Type-IA variations: questions and answers

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This page lists questions that marketing-authorisation holders (MAHs) may have on type-IA variations. It provides an overview of the European Medicines Agency's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase. Revised topics are marked 'New' or 'Rev.' upon publication.

A PDF version of the entire post-authorisation guidance is available:

These questions and answers have been produced for guidance only and should be read in conjunction with the rules governing medicinal products in the European Union, volume 2, notice to applicants.

MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.

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1. When should I submit my type-IA or -IAIN variation?

Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’) and the Commission guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 and on the documentation to be submitted pursuant to those procedures (‘the Variations Guidelines’) set out a list of changes to be considered as type-IA variations. Such minor variations have only a minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal product, and do not require prior approval before implementation ('do-and-tell' procedure). The Classification Guideline clarifies the conditions that must be met in order for a change to be considered a type-IA variation.

Such minor variations are classified in two subcategories, which impact on their submission:

  • Type-IA variations requiring immediate notification (‘IAIN’)
    The Classification Guideline specifies the type-IA variations that must be notified (submitted) immediately to the national competent authorities or European Medicines Agency following implementation, in order to ensure the continuous supervision of the medicinal product.
  • Type-IA variations not requiring immediate notification (‘IA’)
    Variations that do not require immediate notification may be submitted by the MAH within 12 months after implementation, or may be submitted earlier should this facilitate dossier lifecycle maintenance or when necessary,  to ensure that the latest product information is reflected in certificates of pharmaceutical products, for example.

The 12-month deadline to notify minor variations of type IA allows for an annual reporting for these variations, where a MAH submits several minor variations of type IA that have been implemented during the previous 12 months.

Most of these type-IA variations do not have an impact on the product information. However, in case of an upcoming submission of a variation, extension or other regulatory procedure that will affect the product information, the MAH should also include any type-IA changes affecting the product information, in order to keep the product information up-to-date and to facilitate document management.

There are no recommended submission dates for type-IA variations.. However, MAHs are encouraged to avoid submitting type-IA notifications shortly before or during the Agency holiday periods (e.g. the end of July and Christmas).

Meaning of implementation for type-IA variations

For quality changes, 'implementation' is when the company makes the change in its own quality system. This interpretation allows companies to manufacture conformance batches and generate any needed stability studies to support a type-IAIN variation before making an immediate notification1 because the change will not be made in their own quality system until these data are available.

For changes to the pharmacovigilance system (DDPS), ‘implementation’ is when the company makes the change in its DDPS (i.e. when it internally approves the DDPS incorporating the changes).

For product information, it is when the company internally approves the revised product information. The revised product information will then be used in the next packaging run.


1For example, the type IAIN for addition, deletion or replacement of components in the flavouring or colouring system requires stability data on at least two pilot-scale or industrial-scale batches.

2. Can I group the submission of type-IA and -IAIN variations? Can they be grouped with other types of variation?

Article 7(2)(a) of the Variations Regulation sets out the possibility for a MAH to group several type-IA or -IAIN variations under a single notification to the same relevant authority, or to group them with other types of variation.

Possible grouping of type-IA and -IAIN changes only

  • Several type IA or IAIN affecting one medicinal product:
    This means, for instance, that a type-IA variation, which is normally not subject to immediate notification, can be included in the submission of a type-IAIN variation;
  • One type IA or IAIN affecting several medicinal products from the same MAH:

  • Several type IA and / or IAIN affecting several medicinal products from the same MAH, provided that those variations are the same for all medicinal products and are submitted to the same relevant authority:

 

Possible grouping of type IA and IAIN with other types of variation

  • Type IA/IAIN can also be grouped with other variations (e.g. Type IB, Type II, Extension), as listed in Annex III of Commission Regulation 1234/2008. Groupings not included in the aforesaid Annex should be discussed and agreed with the Agency prior to submission.
  • Such grouped submissions will follow the review procedure of the highest variation in the group. Please also refer to “What type of variations can be grouped?”.

It must be noted, however, that when submitting type-IA or -IAIN variations as part of a group, the legal deadlines for submission of each variation should be respected, i.e. a type IAIN should always be submitted immediately, whether or not it is grouped with other variations, and any type-IA variations should always be submitted within 12 months following their implementation.

3. Is the (co-)rapporteur involved in the review of type-IA and -IAIN variations?

The Agency will review the notification within 30 days following receipt, without involvement of the Rapporteur or Co-Rapporteur.

However, a copy of the complete Type IA/ IAIN notification must be submitted to the Rapporteur and other Committee members at the time of submission (for information) to maintain the life cycle of the eCTD dossier (See also “How shall I present and submit my Type IA/ IAIN Variation”).

The same principle applies whether a single or a group of Type IA/ IAIN variations is being submitted.

However, if the Type IA/ IAIN Variations are grouped with other variations (Type IB, Type II, Extension), the grouped submission will follow the review procedure and timelines of the highest variation in the group and the Rapporteur will provide an assessment report for the group. Although the Rapporteur is not expected to assess the Type IA/IAIN variations in the group the Rapporteur will confirm in the assessment report whether non-acceptance of (part of) the change(s) in the group leads to non-acceptance of the Type IA/ IAIN changes in the group.

4. How shall I present and submit my type-IA or -IAIN variation? Rev. July 2015

A type IA/ IAIN variation notification 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 EU-CTD format. The Commission variations guidelines further specifies which elements should be included in a type IA/ IAIN variation notification.

In order to help MAHs ensuring that their type IA/IAIN variations are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-notification checklist before submission of any type IA or type IAIN variation.

Also, in order to facilitate the completion of the application form, MAHs are advised to consult the EMA/CMDh explanatory notes on variation application form and the European Medicines Agency practical guidance on the application form for centralised type IA and IB variations.

Type IA variations are intended to provide for a simple, rapid and efficient procedure for minor changes. The MAH should be aware that the submission of redundant information or a confusing dossier presentation will not facilitate such procedures. Similarly, deficient and missing documentation can lead to rejection of the variation. However, in exceptional cases the Agency may issue a single request for supplementary information, for which a response should be provided within 4 working days in the mandatory eCTD format for electronic submissions. Failure to provide the requested information, or submission of incomplete and/or unsatisfactory responses within 4 working days may lead to an unfavourable outcome.

The following elements should be included in a Type IA/ IAIN variation notification, as specified in the Variations Guidelines:

  • Cover letter (for groupings, include a short overview of the nature of the changes). The cover letter should contain the template table to facilitate submission and registration.
  • Procedure number - The procedure number will be assigned by the EMA only upon receipt of an eCTD application.For further details please refer to EMA Pre-submission GuidanceHow is an EMA Application/Procedure Number attributed?
  • The completed electronic EU variation application form (eAF) , including the details of the marketing authorisation(s) concerned, as well as a description of all variations submitted together with their date of implementation. As of 1July 2015, the use of the Electronic Application Form is mandatory for all centralised procedures. Information on the electronic Application Form for variations can be found in the eSubmissions eAF webpage. Where a variation leads to or is the consequence of other variations, a description of the relation between these variations should be provided in the appropriate section of the application form.
  • MAHs are reminded that the variation application form should be signed by the official contact person as specified in section 2.4.3 of Part IA/Module 1. 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. For a grouping affecting several medicinal products, MAHs are reminded to confirm in the application form under “Declaration of the applicant” that the MAs concerned belong to the same MAH and that the main signatory confirms authorisation to sign on behalf of the designated contacts.
  • Reference to the variation code as laid down in the Annex to the Variations Guidelines, indicating that all conditions and documentation requirements are met, or reference to the published Article 5 Recommendation, if applicable, used for the relevant application. Applicable conditions and documentation should be clearly ticked on the extract provided, or marked as n/a. if that is the case. If a condition and or documentation is n/a. a justification for its absence should be provided.
  • Relevant documentation in support of the proposed variation, including all documentation as specified in the Annex.
  • If applicable, the revised summary of product characteristics (SmPC or Annex I), annex II, labelling (Annex IIIA) and/or package leaflet (Annex IIIB) as a full set of annexes. If the change applied for affects Annex A, this should be provided as a separate set of one document per EU language. (See also 10. When do I have to submit revised product information? In all languages?) Additional information on how to comply with this in a required technical format can be found in the TIGes Harmonised Guidance.
  • Where the overall design and readability of the outer and immediate packaging and/or package leaflet is affected, the need for the provision of mock-ups or specimens should be discussed with the Agency Medical Information Sector on a case-by-case basis.

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 Type IA variation complies fully with the conditions and documentation requirements as specified in the Variations guidelines.

Grouped Type IA/ IAIN variations

  • For grouped Type IA/ IAIN variations concerning one marketing authorisation, all Type IA variations must be declared in the variation application form. 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). However, the present-proposed section of the application form should clearly identify the relevant CTD sections in support of each variation.
  • For a (group of) Type IA/ IAIN variation(s) concerning several marketing authorisations, one eCTD sequence per medicinal product should be submitted. This will include a common cover letter and common application form referring to all medicinal products and variations concerned. In addition, for each medicinal product the relevant supportive documentation and revised product information (if applicable) should be provided, in order to allow the Agency to update the dossier of each marketing authorisation with the relevant updated/new information. Cross-references to any documentation submitted for another medicinal product can therefore not be accepted. For further details, please refer to “How shall I present a grouped variations application?” and to TIGes Harmonised Guidance.

For procedural matters related to a type IA/ IAIN Variation for a specific product and in order to avoid rejection, please contact IAquery@ema.europa.eu.

For more detailed queries on technical matters please contact the PA-BUS department.

Submission of Type IA/ IAIN Variation Notifications

Please refer to Other question 5. How and to whom shall I submit my application?.

References

5. How will my type-IA or -IAIN variation be handled (timetable)?

The Agency will review the (grouped) type-IA and -IAIN variations within 30 calendar days following receipt. The Agency will check the correctness of the application form, the presence of the required documentation and compliance with the required conditions, in accordance with the Classification Guideline.

Day 0: Receipt of type-IA or -IAIN-variation notification;

Day 1: Start of Agency check;

By day 30: Favourable or unfavourable review outcome.

By day 30, the Agency will inform the MAH by Eudralink about the outcome of the review.

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

Where one or several type-IA or -IAIN variations are submitted as part of one notification, the Agency will clearly inform the MAH about which variations have been accepted or rejected following its review.

Type-IA and -IAIN changes can be implemented prior to submission of the notification. However, in case of unfavourable outcome, the Variations Regulation requires the MAH to immediately cease applying the rejected variations. Please refer to 'what should I do in case of an unfavourable review outcome for my type-IA or -IAIN variation?' for further details.

It is still possible for MAHs to submit type-IA notifications prior to their implementation, particularly when the proposed changes are related to other notifications or variations requiring prior approval.

6. Can my type-IA or IAIN be part of worksharing?

In accordance with the provisions of Article 20 of the Variations Regulation, the worksharing procedure does not apply to type-IA or -IAINvariations.

However, the submission of one or several type-IA or -IAIN variations affecting more than one marketing authorisation of the same MAH in one notification to the same relevant authority (similar to worksharing) is possible under Article 7(2) of the Regulation (see also 'can I group the submission of type-IA or IAIN variations? Can they be grouped with other types of variations?'.

This type of grouping is referred to as ’IG’ by the Agency.

In addition, it is also possible to group a type-IA or -IAIN variations with a type-IB or a type-II variation, which is submitted for a worksharing procedure. In such cases, the rapporteur will be asked to confirm whether the non-acceptance of (part of) the change(s) leads to non-acceptance of the type IA or IAIN in the group.

7. What should I do in case of an unfavourable outcome for my type-IA or -IAIN variation?

A type-IA or -IAIN variation will be rejected when:

  • the classification of the proposed changes is incorrect;
  • not all of the conditions for the type-IA or -IAIN variation are met;
  • the submitted documentation as required by the Variations Guideline is deficient or inaccurate, including provision of the product information annexes and annex A, if affected by the changes applied for.

In such cases, the MAH should immediately cease to apply the rejected changes.

In the case of a negative outcome of a type-IA application because the conditions for type-IA variations are not met and consequently a resubmission (as a type-IB or type-II variation or an extension) is needed or because documentation is deficient, it is the MAH's responsibility to judge whether the rejected type-IA variation has an impact on the quality, safety or efficacy of the medicinal product. If this is the case, the MAH has to take appropriate action.

The Agency may ask the MAH to complete a suspected quality-defect notification form and provide a risk-assessment report on the impact of the product on the market to qdefect@ema.europa.eu within seven calendar days from the date of the rejection letter. Such requests are expected to be very exceptional. The MAH has to follow the instructions under notifying quality defects or product recalls.

8. What fee do I have to pay for a type-IA or -IAIN variation?

For information on the fees applicable for type-IA and -IAIN variations, please refer to fees payable to the European Medicines Agency. Such fees cover all authorised strengths, pharmaceutical forms and presentations of a given medicinal product.

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 or pack size should therefore be declared as a separate variation on the variation application form under the section ‘variations included in this application’.

Grouped type-IA or -IAIN variations, whether consequential or not, will each attract a separate type-IA fee.

The fee will become due on the date of receipt of the type-IA or -IAIN-variation notification and fees will be payable within 45 calendar days of the date of the said notification. After approximately 15 days, an invoice will be sent to the applicants billing address held on the Agency’s file.

The invoice will contain details of the product and type of procedure involved, the fee amount, the customer purchase order number associated with the procedures invoiced and financial information.

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. The Agency does not accept standalone notifications of purchase order numbers that are not associated with a dossier. Applicants not requiring a purchase order number on the invoice should also clearly state this in the cover letter. Applicants are requested to provide this information in the formatted table template.

The Agency will charge the fee for type-IA variations or grouped type-IA variations at the start of the procedure, irrespective of its outcome (positive, negative, or partial or full withdrawal).

Type-IA variations that are grouped with other type of variations or extensions or which are part of a worksharing procedure will continue to be charged on conclusion of the validation of the application.

References

9. Do I have to submit mock-ups and specimens?

For information concerning submission of mock-ups and specimens in the framework of post-authorisation procedures, please refer to checking process of mock-ups and specimens of outer / immediate labelling and package leaflets of human medicinal products in the centralised procedure, 3.4 other post-authorisation procedures.

10. What changes will trigger new EU number(s) (additional presentation(s))?

Any changes in the number of units of medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) 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 medicinal product or medical device being an integral part of the medicinal product (e.g. prefilled syringes) 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,
  • Changes in the number of medical devices not being integral part of the medicinal product,
  • Change in composition (e.g. change in excipients),
  • Change in units per blisters (without change to the total number of units per pack).

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

  • 30 to 60 tablets,
  • 2 prefilled syringes containing the medicinal product instead of one prefilled syringe.

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

Examples of changes that will trigger new EU numbers (this is not an exhaustive list):

  • Introduction of an alternative injection kit with a different number of syringes or swabs,
  • Introduction of an alternative syringe of different volume or an alternative syringe with a needle guard,
  • Introduction of an alternative immediate (primary) packaging made from a different material,
  • Introduction of an alternative shape/dimension of a pharmaceutical form (pre-rolled sealant matrix versus flat, change in size of patch).

If you have any questions on any upcoming submission, please contact us using the relevant email addresses: IAquery@ema.europa.eu, IBquery@ema.europa.eu or IIquery@ema.europa.eu.

11. How do I obtain new European Union sub-numbers for a type-IAIN variation concerning an additional presentation (e.g. new pack size)?

In the specific case of a Type IAIN Variation for an additional presentation, the new EU marketing authorisation sub-number should be requested from the Agency before implementation.

The request should be sent together with a draft Annex A (in English only) to newEUnumber@ema.europa.eu with a copy to the product shared mailbox and should be made at least 5 working days in advance of the intended submission of the variation. Once a number has been allocated, this number should subsequently be included in the Annex A and product information annexes submitted together with the Variation notification.

12. When do I have to submit revised product information? In all languages?

In case the Type IA/ IAIN notification affects any of the annexes, i.e. annex A, SmPC, annex II, labelling and/or package leaflet, the affected revised product information Annexes must be submitted as follows:

  • All EU language versions -   Complete set of Annexes electronically only in Word format (highlighted) and in PDF (clean)

The ‘complete set of Annexes’ includes Annex A (if applicable), I, II, IIIA and IIIB i.e. all authorised presentations (if applicable), SmPC, 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. If annex A is affected, the document should also be provided in all EU official languages as a separate set. 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. A user guide on how to generate PDF versions of the product information and annexes is also available.

The electronic copy of all languages should be provided as part of the variation application. 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 or typographical corrections 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 or typographical corrections 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.

When the Type IA/ IAIN Notification concerns several medicinal products, the relevant complete set of product information Annexes should be included in the eCTD sequence for each product concerned.

For Type IA/ IAINvariations affecting 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 clean PDF format and EN tracked Word, together with the variation application. Where the variation introduces (a) new EU sub-number(s), this/these should be included in the Annex A and in the product information texts as part of the variation application (see also “How to obtain new EU sub-numbers for a Type IAIN variation concerning an additional presentation (e.g. new pack-size)”?).

Similarly, in case of a deletion of a pharmaceutical form/strength/pack-size(s), the amended Annex A and product information Annexes should be provided as part of the Variation application.

13. How and when will the updated product-information annexes become part of the marketing authorisation?

For type-IA and -IAIN variations affecting the product-information annexes to the Commission decision, the Commission decision will be updated within one year.

By the end of this period, the Agency will send the complete set of annexes, based on the latest (previously) approved annexes and reflecting the type-IA or -IAIN changes agreed during the past year together with a line-listing of those type-IA and -IAIN notifications. The Commission will subsequently issue a Commission decision on the type-IA and -IAIN notifications concerned.

However, where an opinion affecting the annexes that is followed by an immediate Commission decision, e.g. one listed in the Article 23.1a(a), is transmitted to the Commission within this yearly period, the changes of the type-IA and -IAIN notifications concerned will already be included in the annexes to that opinion and will consequently be reflected in the resulting Commission decision. This Commission decision will therefore replace the yearly updating of the marketing authorisation for the type-IA and -IAIN notifications concerned.

At the occasion of the next type-IA or -IAIN variation affecting the annexes, the procedure outlined above will be repeated based on the new reference point of the next type IA or IAIN concerned. Also see the diagram below, which illustrates the updating process.

In addition, it is important that in case of an upcoming submission of a variation, extension or other regulatory procedure that will affect the product information, the MAH should also include as a grouping application any type-IA changes affecting the product information that have not been previously notified, in order to keep the product information up-to-date and to facilitate document management.

Where a type-IA or -IAIN notification concerns several marketing authorisations, the Commission will update the marketing authorisation with one decision per marketing authorisation concerned.

14. What should be the date of revision of the text for type-IA Variations?

Type-IA and -IAIN variations do not require prior approval before implementation ('do-and-tell' procedure), i.e. they can be implemented and notified to the Agency either immediately for type-IA variations requiring immediate notification (‘IAIN’) or within 12 months for type-IA variations not requiring immediate notification (‘IA’).

For type-IA variations affecting the product information, the date of revision of the text to be included in section 10 of the summary of product characteristics and in the corresponding section of the package leaflet at the time of printing should be the date of implementation of the change by the MAH.

The meaning of 'implementation' is explained in question 1 above ('when shall I submit my type-IA or -IAIN variation?').

15. Who should I contact if I have a question when preparing my application or during the procedure? Rev. June 2016

If you cannot find the answer to your question in the Q&A when preparing your application, please contact us using the following email address: IAquery@ema.europa.eu.

The Agency aims to respond to your query within 5 working days. To help us deal with your enquiry, please provide as much information as possible including the name of the product in your correspondence.

You should submit your query once and it is important that you submit it only to one dedicated email address. If you are uncertain on a classification of a variation as type IA or type IB please choose one of the relevant email addresses available to you (either IAquery@ema.europa.eu or IBquery@ema.europa.eu). Your query will be channelled internally to the relevant service(s) that will respond to you.

The above email address is only applicable when you have a pre-submission query.

Type IA variations will be handled by a dedicated team of Procedure Managers (PM). A PM will be nominated upon receipt of the variation. You will be able to contact this PM throughout the procedure.

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