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GMP-News Nr. 385
11 February 2004
NewVariations Regulations 1084/2003 and 1085/2003
The former Variation Regulations (EC) 541/95 (1) and (EC) 542/95 (2) were revised by the European Commission. The revision wasnecessary to provide the same regulatory framework for variations in theMutual Recognition Procedure (MRP) and the Centralised Procedure and tofulfil the requirements of Directive 2001/83/EC (of 6 November 2001) (3).
The new Variations Regulations (Commission Regulation) EC No 1084/2003(4) for the Mutual Recognition Procedure and EC No 1085/2003 (5) for thecentralised procedure are in force since 01 October 2003 for notificationsand applications submitted on or after this date.
The new Variations Regulations list two different Type I variations(Type IA and Type IB according to Annex I of CR 1084/2003) and lineextensions (according to Annex II of CR 1084/2003). Type IA and IBvariations follow the notification procedure, Type II variations needapproval.
The new variation categories are summarized below:
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 'Tell, wait, thenand do'-procedure and was set out to provide for rapidprocessing of variations. Type IA changes that are listed in Annex I of CR1084/2003 are defined as administrative changes and/or simple changes withno possible impact on the safety of the medicinal product. All possiblevariations that are not listed in Annex I are classified as Type IIvariations.
Validation of Type IA variations areis done by the Reference MemberState (RMS) in case of the decentralised Mutual Recognition Pproceduresand areis done by EMEA in case of the centralised procedure. In case ofthe Mutual Recognition Pdecentralised procedure the RMS will inform theother national competent authorities concerned and the marketingauthorisation holder in the RMS accordingly.
Type IB (Notification)
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.
For acceptance of a Type IA and IB notification, documentation insupport of the notified changes must be submitted. In order to clarifywhat documentation should be submitted with these notifications, the Guidelineon Dossier requirements for Type IA and Type IB Notifications (July2003) (6) has been prepared
Type II (Approval)
The Type IIB Variations are the 'major' changes that need approvalthat. An approval has to be waited for (timeframe: 960 days with an optionfor changes to indications to extend to 1290 days). All possible changesthat are not listed in Annex I are defined as Type II variations. Allthose changes that are neither covered by Annex I of CR 1084/2003 (TypeIA/IB variations) nor are MR-Variations at all (in case the change has tobe done according to national law, if the change is a line extensionaccording to Annex II of CR 1084/2003 or if the change is a new marketingapplication) are Type II variations. With regard to the approval procedurefor major variations type II, the marketing authorisation holder has tosubmit an application accompanied by different documents summarized in CR1084/2003 (MR procedure) and CR 1085/2003 (centralised procedure)respectively. Validation of Type II variations are done by the ReferenceMember State (RMS) in case of the Mutual Recognition Procedures and aredone by EMEA in case of the centralised procedure.
Extension (Marketing authorisation)
New is the fourth category for line extensions that have been legallydefined for the first time in the European Union. 'Extension' applies toproducts with the same legal name, but where defined changes have beenmade, e.g. replacement of the active substance(s) by a differentsalt/ester complex or derivative, where the efficacy/safety remains thesame, changes to strenght, pharmaceutical form and route ofadministration, etc.