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Variations after 1 January 2010 - questions and answers
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.
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.
Does the Variations Regulation also apply to the purely national variations?
The Variations Regulation applies to medicinal products approved under the Centralised Procedure, the Mutual Recognition Procedure or the Decentralised Procedure. However, the Danish Health and Medicines Authority has decided that medicinal products approved under the purely national procedure must also – to the greatest extent possible – be assessed pursuant to the new regulation.
One implication is that the same application form must be used for all variation applications (regardless of approval procedure).
Does the Variations Regulation affect Medicine Prices?
No. As regards Medicine Prices, any changes must be notified to the Danish Health and Medicines Authority no later than 14 days before the changes are to enter into force in Medicine Prices.
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 Health and Medicines Authority and must be notified to the Danish Health and Medicines Authority 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.
Does the Danish Health and Medicines Authority make a decision on all variations in a grouping at once?
As regards an application with a grouping of variations, the Danish Health and Medicines Authority makes one decision that covers all variations in the group. This decision can include both approvals and rejections.
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 Health and Medicines Authority 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 Health and Medicines Authority’s charge of fees.
How is a reduced fee calculated pursuant to section 12 of the Danish executive order on fees?
The fundamental principle is that a full fee must be paid for each medicinal product (each Danish speciality number - D.Sp.No.), and a reduced fee must be paid for subsequent pharmaceutical forms and strengths, if they are subject to the same variation. This applies regardless if the application covers several variations gathered in an a- or b-grouping under section 7(2)(a) and (b) of the Variations Regulation or if the application only concerns a single variation.
Examples
Single variation:
An application is submitted for a new manufacturer of starting material (B.I.a.1.b) for a pharmaceutical form with several strengths. Provided that the specialist assessment of the Active Substance Master File/European Drug Master File (ASMF/EDMF) and the documentation from the applicant are the same for all strengths, a full fee is paid for the first strength and a reduced fee is paid for the subsequent strengths.
An application is submitted for extension of the storage period for several strengths of the same pharmaceutical form (B.II.f.1.b.1). Provided that the specialist assessment is the same for all strengths (a stability protocol), a full fee is paid for the first strength and a reduced fee for the subsequent strengths.
A-grouping:
An application is submitted for deletion of obsolete requirement (B.II.d.1.d) and tightening of limit (B.II.d.1.a) in the specification of the finished product used in a medicinal product (same D.Sp.No.). Provided that the specialist assessment is the same for all pharmaceutical forms and strengths, a full fee is paid for the two first type IA variations, and a reduced fee is paid for all subsequent pharmaceutical forms and strengths.
An application is submitted for deletion of obsolete requirement (B.II.d.1.d) and tightening of limit (B.II.d.1.a) in the specification of a finished product used in several medicinal products (several D.Sp. Nos) from the same marketing authorisation holder. Provided that the specialist assessment is the same for all pharmaceutical forms and strengths, a full fee is paid for the two first type IA variations for each medicinal product (D.Sp.No.), and a reduced fee is paid for all subsequent pharmaceutical forms and strengths under the same D.Sp.No. A full fee is paid for the first type IA variation for each medicinal product (D.Sp.No.), and a reduced fee is paid for all subsequent pharmaceutical forms and strengths under the same D.Sp.No.
B-grouping:
An application is submitted for extension of a limit in the specification of the finished product (B.II.d.1.e), and in consequence, an extension of the storage period (B.II.f.1.b1) for several strengths of a pharmaceutical form under the same medicinal product (D.Sp.No.). Provided that the specialist assessment is the same for all strengths (i.e. the same extension of limit and stability protocol), a full fee is paid for the first strength for each variation in the group, and a reduced fee is paid for each subsequent variation in the group.
Exceptions (under the purely national procedure)
Changes made for several medicinal products (several D.Sp.Nos) that do not entail an update of the summary of product characteristics:
Changes of starting materials contained in several medicinal products or several pharmaceutical forms and strengths.
For each of the mentioned variations of type IA, IAIN, IB and II within the classifications A.3-4 and A.7, B.I.a.1-4, B.I.b.1.a-d, B.I.b.2.a-c, B.I.c-d B.II.c and B.III.1-2, a full fee must be paid for the first variation, and a reduced fee must be paid for the same variation for each subsequent pharmaceutical form, strength and other affected medicinal products (D.Sp.Nos).
Changes concerning packaging, comprising several medicinal products or several pharmaceutical forms and strengths.
For type IA, IAIN, IB and II variations within the classifications B.II.e.2-3 and B.II.e.6-7, a full fee must be paid for the first variation, and a reduced fee must be paid for the same variation for each subsequent pharmaceutical form, strength and other affected medicinal products (D.Sp.Nos).
Change of manufacturer of finished products concerning several medicinal products or several pharmaceutical forms and strengths.
For type IA and IAIN variations within the classification A.5-7, a full fee must be paid for the first variation, and a reduced fee must be paid for the same variation for each subsequent pharmaceutical form, strength and other affected medicinal products (D.Sp.Nos).
Exceptions (National and Mutual Recognition Procedure)
Changes to the summaries of product characteristics for the same medicinal product with different pharmaceutical forms and strengths.
Changes with regard to indications (section 4.1 – human medicinal products and section 5.1 - veterinary medicinal products) are subject to a full fee in respect of the first variation and a reduced fee in respect of subsequent pharmaceutical forms and strengths.
Changes with regard to dosage (section 4.2. – human medicinal products and section 5.7 – veterinary medicinal products) are subject to a full fee in respect of the first variation and a reduced fee in respect of subsequent pharmaceutical forms and strengths.
Other changes to the summary of product characteristics (sections 4.3-5.3 – human medicinal products and sections 4.0-4.2, 5.2-5.6 and 5.8-5.12 – veterinary medicinal products) are subject to a full fee in respect of the first variation and a reduced fee in respect of subsequent pharmaceutical forms and strengths.
Will the Variations Regulation ease the Danish Health and Medicines Authority’s administration?
No, the Danish Health and Medicines Authority 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.
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).
Furthermore, you should be aware that for MRP/DCP products, one total product is defined according to the main procedure number and not the D.Sp.No. Since there may be more than one main procedure number linked to one D.Sp.No., any deregistration of the last strength linked to a main procedure number should not be submitted as a variation, but as a deregistration via DKMA, even though several pharmaceutical forms/strengths linked to the same D.Sp.No. still remain.
However, for nationally authorised products, the D.Sp.No. will determine whether the product is to be deregistered (all forms and strengths) or whether it is a variation (strengths or pharmaceutical forms linked to the D.Sp.No. still exist).
Must the mandatory supplementary page still be used for purely national variations after 1 January 2010?
No, the supplementary page should no longer be used.
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.
Currently, it is uncertain if something similar will be accepted under the MRP/DCP.
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.
If we need to reduce the shelf life 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 II variation.
When a change is made in response to a stability issue, it cannot be submitted as a type IA(IN) – B.II.f.1.a (shelf-life) or a type IB – B.II.f.1.d (storage condition), because the change is expected to have an impact on the medicinal product's quality, safety or efficacy, cf. annex II of the Variations Regulation.
Even though the application is submitted as a type II variation, it will be processed according to the deadlines of a type IB variation.
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.
Is it true that the Danish Health and Medicines Authority encourages companies to enclose an electronic version with a grouped variation application in paper form?
Yes, the administrative handling and evaluation of grouped variations are made easier for the Danish Health and Medicines Authority when a grouped paper application is accompanied by an electronic version.
We prefer to receive eCTD rather than NeeS, and NeeS (or VNeeS for veterinary applications) rather than less structured documents and finally, text searchable files rather than scanned documents.
This is not a requirement, but it is of utmost importance that the electronic version and paper version are identical, and scanned documents are therefore also welcome.
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.
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).
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).
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.
Is it true that the Danish Health and Medicines Authority 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.
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, 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.
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).
