.

The co-rapporteur is normally not involved in the assessment of a Type II variation application 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 and new non-food-producing target species.

The involvement of the co-rapporteur in other Type II variations will be decided by the CVMP on a case-by-case basis. The Agency will inform the MAH accordingly.

Regarding the submission of a Type II variation application to the (co-)rapporteurs, please see also 'How and to whom shall I submit my Type II variation application'.

Marketing authorisation holders may choose to group the submission of several Type II variations for the same product into one application, provided that this corresponds to one of the cases listed in Annex III of the Variations Regulation or when this has been agreed previously with the Agency.

It is also possible for a marketing authorisation holder to group a Type II variation with other variation submission (e.g. Extension, Type IB or IA variations), where applicable. Such grouped submissions will follow the review procedure of the highest level of variation in the group. Please also refer to the Q&A on grouping of variations.

Where the same Type II variation(s) affects one or more marketing authorisations from the same holder, the marketing authorisation holder may choose to submit these variations as one application for ‘worksharing’. Please also refer to the Q&A on worksharing of variations.

References

• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Q&A: Grouping of variations
• Q&A: Worksharing of variations

A Type II variation application should contain the elements listed in Annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the dossier format.

The Variations Guidelines further specify which elements should be included in a Type II variation application:

• Cover letter (for groupings, include a short overview of the nature of the changes and indicate whether it is an allowed grouping in Annex III of the Variations Regulation or the grouping has 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 (or contact vet.applications@ema.europa.eu to check for the PAM reference number).
• The completed 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.
  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 applicant may instead provide the 'present/proposed' comparison as part of a separate annex to the application form. In this case, the applicant should include in the 'present/proposed' section of the application form a cross-reference to this annex.
  For type II variations concerning quality changes, the 'present/proposed' table (or attachment) 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 Variations Guidelines or reference to the published Article 5 Recommendation, if applicable, used for the relevant application. The extract(s) of the Variations Guidelines should preferably be submitted as a separate annex in Part 1a administrative information. 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 Addendum to the detailed critical summaries (quality, safety, efficacy as appropriate). When safety or clinical study reports are submitted, even if only one, their relevant summary(ies) should be included.
• For variations submitted to implement changes requested by the Agency or for generic/hybrid/biosimilar 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 preferably 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 is crucial to the overall process.

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

References

• Commission Regulation (EC) No 1234/2008
• Classification guideline
• Electronic application forms website
• Article 5 procedure: Regulatory and procedural guidance

All submissions should be made in accordance with the guideline on e-submissions.

Applicants should use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. For more information, including links to guidance on registration with the system, see the Veterinary eSubmission website.

All submissions for centrally authorised products (CAP) sent to EMA via the eSubmission Gateway/Web Client will be considered delivered to all National Competent Authorities (NCA) representatives, alternates and scientific experts.

References

• Electronic application forms website
• Dossier requirements for submission of MA and MRL applications to the EMA and to members of the CVMP
• Veterinary eSubmission website
• eSubmission Gateway and Web Client information website

The MAH should submit Type II applications at the latest by the  Recommended submission dates for centralised and maximum-residue-limit procedures published on the Agency’s website.

MAHs are reminded, especially for safety issues, that once new information becomes available which might entail the variation of the MA, MAHs should submit any variation application resulting from the fulfilment of post-authorisation measures (recommendations, conditions or specific obligations) and periodic safety update reports (PSURs) at the same time as the fulfilment of the post-authorisation measure or submission of the PSUR, rather than awaiting the assessment of those data by CVMP. Please see also the Post-authorisation measures (recommendations, conditions and specific obligations)

Where the CVMP requests the submission of a variation following the assessment of a PSUR or 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 conclusion.

Variation applications reflecting the outcome of an Urgent Safety Restriction (USR) shall be submitted immediately and in any case no later than 15 days after the initiation of the USR to the Agency. This applies to USRs initiated by the MAH or imposed by the European Commission.

Implementation of agreed wording changes following the above mentioned procedures for which no additional data are submitted by the MAH will follow a Type IB variation procedure.

References

• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Recommended submission dates for centralised and maximum-residue-limit procedures
• Post-authorisation measures (recommendations, conditions and specific obligations)

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 can be found in the  Recommended submission dates for centralised and maximum-residue-limit procedures

Assessment of Type II variations following a 90-day, 60-day or 30-day timetable will follow the recommended submission dates (see also question 'When shall I submit my application?' above).

One of the following timetables (TT) shall apply:

For a 60-day TT (standard timetable):

Conditions:

All standard Type II variations; i.e. excluding those qualifying for a 30- or 90-day TT(see below)

For a 30-day TT:

Condition:

For variations concerning changes which, in the opinion of the Committee, would benefit from a shortened assessment having regard to the urgency of the matter, in particular for safety issues. Please note, if the 30-day Type II procedure requires a linguistic review of the product information, this will take place in parallel with the scientific assessment.

In exceptional cases, this timetable could be further shortened.

For a 90-day TT:

Condition:
For variations concerning changes to or addition of therapeutic indications, and other variations listed in Part 2 of Annex V of the Variations Regulation.

MAHs are encouraged to contact vet.applications@ema.europa.eu in advance of the submission, in case clarification on the timetable for a specific variation is needed.

Where issues are identified which prevent the adoption of an opinion, the CVMP will adopt a request for supplementary information 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.

As a general rule, a clock-stop of up to one month will apply. For clock-stops 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. new indications or where the variation requires an inspection) a clock-stop of up to a maximum of six months may be applied.

For any follow-on request for supplementary information, an additional clock-stop of up to one month will be applied in general; a maximum of two months may be applied when justified.

The CVMP assessment of responses to the request for supplementary information will take up to 60 days for assessment of responses to a list of questions or 30 days for assessment of responses to a list of outstanding issues.

An oral explanation to the CVMP can be held at the request of the CVMP or the MAH, where appropriate.

References:

• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Variations Guidelines (2013/C 223/01)
•  Recommended submission dates
• Guidance to applicants / marketing authorisation holders on oral explanations at CVMP

When two or several stand-alone Type II variation applications 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, if allowed by grouping rules or if agreed in advance with the Agency.

Once a CVMP opinion has been adopted for a Type II variation, or a Commission decision has been granted in case an immediate EC decision applies, 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. It should be noted that 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 the unfavourable outcome), as well as whether the Commission decision granting the marketing authorisation requires any amendments.

Where the outcome of the procedure is favourable and the Commission decision granting the marketing authorisation requires amendments, the Agency will inform the Commission accordingly.

Re-examination

Article 34(2) of Regulation (EC) No 726/2004 also applies to CVMP opinions adopted for Type II variation applications. This means that the MAH may give written notice to the Agency/CVMP that it wishes to request a re-examination within 15 days of receipt of the opinion.

A positive opinion may be subject to re-examination as long as the request to 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 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 guidance on re-examination of CVMP opinions.

Linguistic review

Where the product information is affected, a linguistic review of the product information changes 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 guidance on the linguistic review process 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 would be necessary.

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

Decision-making process

Upon receipt of the final CVMP opinion that requires amendments to the decision granting the marketing authorisation, the Commission shall amend the marketing authorisation to reflect the variation within two months for the variations listed under Article 23(1a)(a) or within one year for the other variations.

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. The Agency, in cooperation with the QRD members and the MAH, will aim to providing final, checked translations to the Commission by Day +27. (See also: “When do I have to submit revised product information? In all languages?”)

The below timeline only applies in case of 2-monthly update.

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 to cover all the approved variations.

Implementation

Type II variations listed in Article 23(1a)(a) may only be implemented once the Commission has amended the marketing authorisation and has notified the MAH accordingly. Variations related to safety issues, including urgent safety restrictions, must be implemented within a timeframe agreed by the MAH and the Agency.

Type II variations which do not require any amendment of the marketing authorisation or which follow a yearly update of the respective Commission decision can be implemented once the MAH has been informed of the favourable outcome by the Agency. However, it is expected that, where the variation includes changes to the product information, the MAH waits for the finalisation of the linguistic review process by the Agency before implementing the variation, as appropriately checked translations are considered essential for a correct implementation of the variation.

The agreed changes should be included in the product information annexes of any subsequent regulatory procedure.

References

• Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Variations Guidelines (2013/C 223/01)
• Procedural advice to applicants/marketing authorisation holders on re-examination of CVMP opinions
• The linguistic review process of product information in the centralised procedure - veterinary

For information on the fee applicable for Type II variations, please refer to Fees payable to the European Medicines Agency. The fee covers all authorised strengths, pharmaceutical forms and presentations of a given medicinal product. Reduced Type II fees may apply to certain variations.

For Type II variations which introduce additional presentation/pack-sizes, each additional presentation/pack-size attracts separate fees (x additional presentations x separate fees). Each presentation/pack-size should therefore be declared as a separate variation on the variation application form. However, in the case of a Type II variation concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine against avian influenza, foot-and-mouth disease or bluetongue (variation classification C.II.4), when authorised on the basis of a multi-strain dossier, the single Type II variation will also cover within its scope the addition of associated presentations.

Grouped Type II variations, whether consequential or not, will each attract a separate Type II fee.

The Agency will issue an invoice following the notification of the administrative validation to the applicant and fees will be payable within 30 calendar days of the date of the invoice. The invoice will be sent to the billing address indicated by the MAH and will contain clear details of the product and procedures involved, the type of fee, the amount of the fee, the bank account to where the fee should be paid and the due date for payment.

Applicants requiring a purchase order number or similar references on the invoice are requested to clearly indicate it on the cover letter or application form accompanying the dossier, as well as in the “Customer reference” box of the delivery file to be generated for submission via the EMA Gateway. The Agency does not accept standalone notifications of purchase order numbers that are not associated with a dossier.

If the Type II variation is considered ‘invalid’ (i.e. an assessment process cannot be started), an administrative fee will be charged by the 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

• Fees payable to the European Medicines Agency
• How to pay

Please consult the .

Where the Type II Variation affects

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

• At submission (Day 0)
  • 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 and the highlighted version should be provided as a word document as part of the 'working documents' – Add Info. 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 that is provided at these procedural milestones 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 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 by Eudralink/email in Word format. 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 part of formal responses to a CVMP list of questions/outstanding issues).
• After CVMP opinion (Day +5)
  • All EU languages (incl. NO+IS):
    - 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)
• After linguistic review (Day +25)
  • All EU languages (incl. NO+IS): complete set of annexes electronically only in Word format (highlighted) and in PDF (clean bookmarked)

According to Article 23 of the Variations Regulation, Commission decisions on Type II variations will be adopted without a Standing Committee procedure. Consequently, there will be no further revision of the translations of the Annexes after Day +25.

Overview in case of linguistic review:

* = 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. all 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. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. All Annexes should be in compliance with the QRD Convention  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  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.

For those variations which affect the Annex A (e.g. introduction of a new presentation), the Agency will prepare and send to the MAH the revised English Annex A reflecting the new/amended presentation upon adoption of the CVMP opinion. At Day +5 after CVMP opinion, the MAH provides the Agency with the electronic versions of the complete set of Annexes in all languages as well as the translations of the revised Annex A as separate word documents.

References

• Product information: Reference documents and guidelines
•  QRD Convention to be followed for the EMA-QRD templates
•  user guide on how to generate PDF versions of the product information

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

Differentiation should be made between the addition of a presentation where the two presentations will co-exist on the market on a long-term basis versus a 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, as the presentations will co-exist on the market, two packs with different contents cannot be covered by the same EU number and will be considered as different presentations.

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 a 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 vet.applications@ema.europa.eu.

At the time of the adoption of a CVMP opinion for a type II variation which includes additional presentations, the Agency will assign the new EU sub-numbers and include them in the revised Annex A of the veterinary medicinal product, which will be transmitted to the MAH together with the CVMP opinion and respective annexes.

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

The CVMP press release following each CVMP meeting gives information on opinions on 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. The published information will include the invented name of the product and the indications. For these variations, the variation assessment report, with all commercially confidential information deleted, will also be published after the adoption of the Commission decision.

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 Type II variations) for veterinary medicinal products.

For information on publication principles to be followed in case of withdrawal of a Type II variation, please refer to the respective CVMP reflection paper on publication of withdrawals of marketing authorisation applications for veterinary medicinal products (EMEA/CVMP/425558/2006-rev.1) .

References

• CVMP: Agendas, minutes and reports
•   CVMP reflection paper on publication of withdrawals of marketing authorisation applications for veterinary medicinal products(EMEA/CVMP/425558/2006-rev.1)

General principles

The European Commission Variations Guidelines specify that “If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that part of the dossier. 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 Variations Guidelines 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 (e.g. type IB or type II variations. This allows the appropriate review of proposed editorial changes during validation and the consequential amendment of the submission prior to assessment, if needed. The editorial changes proposed should affect the same part of the dossier concerned by the variation procedure. For example, if a variation affects Part 2.C, editorial changes can be submitted in Part 2.C.

Exceptionally, the Agency may accept minor editorial changes as part of IA variations, if affecting the same dossier sub-section impacted by the variation submitted. This is due to the fact that IA notifications are administrative in nature and do not have a validation phase. The Agency expects MAHs to keep proportionality between the submissions of editorial changes versus the real change of the variation. In case of doubt about the acceptability of editorial changes in future type IA applications, MAHs are advised to contact vet.applications@ema.europa.eu in advance of the submission.

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

Editorial changes should generally not be submitted as a separate variation and therefore 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 vet.applications@ema.europa.eu 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 variation type IB or type II 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 as a separate, default Type IB variation (B.I.z or B.II.z, as appropriate).

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

Editorial changes in Parts 3 and 4 are not foreseen. Please contact vet.applications@ema.europa.eu in advance of an upcoming submission.

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 Variations Guidelines (e.g. Type II, C.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 variation Type IB or Type II under chapter C (of the Variations Guidelines) 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, default Type IB variation e.g. under C.I.z 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 vet.applications@ema.europa.eu to discuss how to handle these necessary changes.

The MAH should liaise with the Agency without delay if the mistake concerns an 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

• Commission Regulation (EC) No 1234/2008
• Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
• Variations Guidelines (2013/C 223/01)

The following complex, related changes could be considered for submission under a single type II scope B.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 type II should always be clearly identified in the application form as following: 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 type II scope should be addressed to vet.applications@ema.europa.eu.

The introduction of a new manufacturing site for an active substance supported by an ASMF should be submitted under a single Type II scope B.I.a.1.b). The introduction of a new manufacturer of the active substance not supported by an ASMF that requires significant updates to Part 2C should be submitted under a single Type II scope B.I.a.1.g).

It should be noted that in cases where the introduction of the new manufacturer has an impact at the level of the finish product manufacturer (e.g. changes to the active substance specifications or related analytical methods) separate variations have to be submitted under the corresponding categories B.I.b. and may be grouped together, if related to the introduction of the new active substance manufacturer.

Any pre-submission queries of any intended submission related to these changes should be addressed to vet.applications@ema.europa.eu.

In principle, one change to the PI supported by one set of data constitutes one assessment and subsequently one Type II variation.

All data/study reports provided as part of a variation must support the same changes to the PI. 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 PI update A including the data supporting A, and one variation for PI update B including the data supporting B.

Thus, only when changes are consequential to the same supporting data, can one Type II variation application propose changes to several different sections of the SPC, as well as corresponding changes to the package leaflet. Any additional changes to the PI 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 related to these changes should be addressed to vet.applications@ema.europa.eu.