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 (Text with EEA relevance)
Date: 2003-06-03
Institutions: European Commission
Subjects: market approval, marketing standard, medicinal product, pharmaceutical legislation, public health, veterinary drug

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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

(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

(4)

Having regard to the Treaty establishing the European Com-
munity,

Having regard to Council Regulation (EEC) No 2309/93 of
22 July 1993 laying down Community procedures for the
authorisation and supervision of medicinal products for
human and veterinary use and establishing a European Agency
for the Evaluation of Medicinal Products (1), as amended by
Commission Regulation (EC) No 649/98 (2) and in particular
Articles 15(4) and 37(4) thereof,

Whereas:

(1)

(2)

(3)

In the light of practical experience in the application of
Commission Regulation (EC) No 542/95 of 10 March
1995 concerning the examination of variations to the
terms of a marketing authorisation falling within the
scope of Council Regulation (EEC) No 2309/93 (3), as
amended by Regulation (EC) No 1069/98 (4),
is
appropriate to simplify the procedure for varying the
terms of a marketing authorisation.

it

Due to the technical adaptation of Annex I to Directive
2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code
related to medicinal products for human use (5), it is
appropriate to introduce in this Regulation provisions
on variations related to plasma master files and vaccine
antigen master files.

Some of the procedures laid down in Regulation (EC)
No 542/95 should therefore be adjusted but without
departing from the general principles on which those
procedures are based.

( 1) OJ L 214, 24. 8.1993, p. 1.
( 2) OJ L 88, 24.3.1998, p. 7.
( 3) OJ L 55, 11.3.1995, p. 15.
( 4) OJ L 153, 27.5.1998, p. 11.
( 5) OJ L 311, 28.11.2001, p. 67.

It is appropriate to provide for a simplified and rapid
notification procedure to enable the introduction of
certain minor changes, which do not affect the approved
quality, safety or efficacy of the product, without prior
evaluation by the European Agency for the evaluation
of medicinal products (hereinafter referred to as ‘the
Agency’). However, for other types of minor variations
evaluation of
the submitted documentation by the
Agency should still be required.

(5)

(6)

(7)

(8)

The various types of minor variation should be classified
in order to determine the procedure to follow;
it is
particularly necessary to give a precise definition of the
type of minor variation for which no prior evaluation is
needed.

It is necessary to clarify the definition of an ‘extension’
to a marketing authorisation, although it should still be
full application for
possible to submit a separate,
marketing authorisation for a medicinal product which
has already been authorised but under a different name
and with summary of product characteristics.

It is appropriate to allow the Agency to reduce the
evaluation period in urgent cases or to extend it in the
case of a major variation entailing important changes.

It is necessary to simplify the administrative procedures
for minor variations regarding the updating of marketing
authorisations by allowing the Commission to group
these updates every six months in one single decision.

(9)

The time-frame for the procedure to be followed where
the Commission imposes urgent safety restrictions
should be clarified.

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(10)

Further clarification should be introduced as regards
revision of the labelling, the package leaflet/insert or the
summary of product characteristics; nevertheless the
procedures laid down in this Regulation should not
apply to changes to the labelling or to the package
leaflet/insert which are not consequential to changes to
the summary of product characteristics.

(11)

For the sake of clarity,
it
Regulation (EC) No 542/95.

is appropriate to replace

(12) The measures provided for in this Regulation are in
accordance with the opinion of the Standing Committee
on Medicinal products for Human Use and the Standing
Committee on Veterinary Medicinal Products,

HAS ADOPTED THIS REGULATION:

Article 1

Subject matter

1.
This Regulation lays down the procedure for the examin-
ation of applications for variations to the terms of a marketing
authorisation granted in accordance with Regulation (EEC)
No 2309/93.

2.
This Regulation also applies for the examination of
applications of variations to the terms of a plasma master file
and of a vaccine antigen master file, as defined in Annex I of
Directive 2001/83/EC.

Article 2

Scope

This Regulation shall not apply to:

(a)

extensions of marketing authorisations which fulfil the
conditions set out in Annex II to this Regulation;

(b)

transfers of a marketing authorisation to a new holder;

(c)

changes to the maximum residue limit as defined in
Article 1(1)(b) of Council Regulation (EEC) No 2377/
90 (1).

The extension referred to in point (a) of the first paragraph
shall be evaluated in accordance with the procedures set out in
Articles 6 to 10 and Articles 28 to 32 of Regulation (EEC)
No 2309/93 for medicinal products for human use and
veterinary medicinal products, respectively.

Article 3

Definitions

1.

2.

3.

4.

‘variation to the terms of a marketing authorisation’
means an amendment to the contents of the documents
referred to in Article 6(1) and (2) or Article 28(1) and (2)
of Regulation (EEC) No 2309/93, such as they existed at
the moment the decision on the marketing authorisation
was adopted, in accordance with Article 10 or Article 32
of that Regulation or after approval of any previous
variations;

a ‘minor variation’ of type IA or type IB means a variation
listed in Annex I which fulfils the conditions set out
therein;

a ‘major variation’ of type II means a variation that cannot
be deemed to be a minor variation or an extension of the
marketing authorisation;

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

Article 4

Notification procedure for minor variations type IA

1. With regard to minor variations of type IA, the marketing
authorisation holder (hereinafter referred to as ‘the holder’)
shall submit to the Agency a notification accompanied by

(a)

(b)

all necessary documents including those amended as a
result of the variation;

the relevant fee provided for in Council Regulation (EC)
No 297/95 (2).

A notification shall only concern one type IA variation.
2.
Where several type IA variations are to be made to the terms
of a single marketing authorisation, a separate notification
shall be submitted in respect of each type IA variation sought;
each such notification shall also contain a reference to the
other notifications.

3.
By way of derogation from paragraph 2, where a type IA
variation to the marketing authorisation leads to consequential
type IA variations, a single notification may cover all such
consequential variations. The single notification shall contain
a description of the relation between these consequential
type IA variations.

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

4. Where a variation requires consequential revision of the
summary of product characteristics,
labelling and package
leaflet/insert, this is considered as part of the variation.

( 1) OJ L 224, 18.8.1990, p. 1.

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

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5.
If the notification fulfils the requirements set out in
paragraphs 1 to 4, the Agency shall, within 14 days following
receipt of the notification, acknowledge the validity of this
notification and shall inform the holder accordingly.

5.
If the notification fulfils the requirements set out in
paragraphs 1 to 4, the Agency shall acknowledge receipt of a
valid notification and shall start the procedure set out in
paragraphs 6 to 10.

The Agency shall, where appropriate, disseminate the amended
documents referred to in Article 3(1).

The Commission shall, where necessary and based on a
proposal prepared by the Agency, update every six months the
marketing authorisation which has been granted pursuant to
Article 10 or Article 32 of Regulation (EEC) No 2309/93.

The updated marketing authorisation shall be notified by the
Commission to the holder.

The Community Register of Medicinal Products provided for
in Articles 12 and 34 of Regulation (EEC) No 2309/93 shall
be updated as necessary.

Article 5

Notification procedure for minor variations type IB

1. With regard to minor variations of type IB, the holder
shall submit to the Agency a notification accompanied by:

(a)

all necessary documents demonstrating that the con-
ditions laid down in Annex I for the requested variation
are met, including all documents amended as a result of
the application;

(b)

the relevant fee provided for in Regulation (EC) No 297/
95.

A notification shall only concern one type IB variation.
2.
Where several
type IB variations are to be made to a
single marketing authorisation, a separate notification shall be
submitted in respect of each type IB variation sought; each
such notification shall also contain a reference to the other
notifications.

3.
By way of derogation from paragraph 2, where a type IB
variation to the marketing authorisation leads to consequential
type IA or type IB variations, a single type IB notification may
cover all such consequential variations. The single application
shall contain a description of the relation between these
consequential type I variations.

4. Where a variation requires consequential revision of the
summary of product characteristics, labelling and package
leaflet/insert, this is considered as part of the variation.

6.
If, within 30 days of the date of the acknowledgement of
receipt of a valid notification the Agency has not sent the
holder its opinion provided for in paragraph 8, the variation
applied for shall be deemed to have been accepted.

The Agency shall inform the holder accordingly.

The Agency shall, where appropriate, disseminate the amended
documents referred to in Article 3(1).

7.
The Commission shall, where necessary and based on a
proposal prepared by the Agency, update every six months the
marketing authorisation which has been granted pursuant to
Article 10 or Article 32 of Regulation (EEC) No 2309/93.

The updated marketing authorisation shall be notified by the
Commission to the holder.

The Community Register of Medicinal Products provided for
in Articles 12 and 34 of Regulation (EEC) No 2309/93 shall
be updated as necessary.

8. Where the Agency is of the opinion that the notification
cannot be accepted, it shall, within the period referred to in
inform the holder who has submitted the
paragraph 6,
notification, stating the grounds on which its opinion is based.

9. Within 30 days of receipt of the opinion referred to in
paragraph 8, the holder may amend the notification in order
to take due account of the grounds set out in the opinion. In
that case the provisions of paragraphs 6 and 7 shall apply to
the amended notification.

10.
If the holder does not amend the notification, the
notification shall be deemed to have been rejected. The Agency
shall inform the holder accordingly.

Article 6

Approval procedure for major variations type II

1. With regard to major variations of type II, the holder
shall submit to the Agency an application accompanied by:

(a)

the relevant particulars and supporting documents
referred to in Article 3(1);

(b)

the supporting data relating to the variation applied for;

(c)

all documents amended as a result of the application;

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(d)

an addendum to or update of existing expert reports/
overviews/summaries to take account of the variation
applied for;

(e)

the relevant fee provided for in Regulation (EC) No 297/
95.

8. Where the competent Committee delivers an opinion,
the Agency shall inform the holder and the Commission
forthwith and shall send to the Commission, where appropri-
ate, the amendments to be made to the terms of the marketing
authorisation accompanied by the documents set out in
Article 9(3) and 31(3) of Regulation (EEC) No 2309/93.

2.
An application shall only concern one type II variation.
Where several type II variations are to be made to a single
marketing authorisation, a separate application shall be sub-
mitted in respect of each variation sought; each such appli-
cation shall also contain a reference to the other applications.

3.
By way of derogation to paragraph 2, where a type II
variation leads to consequential variations, a single application
may cover all such consequential variations. The single appli-
cation shall contain a description of the relation between these
consequential variations.

4. Where a variation requires consequential revision of the
summary of product characteristics, labelling and package
leaflet/insert, this is considered as part of the variation.

9.
Article 9(1) and (2) or Article 31(1) and (2) of Regulation
(EEC) No 2309/93 shall apply to the opinion adopted by the
competent Committee.

10.
The Commission shall, where necessary and based on
the proposal prepared by the Agency, amend the marketing
authorisation that has been granted pursuant to Article 10 or
Article 32 of the Regulation (EEC) No 2309/93.

Decisions concerning variations related to safety issues shall
be implemented within a time-frame as agreed between the
Commission and the holder.

The amended marketing authorisation shall be notified by the
Commission to the holder.

11.
The Community Register of Medicinal Products pro-
vided for in Articles 12 and 34 of Regulation (EEC) No 2309/
93 shall be updated as necessary.

5.
If the application fulfils the requirements set out in
paragraphs 1 to 4, the Agency shall acknowledge receipt of a
valid application and shall start the procedure set out in
paragraphs 6 to 11.

Article 7

Human influenza vaccines

The competent Committee of the Agency shall give its

6.
opinion within 60 days from the start of the procedure.

This period can be reduced having regard to the urgency of
the matter, particularly for safety issues.

1. With regard to variations to the terms of the marketing
authorisations for human influenza vaccines, the procedure
set out in paragraphs 2 to 6 shall apply.

2. Within 45 days following the date of the receipt of a
valid application, the Agency shall give its opinion on the
quality documents referred to in Module 3 of Annex I to
Directive 2001/83/EC, based on an assessment report.

This period can be extended to 90 days for variations
concerning changes to or addition of the therapeutic indi-
cations.

3. Within the period laid down in paragraph 2, the Agency
may request the holder to provide supplementary information.

This period will be extended to 90 days for variations
concerning a change to or addition of a non-food-producing
target species.

The Agency shall address forthwith its opinion to the

4.
Commission.

The Commission shall adopt a decision updating the marketing
authorisation that has been granted pursuant to Article 10 of
the Regulation (EEC) No 2309/93.

7. Within the periods laid down in paragraph 6,
the
competent Committee may send the holder a request for
supplementary information within a time limit set by that
Committee. The procedure shall be suspended until such time
as the supplementary information has been provided. In this
case the periods laid down in paragraph 6 may be extended
for a further period to be determined by that Committee.

This decision shall be implemented on condition that the final
opinion of the Agency as provided for in paragraph 5 is
favourable.

The updated marketing authorisation shall be notified by the
Commission to the holder.

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5.
The clinical data and, where appropriate, those concern-
ing the stability of the medicinal product shall be addressed by
the holder to the Agency at the latest 12 days following the
end of the time limit laid down in paragraph 2.

The Agency shall evaluate these data and shall give its final
opinion within 10 days of the reception of the data referred to
in the first subparagraph. The Agency shall address the final
opinion to the Commission and to the marketing authorisation
holder within the three following days.

6.
The Community Register of Medicinal Products provided
for in Article 12 of Regulation (EEC) No 2309/93 shall be
updated as necessary.

Article 8

Pandemic situation with respect to human diseases

In case of a pandemic situation with respect to the human
influenza virus, duly recognised by the World Health Organis-
ation or by the Community in the framework of Decision
2119/98/EC of the European Parliament and of the Council (1),
the Commission may exceptionally and temporarily consider
the variation to the terms of the market authorisation for
human influenza vaccines to be accepted after an application
has been received and before the end of the procedure laid
down in Article 7. Nevertheless, complete clinical safety and
efficacy data can be submitted during this procedure.

The urgent safety restrictions shall be implemented within a
time-frame, as agreed with the Agency.

The corresponding variation application reflecting the urgent
safety restrictions shall be submitted immediately and in any
case no later than 15 days after the initiation of the urgent
safety restrictions to the Agency for the application of the
procedures set out in Article 6.

2. Where the Commission imposes urgent safety restric-
tions on the holder, the holder shall be obliged to submit an
the safety
application for a variation taking account of
restrictions imposed by the Commission.

The urgent safety restrictions shall be implemented within a
time-frame, as agreed with the Agency.

For the application of the procedures set out in Article 6, the
corresponding variation application reflecting the urgent safety
restrictions, including appropriate documentation in support
of the change, shall be submitted to the Agency immediately
and in any case no later than 15 days after the initiation of the
urgent safety restrictions.

The first and second subparagraphs are without prejudice to
Articles 18 and 40 of Regulation (EEC) No 2309/93.

Article 10

Repeal

Regulation (EC) No 542/95 is repealed.

In case of a pandemic situation with respect to human diseases
other than the human influenza virus, the first paragraph and
Article 7 may be applied mutatis mutandis.

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

Article 9

Urgent safety restrictions

Article 11

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

1.
If the holder in the event of risk to public or animal
health takes urgent safety restrictions, he/she shall forthwith
inform the Agency thereof. If the Agency has not raised
any objections within 24 hours following receipt of that
information, the urgent safety restrictions shall be deemed as
accepted.

It shall apply from 1 October 2003. However, as regards the
examination of applications of variations to the terms of
plasma master files and of vaccine antigen master files, this
Regulation shall apply from the date of entry into force of the
Commission Directive amending Annex I of Directive 2001/
83/EC.

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

Done at Brussels, 3 June 2003.

For the Commission

Erkki LIIKANEN

Member of the Commission

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

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ANNEX I

LIST AND CONDITIONS FOR MINOR VARIATIONS (TYPES IA AND IB) TO A MARKETING AUTHORIS-
ATION AS REFERRED TO IN ARTICLES 3 TO 5

Introductory statements

The titles of the variations are numbered and subcategories depicted by letters and numbers in smaller font. The
conditions necessary for a given variation to follow either a type IA or a type IB procedure are outlined for each
subcategory and listed below each variation.

To cover any other changes, it is necessary to submit applications for any consequential or parallel variations, which
may be linked to the change applied for, at the same time and to clearly describe the relation between these variations.

For notifications including a certificate of suitability from the European pharmacopoeia and when the variation
concerns the dossier submitted for the certificate, the documentation required for this change is to be submitted to
the European Directorate for the Quality of Medicines (EDQM). If the certificate is revised following evaluation of
this change, any marketing authorisation concerned must be updated. In many cases this can be done through a
type IA notification.

A biological medicinal product is a product, the active substance of which is a biological substance. A biological
substance is a substance that is produced by or extracted from a biological source and for which a combination of
physico-chemical-biological testing and the production process and its control is needed for its characterisation and
the determination of its quality.

As a result, the following shall be considered as biological medicinal products: immunological medicinal products
and medicinal products derived from human blood and human plasma as defined in Article 1(4) and (10) of Directive
2001/83/EC, respectively; immunological veterinary medicinal products as defined in Article 1(7) of Directive 2001/
82/EC; medicinal products falling within the scope of Part A of the Annex to Regulation (EEC) No 2309/93; advanced
therapy medicinal products as defined in Part IV of Annex I to Directive 2001/83/EC.

A change in the manufacturing process of a non-proteinaceous component due to a subsequent introduction of a
biotechnology step can be made in accordance with the provisions of variations type I No 15 or No 21, as
appropriate. This specific variation is without prejudice to other variations listed in this Annex which can be applied
in this particular context. Introduction of a proteinaceous component obtained through a biotechnology process
listed in Part A of the Annex to Council Regulation (EEC) No 2309/93 in a medicinal product fall within the scope
of said Regulation. Community legislation applicable to specific groups of products (1) shall be complied with.

There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or a
national pharmacopoeia of a Member State in the case that compliance with the updated monograph is implemented
within six months of its publication and reference is made to the ‘current edition’ in the dossier of an authorised
medicinal product.

For the purposes of this document, ‘test procedure’ has the same meaning as ‘analytical procedure’ and ‘limits’ have
the same meaning as ‘acceptance criteria’.

The Commission, in consultation with Member States, the Agency and interested parties, will draw up and publish
detailed guidance on the documentation to be submitted.

(1) Food and food ingredients compliant with Regulation (EC) No 258/97 of the European Parliament and the Council (OJ L 43,
14.2.1997, p. 1), colours for use in foodstuffs within the scope of Council Directive 94/36/EEC (OJ L 237, 10.9.1994, p. 13),
food additives within the scope of Council Directive 88/388/EEC (OJ L 184, 15.7.1988, p. 61), extraction solvents within the
meaning of Council Directive 88/344/EEC (OJ L 157, 24.6.1988, p. 28) as last amended by Directive 92/115/EEC (OJ L 409,
31.12.1992, p. 31) and foods or food ingredients derived from a biotechnology step which has been introduced in the
manufacturing/production are not required to be notified as a variation to the terms of the marketing authorisation.

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Title of variation/conditions to be fulfilled

1.

Change in the name and/or address of the marketing authorisation holder

Conditions:

The marketing authorisation holder shall remain the same legal entity.

2.

Change in the name of the medicinal product

Conditions:

1.

2.

3.

No confusion with the names of existing medicinal products or with the international non-proprietary
name (INN).

The check by the EMEA on the acceptability of the new name by the Member States should be finalised
before the variation application is submitted.

The change does not concern the addition of a name.

3.

Change in the name of the active substance

Conditions:

The active substance shall remain the same.

4.

Change in the name and/or address of a manufacturer of the active substance where no European
Pharmacopoeia certificate of suitability is available

Conditions:

The manufacturing site shall remain the same.

5.

Change in the name and/or address of a manufacturer of the finished product

Conditions:

The manufacturing site shall remain the same.

6.

Change in ATC Code

(a) Medicinal products for human use

Conditions:

Change following granting of or amendment to ATC Code by WHO.

(b)

Veterinary medicinal products

Conditions:

Change following granting of or amendment to ATC Vet Code.

Type

IA

IB

IA

IA

IA

IA

IA

7.

Replacement or addition of a manufacturing site for part or all of the manufacturing process of the
finished product

(a)

Secondary packaging for all types of pharmaceutical
forms

Conditions: 1, 2 (see below)

IA

(b)

Primary packaging site

1.

2.

3.

Solid pharmaceutical forms, e.g. tablets and cap-
sules

Conditions: 1, 2, 3, 5

Semi-solid or liquid pharmaceutical forms

Conditions: 1, 2, 3, 5

Liquid pharmaceutical forms (suspensions, emul-
sions)

Conditions: 1, 2, 3, 4, 5

(c)

All other manufacturing operations except batch release

Conditions: 1, 2, 4, 5

IA

IB

IB

IB

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Title of variation/conditions to be fulfilled

Type

Conditions:

1.

2.

3.

4.

5.

Satisfactory inspection in the last three years by an inspection service of one of the Member States of the
EEA or of a country where an operational good manufacturing practice (GMP) mutual recognition
agreement (MRA) exists between the country concerned and the EU.

Site appropriately authorised (to manufacture the pharmaceutical form or product concerned).

Product concerned is not a sterile product.

Validation scheme is available or validation of the manufacture at the new site has been successfully
carried out according to the current protocol with at least three production scale batches.

Product concerned is not a biological medicinal product.

8.

Change in batch release arrangements and quality control testing of the finished product

(a)

Replacement or addition of a site where batch control/
testing takes place

Conditions: 2, 3, 4 (see below)

IA

(b)

Replacement or addition of a manufacturer responsible
for batch release

1.

Not including batch control/testing

Conditions: 1, 2

2.

Including batch control/testing

Conditions: 1, 2, 3, 4

IA

IA

Conditions:

1.

2.

3.

4.

The manufacturer responsible for batch release must be located within the EEA.

The site is appropriately authorised.

The product is not a biological medicinal product.

Method transfer from the old to the new site or new test laboratory has been successfully completed.

9.

Deletion of any manufacturing site (including for an active substance, intermediate or finished
product, packaging site, manufacturer responsible for batch release and site where batch control
takes place)

IA

Conditions:

None

10.

Minor change in the manufacturing process of the active substance

IB

Conditions:

1.

2.

3.

No change in qualitative and quantitative impurity profile or in physico-chemical properties.

The active substance is not a biological substance.

The synthetic route remains the same, i.e. intermediates remain the same. In the case of herbal medicinal
products, the geographical source, production of the herbal substance and the manufacturing route
remain the same.

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Title of variation/conditions to be fulfilled

Type

11. Change in batch size of active substance or intermediate

(a)

Up to 10-fold compared to the original batch size
approved at the grant of the marketing authorisation

Conditions: 1, 2, 3, 4 (see below)

IA

(b)

Downscaling

Conditions: 1, 2, 3, 4, 5

(c) More than 10-fold compared to the original batch size

Conditions: 1, 2, 3, 4

approved at the grant of the marketing authorisation

Conditions:

1.

2.

3.

4.

5.

Any changes to the manufacturing methods are only those necessitated by scale-up, e.g. use of different-
sized equipment.

Test results of at least two batches according to the specifications should be available for the proposed
batch size.

The active substance is not a biological substance.

The change does not affect the reproducibility of the process.

The change should not be the result of unexpected events arising during manufacture or because of
stability concerns.

12. Change in the specification of an active substance or a starting material/intermediate/reagent used

in the manufacturing process of the active substance

(a)

Tightening of specification limits

Conditions: 1, 2, 3 (see below)

Conditions: 2, 3

(b)

Addition of a new test parameter to the specification
of

1.

an active substance

Conditions: 2, 4, 5

2.

a starting material/intermediate/ reagent used in
the manufacturing process of the active substance

Conditions: 2, 4

Conditions:

1.

2.

3.

4.

5.

The change is not a consequence of any commitment from previous assessments to review specification
limits (e.g. made during the procedure for the marketing authorisation application or a type II variation
procedure).

The change should not be the result of unexpected events arising during manufacture.

Any change should be within the range of currently approved limits.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

The active substance is not a biological substance.

13. Change in test procedure for active substance or starting material, intermediate, or reagent used in

the manufacturing process of the active substance

(a) Minor change to an approved test procedure

Conditions: 1, 2, 3, 5 (see below)

(b)

Other changes to a test procedure, including replace-
ment or addition of a test procedure

Conditions: 2, 3, 4, 5

IA

IB

IA

IB

IB

IB

IA

IB

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Title of variation/conditions to be fulfilled

Type

Conditions:

1.

2.

3.

4.

5.

The method of analysis should remain the same (e.g. a change in column length or temperature, but not
a different type of column or method); no new impurities are detected.

Appropriate (re-)validation studies have been performed in accordance with relevant guidelines.

Results of method validation show new test procedure to be at least equivalent to the former procedure.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

The active substance, starting material, intermediate or reagent is not a biological substance.

14. Change in the manufacturer of the active substance or starting material/reagent/intermediate in the
manufacturing process of the active substance where no European Pharmacopoeia certificate of
suitability is available

(a)

Change in site of the already approved manufacturer
(replacement or addition)

Conditions: 1, 2, 4 (see below)

(b)

New manufacturer (replacement or addition)

Conditions: 1, 2, 3, 4

Conditions:

1.

The specifications (including in-process controls, methods of analysis of all materials), method of
preparation (including batch size) and detailed route of synthesis are identical to those already approved.

2. Where materials of human or animal origin are used in the process, the manufacturer does not use any
new supplier for which assessment is required of viral safety or of compliance with the current Note for
Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and
Veterinary Medicinal Products.

3.

4.

The current or new active substance manufacturer does not use a drug master file.

The change does not concern a medicinal product containing a biological active substance.

IB

IB

15.

Submission of a new or updated European Pharmacopoeia certificate of suitability for an active
substance or starting material/reagent/intermediate in the manufacturing process of the active
substance

(a)

From a manufacturer currently approved

Conditions: 1, 2, 4 (see below)

IA

(b)

From a new manufacturer (replacement or addition)

1.

2.

Sterile substance

Other substances

Conditions: 1, 2, 3, 4

Conditions: 1, 2, 3, 4

(c)

Substance in veterinary medicinal product for use in
animal species susceptible to TSE

Conditions: 1, 2, 3, 4

Conditions:

1.

2.

3.

4.

The finished product release and end of shelf life specifications remain the same.

Unchanged additional (to European Pharmacopoeia) specifications for impurities and product specific
requirements (e.g. particle size profiles, polymorphic form), if applicable.

The active substance will be tested immediately prior to use if no retest period is included in the European
Pharmacopoeia certificate of suitability, or if data to support a retest period is not provided.

The manufacturing process of the active substance, starting material/reagent/intermediate does not
include the use of materials of human or animal origin for which an assessment of viral safety data is
required.

IB

IA

IB

L 159/34

EN

Official Journal of the European Union

27.6.2003

Title of variation/conditions to be fulfilled

Type

16.

Submission of a new or updated TSE European Pharmacopoeia certificate of suitability for an
active substance or starting material/reagent/intermediate in the manufacturing process of the
active substance for a currently approved manufacturer and currently approved manufacturing
process

(a)

Substance in veterinary medicinal product for use in
animal species susceptible to TSE

Conditions: None

(b)

Other substances

Conditions: None

17. Change in:

(a)

the re-test period of the active substance

Conditions: 1, 2, 3 (see below)

(b)

the storage conditions for the active substance

Conditions: 1, 2

Conditions:

1.

2.

3.

Stability studies have been done according to the currently approved protocol. The studies must show
that the agreed relevant specifications are still met.

The change should not be the result of unexpected events arising during manufacture or because of
stability concerns.

The active substance is not a biological substance.

18.

Replacement of an excipient with a comparable excipient

Conditions:

1.

2.

3.

4.

5.

Same functional characteristics of the excipient.

The dissolution profile of the new product determined on a minimum of two pilot scale batches is
comparable to the old one (no significant differences regarding comparability cf Note for Guidance on
Bio-availability and Bio-equivalence, Annex II; the principles contained in this note for guidance for
medicinal products for human use should still be taken into account for veterinary medicinal products, if
relevant). For herbal medicinal products where dissolution testing may not be feasible, the disintegration
time of the new product is comparable to the old one.

Any new excipient does not include the use of materials of human or animal origin for which assessment
is required of viral safety data. For excipients in a veterinary medicinal product for use in animal species
susceptible to TSE, a risk assessment has been carried out by the competent authority.

It does not concern a medicinal product containing a biological active substance.

Stability studies in accordance with the relevant guidelines have been started with at least two pilot scale
or industrial scale batches and at least three months’ satisfactory stability data are at the disposal of the
applicant and assurance that these studies will be finalised. Data will be provided immediately to the
competent authorities if outside specifications or potentially outside specifications at the end of the
approved shelf life (with proposed action).

19. Change in specification of an excipient

(a)

Tightening of specification limits

Conditions: 1, 2, 3 (see below)

(b)

Addition of a new test parameter to the specification

Conditions: 2, 4, 5

Conditions: 2, 3

IB

IA

IB

IB

IB

IA

IB

IB

27.6.2003

EN

Official Journal of the European Union

L 159/35

Title of variation/conditions to be fulfilled

Type

Conditions:

1.

2.

3.

4.

5.

The change is not a consequence of any commitment from previous assessments (e.g. made during the
procedure for the marketing authorisation application or a type II variation procedure).

The change should not be the result of unexpected events arising during manufacture.

Any change should be within the range of currently approved limits.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

The change does not concern adjuvant for vaccines or a biological excipient.

20. Change in test procedure for an excipient

IA

IB

IB

(a) Minor change to an approved test procedure

Conditions: 1, 2, 3, 5 (see below)

(b) Minor change to an approved test procedure for a

Conditions: 1, 2, 3

biological excipient

(c)

Other changes to a test procedure, including replace-
ment of an approved test procedure by a new test
procedure

Conditions: 2, 3, 4, 5

Conditions:

1.

2.

3.

4.

5.

The method of analysis should remain the same (e.g. a change in column length or temperature, but not
a different type of column or method); no new impurities are detected.

Appropriate (re-)validation studies have been performed in accordance with relevant guidelines.

Results of method validation show new test procedure to be at least equivalent to the former procedure.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

The substance is not a biological excipient.

21.

Submission of a new or updated European Pharmacopoeia certificate of suitability for an excipient

(a)

From a manufacturer currently approved

Conditions: 1, 2, 3 (see below)

IA

(b)

From a new manufacturer (replacement or addition)

1.

Sterile substance

Conditions: 1, 2, 3

2.

Other substances

Conditions: 1, 2, 3

(c)

Substance in veterinary medicinal product for use in
animal species susceptible to TSE

Conditions: 1, 2, 3

Conditions:

1.

2.

3.

The finished product release and end of shelf-life specifications remain the same.

Unchanged additional (to European Pharmacopoeia) specifications for product specific requirements (e.g.
particle size profiles, polymorphic form), if applicable.

The manufacturing process of the excipient does not include the use of materials of human or animal
origin for which an assessment of viral safety data is required.

IB

IA

IB

L 159/36

EN

Official Journal of the European Union

27.6.2003

Title of variation/conditions to be fulfilled

Type

22.

Submission of a new or updated TSE European Pharmacopoeia certificate of suitability for an
excipient

(a)

(b)

From a manufacturer currently approved or a new Conditions: None
manufacturer (replacement or addition)

Excipient in veterinary medicinal product for use in
animal species susceptible to TSE

Conditions: None

23. Change in source of an excipient or reagent from a TSE risk to a vegetable or synthetic material

(a)

Excipient or reagent used in manufacture of biological
active substance or manufacture of a finished product
containing biological active substance

Conditions: (see below)

(b)

Other cases

Conditions:

Conditions: (see below)

Excipient and finished product release and end of shelf-life specifications remain the same.

IA

IB

IB

IA

24.

Change in synthesis or recovery of a non-pharmacopoeial excipient (when described in the dossier)

IB

Conditions:

1.

2.

Specifications are not adversely affected; no change in qualitative and quantitative impurity profile or in
physico-chemical properties.

The excipient is not a biological substance.

25. Change to comply with European Pharmacopoeia or with the national pharmacopoeia of a Member

State

(a)

Change of specification(s) of a former non-European
pharmacopoeial substance to comply with European
Pharmacopoeia or with the national pharmacopoeia of
a Member State

1.

Active substance

Conditions: 1, 2 (see below)

2.

Excipient

Conditions: 1, 2

(b)

Change to comply with an update of the relevant
monograph of
the European Pharmacopoeia or
national pharmacopoeia of a Member State

1.

Active substance

Conditions: 1, 2

2.

Excipient

Conditions: 1, 2

IB

IB

IA

IA

Conditions:

1.

2.

The change is made exclusively to comply with the pharmacopoeia.

Unchanged specifications (additional to the pharmacopoeia) for product specific properties (e.g. particle
size profiles, polymorphic form), if applicable.

27.6.2003

EN

Official Journal of the European Union

L 159/37

Title of variation/conditions to be fulfilled

Type

26. Change in the specifications of the immediate packaging of the finished product

(a)

Tightening of specification limits

Conditions: 1, 2, 3 (see below)

Conditions: 2, 3

(b)

Addition of a new test parameter

Conditions: 2, 4

Conditions:

1.

2.

3.

4.

The change is not a consequence of any commitment from previous assessments to review specification
limits (e.g. made during the procedure for the marketing authorisation application or a type II variation
procedure).

The change should not be the result of unexpected events arising during manufacture.

Any change should be within the range of currently approved limits.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

27. Change to a test procedure of the immediate packaging of the finished product

(a) Minor change to an approved test procedure

Conditions: 1, 2, 3 (see below)

(b)

Other changes to a test procedure, including replace-
ment or addition of a test procedure

Conditions: 2, 3, 4

Conditions:

1.

2.

3.

4.

The method of analysis should remain the same (e.g. a change in column length or temperature, but not
a different type of column or method).

Appropriate (re-)validation studies were performed in accordance with relevant guidelines.

Results of method validation show new test procedure to be at least equivalent to the former procedure.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

IA

IB

IB

IA

IB

28.

Change in any part of the (primary) packaging material not in contact with the finished product
formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield
(different plastic used))

IA

Conditions:

The change does not concern a fundamental part of the packaging material, which affects the delivery, use,
safety or stability of the finished product.

29. Change in the qualitative and/or quantitative composition of the immediate packaging material

(a)

Semi-solid and liquid pharmaceutical forms

Conditions: 1, 2, 3, 4 (see below)

(b)

All other pharmaceutical forms

Conditions: 1, 2, 3, 4

Conditions: 1, 3, 4

IB

IA

IB

L 159/38

EN

Official Journal of the European Union

27.6.2003

Title of variation/conditions to be fulfilled

Type

Conditions:

1.

2.

3.

4.

The product concerned is not a biological or sterile product.

The change only concerns the same packaging type and material (e.g. blister to blister).

The proposed packaging material must be at least equivalent to the approved material in respect of its
relevant properties.

Relevant stability studies in accordance with the relevant guidelines have been started with at least two
pilot scale or industrial scale batches and at least three months’ stability data are at the disposal of the
applicant. Assurance is given that these studies will be finalised and that the data will be provided
immediately to the competent authorities if outside specifications or potentially outside specifications at
the end of the approved shelf life (with proposed action).

30. Change (replacement, addition or deletion) in supplier of packaging components or devices (when

mentioned in the dossier); spacer devices for metered dose inhalers are excluded

(a)

Deletion of a supplier

Conditions: 1 (see below)

(b)

Replacement or addition of a supplier

Conditions: 1, 2, 3, 4

Conditions:

1.

2.

3.

4.

No deletion of packaging component or device.

The qualitative and quantitative composition of the packaging components/device remains the same.

The specifications and quality control method are at least equivalent.

The sterilisation method and conditions remain the same, if applicable.

31. Change to in-process tests or limits applied during the manufacture of the product

(a)

Tightening of in-process limits

Conditions: 1, 2, 3 (see below)

Conditions: 2, 3

(b)

Addition of new tests and limits

Conditions: 2, 4

Conditions:

1.

2.

3.

4.

The change is not a consequence of any commitment from previous assessments (e.g. made during the
procedure for the marketing authorisation application or a type II variation procedure).

The change should not be the result of unexpected events arising during manufacture or because of
stability concerns.

Any change should be within the range of the currently approved limits.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

32. Change in batch size of the finished product

(a)

Up to 10-fold compared to the original batch size
approved at the grant of the marketing authorisation

Conditions: 1, 2, 3, 4, 5 (see
below)

(b)

Downscaling down to 10-fold

Conditions: 1, 2, 3, 4, 5, 6

(c)

Other situations

Conditions: 1, 2, 3, 4, 5, 6, 7

IA

IB

IA

IB

IB

IA

IA

IB

27.6.2003

EN

Official Journal of the European Union

L 159/39

Title of variation/conditions to be fulfilled

Type

Conditions:

1.

2.

3.

4.

5.

6.

7.

The change does not affect the reproducibility and/or consistency of the product.

The change relates only to standard immediate release oral pharmaceutical forms and to non-sterile liquid
forms.

Any changes to the manufacturing method and/or to the in-process controls are only those necessitated
by the change in batch size, e.g. use of different-sized equipment.

Validation scheme is available or validation of the manufacture has been successfully carried out according
to the current protocol with at least three batches at the proposed new batch size in accordance with the
relevant guidelines.

It does not concern a medicinal product containing a biological active substance.

The change should not be a result of unexpected events arisen during manufacture or because of stability
concerns.

Relevant stability studies in accordance with the relevant guidelines have been started with at least one
pilot scale or industrial scale batch and at least three months’ stability data are at the disposal of the
applicant. Assurance is given that these studies will be finalised and that the data will be provided
immediately to the competent authorities if outside specifications or potentially outside specifications at
the end of the approved shelf life (with proposed action).

33.

Minor change in the manufacture of the finished product

IB

Conditions:

1.

2.

3.

4.

5.

The overall manufacturing principle remains the same.

The new process must lead to an identical product regarding all aspects of quality, safety and efficacy.

The medicinal product does not contain a biological active substance.

In case of a change in the sterilisation process, the change is to a standard pharmacopoeial cycle only.

Relevant stability studies in accordance with the relevant guidelines have been started with at least one
pilot scale or industrial scale batch and at least three months’ stability data are at the disposal of the
applicant. Assurance is given that these studies will be finalised and that the data will be provided
immediately to the competent authorities if outside specifications or potentially outside specifications at
the end of the approved shelf life (with proposed action).

34. Change in the colouring system or the flavouring system currently used in the finished product

(a)

Reduction or deletion of one or more components of
the

1.

colouring system

Conditions: 1, 2, 3, 4, 7 (see
below)

2.

flavouring system

Conditions: 1, 2, 3, 4, 7

(b)

Increase, addition or replacement of one or more
components of

1.

colouring system

Conditions: 1, 2, 3, 4, 5, 6, 7

2.

flavouring system

Conditions: 1, 2, 3, 4, 5, 6, 7

Conditions:

1.

2.

3.

No change in functional characteristics of the pharmaceutical form e.g. disintegration time, dissolution
profile.

Any minor adjustment to the formulation to maintain the total weight should be made by an excipient
which currently makes up a major part of the finished product formulation.

The finished product specification has only been updated in respect of appearance/odour/taste and if
relevant, deletion or addition of an identification test.

IA

IA

IB

IB

L 159/40

EN

Official Journal of the European Union

27.6.2003

Title of variation/conditions to be fulfilled

Type

4.

5.

6.

7.

Stability studies (long-term and accelerated) in accordance with relevant guidelines have been started with
at least two pilot scale or industrial batches and at least three months’ satisfactory stability data are at the
disposal of the applicant and assurance that these studies will be finalised. Data shall be provided
immediately to the competent authorities if outside specifications or potentially outside specifications at
the end of the approved shelf life (with proposed action). In addition, where relevant, photo-stability
testing should be performed.

Any new components must comply with the relevant Directives (e.g. Council Directive 78/25/EEC (OJ
L 229, 15.8.1978, p. 63) as amended for colorants and Directive 88/388/EEC for flavours).

Any new component does not include the use of materials of human or animal origin fir which
assessment is required of viral safety data or compliance with the current Note for Guidance on
Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and
Veterinary Medicinal Products.

Biological veterinary medicinal products for oral use for which the colouring or flavouring agent is
important for the uptake by the target animal species are excluded.

35. Change in coating weight of tablets or change in weight of capsule shells

IA

IB

(a)

Immediate release oral pharmaceutical forms

Conditions: 1, 3, 4 (see below)

(b)

Gastro-resistant, modified or prolonged release phar-
maceutical forms

Conditions: 1, 2, 3, 4

Conditions:

1.

2.

3.

4.

The dissolution profile of the new product, determined on a minimum of two pilot scale batches, is
comparable to the old one. For herbal medicinal products where dissolution testing may not be feasible,
the disintegration time of the new product is comparable to the old one.

The coating is not a critical factor for the release mechanism.

The finished product specification has only been updated in respect of weight and dimensions,
applicable.

if

Stability studies in accordance with the relevant guidelines have been started with at least two pilot scale
or industrial scale batches and at least three months’ satisfactory stability data are at the disposal of the
applicant and assurance that these studies will be finalised. Data will be provided immediately to the
competent authorities if outside specifications or potentially outside specifications at the end of the
approved shelf life (with proposed action).

36. Change in shape or dimensions of the container or closure

(a)

Sterile pharmaceutical forms and biological medicinal
products

Conditions: 1, 2, 3 (see below)

IB

(b)

Other pharmaceutical forms

Conditions: 1, 2, 3

IA

Conditions:

1.

2.

3.

No change in qualitative or quantitative composition of the container.

The change does not concern a fundamental part of the packaging material, which affect the delivery,
use, safety or stability of the finished product.

In case of a change in the head space or a change in the surface/volume ratio, stability studies in
accordance with the relevant guidelines have been started with at least two pilot scale (three for biological
medicinal products) or industrial scale batches and at least three months’ (six months for biological
medicinal products) stability data are at the disposal of the applicant. Assurance is given that these studies
will be finalised and that the data will be provided immediately to the competent authorities if outside
specifications or potentially outside specifications at the end of the approved shelf life (with proposed
action).

27.6.2003

EN

Official Journal of the European Union

L 159/41

Title of variation/conditions to be fulfilled

Type

37. Change in the specification of the finished product

IA

IB

IB

IA

IB

IB

(a)

Tightening of specification limits

Conditions: 1, 2, 3 (See below)

Conditions: 2, 3

(b)

Addition of a new test parameter

Conditions: 2, 4, 5

Conditions:

1.

2.

3.

4.

5.

The change is not a consequence of any commitment from previous assessments to review specification
limits (e.g. made during the procedure for the marketing authorisation application or a type II variation
procedure).

The change should not be the result of unexpected events arising during manufacture.

Any change should be within the range of currently approved limits.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

The test procedure does not apply to a biological active substance or biological excipient in the medicinal
product.

38. Change in test procedure of the finished product

(a) Minor change to an approved test procedure

Conditions: 1, 2, 3, 4, 5 (see
below)

(b) Minor change to an approved test procedure for
biological active substance or biological excipient

Conditions: 1, 2, 3, 4

(c)

Other changes to a test procedure, including replace-
ment or addition of a test procedure

Conditions: 2, 3, 4, 5

Conditions:

1.

2.

3.

4.

5.

The method of analysis should remain the same (e.g. a change in column length or temperature, but not
a different type of column or method).

Appropriate (re-)validation studies have been performed in accordance with relevant guidelines.

Results of method validation show new test procedure to be at least equivalent to the former procedure.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

The test procedure does not apply to a biological active substance or biological excipient in the medicinal
product.

39.

Change or addition of imprints, bossing or other markings (except scoring/break lines) on tablets
or printing on capsules, including replacement, or addition of inks used for product marking

IA

Conditions:

1.

2.

Finished product release and end of shelf-life specifications have not been changed (except for appearance).

Any new ink must comply with the relevant pharmaceutical legislation.

L 159/42

EN

Official Journal of the European Union

27.6.2003

Title of variation/conditions to be fulfilled

Type

40. Change of dimensions of tablets, capsules, suppositories or pessaries without change in qualitative

or quantitative composition and mean mass

(a)

Gastro-resistant, modified or prolonged release phar-
maceutical forms and scored tablets

Conditions: 1, 2 (see below)

(b)

All other tablets, capsules, suppositories and pessaries

Conditions: 1, 2

Conditions:

1.

The dissolution profile of the reformulated product is comparable to the old one. For herbal medicinal
products, where dissolution testing may not be feasible, the disintegration time of the new product
compared to the old one.

2.

Release and end of shelf-life specifications of the product have not been changed (except for dimensions).

41. Change in pack size of the finished product

(a)

Change in the number of units (e.g. tablets, ampoules,
etc.) in a pack

1.

2.

Change within the range of the currently approved
pack sizes

Conditions: 1, 2 (see below)

Change outside
approved pack sizes

the range of

the currently

Conditions: 1, 2

(b)

Change in the fill weight/fill volume of non-parenteral
multi-dose products

Conditions: 1, 2

Conditions:

1.

2.

New pack size should be consistent with the posology and treatment duration as approved in the
summary of product characteristics.

The primary packaging material remains the same.

42. Change in:

(a)

the shelf life of the finished product

1.

As packaged for sale

Conditions: 1, 2, 3 (see below)

2.

After first opening

Conditions: 1, 2

3.

After dilution or reconstitution

Conditions: 1, 2

(b)

the storage conditions of the finished product or the
diluted/reconstituted product

Conditions: 1, 2, 4

Conditions:

1.

2.

3.

4.

Stability studies have been done according to the currently approved protocol. The studies must show
that the agreed relevant specifications are still met.

The change should not be the result of unexpected events arising during manufacture or because of
stability concerns.

The shelf life does not exceed five years.

The product is not a biological medicinal product.

IB

IA

IA

IB

IB

IB

IB

IB

IB

27.6.2003

EN

Official Journal of the European Union

L 159/43

Title of variation/conditions to be fulfilled

Type

43. Addition, replacement or deletion of a measuring or administration device not being an integrated

part of the primary packaging (spacer devices for metered dose inhalers are excluded)

(a) Medicinal products for human use

1.

Addition or replacement

Conditions: 1, 2 (see below)

2.

Deletion

Conditions: 3

(b)

Veterinary medicinal products

Conditions: 1, 2

Conditions:

1.

2.

3.

The proposed measuring device must accurately deliver the required dose for the product concerned in
line with the approved posology and the results of such studies should be available.

The new device is compatible with the medicinal product.

The medicinal product can still be accurately delivered.

44. Change in specification of a measuring device or administration device for veterinary medicinal

products

(a)

Tightening of specification limits

Conditions: 1, 2, 3 (see below)

Conditions: 2, 3

(b)

Addition of a new test parameter

Conditions: 2, 4

Conditions:

1.

2.

3.

4.

The change is not a consequence of any commitment from previous assessments to review specification
limits (e.g. made during the procedure for the marketing authorisation application or a type II variation
procedure).

The change should not be the result of unexpected events arising during manufacture.

Any change should be within the range of currently approved limits.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

45. Change in test procedure of a measuring or administration device for veterinary medicinal products

(a) Minor change to an approved test procedure

Conditions: 1, 2, 3 (see below)

(b)

Other changes to a test procedure, including replace-
ment of approved test procedure by new test procedure

Conditions: 2, 3, 4

Conditions:

1.

2.

3.

4.

The new or updated procedure is demonstrated to be at least equivalent to the former test procedure.

Appropriate (re-)validation studies have been performed in accordance with the relevant guidelines.

Results of method validation show new test procedure to be at least equivalent to the former procedure.

Any new test method does not concern a novel non-standard technique or a standard technique used in
a novel way.

IA

IB

IB

IA

IB

IB

IA

IB

L 159/44

EN

Official Journal of the European Union

27.6.2003

Title of variation/conditions to be fulfilled

46.

labelling and package leaflet/insert as a
Change in the summary of product characteristics,
consequence of a final opinion in the context of a referral procedure in accordance with Articles 31
and 32 of Directive 2001/83/EC or Articles 35 and 36 of Directive 2001/82/EC

Conditions:

The variation only concerns the introduction of changes to the summary of product characteristics, labelling
and package leaflet/insert in order to take account of a scientific opinion delivered in the context of a referral in
accordance with Articles 31 and 32 of Directive 2001/83/EC or Articles 35 and 36 of Directive 2001/82/EC.

47. Deletion of:

(a)

a pharmaceutical form

(b)

a strength

(c)

a pack size(s)

Conditions:

The remaining product presentations(s) must be adequate for the dosing instructions and treatment duration as
mentioned in the summary of product characteristics.

Type

IB

IA

IA

IA

27.6.2003

EN

Official Journal of the European Union

L 159/45

ANNEX II

CHANGES TO A MARKETING AUTHORISATION LEADING TO AN EXTENSION APPLICATION AS
REFERRED TO IN ARTICLE 2

These changes, listed below, will be regarded as an ‘extension’ application as referred to in Article 2.

An extension to or a modification of the existing marketing authorisation will have to be granted by the Community.

The name of the medicinal product will be the same for the ‘extension’ as it is for the existing marketing authorisation
of the medicinal product.

The Commission, in consultation with Member States, the Agency and interested parties, will draw up and publish
detailed guidance on the documentation to be submitted.

Changes requiring an extension application

1.

Changes to the active substance(s):

(i)

(ii)

(iii)

replacement of the active substance(s) by a different salt/ester complex/derivative (with the same
therapeutic moiety) where the efficacy/safety characteristics are not significantly different,

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,

replacement of a biological substance or product of biotechnology with one of a slightly different
molecular structure. Modification of the vector used to produce the antigen/source material, including a
new master cell bank from a different source where the efficacy/safety characteristics are not significantly
different,

(iv)

a new ligand or coupling mechanism for a radio-pharmaceutical,

(v)

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:

(i)

change of bio-availability;

(ii)

change of pharmaco-kinetics e.g. change in rate of release,

(iii)

change or addition of a new strength/potency,

(iv)

change or addition of a new pharmaceutical form,

(v)

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 intraarterial, 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.