Variation Regulation 1234 Classification Essay

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.


1. Is it possible to apply for an update of the specifications of a former non-pharmacopoeial active substance to comply with a Ph. Eur. monograph, as a type IAIN - B.III.2.a variation if we wish to maintain an in-house method (e.g. for related substances) in place of the official method of the Ph. Eur. monograph?

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.


2. Does the Variations Regulation also apply to the purely national variations?

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).


3. Does the Variations Regulation affect Medicine Prices?

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.


4. Is an a-grouping the same as a so-called “Annual Report”?

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.


5. Does the Danish Medicines Agency make a decision on all variations in a grouping at once?

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.


6. Can a variation application be withdrawn before a decision is made?

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.


7. Will the Variations Regulation ease the Danish Medicines Agency’s administration?

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.


8. Is it correct that the Variations Regulation entails that deletion of individual forms and strengths within the same D.Sp.No. is a variation?

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.


9. Is it still possible to gather several variations in a single variation application in respect of medicines approved under the purely national procedure?

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.


10. If we need to reduce the shelf life and/or change the storage condition of a medicinal product due to a stability issue, what type of variation should we submit?

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.


11. We want to add a blister pack to an existing plastic container. How should we apply for this change?

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.


12. Does the Danish Medicines Agency want an electronic version of the application in addition to the paper version even though it is not possible to submit it in eCTD or NeeS/VNeeS?

Yes.

The Danish Medicines Agency's internal workflow processes are fully electronic, and we will therefore save time if the applicant has scanned the material to us.

Please note that the Danish Medicines Agency must receive the documentation in either eCTD, NeeS/VNeeS or paper format. Consequently, we do not accept material sent in an outdated electronic format. If the applicant cannot submit the documentation in eCTD or NeeS/VNeeS, the information should be submitted on paper. This is partly to avoid that the Danish Medicines Agency, by outlining a set of minimum requirements for such submission, defines another electronic format; and partly to be able to scan the documents ourselves if the applicant's electronic version is not of a sufficiently high quality.

The electronic version must be fully identical with the paper version. The Danish Medicines Agency reserves the right to choose which version to use for the assessment.

If you have any questions as to our format requirements, please write to esubmission@dkma.dk


13. We want to add new tests for impurities/degradation products to the finished product specification, including limits for specified, unspecified and/or total. How should we submit this change?

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


14. How do we apply for an update of the finished product specification resulting from new or changed tests and/or requirements in Ph.Eur.?

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).


15. How should a replacement of in-process controls be applied for?

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).


16. How should the Present/Proposed table in the application form be filled out?

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.


17. Is it true that the Danish Medicines Agency encourages applicants to write applicant’s reference in the box Name and address of the applicant/MA holder?

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.


18. How to apply for changes or updates of an Active Substance Master File (ASMF/DMF)?

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.


19. Is it possible to apply for a default type IA variation, i.e. IA-z variation, as classification, provided that the minor change is not mentioned in the European Commission´s guideline on the various categories of variations and that the change in question does not affect quality/safety/efficacy of the medicinal product?

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).


20. Would it be possible to receive a signed statement certifying that the Danish Medicines Agency does not issue licensing letters related to notifications?

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).


21. How do we add or delete patented indications from a national SmPC?

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).


22. How should addition of a unit-dose blister for the finished product be applied for?

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


23. Is it acceptable to submit a compiled copy of relevant pages from the classification guideline, if a grouped application includes more than one type IA variation within the same main variation? 

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. 


24. What should the applicant be aware of with regard to the applicant´s own active substance documentation, when adding a new or updating an existing certificate of suitability (= CEP)?

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.

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И, что, на взгляд Хейла, было еще хуже, влюбилась в университетского профессора, который к тому же зарабатывал сущие гроши. Очень жаль, если она истратит свой превосходный генетический заряд, произведя потомство от этого выродка, - а ведь могла бы предпочесть его, Грега.

У нас были бы красивые дети, - подумал. - Чем ты занята? - спросил Хейл, пробуя иной подход. Сьюзан ничего не ответила.

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