Type-IB variations: questions and answers
Once a veterinary product has received approval from the Commission (the “Commission Decision”) all further procedures connected with the product will fall under “Post-Authorisation Procedures”.
This guidance provides an overview for a number of procedures that occur frequently and addresses a number of questions which Marketing Authorisation Holders (MAHs) may have.
More information on this post-authorisation procedural advice Q&A.
As of 1 January 2017 it is mandatory for applicants to 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:
- Procedural announcement on mandatory use of eSubmission Gateway for veterinary submissions as of 1 January 2017
- Veterinary eSubmission website
- eSubmission Gateway and Web Client information website
Commission Regulation (EC) No 1234/2008 ('the Variations Regulation') defines a minor variation of Type IB as a variation which is neither a Type IA variation nor a Type II variation nor an Extension. Such minor variations must be notified to the National Competent Authority/European Medicines Agency ('the Agency') by the Marketing Authorisation Holder (MAH) before implementation, but do not require a formal approval. However, the MAH must wait a period of 30 days to ensure that the application is deemed acceptable by the National Competent Authority/the Agency before implementing the change (“Tell, Wait and Do” procedure).
The “Commission guideline on the details of the various categories of variations” ('the Classification Guideline'), contains examples of changes which are considered as Type IB variations. In addition, any change which is not an Extension and whose classification is not determined taking into account the Classification Guideline and the recommendations delivered pursuant to Article 5 of the Variations Regulation, is considered a Type IB variation by default.
When one or more of the conditions established in the Classification Guideline for a Type IA variation are not met, the concerned change may be submitted as a Type IB variation unless the change is specifically classified as a major variation of Type II.
For changes which are submitted as default Type IB variations, the Agency will determine during validation whether the proposed classification as Type IB variation is appropriate before the start of the evaluation procedure (see also “How shall my Type IB variation be handled?”).
The Co-Rapporteur is not involved in the assessment of Type IB variations, however a copy of the complete Type IB notification must also be submitted to all CVMP members (including the Co-Rapporteur) after validation.
MAHs may choose to group the submission of several Type IB variations for the same product into one application. It is also possible for a MAH to group a Type IB variation with other variation(s) for the same product (e.g. Type IA, Type II, Extension), where applicable.
Allowed groupings are listed in Annex III of the Variations Regulation. Other groupings have to be agreed in advance with the Agency. Any proposal to group clinical and quality variations should be adequately justified.
Where the same minor Type IB variation(s) affect more than one marketing authorisations from the same holder, the MAH may choose to submit these variations as one application for 'worksharing'. Please also refer to ”What is worksharing and what type of variations can be subject to worksharing?”.
A Type IB 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 Commission “Guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 “ ('the Procedural Guideline') further specifies which elements should be included in a Type IB 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). The Agency has published a new formatted table template to be inserted in cover letters, found here .
- The completed EU variation application form (as published on the Commission's website in Volume 6C of the Notice to applicants), including the details of the marketing authorisation concerned. Where a variation is considered a Type IB by default, a detailed justification for its submission as a Type IB application must be included. MAHs are reminded that the variation application form should be signed by the official contact person. Should the official contact person not be available, an official letter of authorisation confirming the delegation of signature to a different person should be enclosed.
- Reference to the part of the Classification Guideline, or reference to the published Article 5 Recommendation, if applicable, used for the relevant application.
- Relevant documentation in support of the proposed variation including all documentation as specified in the Commission's Classification Guideline.
- For variations submitted to implement changes requested by the Agency or for generic/hybrid/biosimilar medicinal products, where no new additional data are submitted by the MAH, a copy of the request should be annexed to the cover letter.
- If applicable, the revised summary of product characteristics, labelling and/or package leaflet as a full set of annexes.
For grouped variations concerning one marketing authorisation, all variations must be declared in the variation application form. The documentation requirements for each type of variation in the group must be adhered to. However, the supportive documentation for all variations concerned should be submitted as one integrated package (i.e. there is no need to submit a separate documentation package for each variation).The present-proposed section of the application form should clearly identify the relevant dossier sections in support of each variation. For grouped variations concerning more than one marketing authorisation please refer to ”What is worksharing and what types of variations can be subject to worksharing?".
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. The MAH is responsible for ensuring that the variation complies fully with the data and documentation requirements as specified in the Classification Guideline and in the Procedural Guideline. The MAH should pay particular attention to grouping of variations, for which each change should be clearly identified as well as the related supportive documentation. A confusing dossier presentation will not facilitate rapid procedures.
Submission of Type IB Applications
One electronic copy of the Variation application form and supportive documentation should be submitted to the Agency, together with an original, signed cover letter.
Where applicable, revised product information Annexes should be provided in electronic (Word and PDF) format.
From 1 January 2017 it will be mandatory for applicants to 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.
One electronic copy should also be sent to the Rapporteur at the time of submission for evaluation.
Any electronic submissions should be made in accordance with the guideline on e-submissions.
MAHs are encouraged to avoid submitting Type IB variation applications shortly before or during the Agency holiday periods (e.g. end July and Christmas).
- Commission Regulation (EC) No 1234/2008
- Electronic application form to be used as of 1 July 2015
- Formatted table template to be inserted in application submission cover letters for veterinary procedures
- Recommended submission dates for type IB variations requiring linguistic review (30 day timetable)
- Dossier requirements for submission of MA and MRL applications to the EMA and to members of the CVMP
- Procedural announcement on mandatory use of eSubmission Gateway for veterinary submissions as of 1 January 2017
- Veterinary eSubmission website
- eSubmission Gateway and Web Client information website
In order to facilitate the linguistic review process of product information for certain variations which have been downgraded from Type II to Type IB, the Agency has published recommended submission dates for Type IB variations requiring linguistic review (See also “ Recommended submission dates ”)
Some examples of Type IB variations where a linguistic review will be performed are listed below:
- C.I.3.a) Implementation of change(s) requested by the Agency following the assessment of an Urgent Safety Restriction, class labelling, a Periodic Safety Update report, Risk Management Plan Follow up Measure/Specific Obligation, data submitted under Article 45/46 of Regulation (EC) No 1901/2006, or amendments to reflect a competent authority Core SPC
- Other default safety and efficacy Type IB variations affecting the product information.
Some examples of Type IB variations where a linguistic review will not be performed are:
- C.I.2.a) Change in the Summary of Product Characteristics, Labelling or Package Leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product
- Deletion of information from the product information
The linguistic review process will be normally performed within the 30 day timeframe for assessment of the Type IB variations on the translations submitted at the start of the procedure.
A separate set of recommended submission dates is applicable for type IB variations included in a worksharing submission or for Type IB variations submitted as part of a group including Type II variations and/or extensions (included in the same “ Recommended submission dates ” document).
The Agency considers that despite the downgrading of certain variations to Type IB it is important from a public health protection point of view to continue to ensure high quality and consistent product information of centrally authorised medicinal products in all Member States.
Where the CVMP requests a Type IB variation following the assessment of a PSUR, FUM or SO, following adoption of class-labelling or requests a Type IB variation for generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product, 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.
Upon receipt of a Type IB application, the Agency will handle the application as follows:
The Agency will check within 5 working days whether the variation is correct and complete ('validation') before the start of the evaluation procedure.
DAY ACTION Day x Receipt of Type IB variation Day x+1 Start of Agency validation Day x+5 Agency validation
(in case of missing information, this period will be extended)
Issues identified during validation will be notified to the MAH by Eudralink or fax.
The Agency will send to the MAH a confirmation of the positive outcome of the validation and the start date of the procedure.
DAY ACTION Day 1 Start of evaluation by Day 20 Receipt of Rapporteur's Assessment Report by Day 30 (Non-)acceptance of the variation
Within 30 days following the acknowledgement of receipt of a valid application, the Agency will notify the MAH and the Commission of the outcome of the procedure. If the Agency has not sent the holder its opinion on the application within 30 days, the application shall be deemed acceptable.
In case of an unfavourable outcome the MAH may, within 30 days, amend the application to take due account of the grounds for the non-acceptance of the variation. If the MAH does not amend the application as requested, the application shall be rejected.
Within 30 days of receipt of the amended application, the Agency will inform the MAH and the Commission of its final
(non-)acceptance of the variation and whether the Commission Decision granting the Marketing Authorisation requires any amendments.
Where Type IB Variations affect the Annexes to the Marketing Authorisation, such changes can be implemented without awaiting the 12-monthly update of the Commission Decision and the agreed change(s) should be included in the Annexes of any subsequent Regulatory Procedure.
The Agency will check within 5 working days whether the proposed change can be considered a minor variation of Type IB, and whether the application is correct and complete ('validation') before the start of the evaluation procedure. In exceptional cases, the Agency may have to consult with the Rapporteur on the appropriate classification of the variation, which may lead to a slightly longer validation period (up to 10 working days).
When the Agency is of the opinion that the proposed variation may have a significant impact on the quality, safety or efficacy of the medicinal product, the MAH will be notified that the applied change cannot be handled as a Type IB and that the variation will have to be reclassified as a Type II variation. As a consequence, the
When the Agency is of the opinion that the proposed variation can be considered a Type IB variation, the MAH will be informed of the outcome of the validation and of the start date of the procedure. The Type IB application will be handled as set-out in section a) above.
Where a Type IB by default variation, within a group of variations, has to be reclassified as a Type II variation, the MAH will be requested to confirm whether this variation should remain in the group. If confirmed, the whole group will be handled as a Type II variation, as set out in section b) above.
Where several Type IB variations are submitted as part of one application, it will be clearly specified in the final Agency notification which variation(s) have been accepted or rejected following assessment, unless some of the variations have been withdrawn by the MAH during the procedure (see “How will grouped variation applications be handled (timetable)? What will be the outcome of the evaluation of a grouped application?”).
For information on the fee applicable for Type IB variations, please refer to the Explanatory note on fees payable to the European Medicines Agency. Such fee covers all authorised strengths, pharmaceutical forms and presentations of a given medicinal product.
For variations which introduce additional presentation/pack-size(s), 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.
Grouped Type IB variations, whether consequential or not, will each attract a separate Type IB 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.
To facilitate this operation, applicants/MAHs who are requesting a Purchase Order Number on the Agency invoice should quote this Number clearly on the cover letter of a given application. The Agency will no longer accept separate notifications of Purchase Order Numbers not associated with the dossier.
If the applicants/MAHs do not require a Purchase Order Number on the Agency invoice, this must also be clearly stated in the cover letter.
Please consult the Mock-ups section of this Q&A.
- All EEA language versions: complete set of Annexes electronically only in Word format (highlighted tracked changes) and in PDF (clean)
- The 'complete set of Annexes' includes Annex, I, II, IIIA and IIIB i.e. all SPC, labelling and PL 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. The 'QRD Convention' published on the Agency website should be followed. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed formatting checklist which provides guidance on how to correctly prepare the PDF versions.
- The electronic copy of all languages should be provided as part of the variation application on CD-ROM/DVD. 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 Variation(s) concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts this should be clearly mentioned in the cover letter and in the 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 document attached 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 procedure(s) may affect the product information Annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned.
- For those variations which affect the Annex A (e.g. introduction of a new presentation), translations of the revised Annex A in all EU languages should be provided as separate documents in Word format (clean) and PDF, together with the variation application. Where the variation introduces a new EU sub-number, the sub-number should be requested from the Agency before submission and should subsequently be included in the SPC, labelling and PL texts as part of the variation application (see also “How to obtain new EU sub-numbers before submitting a Type IB variation for an additional presentation?”). In case of a deletion of a pharmaceutical form/strength(s), such prior liaison with Agency is not required, and the amended Annex A and product information Annexes should be provided as part of the Variation application.
Upon finalisation of a valid Type IB application affecting the Annexes to the Commission Decision, the Commission Decision will be updated within 12 months. However, Type IB Variations affecting the Annexes can be implemented without awaiting the update of the marketing authorisation and the agreed Type IB changes should be included in the Annexes of any subsequent Regulatory Procedure.
The European Commission's 'Variations Guidelines' 2013/C 223/01 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.
In practice “that part of the dossier” (referred to above) can be taken to mean concerning Parts 2, 3 or 4, as appropriate.
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 section of the variation application form under the section on 'Precise scope and background…', 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 variation. Proposed editorial changes that cannot be accepted as such will be rejected. In case of doubt, applicants can contact the Agency in advance of the planned submission using email@example.com.
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.
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 firstname.lastname@example.org in advance of an upcoming submission.
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 as per 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 which impacts upon the product information.
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, holders are advised to contact email@example.com 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) that could affect the safe and effective use of the medicinal product and/or lead to a potential medication errors (e.g. wrong strength, wrong posology, wrong route of administration).
The introduction of a new pack size (i.e. additional to currently approved pack sizes) should be submitted as a variation under subindent B.II.e.5.a) according to the variations classification guidelines.
Range is defined from the smallest to the biggest approved pack size (not from '0') for the same pharmaceutical form and strength. The pack size equals to the number of units of the pharmaceutical form (e.g. tablets, sachets, ampoules, etc.) contained per outer packaging. Pack sizes not included within this range are considered to be outside of the range.
For the addition of a new pack size where the number of units of the pack is within the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a variation B.II.e.5.a.1 (IAIN).
For the addition of a new pack size where the number of units of the pack is outside the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a variation B.II.e.5.a.2 (IB).
In support of a timely introduction of new pack sizes to the market, the EMA accepts the following approach for the introduction of various pack sizes falling outside the range within a single grouped submission. The biggest or the smallest pack size per strength outside the range should be classified as B.II.e.5.a.2 (IB). This presentation defines the new limits of the range so that any intermediate pack size for the strength and pharmaceutical form can be classified as B.II.e.5.a.1 (IAIN).
Some examples are provided below to illustrate the principles explained above.
The 20 mg strength of 'Veterinary Medicinal Product A' currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form 'film-coated tablets' and the MAH intends to apply for a new pack size of 45 tablets. The introduction of a new pack size of 45 tablets for the 20 mg strength is considered within the range of approved packs (30-60 tablets) and should be classified as variation B.II.e.5.a.1 (IAIN).
The 20 mg strength of 'Veterinary Medicinal Product A' currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form 'film-coated tablets' and the MAH intends to apply for a new pack size of 90 tablets. The introduction of a new pack size of 90 tablets for the 20 mg strength is considered outside the range of approved packs (30-60 tablets)and should be classified as variation B.II.e.5.a.2 (IB).
The 20 mg strength of 'Veterinary Medicinal Product A' currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form 'film-coated tablets' and the MAH intends to apply for two new pack sizes of 90 and 120 tablets at the same time. The introduction of a new pack size of 120 tablets for the 20 mg strength is considered outsidethe range of packs and should be classified as variation B.II.e.5.a.2 (IB). This pack size defines a new limit for the range (30-120), so that the introduction of a pack size of 90 tablets can be classified as a variation B.II.e.5.a.1 (IAIN). The MAH should therefore apply for a grouped variationof 1 x type IB - B.II.e.5.a.2 and 1 x type IAIN - B.II.e.5.a.1.
The 20 mg and 40 mg strengths of 'Veterinary Medicinal Product B' currently each have two approved pack sizes of 2 and 10 pre-filled syringes for the pharmaceutical form 'solution for injection'. The MAH intends to apply for four new pack sizes:
- 5 and 30 pre-filled syringes for the 20 mg strength;
- 5 and 30 pre-filled syringes for the 40 mg strength
For the 20 mg strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10)and should be classified as variation B.II.e.5.a.1 (IAIN) and the introduction of a new pack size of 30 pre-filled syringes is considered outsidethe range of approved packs (2-10) and should be classified as variation B.II.e.5.a.2 (IB).
For the 40 mg strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10)and should be classified as variation B.II.e.5.a.1 (IAIN) and the introduction of a new pack size of 30 pre-filled syringes is considered outsidethe range of approved packs (2-10)and should be classified as variation B.II.e.5.a.2 (IB).
The MAH should therefore apply to the EMA for a grouped variation for the abovementioned scopes.
The 50 mg strength of 'Veterinary Medicinal Product C' currently has two approved pack sizes of 10 and 30 tablets for the pharmaceutical form'film coated tablets' and the MAH intends to apply for a multipackof 30 (3x10) tablets. The introduction of a multipack 30 (3x10) tablets for the 50 mg strength is considered within the range of approved packs (10-30) and should be classified as variation B.II.e.5.a.1 (IAIN).
- For variations introducing additional presentations or pack sizes, each additional presentation or pack size attracts separate fees (x additional presentations = x separate fees). Each presentation and pack size should therefore be declared as a separate variation on the variation application form under the section 'variations included in this application'. There is an exception to this principle for vaccines authorised as multi-strain dossiers, in which case the single Type II 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) also covers within its scope the addition of associated presentations.
- Changes to strength, pharmaceutical form and route of administration are to be submitted as an extension of a marketing authorisation.
- For additional guidance on changes to existing presentation that can trigger new EU number(s) please see Q10, Q11 and Q15 of the EMA's regulatory guidance for human medicinal products on Type IA, Type IB and Type II variations, respectively.