On 25 October, Nicolas Rossignol from the EU Commission provided attendees of
the APIC Conference (www.api-conference.org)
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
KEY ITEM 1: PURELY NATIONAL AUTHORISATIONS
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).
KEY ITEM 2: ICH
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
KEY ITEM 3: DO AND TELL 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.
KEY ITEM 4: "WORKSHARING"
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.
KEY ITEM 5: TYPE IB BY DEFAULT
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).
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
To introduce a mechanism of scientific recommendation regarding unclassified
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
-The Consultation paper, which gives detailed explanations on the consultation
process as well as on the content of the draft legal proposal, is available
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
Comments from stakeholders are available
Comments on the draft legal proposal and on the Consultation paper should be
sent by e-mail to
firstname.lastname@example.org before Friday 4 January 2008.
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
5 6 June 2008, Munich, Germany