Revision of the Variations Regulation - New Proposal released on 25 October 2002 - New Categories of EU-Variations

GMP News No. 258

6 November 2002

Revisionof the Variations Regulation – New Proposal released on 25 October 2002– New Categories of EU-Variations 1)

The Variation Regulations (EC) 541/95 (1) and (EC) 542/95 (2) are beingrevised by the European Commission.
Proposals for changes to these regulations have been prepared by theNotice to Applicants Group and were released to the industry for commentsin the beginning of February this year (proposed draft 3 of the Revisionof the Variations Regulation). After lots of comments of thepharmaceutical industry, especially with regard to concerns of thedifferent variation types into Type I, IIA and IIB, a new proposal wasreleased to the Notice to Applicants Group, the EMEA, the Working Partiesand the Trade Associations on 25 October 2002. One of the most importantoutcomes was that the Type IIA variations should be moved to the annex Ion minor variations. The new proposal of the Variations Regulations nowlists two different Type I variations (Type IA and Type IB) and one TypeII variation – compared to one Type I and two Type II (Type IIA/B)variations in the former draft (Draft 3) (see Table 1). Type IA and IBvariations follow the notification procedure, but have differenttimeframes (see Table 2). New is that Type IA and IB variations are in theresponsibility of the Reference Member States (RMS).

A comparison between the current variation regulation, the proposeddraft 3 and the New Proposal, the timeframes and a short description ofthese new types of variations are listed below:

Table 1: Comparion of the types of variation between the currentVariation Regulation, the proposed draft 3 and the New Proposal:


Proposed Draft 3

New Proposal


Type I

Type I A

Type I

Type II A

Type I B

Type II

Type II B

Type II

List of Type I Variations (with 34 entries)

Annex I (Draft 6, list with 52 single entries)

Annex I


Annex II (Draft 1, list with 41 changes)



Annex III 'Line Extensions'

Annex II 'Line Extensions'

Table 2: Timeframes of the new proposal for the VariationsRegulation:





Type IA


max. 14 days

Annex I

Type IB


'old Type I'

Annex I

Type II


'old Type II'




see Directive

Annex II

(1) Type IA Variation (Notification)
Type IA variations are a new category of variations that have beenredefined as 'minor' changes which only have to be notified to thecompetent authorities. The notification procedure is also called the 'Telland do'-procedure and was set out to provide for rapid processing ofvariations. Type IA changes that are listed in Annex I are defined asadministrative changes and/or simple changes with no possible impact onthe safety of the medicinal product.
Validation of Type IA variations is done by the Reference Member State(RMS) in case of the Mutual Recognition Procedures and is done by EMEA incase of the centralised procedure. In case of the Mutual RecognitionProcedure the RMS will inform the other national competent authoritiesconcerned and the marketing authorisation holder in the RMS accordingly.

(2) Type IB (the current Type I Variation and the former Type IIA)
The Type IB Variations are the 'minor' changes that implicit approvalwithin a 30-day waiting period. The evaluation and approval of theprocedure is done by the RMS who will inform the other national competentauthorities concerned and the marketing authorisation holder in the RMSaccordingly.
(Remark: Former Annex II of draft 3 of the Revision of the VariationsRegulation with 42 listed variations for Type IIA is integrated into thenew Annex I).

(3) Type II (the current Type II Variation and the former Type IIBvariations)
The Type II Variations are the 'major' changes that need approval. Anapproval has to be waited for (timeframe: 90 days with an option forchanges to indications to extend to 120 days). All possible changes thatare not listed in Annex I are defined as Type II variations.

(4) Extension
New is the fourth category for line extensions that have been legallydefined for the first time in the EU. 'Extension' applies to products withthe same legal name, but where defined changes have been made, e.g.replacement of the active substance(s) by a different salt/ester complexor derivative, where the efficacy/safety remains the same, changes tostrenght, pharmaceutical form and route of administration, etc.

What will be the next steps with the Revision of the VariationsRegulation?
On 28 November 2002 there will be a discussion of open points betweenthe EU-Commission, the Member States (MS), the EMEA and the WorkingParties (WP's). On the next day, 29 November 2002, the members of theNtA/WP's will discuss open points with the Trade Associations. All in all,it will be interesting what further 'changes' will be made. Let's lookforward to the finalised document.


Dr Barbara Jentges

1) The New Proposal of the Variations Regulation was presented byDr. P. Bachmann, BfArM, at the German CONCEPT HEIDELBERG Seminar 'ChangeControl Management', 29-30 October 2002 in Heidelberg.

(1) Commission Regulation (EC) No 541/95 of 10 March 1995 (as amendedin 1998), concerning the examination of variations to the terms of amarketing authorization granted by a competent authority of a Member State

(2) Commission Regulation (EC) No 542/95 of 10 March 1995 (as amendedin 1998), concerning the examination of variations to the terms of amarketing authorization falling within scope of Council Regulation (EEC)No 2309/93


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