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 (Text with EEA relevance)
Date: 2008-11-24
Institutions: European Commission
Subjects: market approval, marketing standard, medicinal product, pharmaceutical legislation, public health, veterinary drug

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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

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

establish a simpler, clearer and more flexible legal
framework, while guaranteeing the same level of public
and animal health protection.

(2)

(3)

(4)

(5)

Having regard to the Treaty
Community,

establishing the European

the European
Having regard to Directive 2001/82/EC of
Parliament and of the Council of 6 November 2001 on the
Community code relating to veterinary medicinal products (1),
and in particular Article 39(1) thereof,

Having regard to Directive 2001/83/EC of
the European
Parliament and of the Council of 6 November 2001 on the
Community code relating to medicinal products for human
use (2), and in particular Article 35(1) thereof,

Having regard to Regulation (EC) No 726/2004 of the European
Parliament and of the Council of 31 March 2004 laying down
Community procedures for the authorisation and supervision of
medicinal products for human and veterinary use and estab­
lishing a European Medicines Agency (3), and in particular of
Article 16(4) and Article 41(6) thereof,

Whereas:

(1)

The Community legal framework regarding variations to
the terms of marketing authorisations is laid down in
Commission Regulation (EC) No 1084/2003 of 3 June
2003 concerning the examination of variations to the
a marketing authorisation for medicinal
terms of
and veterinary medicinal
for human use
products
products granted by a
a
Member State (4) and Commission Regulation (EC) No
1085/2003 of 3 June 2003 concerning the examination
of variations to the terms of a marketing authorisation
for medicinal products for human use and veterinary
medicinal products falling within the scope of Council
Regulation (EEC) No 2309/93 (5). In the light of practical
experience in the application of those two Regulations, it
is appropriate to proceed to their review in order to

authority of

competent

(1) OJ L 311, 28.11.2001, p. 1.
(2) OJ L 311, 28.11.2001, p. 67.
(3) OJ L 136, 30.4.2004, p. 1.
(4) OJ L 159, 27.6.2003, p. 1.
(5) OJ L 159, 27.6.2003, p. 24.

laid down in Regulations

The procedures
(EC) No
1084/2003 and (EC) No 1085/2003 should therefore
be adjusted, without departing from the general prin­
For
ciples on which those procedures
reasons of proportionality, homeopathic and traditional
herbal medicinal products which have not been granted a
marketing authorisation but are subject to a simplified
registration procedure should remain excluded from the
scope of the Regulation.

are based.

Variations to medicinal products can be classified in
different categories, depending on the level of risk to
public or animal health and the impact on the quality,
safety and efficacy of the medicinal product concerned.
Definitions for each of those categories should therefore
In order to bring further predictability,
be laid down.
guidelines on the details of
the various categories of
variations should be established and regularly updated
in the light of scientific and technical progress, taking
in particular account of developments regarding inter­
national
European Medicines
Agency (hereinafter the Agency) and the Member States
should also be empowered to give recommendations on
the classification of unforeseen variations.

harmonisation.

The

It should be clarified that certain changes which have the
highest potential impact on the quality, safety or efficacy
of medicinal products
require a complete scientific
assessment,
in the same way as for the evaluation of
new marketing authorisation applications.

to further

In order
reduce the overall number of
variations procedures and to enable competent auth­
orities to focus on those variations that have a genuine
impact on quality, safety or efficacy, an annual reporting
system should be introduced for certain minor variations.
Such variations should not require any prior approval
and should be notified within 12 months following im­
plementation. However, other types of minor variations
for
whose
the
product
continuous
supervision of
concerned should not be
annual
reporting system.

is necessary
the medicinal
subject

immediate

reporting

to the

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(6)

(7)

(8)

(9)

and

Each variation should require a separate submission.
Grouping of variations should nevertheless be allowed
in certain cases, in order to facilitate the review of the
burden.
the
variations
several
to the
Grouping of
marketing authorisations from the same marketing auth­
orisation holder should be allowed only insofar as all
concerned marketing authorisations are affected by the
exact same group of variations.

administrative
terms of

reduce
variations

In order to avoid duplication of work in the evaluation
of variations to the terms of several marketing authoris­
ations, a worksharing procedure should be established
under which one
the
chosen amongst
competent authorities of
the Member States and the
Agency, should examine the variation on behalf of the
other concerned authorities.

authority,

in Directive

Provisions should be established reflecting those laid
and Directive
2001/82/EC
down
2001/83/EC as regards the role of
the coordination
groups
established under Article 31 of Directive
2001/82/EC and Article 27 of Directive 2001/83/EC,
to increase cooperation between Member States and
in the
allow for
evaluation of certain variations.

settlement of disagreements

the

This Regulation should clarify when the holder of a
marketing authorisation is allowed to implement a
given variation as
for
economic operators.

such clarification is essential

(10) A transitional period should be established in order to
give all
in particular Member States
authorities and the industry, time to adapt to the new
legal framework.

interested parties,

marketing authorisations for medicinal products for human use
and veterinary medicinal products:

(a) authorisations granted in accordance with Council Directive
87/22/EEC (1), Articles 32 and 33 of Directive 2001/82/EC,
Articles 28 and 29 of Directive 2001/83/EC and Regulation
(EC) No 726/2004;

(b) authorisations granted following a referral, as provided for
in Articles 36, 37 and 38 of Directive 2001/82/EC or
Articles 32, 33 and 34 of Directive 2001/83/EC, which
has led to complete harmonisation.

2.
This Regulation shall not apply to transfers of a marketing
authorisation from one marketing authorisation holder (here­
inafter holder) to another.

3.
Chapter II shall apply only to variations to the terms of
marketing authorisations granted in accordance with Directive
87/22/EEC, Chapter 4 of Directive 2001/82/EC or Chapter 4 of
Directive 2001/83/EC.

4.
Chapter III shall apply only to variations to the terms of
marketing authorisations granted in accordance with Regulation
(EC) No
centralised marketing
(hereinafter
authorisations).

726/2004

Article 2

Definitions

For the purposes of this Regulation, the following definitions
shall apply:

1.

‘Variation to the terms of a marketing authorisation’ or
‘variation’ means an amendment
the
particulars and documents referred to in:

to the contents of

(11)

The measures provided for in this Regulation are in
accordance with
Standing
Committee on Medicinal Products for Human Use and
the
Standing Committee on Veterinary Medicinal
Products,

opinions

the

the

of

(a) Articles 12(3), 13, 13a, 13b, 13c, 13d and 14 of
Directive 2001/82/EC and Annex
and
Article 31(2) of Regulation (EC) No 726/2004 in the
case of veterinary medicinal products;

thereto,

I

HAS ADOPTED THIS REGULATION:

CHAPTER I

GENERAL PROVISIONS

Article 1

Subject matter and scope

1.
examination of variations

This Regulation lays down provisions concerning the
the following

to the terms of

(b) Articles 8(3), 9, 10, 10a, 10b, 10c and 11 of Directive
2001/83/EC and Annex I thereto, Article 6(2) of Regu­
lation (EC) No 726/2004, point (a) of Article 7(1) and
Article 34(1) of Regulation (EC) No 1901/2006 of the
European Parliament and of the Council (2) and Articles 7
and 14(1) of Regulation (EC) No 1394/2007 of
the
European Parliament and of the Council (3) in the case
of medicinal products for human use;

(1) OJ L 15, 17.1.1987, p. 38.
(2) OJ L 378, 27.12.2006, p. 1.
(3) OJ L 324, 10.12.2007, p. 121.

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2.

‘Minor variation of type IA’ means a variation which has
only a minimal impact, or no impact at all, on the quality,
safety or efficacy of the medicinal product concerned;

referred to in point (a) of Article 4(1) and, where relevant,
any recommendations delivered pursuant to Article 5, shall by
default be considered a minor variation of type IB.

3.

‘Major variation of type II’ means a variation which is not an
extension and which may have a significant impact on the
quality,
the medicinal product
concerned;

efficacy of

safety or

4.

‘Extension of a marketing authorisation’ or ‘extension’ means
a variation which is listed in Annex I and fulfils the
conditions laid down therein;

5.

‘Minor variation of
type IB’ means a variation which is
neither a minor variation of type IA nor a major variation
of type II nor an extension;

6.

‘Member State concerned’ means a Member State whose
competent authority has granted a marketing authorisation
for the medicinal product in question;

7.

‘Relevant authority’ means:

(a)

competent

the
concerned;

authority of

each Member

State

(b) in the case of centralised marketing authorisations, the

Agency;

8.

‘Urgent safety restriction’ means an interim change to the
information due to new information having a
product
bearing on the safe use of the medicinal product, concerning
in particular one or more of the following items in the
summary of product characteristics: therapeutic indications,
posology, contra-indications, warnings,
target species and
withdrawal periods.

Article 3

Classification of variations

In relation to any variation which is not an extension the

1.
classification laid down in Annex II shall apply.

3.
By way of derogation from paragraph 2, a variation which
is not an extension and whose classification is undetermined
after application of the rules provided for in this Regulation
shall be considered a major variation of
in the
following cases:

type II

(a) upon request
variation;

from the holder when submitting the

(b) where the competent authority of the reference Member
State as referred to in Article 32 of Directive 2001/82/EC
and Article 28 of Directive 2001/83/EC (hereinafter the
in consultation with the other
reference Member State),
Member States concerned or,
in the case of a centralised
marketing authorisation, the Agency concludes, following
the assessment of validity of a notification in accordance
with Article 9(1) or Article 15(1) and taking into account
the recommendations delivered pursuant to Article 5, that
the variation may have a significant impact on the quality,
safety or efficacy of the medicinal product concerned.

Article 4

Guidelines

The Commission shall, after consulting the Member States,

1.
the Agency and interested parties, draw up:

(a) guidelines on the details of

the various categories of

variations;

(b) guidelines on the operation of the procedures laid down in
Chapters II, III and IV of this Regulation as well as on the
documentation
these
procedures.

submitted

pursuant

be

to

to

2.
A variation which is not an extension and whose classifi­
cation is undetermined after application of the rules provided
the guidelines
for

taking into account

in this Regulation,

2.
Guidelines referred to in point (a) of paragraph 1 shall be
drawn up by the date referred to in the second subparagraph of
Article 28 and shall be regularly updated, taking into account
the recommendations delivered in accordance with Article 5 as
well as scientific and technical progress.

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Article 5

Recommendation on unforeseen variations

1.
Prior to submission or examination of a variation whose
classification is not provided for in this Regulation, a holder or
a competent authority of a Member State may request
the
coordination group referred to in Article 31 of Directive
2001/82/EC or in Article 27 of Directive 2001/83/EC (here­
inafter the coordination group) or,
in the case of a variation
the
to the terms of a centralised marketing authorisation,
Agency to provide a recommendation on the classification of
the variation.

(b) where several variations to the terms of the same marketing
authorisation are submitted at
the same time, a single
submission may cover all such variations provided that
the variations concerned fall within one of the cases listed
in Annex III or, if they do not fall within one of those cases,
provided that
the reference
the competent authority of
Member State in consultation with the other Member
States concerned or, in the case of a centralised marketing
authorisation, the Agency agrees to subject those variations
to the same procedure.

The recommendation referred to in the first subparagraph shall
be consistent with the guidelines referred to in point (a) of
It shall be delivered within 45 days following
Article 4(1).
receipt of the request and sent to the holder, the Agency and
the competent authorities of all Member States.

The submission referred to in point (b) of the first subparagraph
shall be made by means of the following:

— a single notification as referred to in Articles 9 and 15
where at least one of the variations is a minor variation
of type IB and all variations are minor variations;

2.
The Agency and the two coordination groups referred to
in paragraph 1 shall cooperate to ensure the coherence of the
recommendations delivered in accordance with that paragraph
and publish those recommendations after deletion of all infor­
mation of commercial confidential nature.

— a single application as referred to in Articles 10 and 16
where at least one of the variations is a major variation of
type II and none of the variations is an extension;

Article 6

— a single application as referred to in Article 19 where at

least one of the variations is an extension.

Variations leading to the revision of product information

Where a variation leads to the revision of the summary of
product
this
revision shall be considered as part of that variation.

labelling or package

characteristics,

leaflet,

Article 7

Grouping of variations

1. Where several variations are notified or applied for, a
separate notification or application as laid down in Chapters
II, III and IV shall be submitted in respect of each variation
sought.

By way of derogation from paragraph 1, the following

2.
shall apply:

CHAPTER II

VARIATIONS TO MARKETING AUTHORISATIONS GRANTED
IN ACCORDANCE WITH DIRECTIVE 87/22/EEC, CHAPTER 4 OF
DIRECTIVE 2001/82/EC OR CHAPTER 4 OF DIRECTIVE
2001/83/EC

Article 8

Notification procedure for minor variations of type IA

1. Where a minor variation of type IA is made, the holder
shall submit simultaneously to all relevant authorities a notifi­
cation containing the elements listed in Annex IV. This notifi­
cation shall be submitted within 12 months following the
implementation of the variation.

However, the notification shall be submitted immediately after
the implementation of
the variation in the case of minor
variations requiring immediate notification for the continuous
supervision of the medicinal product concerned.

(a) where the same minor variations of type IA to the terms of
one or several marketing authorisations owned by the same
holder are notified at the same time to the same relevant
authority, a single notification as referred to in Articles 8
and 14 may cover all such variations;

2. Within 30 days following receipt of the notification, the
measures provided for in Article 11 shall be taken.

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Article 9

Notification procedure for minor variations of type IB

1.
The holder shall submit simultaneously to all relevant
authorities a notification containing the elements listed in
Annex IV.

If the application fulfils the requirements laid down in the first
subparagraph, the competent authority of the reference Member
State shall acknowledge receipt of a valid application and
inform the holder and the other relevant authorities that the
procedure starts from the date of such acknowledgement.

If the notification fulfils the requirement laid down in the first
subparagraph, the competent authority of the reference Member
State shall, after consulting the other Member States concerned,
acknowledge receipt of a valid notification.

2. Within 60 days following the acknowledgement of receipt
of a valid application, the competent authority of the reference
Member State shall prepare an assessment report and a decision
on the application, which shall be communicated to the other
relevant authorities.

2.
If within 30 days following the acknowledgement of
receipt of a valid notification, the competent authority of the
reference Member State has not sent the holder an unfavourable
opinion,
the notification shall be deemed accepted by all
relevant authorities.

The competent authority of the reference Member State may
reduce the period referred to in the first subparagraph, having
regard to the urgency of the matter, or extend it to 90 days for
variations listed in Part 1 of Annex V.

Where the notification is accepted by the competent authority
of the reference Member State, the measures provided for in
Article 11 shall be taken.

The period referred to in the first subparagraph shall be 90 days
for variations listed in Part 2 of Annex V.

3. Where the competent authority of the reference Member
State is of the opinion that the notification cannot be accepted,
it shall
inform the holder and the other relevant authorities,
stating the grounds on which its unfavourable opinion is based.

Within 30 days following the receipt of
the unfavourable
opinion, the holder may submit to all relevant authorities an
amended notification in order to take due account of
the
grounds laid down in that opinion.

If the holder does not amend the notification in accordance
the notification shall be
with the
deemed rejected by all relevant authorities and the measures
provided for in Article 11 shall be taken.

second subparagraph,

4. Where an amended notification has been submitted, the
competent authority of the reference Member State shall assess
it within 30 days following its receipt and the measures
provided for in Article 11 shall be taken.

the
3. Within the period referred to in paragraph 2,
the reference Member State may
competent authority of
request
to provide supplementary information
within a time limit set by that competent authority. In this case:

the holder

(a) the competent authority of the reference Member State shall
inform the other competent authorities concerned of
its
request for supplementary information;

(b) the procedure shall be suspended until such supplementary

information has been provided;

(c) the competent authority of the reference Member State may

extend the period referred to in paragraph 2.

4. Without prejudice to Article 13 and within 30 days
following receipt of the decision and of the assessment report
shall
referred to in paragraph 2,
recognise the decision and inform the competent authority of
the reference Member State accordingly.

the relevant authorities

Article 10

‘Prior Approval’ procedure for major variations of type II

1.
The holder shall submit simultaneously to all relevant
authorities an application containing the elements listed in
Annex IV.

If, within the period referred to in the first subparagraph, a
expressed its disagreement
relevant authority has not
in
accordance with Article 13,
the decision shall be deemed
recognised by that relevant authority.

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5. Where the decision referred to in paragraph 2 has been
recognised by all
in accordance with
relevant authorities
paragraph 4, the measures provided for in Article 11 shall be
taken.

Member State shall prepare an assessment report and a decision
on the application, which shall be communicated to the other
relevant authorities.

Article 11

Measures to close the procedures of Articles 8 to 10

1. Where reference is made to this Article, the competent
authority of the reference Member State shall take the following
measures:

4. Within the period referred to in paragraph 3,
competent authority of
request the holder to provide supplementary information.
shall inform the other relevant authorities accordingly.

the
the reference Member State may
It

(a) it shall inform the holder and the other relevant authorities

as to whether the variation is accepted or rejected;

5. Within 12 days from the date of receipt of the decision
and of the assessment report referred to in paragraph 3, the
relevant authorities shall recognise the decision and inform the
competent authority of the reference Member State accordingly.

(b) where the variation is rejected, it shall inform the holder and
the

relevant authorities of

the grounds

for

the other
rejection;

(c) it shall inform the holder and the other relevant authorities
as to whether the variation requires any amendment to the
decision granting the marketing authorisation.

2. Where reference is made to this Article, each relevant
authority shall, where necessary and within the time limit laid
down in paragraph 1 of Article 23, amend the decision granting
the marketing authorisation in accordance with the accepted
variation.

Article 12

Human influenza vaccines

1.
By way of derogation from Article 10, the procedure laid
down in paragraphs 2 to 6 shall apply to the examination of
variations concerning changes to the active substance for the
purposes of the annual update of a human influenza vaccine.

2.
The holder shall submit simultaneously to all relevant
authorities an application containing the elements listed in
Annex IV.

6. Where requested by the competent authority of
the
reference Member State, the clinical data and data concerning
the stability of the medicinal product shall be submitted by the
holder to all relevant authorities within 12 days from the expiry
of the period referred to in paragraph 5.

The competent authority of the reference Member State shall
evaluate the data referred to in the first subparagraph and draft
a final decision within seven days following receipt of the data.
The other relevant authorities shall, within seven days following
its receipt, recognise that final decision and adopt a decision in
accordance with the final decision.

Article 13

Coordination group and arbitration

1. Where recognition of a decision in accordance with
Article 10(4) or approval of an opinion in accordance with
point (b) of Article 20(8)
is not possible on grounds of a
potential serious risk to public health in the case of medicinal
products for human use or, in the case of veterinary medicinal
products, on grounds of a potential serious risk to human or
animal health or to the environment, a relevant authority shall
request that the matter of disagreement be forthwith referred to
the coordination group.

If the application fulfils the requirements laid down in the first
subparagraph, the competent authority of the reference Member
State shall acknowledge receipt of a valid application and
inform the holder and the other relevant authorities that the
procedure starts from the date of such acknowledgement.

The party in disagreement shall give a detailed statement of the
reasons for its position to all Member States concerned and to
the applicant.

3. Within 30 days following the acknowledgement of receipt
of a valid application, the competent authority of the reference

Article 33(3),

2.
(4) and (5) of Directive 2001/82/EC or
Article 29(3), (4) and (5) of Directive 2001/83/EC shall apply
to the matter of disagreement referred to in paragraph 1.

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CHAPTER III

VARIATIONS TO CENTRALISED MARKETING
AUTHORISATIONS

Article 14

Notification procedure for minor variations of type IA

submit

1. Where a minor variation of type IA is made, the holder
shall
to the Agency a notification containing the
listed in Annex IV. This notification shall be
elements
submitted within 12 months following implementation of the
variation.

However, the notification shall be submitted immediately after
the implementation of
the variation in the case of minor
variations requiring immediate notification for the continuous
supervision of the medicinal product concerned.

2. Within 30 days following receipt of the notification, the
measures provided for in Article 17 shall be taken.

Article 15

Notification procedure for minor variations of type IB

The holder shall submit

1.
containing the elements listed in Annex IV.

to the Agency a notification

order to take due account of the grounds laid down in that
opinion.

If the holder does not amend the notification in accordance
with the
the notification shall be
deemed rejected and the measures provided for in Article 17
shall be taken.

second subparagraph,

4. Where an amended notification has been submitted, the
Agency shall assess it within 30 days following its receipt and
the measures provided for in Article 17 shall be taken.

Article 16

‘Prior Approval’ procedure for major variations of type II

The holder shall submit to the Agency an application

1.
containing the elements listed in Annex IV.

If the application fulfils the requirements laid down in the first
subparagraph, the Agency shall acknowledge receipt of a valid
application.

The Agency shall issue an opinion on the valid application
2.
referred to in paragraph 1 within 60 days following its receipt.

If the notification fulfils the requirement laid down in the first
subparagraph, the Agency shall acknowledge receipt of a valid
notification.

The Agency may reduce the period referred to in the first
subparagraph, having regard to the urgency of the matter, or
extend it to 90 days for variations listed in Part 1 of Annex V.

2.
If within 30 days following the acknowledgement of
receipt of a valid notification the Agency has not sent the
holder an unfavourable opinion,
its opinion shall be deemed
favourable.

the Agency on the notification is
Where the opinion of
favourable, the measures provided for in Article 17 shall be
taken.

The period referred to in the first subparagraph shall be 90 days
for variations listed in Part 2 of Annex V.

3. Within the period referred to in paragraph 2, the Agency
may request the holder to provide supplementary information
within a time limit set by the Agency. The procedure shall be
suspended until such time as the supplementary information
has been provided. In this case the Agency may extend the
period referred to in paragraph 2.

3. Where the Agency is of the opinion that the notification
cannot be accepted,
inform the holder, stating the
it shall
grounds on which its unfavourable opinion is based.

4.
Article 9(1) and (2) and Article 34(1) and (2) of Regu­
lation (EC) No 726/2004 shall apply to the opinion on the valid
application.

Within 30 days of receipt of the unfavourable opinion, the
holder may submit to the Agency an amended notification in

Within 15 days from the adoption of the final opinion on the
valid application, the measures provided for in Article 17 shall
be taken.

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Article 17

Measures to close the procedures of Articles 14 to 16

1. Where reference is made to this Article, the Agency shall
take the following measures:

The Commission shall, where necessary and on the basis of that
opinion, adopt a decision on the variation to the terms of the
marketing authorisation and inform the holder accordingly.

(a) it shall

inform the holder and the Commission as to
whether its opinion on the variation is favourable or un­
favourable;

6. Where requested, the holder shall submit the clinical data
and the data concerning the stability of the medicinal product
to the Agency within 12 days from the expiry of the period
referred to in paragraph 3.

(b) where its opinion on the variation is unfavourable, it shall
inform the holder and the Commission of the grounds for
that opinion;

(c) it shall
whether
decision granting the marketing authorisation.

inform the holder and the Commission as to
to the
the variation requires any amendment

2. Where reference is made to this Article, the Commission
shall, where necessary, based on a proposal from the Agency
and within the time limit
laid down in paragraph 1 of
Article 23, amend the decision granting the marketing author­
isation and update the Community Register of Medicinal
Products provided for in Article 13(1) and Article 38(1) of
Regulation (EC) No 726/2004 accordingly.

Article 18

Human influenza vaccines

By way of derogation from Article 16, the procedure laid
1.
down in paragraphs 2 to 7 shall apply to the examination of
variations concerning changes to the active substance for the
purposes of the annual update of a human influenza vaccine.

The holder shall submit to the Agency an application

2.
containing the elements listed in Annex IV.

The Agency shall evaluate the data referred to in the first sub­
paragraph and shall give its final opinion within 10 days
following receipt of the data. The Agency shall communicate
its final opinion to the Commission and to the holder within
three days from the date of issue of its final opinion.

7. Where necessary and based on the final opinion of the
Agency, the Commission shall amend the decision granting the
marketing authorisation and update the Community Register of
Medicinal Products provided for in Article 13(1) of Regulation
(EC) No 726/2004 accordingly.

CHAPTER IV

SECTION 1

Special procedures

Article 19

Extensions of marketing authorisations

1.
An application for an extension of a marketing authoris­
ation shall be evaluated in accordance with the same procedure
as for the initial marketing authorisation to which it relates.

If the application fulfils the requirements laid down in the first
subparagraph, the Agency shall acknowledge receipt of a valid
application and inform the holder that the procedure starts
from the date of such acknowledgement.

2.
An extension shall either be granted a marketing author­
isation in accordance with the same procedure as for the
granting of
the initial marketing authorisation to which it
relates or be included in that marketing authorisation.

3. Within 45 days following the acknowledgement of receipt
of a valid application, the Agency shall give its opinion on the
application.

Article 20

Worksharing procedure

4. Within the period referred to in paragraph 3, the Agency
may request the holder to provide supplementary information.

The Agency shall submit

5.
Commission.

forthwith its opinion to the

(b) of Article 7(2) which does not

By way of derogation from Article 7(1) and Articles 9, 10,
1.
15 and 16, where a minor variation of
type IB, a major
variation of type II or a group of variations in the cases of
point
contain any
extension relates to several marketing authorisations owned
by the same holder, the holder of such authorisations may
follow the procedure laid down in paragraphs 3 to 9 of this
Article.

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For

2.
authority’ shall mean one of the following:

the purposes of paragraphs 3 to 9,

‘reference

6. Within the period referred to in paragraph 4, the reference
authority may request
the holder to provide supplementary
information within a time limit set by the reference authority.
In this case:

(a) the Agency where at least one of the marketing authoris­
ations referred to in paragraph 1 is a centralised marketing
authorisation;

(a) the reference authority shall inform the other relevant auth­

orities of its request for supplementary information;

(b) the competent authority of a Member State concerned
chosen by the coordination group, taking into account a
recommendation of the holder, in the other cases.

(b) the procedure shall be suspended until such supplementary

information has been provided;

The holder shall submit to all relevant authorities an appli­
3.
cation containing the elements listed in Annex IV, with an
indication of the recommended reference authority.

(c) the reference authority may extend the period referred to in

point (a) of paragraph 4.

If the application fulfils the requirements laid down in the first
subparagraph, the coordination group shall chose a reference
authority and that reference authority shall acknowledge receipt
of a valid application.

7. Where the reference authority is the Agency, Article 9(1),
(2) and (3) and Article 34(1), (2) and (3) of Regulation (EC) No
726/2004 shall apply to the opinion on a valid application
referred to in paragraph 4.

Where the opinion on a valid application is favourable:

the

authority is

chosen reference

competent
Where
authority of a Member State which has not granted a
marketing authorisation for all the medicinal products affected
by the application, the coordination group may request another
the reference authority in the
relevant authority to assist
evaluation of that application.

the

The reference authority shall issue an opinion on the valid
the

4.
application referred to in paragraph 3 within one of
following periods:

(a) a period of 60 days following acknowledgement of receipt
of a valid application in the case of minor variations of type
IB or major variations of type II;

(b) a period of 90 days following acknowledgement of receipt
of a valid application in the case of variations listed in Part 2
of Annex V.

(a) the Commission shall, within 30 days following receipt of
the final opinion and on the basis of a proposal from the
Agency, amend where necessary the concerned centralised
the Community
marketing authorisations
Register
in
of Medicinal
Article 13(1) and Article 38(1) of Regulation (EC) No
726/2004 accordingly;

and update
Products

provided

for

concerned shall, within 30 days
(b) the Member States
following receipt of
the Agency,
the final opinion of
approve that final opinion, inform the Agency thereof and
amend where necessary the concerned marketing authoris­
ations accordingly, unless a referral procedure in accordance
with Article 35 of Directive 2001/82/EC or Article 31 of
Directive 2001/83/EC is initiated within 30 days following
receipt of the final opinion.

8. Where the reference authority is the competent authority
of a Member State:

5.
The reference authority may reduce the period referred to
in point (a) of paragraph 4, having regard to the urgency of the
matter, or extend it to 90 days for variations listed in Part 1 of
Annex V.

(a) it shall send its opinion on the valid application to the

holder and to all relevant authorities;

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(b) without prejudice to Article 13 and within 30 days
following receipt of the opinion, the relevant authorities
inform the reference authority
shall approve that opinion,
and
authorisations
amend
accordingly.

concerned marketing

the

In the event of a risk to public health in the case of
2.
medicinal products for human use or, in the case of veterinary
medicinal products, in the event of a risk to human or animal
health or to the environment, relevant authorities or, in the case
of centralised marketing authorisations, the Commission may
impose urgent safety restrictions on the holder.

9.
Upon request from the reference authority, the Member
States concerned shall provide information related to the
marketing authorisations affected by the variation for
the
purpose of verifying the validity of
the application and of
issuing the opinion on the valid application.

Article 21

Pandemic situation with respect to human influenza

By way of derogation from Articles 12, 18 and 19, where
1.
a pandemic situation with respect to human influenza is duly
recognised by the World Health Organisation or by the
Community in the framework of Decision 2119/98/EC of the
European Parliament and of the Council (1), the relevant auth­
in the case of centralised marketing authorisations,
orities or,
the Commission may exceptionally and temporarily accept a
variation to the terms of a marketing authorisation for a
human influenza vaccine, where certain non-clinical or clinical
data are missing.

2. Where a variation is accepted pursuant to paragraph 1,
the holder shall submit the missing non-clinical and clinical data
within a time limit set by the relevant authority.

Article 22

Urgent safety restrictions

1. Where, in the event of a risk to public health in the case
of medicinal products for human use or,
in the case of
veterinary medicinal products,
in the event of a risk to
human or animal health or to the environment, the holder
takes urgent safety restrictions on its own initiative,
it shall
forthwith inform all relevant authorities and, in the case of a
centralised marketing authorisation, the Commission.

3. Where an urgent safety restriction is taken by the holder
or imposed by a relevant authority or the Commission, the
application for
holder
the
variation within 15 days
that
restriction.

following the initiation of

corresponding

submit

shall

SECTION 2

Amendments to the decision granting the marketing
authorisation and implementation

Article 23

Amendments to the decision granting the marketing
authorisation

The amendment to the decision granting the marketing
laid down in

1.
authorisation resulting from the procedures
Chapters II and III shall be made:

(a) within 30 days following receipt of the information referred
to in Article 11(1)(c) and Article 17(1)(c), where the
concerned variation leads to a six-month extension of the
period referred to in Article 13(1) and (2) of Council Regu­
lation (EEC) No 1768/92 (2), in accordance with Article 36
of Regulation (EC) No 1901/2006;

(b) within two months following receipt of the information
referred to in Article 11(1)(c) and Article 17(1)(c),
in the
case of major variations of type II and minor variations of
type IA which do not require immediate notification for the
continuous supervision of the medicinal product concerned;

(c) within six months following receipt of

referred to in Article 11(1)(c) and Article 17(1)(c),
other cases.

the information
in the

in the case of a centralised
If no relevant authority or,
marketing authorisation, the Commission has raised objections
within 24 hours following receipt of
the
urgent safety restrictions shall be deemed accepted.

information,

that

2. Where the decision granting a marketing authorisation is
amended as a result of one of the procedures laid down in
Chapters II, III and IV, the relevant authority or,
in the case
of centralised marketing authorisations, the Commission shall
notify the amended decision without delay to the holder.

(1) OJ L 268, 3.10.1998, p. 1.

(2) OJ L 182, 2.7.1992, p. 1.

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Article 24

Implementation of variations

1.
A minor variation of type IA may be implemented any
time before completion of the procedures laid down in Articles
8 and 14.

An extension may only be implemented after the relevant
4.
authority or, in the case of extensions to a centralised marketing
authorisation,
the Commission has amended the decision
granting the marketing authorisation in accordance with the
approved extension and notified the holder accordingly.

Where a notification concerning one or several minor variations
the holder shall cease to apply the
of
concerned
the
receipt of
immediately
information referred to in Articles 11(1)(a) and 17(1)(a).

type IA is rejected,
variation(s)

after

2. Minor variations of type IB may only be implemented in
the following cases:

(a) after the competent authority of the reference Member State
has informed the holder that it has accepted the notification
pursuant to Article 9, or after the notification is deemed
accepted pursuant to Article 9(2);

(b) after the Agency has informed the holder that its opinion
referred to in Article 15 is favourable, or after that opinion
is deemed favourable pursuant to Article 15(2);

(c) after the reference authority referred to in Article 20 has

informed the holder that its opinion is favourable.

3. Major variations of type II may only be implemented in
the following cases:

(a) 30 days after the competent authority of

the reference
Member State has informed the holder that it has accepted
the variation pursuant to Article 10, under the condition
that the documents necessary for the amendment to the
marketing
authorisation have been provided to the
Member States concerned;

(b) after the Commission has amended the decision granting the
marketing authorisation in accordance with the accepted
variation and notified the holder accordingly;

(c) 30 days after

the

reference authority referred to in
Article 20 has informed the holder that its final opinion
is favourable, unless an arbitration procedure in accordance
with Article 13 or a referral procedure in accordance with
Article 35 of Directive 2001/82/EC or Article 31 of
Directive 2001/83/EC has been initiated.

5.
Urgent safety restrictions and variations which are related
to safety issues shall be implemented within a time frame
agreed by the holder and the relevant authority and,
in the
case of a centralised marketing authorisation, the Commission.

By way of derogation from the first subparagraph, urgent safety
restrictions and variations related to safety issues which concern
marketing authorisations granted in accordance with Chapter 4
of Directive 2001/82/EC or Chapter 4 of Directive 2001/83/EC
shall be implemented within a time frame agreed by the holder
and the competent authority of the reference Member State, in
consultation with the other relevant authorities.

CHAPTER V

FINAL PROVISIONS

Article 25

Continuous monitoring

Where requested by a relevant authority, the holder shall supply
without delay any information related to the implementation of
a given variation.

Article 26

Review

By two years from the date referred to in the second subpara­
graph of Article 28, the Commission services shall assess the
application of this Regulation as regards the classification of
variations, with a view to proposing any necessary amendments
to adapt Annexes I, II and V to take account of scientific and
technical progress.

Article 27

Repeal and transitional provision

Regulations (EC) No 1084/2003 and (EC) No 1085/2003

1.
are hereby repealed.

References to the repealed Regulations shall be construed as
references to this Regulation.

2.
By way of derogation from paragraph 1, Regulations
(EC) Nos 1084/2003 and 1085/2003 shall continue to apply
to valid notifications or applications for variations which are
pending at the date referred to in the second subparagraph of
Article 28.

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Article 28

Entry into force
This Regulation shall enter into force on the 20th day following its publication in the Official Journal of the
European Union.

It shall apply from 1 January 2010.

By way of derogation from the second subparagraph, the recommendations on unforeseen variations
provided for in Article 5 may be requested, delivered and published from the date of entry into force
referred to in the first subparagraph.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Brussels, 24 November 2008.

For the Commission

Günter VERHEUGEN
Vice-President

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ANNEX I

Extensions of marketing authorisations

1. Changes to the active substance(s):

(a) replacement of a chemical active substance by a different salt/ester complex/derivative, with the same therapeutic

moiety, where the efficacy/safety characteristics are not significantly different;

(b) replacement by a different isomer, a different mixture of isomers, of a mixture by an isolated isomer (e.g. racemate

by a single enantiomer), where the efficacy/safety characteristics are not significantly different;

(c) replacement of a biological active substance with one of a slightly different molecular structure where the

efficacy/safety characteristics are not significantly different, with the exception of:

— changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza;

— replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a

veterinary vaccine against avian influenza, foot-and-mouth disease or bluetongue;

— replacement of a strain for a veterinary vaccine against equine influenza;

(d) modification of the vector used to produce the antigen or the source material, including a new master cell bank

from a different source, where the efficacy/safety characteristics are not significantly different;

(e) a new ligand or coupling mechanism for a radiopharmaceutical, where the efficacy/safety characteristics are not

significantly different;

(f) change to the extraction solvent or the ratio of herbal drug to herbal drug preparation where the efficacy/safety

characteristics are not significantly different.

2. Changes to strength, pharmaceutical form and route of administration:

(a) change of bioavailability;

(b) change of pharmacokinetics e.g. change in rate of release;

(c) change or addition of a new strength/potency;

(d) change or addition of a new pharmaceutical form;

(e) change or addition of a new route of administration (1).

3. Other changes specific to veterinary medicinal products to be administered to food-producing animals: change or

addition of target species.

(1) For parenteral administration, it is necessary to distinguish between intra-arterial, intravenous, intramuscular, subcutaneous and other
routes. For administration to poultry, respiratory, oral and ocular (nebulisation) routes used for vaccination are considered to be
equivalent routes of administration.

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ANNEX II

Classification of variations

1. The following variations shall be classified as minor variations of type IA:

(a) variations of purely administrative nature that are related to the identity and contact details of:

— the holder;

— the manufacturer or supplier of any starting material, reagent,

intermediate, active substance used in the

manufacturing process or finished product;

(b) variations related to the deletion of any manufacturing site, including for an active substance, intermediate or
finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place;

(c) variations related to minor changes to an approved physico-chemical test procedure, where the updated procedure
is demonstrated to be at least equivalent to the former test procedure, appropriate validation studies have been
performed and the results show that the updated test procedure is at least equivalent to the former;

(d) variations related to changes made to the specifications of the active substance or of an excipient in order to
comply with an update of the relevant monograph of the European Pharmacopoeia or of the national pharma­
copoeia of a Member State, where the change is made exclusively to comply with the pharmacopoeia and the
specifications for product specific properties are unchanged;

(e) variations related to changes in the packaging material not in contact with the finished product, which do not

affect the delivery, use, safety or stability of the medicinal product;

(f) variations related to the tightening of specification limits, where the change is not a consequence of any
commitment from previous assessment to review specification limits and does not result from unexpected
events arising during manufacture.

2. The following variations shall be classified as major variations of type II:

(a) variations related to the addition of a new therapeutic indication or to the modification of an existing one;

(b) variations related to significant modifications of the summary of product characteristics due in particular to new

quality, pre-clinical, clinical or pharmacovigilance findings;

(c) variations related to changes outside the range of approved specifications, limits or acceptance criteria;

(d) variations related to substantial changes to the manufacturing process, formulation, specifications or impurity
profile of the active substance or finished medicinal product which may have a significant impact on the quality,
safety or efficacy of the medicinal product;

(e) variations related to modifications in the manufacturing process or sites of the active substance for a biological

medicinal product;

(f) variations related to the introduction of a new design space or the extension of an approved one, where the design
space has been developed in accordance with the relevant European and international scientific guidelines;

(g) variations concerning a change to or addition of a non-food producing target species;

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(h) variations concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes,
strains or antigens for a veterinary vaccine against avian influenza, foot-and-mouth disease or bluetongue;

(i) variations concerning the replacement of a strain for a veterinary vaccine against equine influenza;

(j) variations related to changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against

human influenza;

(k) variations related to changes to the withdrawal period for a veterinary medicinal product.

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ANNEX III

Cases for grouping variations referred to in Article 7(2)(b)

1. One of the variations in the group is an extension of the marketing authorisation.

2. One of the variations in the group is a major variation of type II; all other variations in the group are variations

which are consequential to this major variation of type II.

3. One of the variations in the group is a minor variation of type IB; all other variations in the group are minor

variations which are consequential to this minor variation of type IB.

4. All variations in the group relate solely to changes of administrative nature to the summary of product characteristics,

labelling and package leaflet or insert.

5. All variations in the group are changes to an Active Substance Master File, Vaccine Antigen Master File or Plasma

Master File.

6. All variations in the group relate to a project intended to improve the manufacturing process and the quality of the

medicinal product concerned or its active substance(s).

7. All variations in the group are changes affecting the quality of a human pandemic influenza vaccine.

8. All variations in the group are changes to the pharmacovigilance system referred to in points (ia) and (n) of

Article 8(3) of Directive 2001/83/EC or points (k) and (o) of Article 12(3) of Directive 2001/82/EC.

9. All variations in the group are consequential to a given urgent safety restriction and submitted in accordance with

Article 22.

10. All variations in the group relate to the implementation of a given class labelling.

11. All variations in the group are consequential to the assessment of a given periodic safety update report.

12. All variations in the group are consequential to a given post-authorisation study conducted under the supervision of

the holder.

13. All variations in the group are consequential to a specific obligation carried out pursuant to Article 14(7) of

Regulation (EC) No 726/2004.

14. All variations in the group are consequential to a specific procedure or condition carried out pursuant to Articles
14(8) or 39(7) of Regulation (EC) No 726/2004, Article 22 of Directive 2001/83/EC or Article 26(3) of Directive
2001/82/EC.

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ANNEX IV

Elements to be submitted

1. A list of all the marketing authorisations affected by the notification or application.

2. A description of all the variations submitted, including:

(a)

in the case of minor variations of type IA, the date of implementation for each variation described;

(b) in the case of minor variations of type IA which do not require immediate notification, a description of all minor
variations of type IA made in the last 12 months to the terms of the concerned marketing authorisation(s) and
which have not been already notified.

3. All necessary documents as listed in the guidelines referred to in point (b) of Article 4(1).

4. Where a variation leads to or is the consequence of other variations to the terms of the same marketing authorisation,

a description of the relation between these variations.

5. In the case of variations to centralised marketing authorisations, the relevant fee provided for in Council Regulation

(EC) No 297/95 (1).

6. In the case of variations to marketing authorisations granted by the competent authorities of Member States:

(a) a list of those Member States with an indication of the reference Member State if applicable;

(b) the relevant fees provided for in the applicable national rules in the Member States concerned.

(1) OJ L 35, 15.2.1995, p. 1.

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ANNEX V

PART 1

Variations concerning a change to or addition of therapeutic indications.

PART 2

1. Variations concerning a change to or addition of a non-food producing target species.

2. Variations concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or

antigens for a veterinary vaccine against avian influenza, foot-and-mouth disease or bluetongue.

3. Variations concerning the replacement of a strain for a veterinary vaccine against equine influenza.