Variations after 1 January 2010 - questions and answers

Updated 02 October 2019

A New European Variations Regulation came into force on 1 January 2010: Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products, most recently amended by Commission Regulation (EU) No 712/2012.

No, the change cannot be applied as a type IAIN - B.III.2.a variation.

In case an in-house method is maintained instead of the Ph. Eur. method, conditions no. 1 (the change is made exclusively to comply with the Ph. Eur. monograph) and condition no. 4 (additional validation of a new or changed pharmacopoeial method is not required) of a type IAIN B.III.2.a are not considered fulfilled.

Cross-validation of the in-house method towards the Ph. Eur. method is needed to verify the equivalency between the methods – this is interpreted as additional validation of the Ph. Eur. method is necessary.

Instead, the change should be applied for as a type IB variation - B.III.2.a.

Yes, according to the most recent Commission Regulation (EU) No 712/2012, the Variations Regulation now applies to medicinal products approved under the Centralised Procedure, the Mutual Recognition Procedure or the Decentralised Procedure and authorisations granted according to the purely national procedure.

This means that the same application form must be used for all variation applications (regardless of approval procedure).

No. As regards Medicine Prices, any changes must be notified to the Danish Medicines Agency no later than 14 days before the changes are to enter into force in Medicine Prices.

Type IA variations can be gathered in an a-grouping when:

  • the same type IA variation covers several marketing authorisations,
  • or several identical type IA variations cover several marketing authorisations,
  • or several type IA variations cover one marketing authorisation. 

Type IA variations can be implemented without prior approval by the Danish Medicines Agency and must be notified to the Danish Medicines Agency within 12 months following implementation of the variation. An Annual Report is a notification about one or more of such type IA variations, and an Annual Report can include one or more a-groupings.

As regards an application with a grouping of variations, the Danish Medicines Agency makes one decision that covers all variations in the group. This decision can include both approvals and rejections.

If an applicant does not wish that the assessment of a variation application be completed, the applicant must inform the Danish Medicines Agency of this as soon as possible. This also applies to a full or partial withdrawal of an application with a grouping of variations.

Withdrawal of a variation application does not normally affect the Danish Medicines Agency’s charge of fees.

No, the Danish Medicines Agency does not believe that the Variations Regulation and its guidelines will cause a lower resource consumption. The options of Annual Reports, groupings and worksharing are thus not expected to reduce the Authority’s workload.

Yes. According to the European Commission’s guideline on the various categories of variations, deletion of a form or a strength (partial deregistration) must be classified as a type IB variation (no. C.I.7.a or b).

However, the Danish Medicines Agency has decided that for products approved under DCP, MRP and national procedures it is acceptable to submit a deregistration notification. This notification may be sent via DKMAnet, e-mail or ordinary post. For marketed products, the notification must be sent via DKMAnet. If the deletion of a form or a strength implies changes to the summary of product characteristics, the marketing authorisation holder must send a revised summary of product characteristics by e-mail to the Danish Medicines Agency.

Yes, so far several variations can be gathered in one variation application, if they fall within the same main variation and sub-number – like in the previous variation procedure.

For example, several additions of tests for the specification of a finished product can be applied for as a single type IA variation, if each variation meets the requirements in the variations guideline under B.II.d.1.c.

This rule only applies to medicines approved under the purely national procedure.

The exception from the rule is applications for several manufacturers of active substances (B.I.a.1, B.III.1) or finished products (B.II.b.1-2), which cannot be gathered in a single variation application.

The change should be submitted as a type IB variation. For appropriate classification, refer to “Guidelines on the details of the variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures”.

It is emphasised that any out of specification result (OOS) should always be reported directly to the Danish Medicines Agency using rapidalert@dkma.dk.

When submitting the variation application to change the shelf-life and/or storage condition due to a stability concern, it should be clearly stated in the cover letter and the application form if an OOS result has been reported to rapidalert@dkma.dk. If the latter is applicable, the cover letter and the application form should also state the case number given by the Danish Medicines Agency for the case concerning OOS result.

When submitting the variation application, a justification should also be included addressing whether the concerned finished product needs to be withdrawn from the market or not. The cause of the reduced stability of the product should be presented and discussed along with the relevant preventive actions.

Changes to the immediate packaging for medicines in fixed doses are classified as type IB variations (B.II.e.1). In the event that the new packaging is less protective, the change must be submitted as a type II variation as it cannot be ruled out that the new packaging will have an impact on the medicinal product's quality, safety or efficacy, cf. annex II of the Variations Regulation.

Question 12 was deleted in September 2019

The addition of new tests for impurities/degradation products to the finished product specification must always be submitted as a type IB variation.

By law, the marketing authorisation holder is obliged to comply with the requirements described in Ph. Eur.

Changes implemented before the Ph. Eur. Monograph enters into force need not be applied for, but may be notified in connection with the submission of another variation.

Changes implemented after the monograph enters into force, or if a specific monograph version is mentioned in the dossier, must be submitted as a change in the finished product specification (B.II.d.1) or as a change in test procedure for the finished product (B.II.d.2).

Replacement of in-process controls should be submitted as a type IB variation (B.II.b.5.f) or (B.II.b.5.z), unless the change is a type II variation.

If the marketing authorisation holder wants to add a new manufacturing site whose in-process controls are slightly different compared to the approved in-process controls, the replacement of in-process controls should be submitted as a type IB variation (B.II.b.5.f). This is because the addition of a new manufacturing site is interpreted as a quality issue.

It is not acceptable to apply for a replacement of in-process controls as a type IA variation addition of new in-process controls (B.II.b.5.b) while at the same time applying for deletion of the old in-process controls as a type IA variation (B.II.b.5.c).

The Present and Proposed columns should be completed to specify what is approved now (Present) and what is being applied for (Proposed).

The purpose is to provide an overview of all the changes applied for.

The text must be unambiguous and as short and precise as possible. The specific changes should be highlighted (e.g. in bold).

It is not sufficient to refer to an enclosed appendix – unless such appendix is presented as a Present/Proposed table in itself.

For each change, a reference to the relevant dossier section number(s) should be specified (e.g. Module 3.2.P.5.4).

For grouped applications it must be clear, which changes belong to which variations. This can be done by adding the variation number to each of the changes, or by inserting a separate Present/Proposed table for each variation.

Yes, the administrative handling of the variation application is made easier when the Applicant’s own internal reference number is included in the application form.

We recommend MAHs to apply for changes to an ASMF as a single type II variation (l.B.z), e.g. update from version 01 to version 02. This allows for all changes to both AP and RP to be applied for simultaneously in one single application, thus avoiding any unnecessary discussion about categorisation of changes. Furthermore, it ensures that all changes are included in the application, which makes submission of subsequent follow-up variations unnecessary. In addition, situations are avoided in which the AP and RP within the same version of the ASMF are not approved at the same time.

Although all changes can be applied for as one single type II variation, the MAH in cooperation with the ASM are of course responsible for distinctly describing in the application scheme the changes made between two versions of an ASMF. PRESENT/PROPOSED in the application scheme should include information about version numbers of AP and RP together with an overall description of the present and proposed changes to the AP and RP.

No, with the exception of the situation outlined below.

The use of IA-z as classification is only a possibility, provided that a type IA variation recommendation has been given subsequent to an Article 5 application (cf. variation regulation 1234/2008 as amended).

Therefore, it is not possible to “create” an IA-z variation if the change cannot be identified in the European Commission´s guideline on the various categories of variations, which means that the change should be applied for as a default type IB variation (IB-z).

The information could be relevant in cases where countries outside EU/EEA requires a copy of the approval letter from the Danish Medicines Agency, for further handling of cases concerning variations.

This is to certify that the Danish Medicines Agency does not issue formal approval letters for purely quality variations classified as notifications under section B, type IA in accordance with COMMISSION REGULATION (EU) No 712/2012 of 3 August 2012 amending Regulation (EC) No 1234/2008, which are submitted cf. the European Commission Guidelines on the details of the variations categories of variations, on the operation of the procedures laid down in Chapter II, III and IV of Commission Regulation(EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures (2013/C 223/01).

It may be relevant in situations when countries outside the EU/EEA demand to receive a copy of the Danish authorisation in order to process a variation application.

The Danish Medicines Agency stresses that it is not issuing formal licensing letters for variations concerning the quality of medicines classified as notifications under section B, type IA pursuant to the Commission Regulation (EU) No 712/2012 of 3 August 2012 amending Regulation (EC) No 1234/2008, submitted according to the European Commission’s 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 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures (2013/C 223/01).

According to CMDh’s Q&A about usage patents, patented indications are deleted from a national SmPC via a national variation procedure. When the patent expires, an indication must be added via a similar national procedure or the completion of another relevant SmPC variation.

According to Commission Regulation No. 1234/2008, such variations can be applied for via a national type IB per default (variation no. C.I.z in the application form).

If the pack size of the proposed unit-dose blister is within the range of the currently approved pack sizes, the change should be submitted as a type IAIN variation (B.II.e.5.a.1).

If the pack size of the proposed unit-dose blister is outside the range of the currently approved pack sizes, the change should be submitted as a type IB variation (B.II.e.5.a.2).

When submitting the variation application to introduce a unit-dose blister, an updated summary of product characteristics (section 6.5) should be included. Section 6.5 should be updated in accordance with entry “Unit dose pack sizes” in this document

Furthermore, the applicant should be aware that each single blister must be labelled in accordance with section 19 of the executive order no. 869 of 21 July 2011 on labelling etc. of medicinal products.

For more information on labelling requirements and documentation for unit-dose blisters, please see the separate questions-answers on the website of the Danish Medicines Agency

No. A separate ticked copy of relevant pages of the classification guideline should be submitted for each individual variation.

Example: A grouped application consists of a type IA variation (B.II.d.1.a) and a type IA variation (B.II.d.1.c). A copy of relevant pages from the guideline for variation B.II.d.1.a, where relevant conditions and documentation related to that variation are ticked off, and a copy of relevant pages from the guideline for variation B.II.d.1.c where relevant conditions and documentation related to that variation are ticked off should be attached. 

When adding a new or updating an existing CEP, the applicant´s own active substance documentation (if applicable, e.g. 3.2.S.2.1, 3.2.S.4.1 to 3.2.S.4.5, 3.2.S.5 and 3.2.S.7) should be updated and submitted with the CEP applied for. If changes to the applicant´s own active substance documentation are identical to those introduced by the new or the updated CEP, these changes are included in the variation application concerning CEP addition or update. Other changes to the applicant´s active substance documentation should be applied for separately, however can be grouped with the variation application concerning CEP addition or update.

In the situation of adding a new CEP, the applicant should be particularly aware of the requirement of the applicant´s own active substance documentation being compiled covering all active substance manufacturers.

If changes to the active substance documentation also influence the finished product specification, such changes to the finished product specification should be applied for separately, however may be grouped with the variation application concerning CEP addition or update as well as variation application(s) concerning changes to applicant´s own active substance documentation.

No. A type IA variation will be rejected if it is not submitted to the Danish Medicines Agency within the 12-month period. Such variation should then be submitted as a type IB variation per default.

Type IA variations can be implemented without the prior approval of the Danish Medicines Agency, but the Danish Medicines Agency must be notified within 12 months from implementation. However, certain type IA variations must be notified to the Danish Medicines Agency immediately after implementation due to administrative circumstances. Type IA variations carry the suffix »IN« (IN = immediate notification).

Pursuant to article 8 in Commission Regulation (EU) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products as amended by Commission Regulation No 712/2012, a prerequisite for a type IA variation is that the notification of the implementation of the change to the Danish Medicines Agency is made within 12 months after its implementation. If the Danish Medicines Agency is notified of the change later than 12 months, the condition for a type IA variation is no longer fulfilled.

Yes, if agreed with the Danish Medicines Agency.

Reference is given to the current "Guideline on variations to marketing authorisations for medicinal products”. One or more variations to the terms of several purely national marketing authorisations (several D.Sp.nr.) owned by the same holder and granted by the Danish Medicines Agency can be applied for in the same application form. The situation constitutes grouping as it concerns several purely national marketing authorisations (several D.Sp.nr.).

Subsequently, section “1. Application for variation to a marketing authorisation” must be ticked in “Grouping of variations” in the current application form. Fee will be charged in accordance with the current Danish executive order on fees payable for medicinal products and pharmaceutical companies etc., see Schedule 2, type of application “Grouping and worksharing”. It is emphasised that the variation(s) should be identical and applicable to all marketing authorisations in the application form.

Extension of an in-use shelf-life period should be submitted as a type II variation (B.II.f.1.z) in accordance with article 3(3b) in Commission Regulation (EU) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products as amended by Commission Regulation No 712/2012. When submitting the variation application, data for relevant studies should be provided, including microbiological stress studies, as well as an updated quality overall summary and a justification for influence of the change on the quality/safety/efficacy of the finished product.

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