EU Commission Publishes Draft of New Variation Regulation

GMP News
7 November 2007

EU Commission Publishes Draft of New Variation Regulation

On 25 October, Nicolas Rossignol from the EU Commission provided attendees of the APIC Conference ( with first hand information on the new draft on the Variation Regulation. On the same day, the EU Commission issued the draft along with a comprehensive explanation and industry association proposals.

The new proposal takes into account many of the industry favoured improvements. Considering the ICH Guidelines Q8, Q9 and Q10, the substantial changes are illustrated in five key items. The following information has been taken from the document published by the EU Commission

It has been proposed to amend the legal basis of the Variations Regulations in order to include purely national authorisations within the scope of the revised Variations legislative framework. Thus, all authorised medicinal products would be subject to the same rules for the approval and administrative handling of changes, regardless of the procedure under which those medicines have been authorised (purely national, mutual recognition/ decentralised, centralised).

Design space
In the Issue paper released in October 2006, it was suggested to formally introduce in the Variations Regulations certain notions developed at the level of the International Conference on Harmonisation (ICH), namely the notion of ‘design space’. The introduction of the ‘design space’ creates the basis for a less prescriptive, more flexible regulatory approach, whereby changes within an approved design space would not be considered to require any variation application. The use of the 'design space' notion remains optional for the marketing authorisation holder. The design space is established and reviewed either (i) as part of the initial marketing authorisation application, or (ii) later, independently. Introduction of a new design space or changes to an approved design space is evaluated as a Type II variation.

Continuous improvement of manufacture
Beyond the notion of 'design space', ICH developments -namely the Q8, Q9 and Q10 guidelines- introduce modern tools (risk management, quality systems) that could facilitate continuous improvement of the manufacture over the products' life cycle, while maintaining a state of control that ensures high standards of quality. It is therefore proposed to take the opportunity of the drafting of the detailed guideline referred to in Section 8.1 to discuss case-by-case with Member States, the EMEA and interested parties, where and how these ICH quality tools could be implemented (e.g. in which cases the fact that a manufacturer is in compliance with ICH Q9-Q10 could be sufficient to consider a given variation less risky for public or animal health and to validate it through a more flexible procedure).

In order to further reduce the overall number of variations procedures and to enable competent authorities to focus on those changes that have a genuine impact on quality, safety or efficacy, a "Do and Tell" procedure for Type IA variations is introduced. Such variations do not require any prior approval and can be implemented anytime before notifying the competent authorities.

In the light of the comments received on the Issue paper, it is proposed to introduce a 'worksharing' procedure in the following two cases: (a) where the change concerns one given medicinal product that is authorised at purely national level in several Member States; (b) where the change is common to several, distinct medicinal products.

It is proposed that variations which are not explicitly recognised as Type IA, II or line extensions are handled, by default, as Type IB variations (and no longer as Type II).

Other Proposals

Classification of Variations
At the moment, variations conditions are listed in the Annexes to the Commission Regulations. In order to bring further flexibility, it is proposed:
– To introduce generic definitions of variations (Type IA, IB, II, line extensions) in the legal text;
– To replace the current Annexes by detailed guidelines on the conditions for classification of variations (except for line extensions), to be drawn up by the Commission in consultation with the Member States, the EMEA and interested parties;
– To introduce a mechanism of scientific recommendation regarding unclassified variations.

Grouping Variations
Today, variations cannot be grouped within one single submission unless they are all consequential to one given change. However, a number of stakeholders requested, during the consultation phase held in 2006-2007, to introduce the notion of grouped variations i.e. to allow several variations to be submitted together, at once. On this basis, the draft proposal outlines a series of cases where grouping of variations could be allowed (see Annex II to the proposal). Those 'grouped variations' are evaluated in accordance with the procedure of the 'highest-risk' variation included in the group (Figure 5). Importantly, grouped variations are also eligible to the 'worksharing' procedure (see Section 6).

-The draft legal proposal is available here.
-The Consultation paper, which gives detailed explanations on the consultation process as well as on the content of the draft legal proposal, is available here.

A public consultation was conducted in July-September 2007 on the co-decision aspects of the review of the Variations Regulations.
A summary of the outcome of this consultation is available here.
Comments from stakeholders are available here.

Comments on the draft legal proposal and on the Consultation paper should be sent by e-mail to before Friday 4 January 2008.

Prepared by:
Oliver Schmidt
On behalf of the European Compliance Academy (ECA)


Tip: Changes in the US, the new EU Variation Regulation as well as all relevant aspects to implement and/ or improve your Change Control System will be discussed at the new ECA Event:
Change Control – News Aspects and Best Practices
5 – 6 June 2008, Munich, Germany



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