Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products
Date: 2001-11-06
Institutions: Council of the European Union, European Parliament
Subjects: approximation of laws, legal code, pharmaceutical legislation, public health, single market, veterinary drug

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I

(Acts whose publication is obligatory)

DIRECTIVE 2001/82/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

of 6 November 2001

on the Community code relating to veterinary medicinal products

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF
THE EUROPEAN UNION,

Having regard to the Treaty establishing the European
Community, and in particular Article 95 thereof,

Having regard to the proposal from the Commission,

Having regard to the opinion of
Committee (1),

the Economic and Social

Acting in accordance with the procedure laid down in Article
251 of the Treaty (2),

Whereas:

(1)

and

analytical,

the Member States

Council Directive 81/851/EEC of 28 September 1981
on the approximation of the laws of the Member States
relating to veterinary medicinal products (3), Council
Directive 81/852/EEC of 28 September 1981 on the
approximation of the laws of the Member States relating
to
clinical
pharmaco-toxicological
standards and protocols in respect of
the testing of
veterinary medicinal products (4), Council Directive
90/677/EEC of 13 December 1990 extending the scope
of Directive 81/851/EEC on the approximation of the
relating to veterinary
laws of
medicinal
additional
provisions
veterinary medicinal
products (5), and Council Directive 92/74/EEC of 22
scope of Directive
September 1992 widening the
81/851/EEC on the approximation of provisions laid
down by law,
action
relating to veterinary medicinal products and laying
down additional provisions on homeopathic veterinary
medicinal products (6) have
and
in the interests of clarity and
substantially amended;
rationality,
should therefore be
the said Directives
codified by assembling them in a single text.

and
immunological

regulation or administrative

products
for

been frequently

laying

down

(1) OJ C 75, 15.3.2000, p. 11.
(2) Opinion of

published in the Official
September 2001.

the European Parliament of 3 July 2001 (not yet
Journal) and Council Decision of 27

(3) OJ L 317, 6.11.1981, p. 1. Directive as

last amended by

Commission Directive 2000/37/EC (OJ L 139, 10.6.2000, p. 25).

(4) OJ L 317, 6.11.1981, p. 16. Directive as

last amended by

Commission Directive 1999/104/EC (OJ L 3, 6.1.2000, p. 18).

(5) OJ L 373, 31.12.1990, p. 26.
(6) OJ L 297, 13.10.1992, p. 12.

(2)

(3)

(4)

(5)

(6)

The primary purpose of any rules for the production
and distribution of veterinary medicinal products must
be the safeguarding of public health.

However,
this objective must be achieved by means
which will not hinder the development of industry and
trade in medicinal products within the Community.

by

laid

down

In so far as the Member States already have certain
provisions
or
administrative action governing veterinary medicinal
products, such provisions differ in essential principles.
trade in medicinal
This results in the hindering of
products within the Community,
thereby directly
affecting the functioning of the internal market.

regulation

law,

Such hindrances must,
whereas
provisions.

this entails approximation of

accordingly,

be
removed;
the relevant

It is necessary from the point of view of public health
and the free movement of veterinary medicinal products
for the competent authorities to have at their disposal
all
veterinary
on
medicinal products in the form of approved summaries
of the characteristics of products.

information

authorized

useful

(7) With the exception of those medicinal products which
are subject to the centralised Community authorization
procedure established by Council Regulation (EEC) No
2309/93 of 22 July 1993 laying down Community
procedures for the authorization and supervision of
medicinal products for human and veterinary use and
establishing a European Agency for the Evaluation of
Medicinal Products (7), a marketing authorization in one
Member State ought to be recognized by the competent
authority of the other Member States unless there are
serious grounds for supposing that the authorization of
the veterinary medicinal product concerned may present

(7) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission

Regulation (EC) No 649/98 (OJ L 88, 24.3.1998, p. 7).

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the quality,

animal health, or

risk to human or

to the
a
in the event of a disagreement between
environment;
Member States about
the safety or the
efficacy of a medicinal product, a scientific evaluation of
the matter should be undertaken at a Community level,
lead to a single decision on the area of disagreement,
binding on the Member States concerned. This Decision
should be adopted by a rapid procedure ensuring close
cooperation between the Commission and the Member
States.

(8)

(9)

For this purpose, a Committee for Veterinary Medicinal
Products should be set up in accordance with the
the Evaluation of Medicinal
European Agency for
Products laid down in the aforementioned Regulation
(EEC) No 2309/93.

aim of

This Directive is only one stage in the achievement of
freedom of movement of veterinary
the
medicinal products. However,
for this purpose, new
measures will prove necessary, in the light of experience
for
gained (cid:151) especially within the Committee
Veterinary Medicinal Products (cid:151) for the removal of the
remaining barriers to freedom of movement.

this Directive. However,

(10) Medicated feedingstuffs do not come within the scope
of
for both
public health and economic reasons, to prohibit the use
of unauthorized medicinal products in the manufacture
of medicated feedingstuffs.

is necessary,

it

(11)

The concepts of harmfulness and therapeutic efficacy
can be examined only in relation to one another and
have only a relative significance, depending on the
progress of scientific knowledge and the use for which
the medicinal product is intended. The particulars and
documents which must accompany an application for
that
marketing
potential hazards are outweighed by the benefits due to
efficacy. Failing such demonstration,
the application
must be rejected.

authorization must

demonstrate

(12) Marketing authorization should be refused where a
medicinal product
lacks therapeutic effect or where
there is insufficient proof of such effect. The concept of
therapeutic effect must be understood as being the effect
promised by the manufacturers.

(13)

(14)

Such marketing authorization should also be refused
where the withdrawal period indicated is not
long
enough to eliminate health hazards
arising from
residues.

Before an authorization to market an immunological
veterinary medicinal product
the
manufacturer must demonstrate his ability to attain
batch-to-batch consistency.

can be granted,

(15)

(16)

(17)

the use of

The competent authorities should also be empowered to
an immunological veterinary
prohibit
medicinal product when the immunological responses
of the treated animal will interfere with a national or
Community programme for the diagnosis, eradication or
control of animal disease.

It is desirable in the first instance to provide users of
homeopathic medicinal products with a very clear
indication of
their homeopathic character and with
sufficient guarantees of their quality and safety.

of

The rules relating to the manufacture, control and
inspection
veterinary medicinal
products must be harmonised to permit the circulation
throughout
the Community of medicinal products
which are safe and of good quality.

homeopathic

(18) Having regard to the particular characteristics of these
homeopathic veterinary medicinal products, such as the
very low level of active principles they contain and the
difficulty of applying to them the conventional statistical
methods relating to clinical
is desirable to
provide a special, simplified registration procedure for
those traditional homeopathic medicinal products which
are
therapeutic
indications in a pharmaceutical form and dosage which
do not present a risk for the animal.

the market without

placed

trials,

on

it

(19)

(20)

The usual rules governing the authorization to market
veterinary medicinal products must be applied to
homeopathic veterinary medicinal products marketed
with therapeutic indications or in a form which may
present risks which must be balanced against the desired
therapeutic effect. Member States should be able to
apply particular rules for the evaluation of the results of
tests and trials intended to establish the safety and
efficacy of these medicinal products for pet animals and
exotic species, provided that they notify them to the
Commission.

for

In order to better protect human and animal health and
avoid any unnecessary duplication of effort during the
a marketing
application
of
examination
authorization, Member States
should systematically
prepare assessment reports in respect of each veterinary
medicinal product which is authorized by them, and
exchange the reports upon request. Furthermore, a
the
be
Member
examination of an application for authorization to place
a veterinary medicinal product on the market which is
currently under active consideration in another Member
State with a view to recognizing the decision reached by
the latter Member State.

suspend

should

State

able

to

(21)

In order
to facilitate the movement of veterinary
medicinal products and to prevent the checks carried

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out
in one Member State from being repeated in
another, minimum requirements for manufacture and
and the grant of
imports
corresponding authorizations,
should be applied to
veterinary medicinal products.

from third countries,

(22)

of

veterinary medicinal
the Community

products
The
quality
manufactured within
be
guaranteed by requiring compliance with the principles
of good manufacturing practice for medicinal products
irrespective of
the medicinal
the final destination of
products.

should

(23) Measures

should

also be

that
distributors of
are
authorized by Member States and maintain adequate
records.

taken to ensure
veterinary medicinal products

(24)

(25)

(26)

(27)

Standards and protocols for the performance of tests
and trials on veterinary medicinal products are an
effective means of control of these products and, hence,
of protecting public health and can facilitate the
movement of these products by laying down uniform
rules applicable to tests and the compilation of dossiers,
allowing the competent authorities to arrive at
their
decisions on the basis of uniform tests and by reference
to uniform criteria, and therefore helping to obviate
differences in evaluation.

It is advisable to stipulate more precisely the cases in
which the results of pharmacological and toxicological
tests or clinical trials do not have to be provided with a
view to obtaining authorization for
veterinary
medicinal product which is essentially similar to an
innovative product, while ensuring that
innovative
forms are not placed at a disadvantage. However, there
are reasons of public policy for not repeating tests
carried out on animals without overriding cause.

a

Following the establishment of
the internal market,
specific controls to guarantee the quality of veterinary
medicinal products imported from third countries can
be waived only if appropriate arrangements have been
made by the Community to ensure that the necessary
controls are carried out in the exporting country.

In order to ensure the continued safety of veterinary
medicinal products in use, it is necessary to ensure that
pharmacovigilance
in the Community are
continually adapted to take account of scientific and
technical progress.

systems

(28)

For public health protection, relevant data on adverse
related to the use of veterinary
effects
medicines should be collected and evaluated.

in humans

(29)

The pharmacovigilance systems
available data on lack of efficacy.

should consider

the

(30)

(31)

(32)

(33)

collection of

information on adverse
In addition,
the
investigations of
reactions due to off-label use,
validity of
the withdrawal period and on potential
environmental problems may contribute to improve
regular monitoring of
veterinary
medicines.

good usage of

It is necessary to take account of changes arising as a
international harmonisation of definitions,
result of
terminology and technological developments in the field
of pharmacovigilance.

use

increasing

electronic means

of
of
The
communication of information on adverse reactions to
veterinary medicinal
the
Community is intended to allow a single reporting point
for adverse reactions, at the same time ensuring that
this
competent
authorities in all Member States.

products marketed

shared with

information

the

in

is

It is the interest of the Community to ensure that the
veterinary pharmacovigilance
centrally
authorised medicinal products and those authorised by
other procedures are consistent.

systems

for

(34) Holders

of marketing

be
proactively responsible for ongoing pharmacovigilance
of the veterinary medicinal products they place on the
market.

authorisations

should

(35)

(36)

The measures necessary for the implementation of this
Directive should be adopted in accordance with Council
Decision 1999/468/EC of 28 June 1999 laying down
the procedures for the exercise of implementing powers
conferred on the Commission (1).

to

specify

foodstuffs

In order to improve the protection of public health, it is
necessary
for human
that
consumption may not be taken from animals which
have been used in clinical trials of veterinary medicinal
products unless a maximum residue limit has been laid
down for residues of the veterinary medicinal product
concerned in accordance with the provisions of Council
Regulation (EEC) No 2377/90 of 26 June 1990 laying
down a Community procedure for the establishment of
maximum residue
veterinary medicinal
products in foodstuffs of animal origin (2).

limits

of

(37)

The Commission should be empowered to adopt the
changes necessary in order to adapt Annex I to scientific
and technical progress.

(1) OJ L 184, 17.7.1999, p. 23.
(2) OJ L 224, 18.8.1990, p. 1. Regulation as

amended by
Commission Regulation (EC) No 1274/2001 (OJ L 175, 28.6.2001,
p. 14).

last

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(38)

This Directive should be without prejudice to the
concerning the
the Member States
obligations of
time-limits for transposition of the Directives set out in
Annex II, Part B,

(cid:151) chemical, e.g.

elements, naturally occurring chemical materials
chemical products obtained by chemical
synthesis.

and
change or

HAVE ADOPTED THIS DIRECTIVE:

TITLE I

DEFINITIONS

Article 1

For the purposes of this Directive, the following terms shall
bear the following meanings:

1. Proprietary medicinal product:

5. Pre-mix for medicated feedingstuffs:

Any veterinary medicinal product prepared in advance with a
view to the subsequent manufacture of medicated feedingstuffs.

6. Medicated feedingstuffs:

Any mixture of a veterinary medicinal product or products
and feed or feeds which is ready prepared for marketing and
intended to be fed to animals without
further processing,
its curative or preventive properties or other
because of
properties as a medicinal product covered by point 2.

Any ready-prepared medicinal product placed on the market
under a special name and in a special pack.

7. Immunological veterinary medicinal product:

2. Veterinary medicinal product:

A veterinary medicinal product administered to animals in
order to produce active or passive immunity or to diagnose
the state of immunity.

Any substance or combination of substances presented for
treating or preventing disease in animals.

8. Homeopathic veterinary medicinal product:

Any substance or combination of substances which may be
administered to animals with a view to making a medical
diagnosis or to restoring, correcting or modifying physiological
functions
likewise considered a veterinary
medicinal product.

in animals

is

3. Ready-made veterinary medicinal product:

Any veterinary medicinal product prepared from products,
substances or compositions called homeopathic stocks
in
accordance with a homeopathic manufacturing procedure
described by the European Pharmacopoeia or, in the absence
thereof, by the pharmacopoeias currently used officially in the
Member States.

A homeopathic veterinary medicinal product may also contain
a number of principles.

Any veterinary medicinal product prepared in advance which
does not comply with the definition of proprietary medicinal
products and which is marketed in a pharmaceutical
form
which may be used without further processing.

9. Withdrawal period:

4. Substance:

Any matter irrespective of origin which may be:

(cid:151) human, e.g.

Period necessary between the last administration of
the
to animals under normal
veterinary medicinal product
conditions of use and the production of foodstuffs from such
animals, in order to ensure that such foodstuffs do not contain
residues in quantities in excess of the maximum limits laid
down in application of Regulation (EEC) No 2377/90.

human blood and human blood products;

10. Adverse reaction:

(cid:151) animal, e.g.

micro-organisms, whole animals, parts of organs, animal
secretions, toxins, extracts, blood products;

A reaction which is harmful and unintended and which occurs
for
at doses normally used in animals
the prophylaxis,
diagnosis or
the modification of
treatment of disease or
physiological function.

(cid:151) vegetable, e.g.

11. Human adverse reaction:

micro-organisms,
secretions, extracts;

plants,

parts

of

plants,

vegetable

A reaction which is noxious and unintended and which occurs
in a human being following exposure to a veterinary medicine.

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12. Serious adverse reaction:

An adverse reaction which results in death, is life-threatening,
is a congenital
results in significant disability or incapacity,
anomaly/birth defect, or which results
in permanent or
prolonged signs in the animals treated.

13. Unexpected adverse reaction:

An adverse reaction, the nature, severity or outcome of which
is not
the product
characteristics.

consistent with the

summary of

14. Periodic safety update reports:

The periodical reports containing the records referred to in
Article 75.

15. Post-marketing surveillance studies:

Pharmacoepidemiological study or a clinical trial carried out in
the marketing authorization,
accordance with the terms of
conducted with the aim of
identifying and investigating a
safety hazard relating to an authorized veterinary medicinal
product.

16. Off-label use:

The use of a veterinary medicinal product
in
accordance with the summary of the product characteristics,
including the misuse and serious abuse of the product.

is not

that

17. Wholesale dealing in veterinary medicinal products:

Any activity which includes the purchase, sale, import, export,
or any other commercial transaction in veterinary medicinal
products, whether or not for profit, except for:

(cid:151) the supply by a manufacturer of veterinary medicinal

products manufactured by himself,

(cid:151) retail supplies of veterinary medicinal products by persons
entitled to carry out such supplies in accordance with
Article 66.

18. Agency:

European Agency for the Evaluation of Medicinal Products
established by Regulation (EEC) No 2309/93.

19. Risk to human or animal health or the environment:

Any risk relating to the quality, safety and efficacy of the
veterinary medicinal product.

TITLE II

SCOPE

Article 2

The provisions of
this Directive shall apply to veterinary
medicinal products intended to be placed on the market inter
alia in the form of medicinal products, ready-made veterinary
medicinal products or pre-mixes for medicated feeedingstuffs.

Article 3

This Directive shall not apply to:

1. Medicated feedingstuffs as defined in Council Directive
90/167/EEC of 26 March 1990 laying down the conditions
governing the preparation, placing on the market and use
of medicated feedingstuffs in the Community (1);

However, medicated feedingstuffs may be prepared only
from pre-mixes which have been authorized under this
Directive;

2.

Inactivated immunological veterinary medicinal products
which are manufactured from pathogens and antigens
obtained from an animal or animals from a holding and
used for the treatment of that animal or the animals of
that holding in the same locality;

3. Any medicinal product prepared in a pharmacy in
accordance with a prescription for an individual animal
(commonly known as the magistral formula);

4. Any medicinal product prepared in a pharmacy in
accordance with the prescriptions of a pharmacopoeia and
is
intended to be supplied directly to the end-user
(commonly known as the officinal formula);

5. Veterinary medicinal products based on radio-active

isotopes;

1970

November

concerning

6. Any additives covered by Council Directive 70/524/EEC of
23
in
feedingstuffs (2), where they are incorporated in animal
feedingstuffs and supplementary animal
feedingstuffs in
accordance with that Directive. Nevertheless, Member
States may, when implementing Articles 10(1)(c) and(2)
take acount of the medicinal products referred to in points
3 and 4 of the first paragraph.

additives

Nonetheless, Member States may, when implementing Article
10(1)(c) and (2)
the medicinal products
referred to in points 3 and 4 of the first paragraph.

take account of

Article 4

1. Member States may provide that this Directive shall not
apply to non-inactivated immunological veterinary medicinal
products which are manufactured from pathogens
and
antigens obtained from an animal or animals from a holding
and used for the treatment of that animal or the animals of
that holding in the same locality.

(1) OJ L 92, 7.4.1990, p. 42.
(2) OJ L 270, 14.12.1970, p. 1. Directive

amended by
Commission Regulation (EC) No 45/1999 (OJ L 6, 12.1.1999, p.
3).

last

as

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2. Member States may permit exemptions on their territory
in respect of veterinary medicinal products intended solely for
aquarium fish, cage birds, homing pigeons, terrarium animals
and small rodents, from the provisions in Articles 5, 7 and 8,
provided that such products do not contain substances the use
of which requires veterinary control and that all possible
measures have been taken to prevent unauthorized use of the
products for other animals.

TITLE III

MARKETING

CHAPTER 1

Marketing authorization

Article 5

No veterinary medicinal product may be placed on the market
of a Member State unless a marketing authorization has been
issued by the competent authorities of that Member State in
accordance with this Directive or a marketing authorization
has been granted in accordance with Regulation (EEC) No
2309/93.

Article 6

In order that a veterinary medicinal product may be the
the purpose of
subject of a marketing authorization for
administering
active
substances which it contains must be shown in Annexes I, II
or III of Regulation (EEC) No 2377/90.

to food-producing

animals,

the

it

Article 10

1. Where there is no authorized medicinal product for a
condition, Member States may exceptionally,
in particular in
order to avoid causing unacceptable suffering to the animals
concerned, permit
the administration by a veterinarian or
under his/her direct personal responsibility to an animal or to
a small number of animals on a particular holding:

(a) of a veterinary medicinal product authorized in the
Member State concerned under this Directive or under
Regulation (EEC) No 2309/93 for use in another animal
species, or for another condition in the same species; or

(b)

if there is no product as referred to in point (a), of a
medicinal product authorized for use in the Member State
concerned in human beings in accordance with Directive
2001/83/EC of
the
Council of 6 November 2001 on the Community Code
relating to medicinal products for human use (1) or under
Regulation (EEC) No 2309/93; or

the European Parliament and of

(c)

if there is no product as referred to in point (b) and within
the limits of the law of the Member State concerned, of a
veterinary medicinal product prepared extemporaneously
by a person authorized to do so under national legislation
in accordance with the terms of a veterinary prescription.

For the purposes of this paragraph, the phrase (cid:145)an animal or a
small number of animals on a particular holding(cid:146) also covers
pets, and shall be interpreted more flexibly for minor or exotic
animal species which do not produce food.

Article 7

Where the health situation so requires, a Member State may
authorise the marketing or administration to animals of
veterinary medicinal products which have been authorized by
another Member State in accordance with this Directive.

2.
The provisions of paragraph 1 shall apply provided that
the medicinal product, where administered to food-producing
animals, contains only substances to be found in a veterinary
medicinal product authorized for such animals in the Member
State concerned and that
food-producing
animals the veterinarian responsible specifies an appropriate
withdrawal period.

in the case of

Article 8

In the event of serious disease epidemic, Member States may
immunological veterinary
provisionally allow the use of
medicinal products without an authorization for placing on
the market, in the absence of a suitable medicinal product and
after informing the Commission of the detailed conditions of
use.

Article 9

No veterinary medicinal product may be administered to
animals unless the marketing authorization has been issued,
except for the tests of veterinary medicinal products referred to
in Article 12(3)(j) which have been accepted by the competent
national authorities, following notification or authorization, in
accordance with the national rules in force.

Unless the medicinal product used indicates a withdrawal
period for the species concerned,
the specified withdrawal
period shall not be less than:

7 days

7 days

28 days

eggs,

milk,

meat from poultry and
mammals including fat and
offal,

500 degree days

meat from fish.

(1) See p. 67 of this edition of the Official Journal.

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With regard to homeopathic veterinary medicinal products in
which the level of active principles is equal to or less than one
part per million, the withdrawal period referred to in the first
and second subparagraphs is reduced to zero.

is administered to animals and when waste therefrom is
disposed of, together with an indication of any potential
risks the medicinal product might pose to the environment
and the health of humans, animals or plants;

Article 11

When a veterinarian has recourse to the provisions of Article
10, he shall keep adequate records of the date of examination
of the animals, details of the owner, the number of animals
treated, the diagnosis, the medicinal products prescribed, the
dosages administered,
treatment and the
withdrawal periods recommended, and make these records
available for inspection by the competent authorities for a
three years. This requirement may be
period of at
least
extended by the Member States
to non food-producing
animals.

the duration of

Article 12

1.
For the purposes of obtaining a marketing authorization
in respect of a veterinary medicinal product, other than under
the procedure established by Regulation (EEC) No 2309/93, an
application shall be lodged with the competent authority of
the Member State concerned.

A marketing authorization may only be granted to an

2.
applicant established in the Community.

(h)

indication of the withdrawal period. Where necessary, the
applicant shall propose and justify a tolerance level
for
residues which may be accepted in foodstuffs without risk
for the consumer, together with routine analysis methods
which could be used by the competent authorities to trace
residues;

(i) description of the control testing methods employed by
the manufacturer (qualitative and quantitative analysis of
the constituents and the finished product, specific tests e.g.
sterility tests, test for the presence of pyrogens, for the
presence of heavy metals, stability tests, biological and
toxicity tests, tests on intermediate products);

(j)

results of:

(cid:151) physico-chemical, biological or microbiological tests,

(cid:151) toxicological and pharmacological tests,

The

3.
documents
accompany an application in accordance with Annex I:

particulars

following

and

(cid:151) clinical trials.

shall

(a) name or business name and permanent

address or
registered place of business of the person responsible for
placing the product on the market and, if different, of the
manufacturer or manufacturers involved and of the sites of
manufacture;

(b) name of the veterinary medicinal product (brand name,
non-proprietary name, with or without a trademark, or
name of the manufacturer or scientific name or formula,
with or without a trademark, or
the
manufacturer);

the name of

(c) qualitative

and

particulars

quantitative

the
constituents of the veterinary medicinal product, using the
formulae
usual terminology, but not empirical chemical
and
name
recommended by the World Health Organization, where
such a name exists;

non-proprietary

international

giving

the

all

of

(d) description of the method of manufacture;

(e)

therapeutic indications, contra indications and adverse
reactions;

(f) dosage for the various species of animal for which the
its
veterinary medicinal
pharmaceutical form, method and route of administration
and proposed shelf life;

intended,

product

is

(g)

if applicable, explanations of the precautionary and safety
measures to be taken when the product is stored, when it

(k) a summary in accordance with Article 14 of the product
characteristics, one or more specimens or mock-ups of the
sales presentation of
the veterinary medicinal product
together with the package insert;

(l) a document showing that the manufacturer is authorized
in his own country to produce veterinary medicinal
products;

in a third country for

(m) copies of any marketing authorization obtained in another
Member State or
the relevant
veterinary medicinal product, together with a list of those
Member States in which an application for authorization
submitted in accordance with this Directive is under
the product
examination. Copies of
characteristics proposed by the applicant
in accordance
with Article 14 or approved by the competent authority of
the Member State in accordance with Article 25 and copies
of the package insert proposed, details of any decision to
refuse authorization, whether in the Community or a third
country and the reasons for that decision.

the summary of

This information shall be updated on a regular basis;

(n)

in the case of medicinal products containing new active
substances which are not mentioned in Annex I, II or III to
Regulation (EEC) No 2377/90, a copy of the documents
submitted to the Commission in accordance with Annex V
to that Regulation.

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Article 13

1.
By way of derogation from point (j) of Article 12(3), and
without prejudice to the law relating to the protection of
industrial and commercial property:

(a)

the applicant shall not be required to provide the results of
toxicological and pharmacological tests and clinical trials if
he can demonstrate:

(i) either

the

that

veterinary medicinal product

is
essentially similar to a medicinal product authorized in
the Member State concerned by the application and
that the marketing authorization holder has agreed that
clinical
the
references
file on the original
veterinary medicinal product may be used for the
purpose of examining the application in question;

toxicological, pharmacological
contained in the

and/or

(ii) or that the constituent or constituents of the veterinary
medicinal product have a well-established medicinal
use, with recognized efficacy and an acceptable level of
safety, by means of detailed references to scientific
literature;

(iii) or that the veterinary medicinal product is essentially
similar
to a medicinal product which has been
authorized within the Community, in accordance with
Community provisions in force, for not less than six
years and is marketed in the Member State for which
the application is made; this period shall be extended
to 10 years in the case of high-technology medicinal
products having been authorized in pursuance of the
established by Article 2(5) of Council
procedure
Directive 87/22/EEC (1). Furthermore, a Member State
may also extend this period to 10 years by a single
Decision covering all the medicinal products marketed
in its territory where it considers this necessary in the
interest of public health. Member States are at liberty
not to apply the six-year period beyond the date of
expiry of a patent protecting the original medicinal
product;

(b)

in the
case of new veterinary medicinal products
containing known constituents not hitherto used in
the results of
combination for
therapeutic purposes,
tests and of clinical
toxicological and pharmacological
trials relating to that combination must be provided, but it
shall
relevant
necessary
documentation for each individual constituent.

provide

not

the

be

to

substances

and constituents of

2. Qualitative and quantitative composition in terms of the
excipient,
active
knowledge of which is essential for proper administration
of the medicinal product; the international non-proprietary
names recommended by the World Health Organization
shall be used, where such names exist, or failing this, the
usual non-proprietary name or chemical description;

the

3. Pharmaceutical form;

4. Pharmacological properties
information is useful
for
pharmacokinetic particulars;

and,
the

in so far
this
therapeutic purposes,

as

5. Clinical particulars;

5.1

target species,

5.2

indications for use, specifying the target species,

5.3

contra-indications,

5.4

undesirable effects (frequency and seriousness),

5.5

special precautions for use,

5.6

use during pregnancy and lactation,

5.7

interaction with other medicaments and other forms
of interaction,

5.8

posology and method of administration,

5.9

overdose
(symptoms,
antidotes) (if necessary),

emergency

procedures,

5.10 special warnings for each target species,

5.11 withdrawal periods,

5.12 special precautions

to be taken by the person

administering the medicinal product to animals;

6. Pharmaceutical particulars:

6.1 major incompatibilities,

Annex I shall apply in like manner where, pursuant to
2.
point (a)(ii) of paragraph 1, references to published data are
submitted.

6.2

shelf life, when necessary after reconstitution of the
medicinal product or when the container is opened
for the first time,

Article 14

6.3

special precautions for storage,

The summary of the product characteristics shall contain the
following information:

6.4

nature and contents of container,

1. Name of the veterinary medicinal products;

6.5

special precautions
medicinal product or waste materials, if any;

the disposal of unused

for

(1) OJ L 15, 17.1.1987, p. 38. Directive
93/41/EEC (OJ L 214, 24.8.1993, p. 40).

repealed by Directive

7. Name or corporate name and address or registered place of

business of the authorization holder.

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Article 15

CHAPTER 2

1. Member States shall make all necessary arrangements to
ensure that
the documents and particulars listed in Article
12(3)(h), (i), (j) and Article 13(1) are drafted by experts with
the requisite technical or professional qualifications before
being submitted to the competent authorities.

These documents and particulars shall be signed by the experts
in question.

According to their particular qualifications, the role of

2.
the experts shall be:

(a)

to carry out such work as falls within their particular
discipline (analysis, pharmacology and similar experimental
sciences, clinical
trials) and to describe objectively the
results obtained in both quantitative and qualitative terms;

(b) to describe their findings in accordance with Annex I and

in particular to state:

Particular provisions applicable to homeopathic
veterinary medicinal products

Article 16

1. Member States shall ensure that homeopathic veterinary
medicinal products manufactured and marketed within the
Community are registered or authorized in accordance with
the provisions of Articles 17(1) and (2), 18 and 19. Each
Member State shall
take due account of registrations and
authorizations previously granted by another Member State.

for

the

registration

A Member State may refrain from establishing a special,
2.
simplified
homeopathic
procedure
veterinary medicinal products referred to in Article 17(1) and
(2). A Member State applying this provision shall inform the
Commission accordingly. The Member State concerned shall,
by 31 December 1995 at the latest, allow use in its territory of
homeopathic veterinary medicinal products registered by other
Member States in accordance with Article 17(1) and (2) and
Article 18.

(i)

in the case of analysts, whether the medicinal product
conforms with the stated composition, providing any
reasons for the control
testing methods which the
manufacturer is to use;

Only homeopathic veterinary medicinal products which
1.
satisfy all of
to
authorization by means of a special, simplified registration
procedure:

the following conditions may be subject

(ii)

in the case of pharmacologists and appropriately
qualified specialists:

(cid:151) they are intended for administration to pet animals or

exotic species which are non food-producing,

Article 17

(cid:151) the toxicity of

the medicinal product and the

pharmacological properties observed,

(cid:151) whether, after administration of

the veterinary
medicinal product under normal conditions of use
and observance of the recommended withdrawal
period,
treated
foodstuffs obtained from the
animals contain residues which might constitute a
health hazard to the consumer;

(iii) in the case of clinicians, whether they have found in
animals treated with the medicinal product effects
corresponding to the information furnished by the
manufacturer pursuant
to Articles 12 and 13(1),
whether the medicinal product is well tolerated, what
dosage
the
recommend
contra-indications and adverse reactions, if any;

and what

they

are

(c)

to give reasons for the use of the references to published
data referred to in point (a)(ii) of Article 13(1).

The experts’ detailed reports shall

the
3.
documentation which the applicant
lodge with the
competent authorities. A brief curriculum vitae of the expert
shall be appended to each report.

form part of

shall

(cid:151) they are administered by a route described in the European
Pharmacopoeia
the
pharmacopoeias currently used officially in the Member
States,

absence

thereof,

or,

by

in

(cid:151) no specific therapeutic indication appears on the labelling
of the veterinary medicinal product or in any information
relating thereto,

(cid:151) there is a sufficient degree of dilution to guarantee the
safety of the medicinal product; in particular, the medicinal
product may not contain either more than one part per
10 000 of the mother tincture or more than 1/100th of
the smallest dose used in allopathy with regard to active
principles whose presence in an allopathic medicinal
product results in the obligation to submit a veterinary
prescription.

At the time of registration, Member States shall determine the
classification for the dispensing of the medicinal product.

The criteria and rules of procedure provided for in
2.
Chapter 3, with the exception of Article 25, shall apply by
analogy to the special, simplified registration procedure for
homeopathic veterinary medicinal products
referred to in
paragraph 1, with the exception of the proof of therapeutic
effect.

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The proof of therapeutic effect shall not be required for
registered in
this Article or, where

3.
homeopathic veterinary medicinal products
accordance with paragraph 1 of
appropriate, admitted in accordance with Article 16(2).

Article 20

This Chapter shall not apply to immunological homeopathic
veterinary medicinal products.

Article 18

The provisions of titles VI and VII shall apply to homeopathic
veterinary medicinal products.

of medicinal products

A special, simplified application for registration may cover a
same
series
homeopathic stock or stocks. The following documents shall
be included with the application in order to demonstrate, in
particular, the pharmaceutical quality and the batch-to-batch
homogeneity of the products concerned:

from the

derived

(cid:151) scientific name or other name given in a pharmacopoeia of
the homeopathic stock or stocks, together with a statement
of
the various routes of administration, pharmaceutical
forms and degree of dilution to be registered,

(cid:151) dossier describing how the homeopathic stock or stocks
is/are obtained and controlled, and justifying its/their
an adequate
homeopathic nature, on the basis of
case of homeopathic veterinary
bibliography;
medicinal products containing biological
substances, a
description of the measures taken to ensure the absence of
pathogens,

in the

(cid:151) manufacturing and control
form and a description of
potentiation,

file for each pharmaceutical
the method of dilution and

(cid:151) manufacturing authorization for the medicinal products

concerned,

(cid:151) copies of any registrations or authorizations obtained for
the same medicinal products in other Member States,

(cid:151) one or more specimens or mock-ups of
packaging and immediate packaging of
products to be registered,

the outer
the medicinal

(cid:151) data concerning the stability of the medicinal product.

Article 19

1.
Homeopathic veterinary medicinal products other than
those referred to in Article 17(1) shall be authorized in
accordance with the provisions of Articles 12 to 15 and
Chapter 3.

trials of homeopathic

A Member State may introduce or retain in its territory
2.
specific rules for the pharmacological and toxicological tests
and clinical
veterinary medicinal
products intended for pet animals and exotic species which are
non food-producing other than those referred to in Article
17(1), in accordance with the principles and characteristics of
homeopathy as practised in that Member State.

CHAPTER 3

Procedure for marketing authorization

Article 21

1. Member States shall
take all appropriate measures to
ensure that the procedure for granting an authorization to
is
place a veterinary medicinal product on the market
completed within 210 days of
the submission of a valid
application.

2. Where a Member State notes that an application for
authorization submitted is already under active examination in
another Member State in respect of that veterinary medicinal
product, the Member State concerned may decide to suspend
the detailed examination of the application in order to await
the assessment report prepared by the other Member State in
accordance with Article 25(4).

The Member State concerned shall inform the other Member
its decision to suspend detailed
State and the applicant of
examination of the application in question. As soon as it has
completed the examination of the application and reached a
decision, the other Member State shall forward a copy of its
assessment report to the Member State concerned.

Article 22

that

Where a Member State is informed in accordance with Article
12(3)(m),
authorized a
another Member State has
veterinary medicinal product which is
the subject of an
application for authorization in the Member State concerned,
that Member State shall forthwith request the authorities of the
Member State which has granted the authorization to forward
to it the assessment report referred to in Article 25(4).

report,

receipt of

the assessment

Within 90 days of
the
Member State concerned shall either recognise the decision of
the first Member State and the summary of
the product
characteristics as approved by it or, if it considers that there
are grounds
the
veterinary medicinal product concerned may present a risk to
human or animal health or the environment, it shall apply the
procedures set out in Articles 33 to 38.

the authorization of

supposing that

for

Article 23

In this case,
Commission of the specific rules in force.

the Member State concerned shall notify the

In order to examine the application submitted pursuant to
Articles 12 and 13(1),
the
Member States:

the competent authorities of

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1.

shall check that the documentation submitted in support
of the application complies with Articles 12 and 13(1)
and, on the basis of the reports drawn up by the experts
pursuant to Article 15(2) and (3), ascertain whether the
conditions for the issue of
the marketing authorization
have been fulfilled;

for

2. may submit the medicinal product, its raw materials and if
constituent
necessary intermediate products or other
testing by a State laboratory or by a
materials
laboratory designated for that purpose, in order to ensure
that the testing methods employed by the manufacturer
and described in the application documents, in accordance
with Article 12(3)(i), are satisfactory;

3. may, where appropriate, require the applicant to provide
further information as regards the items listed in Articles
12 and 13(1). Where the competent authorities take this
course of action, the time-limits specified in Article 21
shall be suspended until the further data required have
been provided.
shall be
suspended for any period which the applicant may be
given to provide oral or written explanations;

time-limits

Similarly,

these

4. may require the applicant

to submit substances in the
quantities necessary to verify the analytical detection
in accordance with
method proposed by the applicant
Article 12(3)(h) and to put it into effect as part of routine
checks to reveal the presence of residues of the veterinary
medicinal products concerned.

Article 24

Member States shall take all appropriate measures to ensure
that:

(a)

the competent authorities ascertain that the manufacturers
and importers of veterinary medicinal products from third
countries are able to manufacture them in compliance with
the details supplied pursuant to Article 12(3)(d), and/or to
carry out control tests in accordance with the methods
described in the application documents under Article
12(3)(i);

(b) the competent authorities may authorize manufacturers
and importers of veterinary medicinal products from third
countries, where circumstances so justify, to have certain
stages of manufacture and/or certain of the control tests
referred to in (a) carried out by third parties; in such cases,
checks by the competent authorities shall also be carried
out in the establishments concerned.

Article 25

1. When the marketing authorization is issued, the holder
shall be informed by the competent authorities of the Member
State concerned, of the summary of the product characteristics
as approved by it.

The

authorities

competent

2.
all necessary
measures to ensure that the information given in the summary
is in conformity with that accepted when the marketing
authorization is issued or subsequently.

shall

take

The competent authorities shall forward to the Agency a
3.
copy of the authorization together with the summary of the
product characteristics.

The competent authorities shall draw up an assessment
4.
report and comments on the dossier as regards the results of
the analytical and pharmacotoxicological tests and the clinical
trials of
the veterinary medicinal product concerned. The
assessment report shall be updated whenever new information
becomes available which is of importance for the evaluation of
the quality, safety or efficacy of
the veterinary medicinal
product concerned.

Article 26

1.
The marketing authorization may require the holder to
indicate on the container and/or the outer wrapping and the
package insert, where the latter is required, other particulars
essential for safety or health protection, including any special
precautions relating to use and any other warnings resulting
from the clinical and pharmacological
trials prescribed in
Articles 12(3)(j) and 13(1) or from experience gained during
the use of the veterinary medicinal product once it has been
marketed.

The authorization may also require the inclusion of a

2.
tracer substance in the veterinary medicinal product.

3.
In exceptional circumstances, and following consultation
with the applicant, an authorization may be granted subject to
certain specific obligations, and subject
review,
including:

to annual

(cid:151) the carrying out of further studies following the granting

of authorization,

(cid:151) the notification of adverse reactions to the veterinary

medicinal product.

These exceptional decisions may only be adopted for objective
and verifiable reasons.

Article 27

After a marketing authorization has been issued,

the
1.
holder must,
in respect of the manufacturing methods and
control methods provided for in Article 12(3)(d) and (i), take
account of scientific and technical progress and introduce any
changes
that may be required to enable that veterinary
medicinal product to be manufactured and checked by means
of generally accepted scientific methods.

These changes
shall be subject
competent authorities of the Member State concerned.

to the approval of

the

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from the

Upon request

2.
the
marketing authorization holder shall also review the analytical
detection methods provided for in Article 12(3)(h) and propose
any changes which may be necessary to take account of
scientific and technical progress.

authorities,

competent

shall

The marketing authorization holder

3.
forthwith
inform the competent authorities of any new information
the particulars and
which might entail
the amendment of
the
documents referred to in Articles 12 and 13(1) or of
approved summary of the product characteristics. In particular,
he shall forthwith inform the competent authorities of any
prohibition
competent
authorities of any country in which the veterinary medicinal
product is marketed and of any serious unexpected adverse
effect occurring in the animals concerned or human beings.

restriction

imposed

the

by

or

(d) the withdrawal period recommended by the applicant is
not long enough to ensure that foodstuffs obtained from
the treated animal do not contain residues which might
constitute
is
insufficiently substantiated; or

a health hazard to the

consumer, or

(e)

the veterinary medicinal product is offered for sale for a
use prohibited under other Community provisions.

competent
However, pending Community
to grant authorization for a
authorities may refuse
veterinary medicinal product where
such action is
necessary for the protection of public health, consumer or
animal health.

rules,

the

4.
The marketing authorization holder shall be required to
maintain records of all adverse reactions observed in animals
or human beings. The records so established shall be kept at
least five years and shall be made available to the competent
authorities upon request.

The marketing authorization holder shall

immediately
5.
inform the
view to
authorization, of any alteration he proposes to make to the
particulars and documents referred to in Articles 12 and 13(1).

authorities, with

competent

a

Article 28

five years and shall be
Authorization shall be valid for
renewable for five-year periods, on application by the holder at
least
and after
consideration of a dossier updating the information previously
submitted.

three months before

expiry date

the

Article 29

The granting of authorization shall not diminish the general
legal liability of the manufacturer and, where appropriate, of
the authorization holder.

Authorization shall
application
documents submitted to the competent authorities do not
comply with Articles 12, 13(1) and 15.

also be withheld if

the

CHAPTER 4

Mutual recognition of authorizations

Article 31

1.
In order to facilitate the adoption of common decisions
by Member States on the authorization of veterinary medicinal
products on the basis of the scientific criteria of quality, safety
and efficacy, and to achieve thereby the free movement of
veterinary medicinal products within the Community, a
for Veterinary Medicinal Products, hereinafter
Committee
referred to as
is hereby set up. The
Committee shall be part of the Agency.

(cid:145)the Committee(cid:146),

2.
In addition to the other responsibilities conferred upon it
by Community law, the Committee shall examine any question
relating to the granting, variation, suspension or withdrawal of
marketing authorization which is submitted to it in accordance
with the provisions of this Directive. It shall also examine any
question relating to tests of veterinary medicinal products.

Article 30

3.

The Committee shall adopt its own rules of procedure.

The marketing authorization shall be withheld if examination
of the documents and particulars listed in Articles 12 and
13(1) establishes that:

(a)

the veterinary medical product
conditions of use stated at
authorization; or

the
is harmful under
the time of application for

(b) has no therapeutic effect or the applicant has not provided
sufficient proof of such effect as regards the species of
animal which is to be treated; or

Article 32

1.
Before submitting an application for mutual recognition
of marketing authorizations, the holder of the authorization
shall inform the Member State which granted the authorization
on which the application is based (hereinafter: the reference
Member State) that an application is to be made in accordance
with this Directive and shall notify it of any additions to the
original dossier; that Member State may require the applicant
to provide it with all the particulars and documents necessary
to enable it to check that the dossiers filed are identical.

(c)

its qualitative or quantitative composition is not as stated;
or

In addition, the holder of the authorization shall request the
reference Member State which granted the initial authorization

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to prepare an assessment report in respect of the veterinary
if necessary, to update it.
medicinal product concerned, or,
That Member State shall prepare it within 90 days of receipt of
the request.

At the same time as the application is submitted in accordance
with paragraph 2 the reference Member Sate which granted
the initial authorization shall forward the assessment report to
the Member State or Member States concerned by the
application.

2.
In order to obtain the recognition according to the
procedure laid down in this Chapter in one or more of the
Member States of a marketing authorization issued by a
Member State, the holder of the authorization shall submit an
application to the competent authority of the Member State or
Member States concerned, together with the information and
particulars referred to in Articles 12, 13(1), 14 and 25. He
shall testify that the dossier is identical to that accepted by the
reference Member State, or shall
identify any additions or
amendments it may contain. In the latter case, he shall certify
that the summary of the product characteristics proposed by
him in accordance with Article 14 is identical to that accepted
by the reference Member State in accordance with Article 25.
Moreover, he shall certify that all the dossiers filed as part of
this procedure are identical.

The holder of the marketing authorization shall transmit
3.
the application to the Agency, inform it of the Member States
concerned and of the dates of submission of the application
and send it a copy of
the authorization granted by the
reference Member State. He shall also send the Agency copies
of any such authorization which may have been granted by
the other Member States in respect of the veterinary medicinal
product concerned, and shall indicate whether any application
for authorization is currently under consideration in any
Member State.

Save in the exceptional case provided for in Article
4.
33(1), each Member State shall
recognise the marketing
authorization granted by the reference Member State within 90
days of receipt of the application and the assessment report. It
inform the reference Member State, the other Member
shall
States concerned by the application,
the Agency, and the
holder of the authorization for placing the product on the
market.

Article 33

supposing that

the marketing authorization of

1. Where a Member State considers that there are grounds
for
the
veterinary medicinal product concerned may present a risk to
human or animal health or the environment, it shall forthwith
inform the applicant, the reference Member State, any other
Member States concerned by the application and the Agency.
The Member State shall state its reason in detail and shall
indicate what action may be necessary to correct any defect in
the application.

with the opportunity to make his point of view known orally
or in writing. However, if the Member States have not reached
agreement within the time-limit referred to in Article 32(4)
they shall forthwith refer the matter to the Agency, for referral
to the Committee, for the application of the procedure laid
down in Article 36.

3. Within the time-limit referred to in Article 32(4), the
Member States concerned shall provide the Committee with a
detailed statement of the matters on which they have been
unable
their
disagreement. The applicant shall be provided with a copy of
this information.

to reach agreement

and the

reasons

for

As soon as he is informed that the matter has been
forthwith
the information and

4.
referred to the Committee,
forward to the Committee a copy of
particulars referred to in Article 32(2).

the applicant

shall

Article 34

adopted divergent decisions

If several applications submitted in accordance with Articles
12, 13(1) and 14 have been made for marketing authorization
for a particular veterinary medicinal product and Member
States have
concerning the
authorization of
veterinary medicinal product, or
that authorization, a Member
suspension or withdrawal of
State, or the Commission, or the marketing authorization
holder may refer the matter to the Committee for application
of the procedure laid down in Article 36.

that

The Member State concerned,
the marketing authorization
holder or the Commission shall clearly identify the question
which is referred to the Committee for consideration and, if
appropriate, shall inform the aforementioned holder thereof.

The Member States and the marketing authorization holder
shall
forward to the Committee all available information
relating to the matter in question.

Article 35

The Member States or the Commission or the applicant or
holder of the marketing authorization may, in specific cases
where the interests of the Community are involved, refer the
matter to the Committee for the application of the procedure
laid down in Article 36 before reaching a decision on a
request for a marketing authorization or on the suspension or
withdrawal of an authorization, or on any other variations to
terms of a marketing authorization which appears
the
necessary,
in particular to take account of the information
collected in accordance with Title VII.

The Member State concerned or the Commission shall clearly
identify the question which is referred to the Committee for
inform the marketing authorization
consideration and shall
holder.

All

2.
the Member States concerned shall use their best
endeavours to reach agreement on the action to be taken in
respect of the application. They shall provide the applicant

The Member States and the holder shall
forward to the
Committee all available information relating to the matter in
question.

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Article 36

1. When reference is made to the procedure described in
this Article, the Committee shall consider the matter concerned
and issue a reasoned opinion within 90 days of the date on
which the matter was referred to it.

However, in cases submitted to the Committee in accordance
with Articles 34 and 35, this period may be extended by 90
days.

In case of urgency, on a proposal
Committee may agree to a shorter deadline.

from its Chairman, the

its members

In order to consider the matter,

the Committee may
2.
appoint one of
rapporteur. The
Committee may also appoint individual experts to advise it on
specific questions. When appointing experts, the Committee
shall define their tasks and specify the time-limit
for the
completion of these tasks.

to act as

3.
In the cases referred to in Articles 33 and 34, before
issuing its opinion, the Committee shall provide the marketing
authorization holder with an opportunity to present written or
oral explanations.

case

the marketing
referred to in Article 35,
In the
authorization holder may be asked to explain himself orally or
in writing.

If it considers it appropriate, the Committee may invite any
other person to provide information relating to the matter
before it.

The Committee may suspend the time-limit referred to in
paragraph 1 in order to allow the marketing authorization
holder to prepare explanations.

The Agency shall

4.
forthwith inform the marketing
authorization holder where the opinion of the Committee is
that:

(cid:151) the

application
authorization, or

does

not

satisfy

the

criteria

for

(cid:151) the summary of the product characteristics proposed by
in accordance with Article 14 should be

the applicant
amended, or

(cid:151) the authorization should be granted subject to conditions,
with regard to conditions considered essential for the safe
the veterinary medicinal product
and effective use of
including pharmacovigilance, or

(cid:151) a marketing authorization should be suspended, varied or

withdrawn.

Within 15 days of the receipt of the opinion, the holder may
notify the Agency in writing of his intention to appeal. In that
case, he shall forward the detailed grounds for appeal to the
Agency within 60 days of receipt of the opinion. Within 60

days of receipt of the grounds for appeal, the Committee shall
its opinion should be revised, and the
consider whether
conclusions reached on the appeal shall be annexed to the
assessment report referred to in paragraph 5.

5. Within 30 days of its adoption, the Agency shall forward
the final opinion of the Committee to the Member States, the
Commission and the marketing authorization holder together
with a report describing the assessment of
the veterinary
medicinal product and the reasons for its conclusions.

In the event of an opinion in favour of granting or
maintaining an authorization to place the veterinary medicinal
product concerned on the market, the following documents
shall be annexed to the opinion:

(a) a draft summary of the product characteristics, as referred
reflect
to in Article 14; where necessary this will
differences in the veterinary conditions pertaining in the
Member States;

(b) any conditions affecting the authorization within the

meaning of paragraph 4.

Article 37

Within 30 days of receipt of the opinion, the Commission
shall prepare a draft of the decision to be taken in respect of
the application, taking into account Community law.

In the event of a draft decision which envisages the granting of
marketing authorization, the documents referred to in Article
36(5)(2), (a) and (b) shall be annexed.

Where, exceptionally, the draft decision is not in accordance
with the opinion of the Agency, the Commission shall also
annex a detailed explanation of the reasons for the differences.

The draft decision shall be forwarded to the Member States
and the applicant.

Article 38

A final decision on the application shall be adopted in

1.
accordance with the procedure referred to in Article 89(2).

The rules of procedure of the Standing Committee set up
2.
by Article 89(1) shall be adjusted to take account of the tasks
incumbent upon it in accordance with this Chapter.

These adjustments shall involve the following:

(cid:151) except in cases referred to in the third paragraph of Article
the Standing Committee shall be

the opinion of

37,
obtained in writing,

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(cid:151) each Member State is allowed at least 28 days to forward
the
written observations on the draft decision of
Commission,

concerned shall forthwith refer the matter to the Agency for
the application of the procedures laid down in Articles 36, 37
and 38.

(cid:151) each Member State is able to require in writing that the
draft decision be discussed by the Standing Committee,
giving its reasons in detail.

the Commission,

in the opinion of

Where,
the written
observations of a Member State raise important new questions
of a scientific or
technical nature which have not been
addressed in the opinion of the Agency, the Chairman shall
suspend the procedure and refer the application back to the
Agency for further consideration.

The provisions necessary for
this
paragraph shall be adopted by the Commission in accordance
with the procedure referred to in Article 89(2).

the implementation of

A decision as

3.
referred to in paragraph 1 shall be
addressed to the Member States concerned by the matter and
communicated to the marketing authorization holder. The
shall either grant or withdraw marketing
Member States
authorization, or vary the terms of a marketing authorization
as necessary to comply with the decision within 30 days of its
notification. They shall
inform the Commission and the
Agency thereof.

Article 39

1.
Any application by the marketing authorization holder to
vary a marketing authorization which has been granted in
accordance with the provisions of
shall be
submitted to all
the Member States which have previously
authorized the veterinary medicinal product concerned.

this Chapter

The Commission shall, in consultation with the Agency, adopt
appropriate arrangements for the examination of variations to
the terms of a marketing authorization.

These arrangements shall
include a notification system or
administration procedures concerning minor variations and
define precisely the concept of (cid:145)a minor variation(cid:146).

These arrangements shall be adopted by the Commission in
the form of an implementing regulation in accordance with
the procedure referred to in Article 89(2).

2.
In case of arbitration submitted to the Commission, the
procedure laid down in Articles 36, 37 and 38 shall apply by
analogy to variations made to marketing authorizations.

Article 40

1. Where a Member State considers that the variation of the
terms of a marketing authorization which has been granted in
accordance with the provisions of
its
suspension or withdrawal
is necessary for the protection of
human or animal health or the environment, the Member State

this Chapter or

2. Without prejudice to the provisions of Article 35,
in
exceptional cases, where urgent action is essential to protect
human or animal health or the environment, until a definitive
decision is adopted, a Member State may suspend the
marketing and the use of the veterinary medicinal product
concerned on its territory. It shall inform the Commission and
the other Member States no later than the following working
day of the reasons for its action.

Article 41

Articles 39 and 40 shall apply by analogy to veterinary
medicinal products authorized by Member States following an
opinion of the Committee given in accordance with Article 4
of Directive 87/22/EEC before 1 January 1995.

Article 42

The Agency shall publish an annual

1.
report on the
operation of the procedures laid down in this Chapter and
shall forward it to the European Parliament and the Council
for information.

By 1 January 2001,

2.
the Commission shall publish a
detailed review of the operation of the procedures laid down
in this Chapter and shall propose any amendments which may
be necessary to improve these procedures.

The Council shall decide, under the conditions provided for in
the Treaty, on the Commission proposal within one year of its
submission.

Article 43

The provisions of Articles 31 to 38 shall not apply to
homeopathic veterinary medicinal products
referred to in
Article 19(2).

TITLE IV

MANUFACTURE AND IMPORTS

Article 44

1. Member States shall
take all appropriate measures to
ensure that the manufacture of veterinary medicinal products
in their territory is subject to the holding of an authorization.
This manufacturing authorization shall likewise be required for
veterinary medicinal products intended for export.

2.
The authorization referred to in paragraph 1 shall be
required both for total and partial manufacture and for the
various processes of dividing up, packaging or presentation.

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such authorization shall not be

However,
required for
preparation, dividing up, changes in packaging or presentation
where these processes are carried out solely for retail supply
by pharmacists in dispensing pharmacies or by persons legally
authorized in the Member States to carry out such processes.

3.
The authorization referred to in paragraph 1 shall also be
required for imports from third countries into a Member State;
this Title and Article 83 shall apply to such imports in the
same way as to manufacture.

Member States shall take all appropriate measures to ensure
that veterinary medicinal products brought into their territory
from a third country and destined for another Member State
are accompanied by a copy of the authorization referred to in
paragraph 1.

Article 45

In order
applicant shall meet at least the following requirements:

to obtain the manufacturing authorization,

the

(a) he shall specify the veterinary medicinal products and
pharmaceutical
forms which are to be manufactured or
imported and also the place where they are to be
manufactured and/or controlled;

(b) he shall have at his disposal,

for the manufacture or
import of
the above, suitable and sufficient premises,
technical equipment and control facilities complying with
the legal requirements which the Member State concerned
lays down as regards both manufacture and control and
the storage of products, in accordance with Article 24;

(c) he shall have at his disposal the services of at least one

qualified person within the meaning of Article 52.

The applicant shall provide particulars in his application to
establish his compliance with the above requirements.

Article 46

1.
The competent authority of the Member State shall not
issue the manufacturing authorization until it has established
the accuracy of the particulars supplied pursuant to Article 45
by means of an inquiry carried out by its representatives.

In order to ensure that the requirements referred to in
2.
Article 45 are complied with, authorization may be made
conditional on the fulfilment of certain obligations imposed
either when authorization is granted or at a later date.

The authorization shall apply only to the premises
3.
specified in the application and to the veterinary medicinal
products
that
application.

pharmaceutical

specified

forms

and

in

Article 47

manufacturing authorization does not exceed 90 days from the
day on which the competent authority receives the application.

Article 48

If the holder of the manufacturing authorization requests a
change in any of the particulars referred to in Article 45, first
paragraph,
the time taken for the procedure
relating to this request shall not exceed 30 days. In exceptional
cases, this period of time may be extended to 90 days.

(a) and (b),

Article 49

The competent authority of the Member States may require
from the applicant further information concerning both the
particulars supplied pursuant to Article 45 and the qualified
person referred to in Article 52; where the competent
the
authority concerned exercises this right, application of
referred to in Articles 47 and 48 shall be
time-limits
suspended until
the additional data required have been
supplied.

Article 50

The holder of a manufacturing authorization shall at least be
obliged to:

(a) have at his disposal the services of staff complying with
requirements existing in the Member State

the legal
concerned as regards both manufacture and controls;

(b) dispose of

the authorized veterinary medicinal products
the Member

only in accordance with the legislation of
States concerned;

(c) give prior notice to the competent authority of any
changes which he may wish to make to any of
the
particulars supplied pursuant to Article 45; the competent
authority shall, in any event, be immediately informed if
the qualified person referred to in Article 52 is replaced
unexpectedly;

(d) allow the representatives of the competent authority of the
Member State concerned access to his premises at any
time;

(e) enable the qualified person referred to in Article 52 to
carry out his duties, particularly by placing at his disposal
all the necessary facilities;

(f) comply with the principles and the guidelines of good
manufacturing practice for medicinal products laid down
by Community law;

(g) keep detailed records of all veterinary medicinal products
supplied by him, including samples, in accordance with the
laws of
following
information at least shall be recorded in respect of each
transaction, whether or not it is made for payment:

countries of destination. The

the

The Member States shall
take all appropriate measures to
ensure that the time taken for the procedure for granting the

(cid:151) name of the veterinary medicinal product,

(cid:151) date,

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(cid:151) quantity supplied,

(cid:151) name and address of the recipient,

(cid:151) batch number.

certificates or other evidence of formal qualifications awarded
on completion of both courses are recognized as equivalent by
the State in question.

The course shall
bearing upon at least the following basic subjects:

include theoretical and practical

tuition

records

These
competent authorities for a period of at least three years.

shall be available

inspection by the

for

Article 51

The principles and guidelines of good manufacturing practice
for veterinary medicinal products referred to in Article 50(f)
shall be adopted in the form of a Directive addressed to the
Member States in accordance with the procedure referred to in
Article 89(2).

Detailed guidelines shall be published by the Commission and
scientific and
revised as appropriate to take account of
technical progress.

Article 52

1. Member States shall
take all appropriate measures to
ensure that the holder of the manufacturing authorization has
permanently and continuously at his disposal the services of at
least one qualified person who fulfils the conditions laid down
in Article 53 and is responsible, in particular, for carrying out
the duties specified in Article 55.

(cid:151) experimental physics,

(cid:151) general and inorganic chemistry,

(cid:151) organic chemistry,

(cid:151) analytical chemistry,

(cid:151) pharmaceutical chemistry, including analysis of medicinal

products,

(cid:151) general and applied biochemistry (medical),

(cid:151) physiology,

(cid:151) microbiology,

(cid:151) pharmacology,

(cid:151) pharmaceutical technology,

(cid:151) toxicology,

2.
If he personally fulfils the conditions laid down in Article
53, the holder of the authorization may himself assume the
responsibility referred to in paragraph 1.

(cid:151) pharmacognosy (study of the composition and effects of
the active principles of natural substances of plant and
animal origin).

Article 53

1. Member States shall ensure that
the qualified person
referred to in Article 52 fulfils the minimum conditions of
qualification set out in paragraphs 2 and 3.

2.
The qualified person shall be in possession of a diploma,
certificate or other evidence of formal qualifications awarded
on completion of a university course of study, or a course
recognized as equivalent by the Member State concerned,
extending over a period of at least four years of theoretical
and practical
following scientific
disciplines: pharmacy, medicine, veterinary science, chemistry,
pharmaceutical chemistry and technology, biology.

study in one of

the

However, the minimum duration of the university course may
be three and a half years where the course is followed by a
period of theoretical and practical training of at least one year
and includes a training period of at least six months in a
pharmacy open to the public, corroborated by an examination
at university level.

Where two university or recognized equivalent courses coexist
in a Member State and where one of these extends over four
years and the other over three years, the diploma, certificate or
other evidence of formal qualifications awarded on completion
of the three-year university course or its recognized equivalent
shall be considered to fulfil the condition of duration referred
the diplomas,
subparagraph in so far as
to in the first

Tuition in these subjects should be so balanced as to enable
the obligations specified in
the person concerned to fulfil
Article 55.

In so far as certain diplomas, certificates or other evidence of
formal qualifications mentioned in this paragraph do not fulfil
the criteria laid down above, the competent authority of the
Member State shall ensure that the person concerned provides
evidence that he has, in the subjects involved, the knowledge
required for
the manufacture and control of veterinary
medicinal products.

at

least

The qualified person shall have
two years,

acquired practical
3.
in one or more
experience over
undertakings which are authorized manufacturers,
in the
activities of qualitative analysis of medicinal products, of
quantitative analysis of active substances and of the testing and
checking necessary to ensure
the quality of veterinary
medicinal products.

The duration of practical experience may be reduced by one
year where a university course lasts for at least five years and
by a year and a half where the course lasts for at least six
years.

Article 54

1.
A person engaging, in a Member State, in the activities of
the person referred to in Article 52 at the date on which

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Directive 81/851/EEC became applicable, without complying
with the provisions of Article 53 shall be eligible to continue
to engage in those activities in the State concerned.

2.
The holder of a diploma, certificate or other evidence of
formal qualifications awarded on completion of a university
course (cid:151) or a course recognized as equivalent by the Member
State concerned (cid:151) in a scientific discipline allowing him to
engage in the activities of the person referred to in Article 52
in accordance with the laws of that State may (cid:151) if he began
his course prior to 9 October 1981 (cid:151) be considered as
qualified to carry out in that State the duties of the person
referred to in Article 52, provided that he has previously
engaged in the following activities for at least two years before
9 October 1991 in one or more undertakings with a
manufacturing authorization; production supervision and/or
qualitative and quantitative analysis of active substances, and
the necessary testing and checking under the direct authority
of a person as referred to in Article 52 to ensure the quality of
veterinary medicinal products.

If the person concerned has acquired the practical experience
referred to in the first subparagraph before 9 October 1971, a
further one year’s practical experience in accordance with the
conditions
subparagraph shall be
completed by him immediately before he engages in such
activities.

referred to in the first

Article 55

1. Member States shall
take all appropriate measures to
ensure that the qualified person referred to in Article 52 is,
without prejudice to his relationship with the holder of the
manufacturing authorization, responsible, in the context of the
procedures referred to in Article 56, for ensuring that:

(a)

(b)

in the case of veterinary medicinal products manufactured
within the Member State
each batch of
veterinary medicinal products has been manufactured and
checked in compliance with the laws in force in that
Member State and in accordance with the requirements of
the marketing authorization;

concerned,

in the case of veterinary medicinal products coming from
third countries, each production batch imported has
undergone in the importing Member State a full qualitative
analysis, a quantitative analysis of at least all the active
substances and all the other tests or checks necessary to
ensure the quality of veterinary medicinal products in
the marketing
accordance with the
authorization.

requirements of

of

Batches
veterinary medicinal products which have
undergone such controls in a Member State shall be exempt
from the above controls if they are placed on the market in
another Member State, accompanied by the control reports
signed by the qualified person.

2.
In the case of veterinary medicinal products imported
from a third country, where appropriate arrangements have
been made by the Community with the exporting country to
ensure that
the veterinary medicinal
product applies standards of good manufacturing practice at

the manufacturer of

least equivalent to those laid down by the Community and to
ensure that the controls referred to under point (b) of the first
subparagraph of paragraph 1 have been carried out in the
exporting country, the qualified person may be relieved of
responsibility for carrying out those controls.

3.
In all cases, and particularly where the veterinary
medicinal products are released for sale, the qualified person
shall certify, in a register or equivalent document provided for
the purpose, that each production batch satisfies the provisions
of this Article; the said register or equivalent document shall
be kept up to date as operations are carried out and shall
remain at the disposal of the representatives of the competent
authority for the period specified in the provisions of
the
in any event, for at least five
Member State concerned and,
years.

Article 56

Member States shall ensure that the obligations of qualified
persons referred to in Article 52 are fulfilled, either by means
of appropriate administrative measures or by making such
persons subject to a professional code of conduct.

Member States may provide for the temporary suspension of
such a person upon the commencement of administrative or
disciplinary proceedings against him for failure to fulfil his
obligations.

Article 57

The provisions of
veterinary medicinal products.

this Title shall apply to homeopathic

TITLE V

LABELLING AND PACKAGE INSERT

Article 58

1.
The following information, which shall conform with the
particulars and documents provided pursuant to Articles 12
and 13(1) and be approved by the competent authorities, shall
appear in legible characters on containers and outer packages
of medicinal products:

(a) Name of the veterinary medicinal product, which may be a
brand name or a non-proprietary name accompanied by a
trade mark or the name of the manufacturer, or a scientific
name or formula, with or without a trade mark, or the
name of the manufacturer.

Where the special name of a medicinal product containing
only one active substance is a brand name, this name must
be accompanied in legible characters by the international
non-propriety name recommended by the World Health
Organization, where such name exists or, where no such
name exists, by the usual non-proprietary name;

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(b) A statement of the active substances expressed qualitatively
and quantitatively per dosage unit or according to the
form of administration for a particular volume or weight,
using
names
recommended by the World Health Organization, where
such names exist or, where no such names exist, the usual
non-proprietary names;

non-proprietary

international

the

(cid:151) manufacturer’s batch number,

(cid:151) date of expiry,

(cid:151) the words (cid:145)For animal treatment only(cid:146).

(c) Manufacturer’s batch number;

(d) Marketing authorization number;

(e) Name or corporate name and permanent address or
registered place of business of the marketing authorization
holder and of the manufacturer, if different;

(f) The species of animal for which the veterinary medicinal
of

the method

intended;

route

and

product
administration;

is

(g) The withdrawal period, even if nil, in the case of veterinary
food-producing

administered

products

to

medicinal
animals;

(h) Expiry date, in plain language;

(i) Special storage precautions, if any;

(j) Special precautions

for disposal of unused medicinal
products or waste material from medicinal products, if any;

(k) Particulars required to be indicated pursuant

to Article

26(1), if any;

(l) The words (cid:145)For animal treatment only(cid:146).

2.
The pharmaceutical form and the contents by weight,
volume or number of dose-units need only be shown on the
outer package.

The provisions of Part 1, A of Annex I, in so far as they
3.
concern the qualitative
composition of
veterinary medicinal products in respect of active substances,
shall apply to the particulars provided for in paragraph 1(b).

and quantitative

4.
The particulars mentioned in paragraph 1(f) to (l) shall
appear on the outer package and on the container of the
medicinal products
the
in the language or
country in which they are placed on the market.

languages of

Article 59

As

small

regards

2.
than
ampoules, on which it is impossible to give the particulars
mentioned in paragraph 1, the requirements of Article 58(1),
(2) and (3), shall apply only to the outer package.

single-dose containers, other

3.
The particulars mentioned in the third and sixth indents
of paragraph 1 shall appear on the outer package and on the
container of
in the language or
languages of the country in which they are placed on the
market.

the medicinal products

Article 60

Where there is no outer package, all the particulars which
should feature on such a package pursuant to the Articles 58
and 59 shall be shown on the container.

Article 61

1.
The inclusion of a package insert in the packaging of
veterinary medicinal products shall be obligatory unless all the
information required by this Article can be conveyed on the
container and the external packaging. Member States shall take
all appropriate measures to ensure that the insert relates solely
to the veterinary medicinal product with which it is included.
The insert shall be in the official language or languages of the
Member State in which the medicinal product is marketed.

2.
The package insert shall contain at least the following
information, which shall conform to the particulars and
documents provided pursuant to Articles 12 and 13(1) and be
approved by the competent authorities:

(a) name or corporate name and permanent address or
registered place of business of the marketing authorization
holder and of the manufacturer, if different;

(b) name of the veterinary medicinal product and a statement
and

expressed qualitatively

substances

its

of
active
quantitatively;

As regards ampoules, the particulars listed in the first
1.
paragraph of Article 58(1) shall be given on the outer package.
On the containers, however, only the following particulars
shall be necessary:

The international non-proprietary names recommended by
the World Health Organization shall be used wherever
they exist;

(cid:151) name of veterinary medicinal product,

(c)

the therapeutic indications;

(cid:151) quantity of the active substances,

(cid:151) route of administration,

(d) contra-indications and adverse reactions in so far as these
the veterinary

particulars are necessary for the use of
medicinal product;

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(e)

(f)

the species of animal for which the veterinary medicinal
the
product
method and route of administration and advice on correct
administration, if necessary;

the dosage for each species,

is intended,

the withdrawal period, even if this is nil, in the case of
veterinary
to
medicinal
food-producing animals;

administered

products

(cid:151) expiry date, in clear terms (month, year),

(cid:151) pharmaceutical form,

(cid:151) contents of the sales presentation,

(cid:151) special storage precautions, if any,

(g) special storage precautions, if any;

(cid:151) target species,

(h) particulars required to be indicated pursuant

to Article

26(1), if any;

(i)

special precautions for the disposal of unused medicinal
products or waste materials from medicinal products,
if
any.

The particulars referred to in paragraph 2 shall appear in
3.
the language or languages of the country in which the product
is marketed. The other information shall be clearly separate
from such particulars.

(cid:151) a special warning if necessary for the medicinal product,

(cid:151) manufacturer’s batch number,

(cid:151) registration number.

TITLE VI

POSSESSION, WHOLESALE DISTRIBUTION AND DISPENSING
OF VETERINARY MEDICINAL PRODUCTS

Article 62

Article 65

Where the provisions of this Title are not observed and a
formal notice addressed to the person concerned has been
ineffectual, the competent authorities of the Member States
may suspend or withdraw marketing authorization.

Article 63

The requirements of Member States concerning conditions of
supply to the public,
the marking of prices on medicinal
products for veterinary use and industrial property rights shall
not be affected by the provisions of this Title.

Article 64

to

prejudice

paragraph

1. Without
homeopathic
veterinary medicinal products shall be labelled in accordance
with the provisions of this title and identified by the inclusion
the words
on their
(cid:145)homeopathic medicinal product for veterinary use(cid:146).

in clearly legible

form, of

labels,

2,

clear mention of

In addition to the

2.
the words
(cid:145)homeopathic veterinary medicinal product without approved
therapeutic indications(cid:146), the labelling and, where appropriate,
package insert
the homeopathic veterinary medicinal
products referred to in Article 17(1) shall bear the following
information and no other information:

for

(cid:151) the scientific name of the stock or stocks followed by the
degree
the
using
pharmacopoeia used in accordance with point 8 of Article
1,

dilution,

symbols

the

of

of

1. Member States shall
take all appropriate measures to
ensure that wholesale distribution of veterinary medicinal
products is subject to the holding of an authorization and to
ensure that the time taken for the procedure for granting this
authorization does not exceed 90 days from the date on which
the competent authority receives the application.

Member States may exclude supplies of small quantities of
veterinary medicinal products from one retailer to another
from the scope of the definition of wholesale distribution.

2.
In order to obtain the authorization for distribution, the
applicant shall have at his disposal technically competent staff
and suitable and sufficient premises complying with the
requirements laid down in the Member State concerned as
regards
the storage and handling of veterinary medicinal
products.

3.
The holder of the authorization for distribution shall be
required to keep detailed records. The following minimum
information shall be recorded in respect of each incoming or
outgoing transaction:

(a) date;

(b) precise identity of the veterinary medicinal product;

(c) manufacturer’s batch number, expiry date;

(d) quantity received or supplied;

(e) name and address of the supplier or recipient.

(cid:151) name and address of the marketing authorization holder

and, where appropriate, of the manufacturer,

(cid:151) method of administration and, if necessary, route,

At least once a year a detailed audit shall be carried out to
compare incoming and outgoing medicinal
supplies with
supplies currently held in stock, any discrepancies being
recorded.

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records

These
competent authorities for a period of at least three years.

shall be available

inspection by the

for

4. Member States shall
take all appropriate measures to
ensure that wholesalers supply veterinary medicinal products
only to persons permitted to carry out retail activities in
accordance with Article 66, or to other persons who are
lawfully permitted to receive veterinary medicinal products
from wholesalers.

Article 66

1. Member States shall
take all appropriate measures to
ensure that the retail supply of veterinary medicinal products
is conducted only by persons who are permitted to carry out
such operations by the legislation of
the Member State
concerned.

Any person permitted under paragraph 1 to sell
2.
veterinary medicinal products
shall be required to keep
detailed records. The following information shall be recorded
in respect of each incoming or outgoing transaction:

Article 67

Without prejudice to stricter Community or national rules
relating to dispensing veterinary medicinal products and to
protect human and animal health, a prescription shall be
required for dispensing to the public the following veterinary
medicinal products;

(a)

those products subject to official restrictions on supply or
use, such as:

(cid:151) the restrictions resulting from the implementation of
the relevant United Nations conventions on narcotic
and psychotropic substances,

(cid:151) the restrictions on the use of veterinary medicinal

products resulting from Community law;

(b) those products in respect of which special precautions
must be taken by the veterinarian in order to avoid any
unnecessary risk to:

(cid:151) the target species,

(a) date;

(cid:151) the person administering the products to the animal,

(b) precise identity of the veterinary medicinal product;

(cid:151) the consumer of foodstuffs obtained from the treated

(c) manufacturer’s batch number;

(d) quantity received or supplied;

(e) name and address of the supplier or recipient;

(f) where relevant, name and address of

the prescribing

veterinarian and a copy of the prescription.

At least once a year a detailed audit shall be carried out, and
incoming and outgoing veterinary medicinal products shall be
reconciled with products
any
discrepancies being recorded.

currently held in stock,

records

These
competent authorities for a period of three years.

shall be available

for

inspection by the

requirements

the number of detailed
3. Member States may limit
referred to in paragraph 2.
documenting
However, these requirements shall always be applied in case of
veterinary medicinal products which are
for
administration to food-producing animals and which are
available only on veterinary prescription or in respect of which
a withdrawal period must be observed.

intended

Not

4.
communicate to the Commission a list of
medicinal products which are available without prescription.

later that 1 January 1992, Member States shall
the veterinary

animal,

(cid:151) the environment;

(c)

those products intended for treatments or pathological
processes which require a precise prior diagnosis or the
use of which may cause effects which impede or interfere
with subsequent diagnostic or therapeutic measures;

(d) magistral formulae intended for animals.

In addition, a prescription shall be required for new veterinary
medicinal products containing an active substance which has
been authorized for use in a veterinary medicinal product for
less than five years unless, having regard to the information
and particulars provided by the applicant, or experience
the veterinary medicinal
acquired in the practical use of
product, the competent authorities are satisfied that none of
the criteria referred to in (a) to (d) of the first paragraph apply.

Article 68

1. Member States shall take all measures necessary to ensure
that only persons empowered under their national legislation
their control veterinary
in force possess or have under
medicinal products or substances which may be used as
veterinary medicinal
anabolic,
products
anti-infectious, anti-parasitic, anti-inflammatory, hormonal or
psychotropic properties.

have

that

After having taken note of
Member States,
suitable measures
Community list of such medicinal products.

the communication from the
examine whether
should be proposed for drawing up a

the Commission shall

2. Member States shall maintain a register of manufacturers
and dealers permitted to be in possession of active substances
which may be used in the manufacture of veterinary medicinal
products having the properties referred to in paragraph 1.

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Such persons must maintain detailed records of all dealings in
substances which may be used in the manufacture of
veterinary medicinal products and keep these records available
for inspection by the competent authorities for a period of at
least three years.

3.
Any amendments to be made to the list of substances
referred to in paragraph 1 shall be adopted in accordance with
the procedure referred to in Article 89(2).

Article 69

the owners or keepers of
Member States shall ensure that
food-producing animals
can provide proof of purchase,
possession and administration of veterinary medicinal products
containing the substances set out in Article 68; Member States
may extend the scope of this obligation to other veterinary
medicinal products.

In particular, Member States may require the maintenance of a
record giving at least the following information:

(a) date;

(b) name of the veterinary medicinal product;

(c) quantity;

(d) name and address of the supplier of the medicinal product;

(e)

identification of the animals treated.

Article 70

Notwithstanding Articles 9 and 67, Member States shall ensure
that veterinarians providing services in another Member State
can take with them and administer to animals small quantities
of ready-made veterinary medicinal products not exceeding
daily
veterinary
medicinal products which are not authorized for use in the
Member State in which the services are provided (hereinafter:
host Member State), providing that the following conditions
are satisfied:

than immunological

requirements other

(a)

the authorization to place the product on the market
provided for in Articles 5, 7 and 8 has been issued by the
competent authorities of the Member State in which the
veterinarian is established;

(b) the veterinary medicinal products are transported by the
veterinarian in the original manufacturer’s packaging;

(c)

products

veterinary medicinal

the
for
administration to food-producing animals have the same
qualitative and quantitative composition in terms of active
substances
authorized in
the medicinal products
accordance with Articles 5, 7 and 8 in the host Member
State;

intended

as

(d) the veterinarian providing services in another Member
State acquaints himself with the good veterinary practices
the
applied in that Member State and ensures
withdrawal period specified on the
the
veterinary medicinal product concerned is complied with,
unless he could reasonably be expected to know that a

that
labelling of

(e)

(f)

longer withdrawal period should be specified to comply
with these good veterinary practices;

the veterinarian shall not furnish any veterinary medicinal
product to the owner or keeper of the animals treated in
the host Member State unless this is permissible on the
basis of the rules of the host Member State; in this case he
shall, however, supply only in relation to animals under
his care and only the minimum quantities of veterinary
medicinal product necessary to complete the treatment of
animals concerned on that occasion;

treated,

the animals

the diagnosis,

the veterinarian shall be required to keep detailed records
of
the veterinary
medicinal products administered, the dosage administered,
the duration of
treatment and the withdrawal period
applied. These records shall be available for inspection by
the competent authorities of the host Member State for a
period of at least three years;

(g) the overall range and quantity of veterinary medicinal
products carried by the veterinarian shall not exceed that
generally required for the daily needs of good veterinary
practice.

Article 71

In the

absence of

specific Community

legislation
1.
concerning the use of
immunological veterinary medicinal
products for the eradication or control of animal disease, a
Member State may, in accordance with its national legislation,
prohibit
sale, supply
and/or use of immunological veterinary medicinal products on
the whole or part of its territory if it is established that:

import, possession,

the manufacture,

(a)

the administration of the product to animals will interfere
with the implementation of a national programme for the
diagnosis, control or eradication of animal disease, or will
cause difficulties in certifying the absence of contamination
in live animals or in foodstuffs or other products obtained
from treated animals;

(b) the disease to which the product is intended to confer
immunity is largely absent from the territory in question.

The competent authorities of the Member States shall
in which the
all

2.
inform the Commission of
provisions of paragraph 1 are applied.

instances

TITLE VII

PHARMACOVIGILANCE

Article 72

1. Member States shall
take all appropriate measures to
encourage the reporting to the competent authorities of
suspected adverse reactions to veterinary medicinal products.

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2.
The Member States may impose specific requirements on
veterinary practitioners and other health care professionals in
respect of the reporting of suspected serious or unexpected
in particular
adverse reactions and human adverse reactions,
where
the marketing
authorization.

such reporting is a condition of

the evaluation of
the benefits and risks afforded by a
and
veterinary medicinal product
promptly, including the provision of information about the
volume of sales or prescriptions of the veterinary medicinal
product concerned;

answered fully

is

Article 73

(d) the provision to the competent authorities, of any other
information relevant to the evaluation of the benefits and
risks afforded by a veterinary medicinal product, including
appropriate information on post-marketing surveillance
studies.

the

regard

concerning

In order to ensure the adoption of appropriate regulatory
veterinary medicinal products
decisions
authorised within
to
having
the Community,
information obtained about suspected adverse reactions to
veterinary medicinal products under normal conditions of use,
the Member
veterinary
shall
pharmacovigilance system. This system shall be used to collect
information useful in the surveillance of veterinary medicinal
products, with particular reference to adverse reactions in
animals and in human beings related to the use of veterinary
medicinal products,
such information
scientifically.

to evaluate

establish

States

and

a

Such information shall be collated with available data on the
sale and prescription of veterinary medicinal products.

lack of

This system also takes into account any available information
related to the
expected efficacy, off-label use,
investigations of the validity of the withdrawal period and on
potential environmental problems, arising from the use of the
product,
interpreted in accordance with the Commission
guidelines referred to in Article 77(1), which may have an
impact on the evaluation of their benefits and risks.

Article 74

The marketing authorization holder shall have permanently
and continuously at his disposal an appropriately qualified
person responsible for pharmacovigilance.

That qualified person shall be responsible for the following:

(a)

that

the establishment and maintenance of a system which
suspected adverse
information about all
ensures
reactions which are reported to the personnel of
the
company,
is collected and
including its representatives,
collated in order to be accessible at least at one point
within the Community;

(b) the preparation for

the competent authorities of

the
reports referred to in Article 75, in such form as may be
in accordance with the
laid down by those authorities,
guidance referred to in Article 77(1);

(c) ensuring that any request from the competent authorities
information necessary for

for the provision of additional

Article 75

1.
The marketing authorization holder shall be required to
maintain detailed records of all suspected adverse reactions
occurring either in the Community or in a third country.

The marketing authorization holder shall be required to
2.
record and to report all suspected serious adverse reactions
and human adverse reactions related to the use of veterinary
medicinal products, of which he can reasonably be expected to
have knowledge, or which are brought
to his attention,
immediately to the competent authority of the Member State
in whose territory the incident occurred, and in no case later
than 15 calendar days following the receipt of the information.

3.
The marketing authorization holder shall ensure that the
suspected serious and unexpected adverse reactions and human
adverse reactions, occurring in the territory of a third country,
are reported immediately in accordance with the guidance
referred to in Article 77(1), so that they are available to the
Agency and to the competent authorities in the Member
State(s) where the veterinary medicinal product is authorized,
and in no case later than 15 calendar days following the
receipt of the information.

4.
In the case of veterinary medicinal products which have
been considered within the scope of Directive 87/22/EEC, or
which have benefited from the procedures of mutual
recognition under Articles 21, 22 and 32(4) of this Directive
and veterinary medicinal products for which there has been a
referral to the procedures under Articles 36, 37 and 38 of this
Directive, the marketing authorisation holder shall additionally
ensure that all suspected serious adverse reactions and human
adverse reactions, occurring in the Community, are reported in
the format and at intervals to be agreed with the reference
Member State or a competent authority designated as reference
in such a way so as to be accessible to the
Member State,
reference Member State.

reactions

Unless other

requirements have been laid down as
5.
the granting of authorization, records of all
condition of
adverse
competent
authorities in the form of a periodic safety update report,
either immediately upon request or periodically as follows: six
monthly for the first two years after authorization, annually
for the subsequent two years, and at the same time of the first

submitted to the

shall be

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renewal. Thereafter, the periodic safety update reports shall be
submitted at five-yearly intervals together with the application
for renewal of the authorization. The periodic safety update
report shall include a scientific evaluation of the benefits and
risks afforded by the veterinary medicinal product.

6.
Following the granting of a marketing authorization, the
marketing authorization holder may request the amendment of
the periods
referred to in this Article according to the
procedure laid down by the Commission Regulation (EC) No
541/95 (1), if applicable.

Article 76

The Agency,

1.
in collaboration with the Member States
and the Commission shall set up a data-processing network to
information
exchange of pharmacovigilance
facilitate
regarding medicinal products marketed in the Community.

the

shall
reactions

the network foreseen in the
ensure

first
2. Making use of
reports of
paragraph, Member States
and human adverse
suspected serious
adverse
in accordance with the guidance referred to in
reactions,
Article 77(1),
that have taken place on their territory are
immediately made available to the Agency and the other
Member States, and in any case within 15 calendar days of
their notification, at the latest.

that

3.
The Member States shall ensure that reports of suspected
serious adverse reactions and human adverse reactions, that
have taken place on their territory are immediately made
available to the marketing authorisation holder, and in any
case within 15 calendar days of their notification at the latest.

Article 77

1.
In order to facilitate the exchange of information about
pharmacovigilance within the Community, the Commission, in
consultation with the Agency, Member States
and the
interested parties, shall draw up guidance on the collection,
verification and presentation of adverse reaction reports,
including technical requirements for electronic exchange of
veterinary pharmacovigilance information in accordance with
internationally agreed terminology.

This guidance shall be published in Volume 9 of the Rules
governing medicinal products in the European Community and
shall take account of international harmonisation work carried
out in the field of pharmacovigilance.

2.
For the interpretation of the definitions referred to in
Article 1 points 10 to 16 and principles outlined in this title,
the marketing authorisation holder
competent
authorities shall refer to the detailed guidance referred to in
paragraph 1.

and the

(1) OJ L 55, 11.3.1995, p. 7. Regulation amended by Regulation (EC)

No 1146/98 (OJ L 159, 3.6.1998, p. 31).

Article 78

1. Where, as a result of
the evaluation of veterinary
pharmacovigilance data, a Member State considers that a
marketing authorization should be suspended, withdrawn or
the indications or availability, amend the
varied to restrict
posology, add a contraindication or add a new precautionary
measure,
the other
Member States and the marketing authorization holder.

forthwith inform the Agency,

it shall

In case of urgency, the Member State concerned may
2.
suspend the marketing authorization of a veterinary medicinal
product, provided the Agency, the Commission and the other
Member States are informed at the latest on the following
working day.

Article 79

Any amendments which may be necessary to update the
provisions of Articles 72 to 78 to take account of scientific
and technical progress shall be adopted in accordance with the
procedure referred to in Article 89(2).

TITLE VIII

SUPERVISION AND SANCTIONS

Article 80

1.
The competent authority of the Member State concerned
shall ensure by means of repeated inspection that the legal
requirements relating to veterinary medicinal products are
complied with.

Such inspections
representatives of
empowered to:

be

authorized
shall
the competent authority who shall be

carried

out

by

(a)

inspect manufacturing or trading establishments and any
laboratories entrusted by the holder of the manufacturing
authorization, with the task of carrying out control tests
pursuant to Article 24;

(b) take samples;

(c) examine any documents relating to the object of

the
inspection, subject to current provisions in the Member
States from 9 October 1981 which place restrictions on
the
these powers with regard to the description of
manufacturing method.

that

take all appropriate measures to
2. Member States shall
the manufacturing processess used in the
ensure
manufacture of immunological veterinary medicinal products
are completely validated and batch-to-batch consistency is
ensured.

The officials representing the competent authority shall
3.
report after each of the inspections mentioned in the first
paragraph on whether the manufacturer complies with the
principles and guidelines of good manufacturing practice
referred to in Article 51. The inspected manufacturer shall be
informed of the content of such reports.

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Article 81

take all appropriate measures to
1. Member States shall
the marketing authorization holder and, where
ensure that
appropriate,
the manufacturing authorization
the holder of
furnish proof of the control tests carried out on the veterinary
medical product and/or on the constituents and intermediate
products of the manufacturing process, in accordance with the
methods
of marketing
the
laid
authorization.

purposes

down

for

2.
For the purposes of implementing paragraph 1, Member
States may require the marketing authorization holder for
immunological veterinary medicinal products to submit to the
competent authorities copies of all the control reports signed
by the qualified person in accordance with Article 55.

authorization holder

immunological
The marketing
veterinary medicinal products shall ensure that an adequate
number of representative samples of each batch of veterinary
medical products is held in stock at least up to the expiry date,
and provide samples promptly to the competent authorities on
request.

for

(a)

the veterinary medicinal product proves to be harmful
the time of
under
application for authorization or subsequently;

the conditions of use stated at

(b) the veterinary medicinal product does not have any
therapeutic effect on the species of animal for which the
treatment is intended;

(c)

its qualitative and quantitative composition is not as stated;

(d) the recommended withdrawal period is

inadequate to
ensure that foodstuffs obtained from the treated animal do
not contain residues which might constitute a health
hazard to the consumer;

(e)

the veterinary medicinal product is offered for sale for a
use which is prohibited by other community provisions.

competent
However, pending Community
to grant authorization for a
authorities may refuse
veterinary medicinal product where
such action is
necessary for the protection of public, consumer or animal
health;

rules,

the

Article 82

1. Where it considers it necessary, a Member State may
require the marketing authorization holder for immunological
products to submit samples from the batches of
the bulk
and/or medical product for examination by a State laboratory
or an approved laboratory before entry into circulation.

In the case of a batch manufactured in another Member State,
examined by the competent authority of another Member State
and declared to be in conformity with national specifications,
such a control may be carried out only after the control
reports of the batch in question have been examined, after the
Commission has been informed, and where the difference in
veterinary
States
concerned justifies it.

conditions between the

two Member

Except where the Commission has been informed that a
2.
longer period is necessary to complete the analyses, Member
States shall ensure that any such examination is completed
the samples. The marketing
within 60 days of receipt of
authorization holder shall be notified of
the results of the
examination within the same time-limit.

Before 1 January 1992, the Member States shall notify
3.
the Commission of
the immunological veterinary medicinal
products subject to compulsory official control before being
placed on the market.

Article 83

(f)

information given in the application documents

the
pursuant to Article 12, 13(1) and 27 is incorrect;

(g) the control tests referred to in Article 81(1) have not been

carried out;

(h) the obligation referred to in Article 26(2) has not been

fulfilled.

Authorization may be suspended, or withdrawn where it

2.
is established that:

(a)

the particulars supporting the application, as provided for
in Articles 12 and 13(1), have not been amended in
accordance with Article 27(1) and (5);

(b) any new information as referred to in Article 27(3) has not

been communicated to the competent authorities.

Article 84

1. Without prejudice to Article 83, Member States shall take
all necessary measures to ensure that supply of a veterinary
medicinal product is prohibited and that the medicinal product
concerned is withdrawn form the market where:

(a)

it is clear that the veterinary medicinal product is harmful
the
under the conditions of use stated at
application for authorization or subsequently, pursuant to
Article 27(5);

the time of

(b) the veterinary medicinal product has no therapeutic effect
for which the treatment was

on the species of animal
intended;

1.
The competent authorities of the Member States shall
suspend or withdraw marketing authorization when it is clear
that:

(c)

the qualitative
veterinary medicinal product is not as stated;

and quantitative

composition of

the

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(d) the recommended withdrawal period is

inadequate to
ensure that foodstuffs obtained from the treated animal do
not contain residues which might constitute a health
hazard to the consumer;

(e)

the control tests referred to in Article 81(1) have not been
carried out, or any other requirement or obligation relating
to the grant of the manufacturing authorization referred to
in Article 44(1) has not been complied with.

The competent authority may confine the prohibition on
2.
supply and withdrawal from the market solely to the contested
production batches.

Article 85

1.
The competent authority of a Member State shall
suspend or withdraw the manufacturing authorization for a
category of preparations or for all preparations if any of the
requirements laid down in Article 45 are no longer met.

2. Where reference is made to this paragraph, Articles 5
and 7 of Decision 1999/468/EC shall apply, having regard to
the provisions of Article 8 thereof.

The period provided for
1999/468/EC shall be set at three months.

in Article 5(6) of Decision

The Standing Committee

3.
procedure.

shall

adopt

its

rules of

TITLE X

GENERAL PROVISIONS

Article 90

2.
in
The competent authority of a Member State may,
addition to the measures provided for in Article 84, either
suspend manufacture or
imports of veterinary medicinal
products from third countries or suspend or withdraw the
manufacturing authorization for a category of preparations or
for all preparations in the event of non-compliance with the
from third
provisions
countries.

regarding manufacture or

imports

Article 86

The provisions of
veterinary medicinal products.

this Title shall apply to homeopathic

Article 87

Member States shall take appropriate measures to encourage
veterinarians and other professionals concerned to report to
the competent authorities any adverse reaction of veterinary
medicinal products.

TITLE IX

STANDING COMMITTEE

Article 88

Any changes which are necessary in order to adapt Annex I to
take account of
shall be adopted in
technical progress
accordance with the procedure referred to in Article 89(2).

Article 89

on Veterinary Medicinal

The Commission shall be

assisted by a Standing
1.
the
Committee
Adaptation to Technical Progress of
the Directives on the
Removal of Technical Barriers to Trade in the Veterinary
Medicinal Products Sector,
the
(cid:145)Standing Committee(cid:146).

referred to as

(hereinafter

Products

for

authorities

competent

Member States shall take all measures necessary to ensure that
the
the
appropriate information to each other, in particular regarding
compliance with the requirements adopted for manufacturing
authorization, or for authorization to place products on the
market.

communicate

concerned

shall

States

Upon reasoned request, Member
forthwith
communicate the reports referred to in Article 80(3) to the
competent authorities of another Member State.
If, after
considering the reports, the Member State receiving the reports
considers that it cannot accept the conclusions reached by the
competent authority of the Member State in which the report
was established,
inform the competent authorities
concerned of its reasons and may request further information.
The Member
to reach
agreement. If necessary, in the event of serious differences of
opinion, one of the Member States concerned shall inform the
Commission.

concerned shall

attempt

it shall

States

Article 91

1.
Each Member State shall take all appropriate measures to
ensure that the Agency is informed immediately of decisions
granting marketing authorization and of all decisions refusing
or withdrawing marketing authorization, cancelling a decision
refusing or withdrawing marketing authorization, prohibiting
supply or withdrawing a product from the market, together
with the reasons on which such decisions are based.

2.
The marketing authorization holder shall be obliged to
notify the Member States forthwith of any action taken by him
to suspend the marketing of a veterinary medicinal product or
to withdraw a product from the market, together with the
reasons for such action if it concerns the effectiveness of the
veterinary medicinal product or
the protection of public
health. Member States shall ensure that this information is
brought to the attention of the Agency.

3. Member States shall ensure that appropriate information
about actions taken pursuant to paragraphs 1 and 2 which
the protection of health in third countries is
may affect

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forthwith brought to the attention of the relevant international
organizations, with a copy to the Agency.

authorizations

Marketing
such
authorizations shall be published by each Member State in its
official gazette.

revocations

and

of

Article 92

Article 95

shall communicate to each other all

Member States
the
information necessary to guarantee the quality and safety of
homeopathic veterinary medicinal products manufactured and
marketed within the Community, and in particular
the
information referred to in Articles 90 and 91.

Article 93

The Member States shall not permit
foodstuffs for human
consumption to be taken from test animals unless maximum
residue limits have been established by the Community in
accordance with the provisions of Regulation (EEC) No
2377/90 and an appropriate withdrawal period has been
established to ensure that
this maximum limit will not be
exceeded in the foodstuffs.

At

the manufacturer or exporter of
1.
the request of
veterinary medicinal products, or
the authorities of an
importing third country, Member States shall certify that such
manufacturer
the manufacturing
authorization. When issuing such certificates, Member States
shall comply with the following conditions:

possession

of

in

is

(a)

they shall have regard to the prevailing administrative
arrangements of the World Health Organization;

(b) for veterinary medicinal products

intended for export
which are already authorized in their territory, they shall
supply the summary of
the product characteristics as
approved in accordance with Article 25 or, in the absence
thereof, an equivalent document.

2. Where the manufacturer is not
in possession of an
authorization to place the product on the market, he shall
provide
establishing the
certificate referred to in the first paragraph with a declaration
explaining why such authorization is not available.

responsible

authorities

the

for

TITLE XI

FINAL MEASURES

Article 96

81/852/EEC,

81/851/EEC,

Directives
and
92/74/EEC referred to in Annex II, Part A are repealed,
without prejudice to the obligations of the Member States in
respect of the deadline for transposition laid down in Annex II,
Part B.

90/677/EEC

The reference made to the said Repealed Directives shall be
construed as references to this Directive and should be read in
accordance with the correlation table set out in Annex III.

Article 97

This Directive enters into force on the 20th day following that
of
the European
Communities.

its publication in the Official

Journal of

Article 94

Article 98

taken by the
Any decision referred to in this Directive,
the Member States, may only be
competent authorities of
taken on the grounds set out in this Directive and shall state in
detail the reasons on which it is based.

This Directive is addressed to the Member States.

Done at Brussels, 6 November 2001.

Such a decision shall be notified to the party concerned who
shall at the same time be informed of the remedies available to
him under current legislation and the time allowed for seeking
such remedies.

For the European Parliament

The President

N. FONTAINE

For the Council

The President

D. REYNDERS

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REQUIREMENTS AND ANALYTICAL PROTOCOL, SAFETY TESTS, PRE-CLINICAL AND CLINICAL FOR
TESTS OF VETERINARY MEDICINAL PRODUCTS

ANNEX I

INTRODUCTION

The particulars and documents accompanying an application for marketing authorization pursuant to Articles 12 and
13(1) shall be presented in accordance with the requirements set out in this Annex and taking account of the guidance
contained in the (cid:145)Notice to applicants for marketing authorizations for veterinary medicinal products in the Member
States of the European Community(cid:146), published by the Commission in The rules governing medicinal products in the
European Community, volume V: Veterinary Medicinal Products.

In assembling the dossier for application for marketing authorization, applicants shall take into account the Community
guidelines relating to the quality, safety and efficacy of veterinary medicinal products published by the Commission in
The rules governing medicinal products in the European Community.

information which is relevant to the evaluation of the medicinal product concerned shall be included in the
All
application, whether favourable or unfavourable to the product. In particular, all relevant details shall be given of any
incomplete or abandoned test or trial relating to the veterinary medicinal product. Moreover, after marketing
authorization, any information not
to the benefit/risk assessment, shall be
submitted forthwith to the competent authority.

in the original application, pertinent

Member States ensure that all experiments on animals are conducted in accordance with Council Directive 86/609/EEC
of 24 November 1986 on the approximation of laws, regulations and administrative provisions of the Member States
regarding the protection of animals used for experimental and other scientific purposes (1).

The provisions of Title I of this Annex shall apply to veterinary medicinal products other than immunological
veterinary medicinal products.

The provisions of Title II of this Annex shall apply to immunological veterinary medicinal products.

Requirements for veterinary medicinal products other than immunological veterinary medicinal products

TITLE I

PART 1

Summary of the dossier

A. ADMINISTRATIVE DATA

The veterinary medicinal product which is the subject of the application shall be identified by name and by name of
the active substance(s), together with the strength and pharmaceutical form, the method and route of administration
and a description of the final sales presentation of the product.

The name and address of the applicant shall be given, together with the name and address of the manufacturers and
the sites involved in the different stages of the manufacture (including the manufacturer of the finished product and the
manufacturer(s) of the active substance(s)), and where relevant the name and address of the importer.

The applicant shall identify the number and titles of volumes of documentation submitted in support of the application
and indicate what samples, if any, are also provided.

Annexed to the administrative data shall be a document showing that the manufacturer is authorized to produce the
veterinary medicinal products concerned, as defined in Article 44,
together with a list of countries in which
authorization has been granted, copies of all the summaries of product characteristics in accordance with Article 14 as
approved by Member States and a list of countries in which an application has been submitted.

B.

SUMMARY OF PRODUCT CHARACTERISTICS

The applicant shall propose a summary of the product characteristics, in accordance with Article 14 of this Directive.

(1) OJ L 358, 18.12.1986, p. 1.

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In addition the applicant shall provide one or more specimens or mock-ups of the sales presentation of the veterinary
medicinal product, together with a package insert where one is required.

C. EXPERT REPORTS

In accordance with Article 15(2) and (3), expert reports must be provided on the analytical documentation, the
pharmacotoxicological documentation, the residues documentation and the clinical documentation.

Each expert report shall consist of a critical evaluation of the various tests and/or trials which have been carried out in
accordance with this Directive, and bring out all the data relevant for evaluation. The expert shall give his opinion as to
whether sufficient guarantees have been provided as to the quality, safety and efficacy of the product concerned. A
factual summary is not sufficient.

All important data shall be summarized in an appendix to the expert report, whenever possible in tabular or graphic
form. The expert report and the summaries shall contain precise cross references to the information contained in the
main documentation.

Each expert report shall be prepared by a suitably qualified and experienced person. It shall be signed and dated by the
training and
expert, and attached to the report shall be brief
occupational experience of the expert. The professional relationship of the expert to the applicant shall be declared.

the educational background,

information about

Analytical (physico-chemical, biological or microbiological) tests of veterinary medicinal products other than
immunological veterinary medicinal products

PART 2

All test procedures shall correspond to the state of scientific progress at the time and shall be validated procedures;
results of the validation studies shall be provided.

All the test procedure(s) shall be described in sufficiently precise detail so as to be reproducible in control tests, carried
out at the request of the competent authority; any special apparatus and equipment which may be used shall be
described in adequate detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall be
supplemented, if necessary, by the method of preparation. In the case of test procedures included in the European
Pharmacopoeia or the pharmacopoeia of a Member State, this description may be replaced by a detailed reference to the
pharmacopoeia in question.

A. QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS

The particulars and documents which must accompany applications for marketing authorization, pursuant to Article
12(3)(c), shall be submitted in accordance with the following requirements.

1.

Qualitative particulars

(cid:145)Qualitative particulars(cid:146) of all the constituents of the medicinal product shall mean the designation or description
of:

(cid:151) the active substance(s),

(cid:151) the constituent(s) of the excipients, whatever their nature or the quantity used, including colouring matter,

preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances, etc,

(cid:151) the constituents, intended to be ingested or otherwise administered to animals, of the outer covering of the

medicinal products-capsules, gelatine capsules, etc.

These particulars shall be supplemented by any relevant data concerning the container and, where appropriate,
its manner of closure, together with details of devices with which the medicinal product will be used or
administered and which will be delivered with the medicinal product.

2.

The (cid:145)usual
notwithstanding the application of the other provisions of Article 12(3)(c):

to be used in describing the constituents of medicinal products,

terminology(cid:146),

shall mean,

(cid:151) in respect of substances which appear in the European Pharmacopoeia or,

in the national
pharmacopoeia of one of the Member States, the main title at the head of the monograph in question, with
reference to the pharmacopoeia concerned,

failing this,

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(cid:151) in respect of other substances, the international non-proprietary name recommended by the World Health
Organization (WHO), which may be accompanied by another non-proprietary name, or, failing these, the
exact scientific designation; substances not having an international non-proprietary name or an exact
scientific designation shall be described by a statement of how and from what
they were prepared,
supplemented, where appropriate, by any other relevant details,

(cid:151) in respect of colouring matter, designation by the (cid:145)E(cid:146) code assigned to them in Council Directive 78/25/EEC
of 12 December 1977 on the approximation of the rules of the Member States concerning the colouring
matters authorized for use in medicinal products (1).

3.

Quantitative particulars

3.1.

In order to give (cid:145)quantitative particulars(cid:146) of all the active substances of the medicinal products, it is necessary,
depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological
activity, either per dosage-unit or per unit of mass or volume, of each active substance.

Units of biological activity shall be used for substances which cannot be defined chemically. Where an
International Unit of biological activity has been defined by the World Health Organization, this shall be used.
Where no International Unit has been defined, the units of biological activity shall be expressed in such a way as
to provide unambiguous information on the activity of the substances.

Whenever possible, biological activity per units of mass or volume shall be indicated.

This information shall be supplemented:

(cid:151) in respect of injectable preparations, by the mass or units of biological activity of each active substance in
the usable volume of the product, after reconstitution, where

taking into account

the unit container,
appropriate,

(cid:151) in respect of medicinal products to be administered by drops, by the mass or units of biological activity of
each active substance contained in the number of drops corresponding to 1 ml or 1 g of the preparation,

(cid:151) in respect of syrups, emulsions, granular preparations and other pharmaceutical forms to be administered in
measured quantities, by the mass or units of biological activity of each active substance per measured
quantity.

3.2. Active substances present in the form of compounds or derivatives shall be described quantitatively by their total

mass, and if necessary or relevant, by the mass of the active entity or entities of the molecule.

3.3.

For medicinal products containing an active substance which is the subject of an application for marketing
authorization in any Member State for the first time, the quantitative statement of an active substance which is a
salt or hydrate shall be systematically expressed in terms of the mass of the active entity or entities in the
molecule. All subsequently authorized medicinal products in the Member States shall have their quantitative
composition stated in the same way for the same active substance.

4.

Development pharmaceutics

An explanation shall be provided with regard to the choice of composition, constituents and container and the
intended function of the excipients in the finished product. This explanation shall be supported by scientific data
on development pharmaceutics. The overage, with justification thereof, shall be stated.

B. DESCRIPTION OF THE MANUFACTURING METHOD

The description of the manufacturing method accompanying the application for marketing authorization pursuant to
Article 12(3)(d), shall be drafted in such a way as to give an adequate synopsis of the nature of the operations
employed.

For this purpose it shall include at least:

(cid:151) mention of the various stages of manufacture, so that an assessment can be made of whether the processes
employed in producing the pharmaceutical form might have produced an adverse change in the constituents,

(cid:151) in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity of the

finished product,

(cid:151) the actual manufacturing formula, with the quantitative particulars of all the substances used, the quantities of
excipients, however, being given in approximate terms in so far as the pharmaceutical form makes this necessary;
mention shall be made of any substances that may disappear in the course of manufacture; any overage shall be
indicated and justified,

(1) OJ L 11, 14.1.1978, p. 18. Directive as last amended by the 1985 Act of Accession.

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(cid:151) a statement of the stages of manufacture at which sampling is carried out for in-process control tests, where other
data in the documents supporting the application show such tests to be necessary for the quality control of the
finished product,

(cid:151) experimental studies validating the manufacturing process, where a non-standard method of manufacture is used or

where it is critical for the product,

(cid:151) for sterile products, details of the sterilization processes and/or aseptic procedures used.

C. CONTROL OF STARTING MATERIALS

1.

For the purposes of this paragraph, (cid:145)starting materials(cid:146) shall mean all the constituents of the medicinal product
and, if necessary, of its container, as referred to in Section A, point 1, above.

In the case of:

(cid:151) an active substance not described in the European Pharmacopoeia or in the pharmacopoeia of a Member State,

(cid:151) an active substance described in the European Pharmacopoeia or in the pharmacopoeia of a Member State
when prepared by a method liable to leave impurities not mentioned in the pharmacopoeial monograph and
for which the monograph is inappropriate to adequately control its quality,

from the applicant,

which is manufactured by a person different
the latter may arrange for the detailed
description of the manufacturing method, quality control during manufacture and process validation to be
supplied directly to the competent authorities by the manufacturer of the active substance. In this case, the
manufacturer shall however provide the applicant with all the data which may be necessary for the latter to take
responsibility for the medicinal product. The manufacturer shall confirm in writing to the applicant that he shall
ensure batch to batch consistency and not modify the manufacturing process or specifications without informing
the applicant. Documents and particulars supporting the application for such a change shall be supplied to the
competent authorities.

The particulars and documents accompanying the application for marketing authorization pursuant to Article
12(3)(i) and (j) and Article 13(1), shall include the results of the tests, including batch analyses particularly for
active substances, relating to quality control of all the constituents used. These shall be submitted in accordance
with the following provisions.

1.1.

Starting materials listed in pharmacopoeias

The monographs of the European Pharmacopoeia shall be applicable to all substances appearing in it.

In respect of other substances, each Member State may require observance of its own national pharmacopoeia
with regard to products manufactured in its territory.

Constituents fulfilling the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the
Member States shall be deemed to comply sufficiently with Article 12(3)(i). In this case the description of the
analytical methods may be replaced by a detailed reference to the pharmacopoeia in question.

However, where a starting material in the European Pharmacopoeia or in the pharmacopoeia of a Member State
has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these
impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described.

Colouring matter shall, in all cases, satisfy the requirements of Council Directive 78/25/EEC.

The routine tests carried out on each batch of starting materials must be as stated in the application for
marketing authorization. If tests other than those mentioned in the pharmacopoeia are used, proof must be
supplied that the starting materials meet the quality requirements of that pharmacopoeia.

In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national
pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent
authorities may request more appropriate specifications from the marketing authorization holder.

The competent authorities shall
inform the authorities responsible for the pharmacopoeia in question. The
marketing authorization holder shall provide the authorities of that pharmacopoeia with the details of the alleged
insufficiency and the additional specifications applied.

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In cases where a starting material is described neither in the European Pharmacopoeia nor in the pharmacopoeia of
a Member State, compliance with the monograph of a third country pharmacopoeia can be accepted; in such
cases, the applicant shall submit a copy of the monograph accompanied where necessary by the validation of the
test procedures contained in the monograph and by a translation where appropriate.

1.2.

Starting materials not in a pharmacopoeia

Constituents which are not given in any pharmacopoeia shall be described in the form of a monograph under
the following headings:

(a)

the name of the substance, meeting the requirements of Section A point 2, shall be supplemented by any
trade or scientific synonyms;

(b)

the definition of the substance, set down in a form similar to that used in the European Pharmacopoeia, shall
be accompanied by any necessary explanatory evidence, especially concerning the molecular structure where
it must be accompanied by an appropriate description of the method of synthesis. Where
appropriate;
substances can only be described by their manufacturing method, the description shall be sufficiently detailed
to characterise a substance which is constant both on its composition and in its effects;

(c) methods of identification may be described in the form of complete techniques as used for production of the

substance, and in the form of tests which ought to be carried out as a routine matter;

(d) purity tests shall be described in relation to the sum total of predictable impurities, especially those which
may have a harmful effect, and, if necessary, those which, having regard to the combination of substances to
which the application refers, might adversely affect the stability of the medicinal product or distort analytical
results;

(e) with regard to complex substances of plant or animal origin, a distinction must be made between the case
where multiple pharmacological effects render chemical, physical or biological control of the principal
components necessary, and the case of substances containing one or more groups of principles having
similar activity, in respect of which an overall method of assay may be accepted;

(f) when materials of animal origin are used, measures to ensure freedom from potentially pathogenic agents

shall be described;

(g) any special precautions that may be necessary during storage of the starting material and, if necessary, the

maximum period of storage before retesting shall be given.

1.3.

Physico-chemical characteristics liable to affect bioavailability

The following items of information concerning active substances, whether or not listed in the pharmacopoeias,
shall be provided as part of the general description of the active substances if the bio-availability of the medicinal
product depends on them:

(cid:151) crystalline form and solubility coefficients,

(cid:151) particle size, where appropriate after pulverization,

(cid:151) state of solvation,

(cid:151) oil/water coefficient of partition (1).

The first three indents are not applicable to substances used solely in solution.

2. Where source materials such as micro-organisms, tissues of either plant or animal origin, cells or fluids (including
blood) of human or animal origin or biotechnological cell constructs are used in the manufacture of veterinary
medicinal products, the origin and history of starting materials shall be described and documented.

The description of
include the manufacturing strategy, purification/inactivation
procedures with their validation and all in-process control procedures designed to ensure the quality, safety and
batch to batch consistency of the finished product.

the starting material shall

2.1. When cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage

level used for the production and beyond.

(1) The competent authorities may also request the pK/pH values if they think that this information is essential.

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2.2.

Seed materials, cell banks, pools of serum and other material of biological origin and, whenever possible, the
source materials from which they are derived shall be tested for adventitious agents.

If the presence of potentially pathogenic adventitious agents is inevitable, the material shall be used only when
further processing ensures their elimination and/or inactivation, and this shall be validated.

D.

SPECIFIC MEASURES CONCERNING THE PREVENTION OF THE TRANSMISSION OF ANIMAL SPONGIFORM
ENCEPHALOPATHIES

The applicant must demonstrate that the veterinary medical product is manufactured in accordance with the Note for
Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via veterinary medicinal
products and its updates, published by the European Commission in Volume 7 of its publication (cid:145)The rules governing
medicinal products in the European Community(cid:146).

E.

CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF THE MANUFACTURING PROCESS

The particulars and documents accompanying an application for marketing authorization, pursuant to Article 12(3)(i)
and (j) and also Article 13(1), shall include particulars relating to the product control tests that may be carried out at an
intermediate stage of the manufacturing process, with a view to ensuring the consistency of the technical characteristics
and the production process.

These tests are essential for checking the conformity of the medicinal product with the formula when, exceptionally, an
applicant proposes an analytical method for testing the finished product which does not include the assay of all the
active substances (or of all the excipient components subject to the same requirements as the active substances).

The same applies where the quality control of the finished product depends on in-process control tests, particularly if
the substance is essentially defined by its manufacturing method.

F.

1.

TESTS ON THE FINISHED PRODUCT

For the control of the finished product, a batch of a finished product comprises all the units of a pharmaceutical
form which are made from the same initial quantity of material and have undergone the same series of
manufacturing and/or sterilization operations or, in the case of a continuous production process, all the units
manufactured in a given period of time.

The application for marketing authorization shall list those tests which are carried out routinely on each batch of
finished product. The frequency of the tests which are not carried out routinely shall be stated. Release limits
shall be indicated.

The particulars and documents accompanying the application for marketing authorization pursuant to Article
12(3)(i) and (j) and also Article 13(1), shall include particulars relating to control tests on the finished product at
release. They shall be submitted in accordance with the following requirements.

The provisions of the general monographs of the European Pharmacopoeia, or failing that, of a Member State, shall
be applicable to all products defined therein.

test procedures and limits other

If
the European
Pharmacopoeia, or failing this, in the national pharmacopoeia of a Member State, are used, proof shall be supplied
that the finished product would, if tested in accordance with those monographs, meet the quality requirements of
that pharmacopoeia for the pharmaceutical form concerned.

than those mentioned in the general monographs of

1.1. General characteristics of the finished product

Certain tests of the general characteristics of a product shall always be included among the tests on the finished
product. These tests shall, wherever applicable, relate to the control of average masses and maximum deviations,
to mechanical, physical or microbiological tests, organoleptic characteristics, physical characteristics such as
density, pH, refractive index, etc. For each of these characteristics, standards and tolerance limits shall be specified
by the applicant in each particular case.

The conditions of the tests, where appropriate, the equipment/apparatus employed and the standards shall be
described in precise details whenever they are not given in the European Pharmacopoeia or the pharmacopoeia of
the Member States; the same shall apply in cases where the methods prescribed by such pharmacopoeias are not
applicable.

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Furthermore, solid pharmaceutical forms having to be administered orally shall be subjected to in vitro studies on
the liberation and dissolution rate of the active substance or substances; these studies shall also be carried out
where administration is by another means if the competent authorities of the Member State concerned consider
this necessary.

1.2.

Identification and assay of active substance(s)

Identification and assay of the active substance(s) shall be carried out either in a representative sample from the
production batch or in a number of dosage-units analysed individually.

Unless there is appropriate justification, the maximum acceptable deviation in the active substance content of the
finished product shall not exceed – 5 % at the time of manufacture.

On the basis of the stability tests, the manufacturer must propose and justify maximum acceptable tolerance
limits in the active substance content of the finished product up to the end of the proposed shelf-life.

In certain exceptional cases of particularly complex mixtures, where assay of active substances which are very
numerous or present in very low amounts would necessitate an intricate investigation difficult to carry out in
respect of each production batch, the assay of one or more active substances in the finished product may be
omitted, on the express condition that such assays are made at intermediate stages in the production process.
This relaxation may not be extended to the characterization of
the substances concerned. This simplified
technique shall be supplemented by a method of quantitative evaluation, enabling the competent authority to
have the conformity of the medicinal product with its specification verified after it has been placed on the
market.

An in vivo or in vitro biological assay shall be obligatory when physico-chemical methods cannot provide
adequate information on the quality of the product. Such an assay shall, whenever possible, include reference
materials and statistical analysis allowing calculation of confidence limits. Where these tests cannot be carried out
on the finished product, they may be performed at an intermediate stage, as late as possible in the manufacturing
process.

Where the particulars given in section B show that a significant overage of an active substance is employed in
the manufacture of the medicinal product, the description of the control tests on the finished product shall
include, where appropriate, the chemical and,
investigation of the
changes that this substance has undergone, and possibly the characterization and/or assay of the degradation
products.

if necessary, the toxico-pharmacological

1.3.

Identification and assay of excipient components

In so far as is necessary, the excipient components shall be subject at least to identification tests.

The test procedure proposed for identifying colouring matters must enable a verification to be made that such
matters appear in the list annexed to Directive 78/25/EEC.

An upper and lower limit test shall be obligatory in respect of preserving agents and an upper limit test for any
other excipient component liable to affect adversely physiological functions; an upper and lower limit test shall
be obligatory in respect of the excipient if it is liable to affect the bio-availability of an active substance, unless
bio-availability is guaranteed by other appropriate tests.

1.4.

Safety tests

from the toxico-pharmacological

tests submitted with the application for marketing authorization,
Apart
particulars of safety tests, such as sterility, bacterial endotoxin, pyrogenicity and local tolerance in animals shall
be included in the analytical particulars wherever such tests must be undertaken as a matter of routine in order
to verify the quality of the product.

G.

STABILITY TEST

The particulars and documents accompanying the application for marketing authorization pursuant to Article 12(3)(f)
and (i) shall be submitted in accordance with the following requirements.

A description shall be given of the investigations by which the shelf life, the recommended storage conditions and the
specifications at the end of the shelf life proposed by the applicant have been determined.

In the case of pre-mixes for medicated feedingstuffs, information shall also be given as necessary on the shelf life of the
medicated feedingstuffs manufactured from these pre-mixes in accordance with the recommended instructions for use.

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Where a finished product requires reconstitution prior to administration, details of the proposed shelf life for the
reconstituted product are required, supported by relevant stability data.

In the case of multi-dose vials, stability data shall be presented to justify a shelf life for the vial after it has been
punctured for the first time.

Where a finished product is liable to give rise to degradation products, the applicant must declare these and indicate
characterization methods and test procedures.

The conclusions shall contain the results of analyses, justifying the proposed shelf life under the recommended storage
conditions and the specifications of the finished product at the end of the shelf life of the finished product under these
recommended storage conditions.

The maximum acceptable level of degradation products at the end of shelf life shall be indicated.

A study of the interaction between product and container shall be submitted wherever the risk of such interaction is
regarded as possible, especially where injectable preparations or aerosols for internal use are concerned.

PART 3

Safety and residues testing

The particulars and documents which shall accompany the application for marketing authorization pursuant to Articles
12(3)(j) and 13(1) shall be submitted in accordance with the requirements below.

Member States shall ensure that the tests are carried out in accordance with the provisions relating to good laboratory
practice laid down by Council Directive 87/18/EEC of 18 December 1986 on the harmonization of laws, regulations
and administrative provisions relating to the application of
the principles of good laboratory practice and the
verification of their applications for tests on chemical substances (1) and Council Directive 88/320/EEC of 9 June 1988
on the inspection and verification of good laboratory practice (GLP) (2).

A.

SAFETY TESTING

C h a p t e r I

Performance of tests

1.

Introduction

The safety documentation shall show:

1.

2.

3.

the potential toxicity of the medicinal product and any dangerous or undesirable effects which may occur
under the proposed conditions of use in animals; these should be evaluated in relation to the severity of the
pathological condition concerned;

the potential harmful effects to man of residues of the veterinary medicinal product or substance in
foodstuffs obtained from treated animals and what difficulties these residues may create in the industrial
processing of foodstuffs;

the potential risks which may result from the exposure of human beings to the medicinal product, for
example during its administration to the animal;

4.

the potential risks for the environment resulting from the use of the medicinal product.

All results shall be reliable and valid generally. Whenever appropriate, mathematical and statistical procedures
shall be used in designing the experimental methods and in evaluating the results. Additionally, clinicians shall
be given information about the therapeutic potential of the product and about the hazards connected with its
use.

In some cases it may be necessary to test the metabolites of the parent compound where these represent the
residues of concern.

An excipient used in the pharmaceutical field for the first time shall be treated like an active substance.

(1) OJ L 15, 17.1.1987, p. 29. Directive as last amended by Commission Directive 1999/11/EC (OJ L 77, 23.3.1999, p. 8).
(2) OJ L 145, 11.6.1988, p. 35. Directive as last amended by Commission Decision 1999/12/EC (OJ L 77, 23.3.1999, p. 22).

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2.

Pharmacology

Pharmacological studies are of fundamental importance in clarifying the mechanisms by which the medicinal
product produces its therapeutic effects and therefore pharmacological studies conducted in experimental and
target species of animal should be included in Part 4.

However, pharmacological studies may also assist in the understanding of toxicological phenomena. Moreover,
where a medicinal product produces pharmacological effects in the absence of a toxic response, or at doses
lower than those required to elicit toxicity, these pharmacological effects shall be taken into account during the
evaluation of the safety of the medicinal product.

Therefore the safety documentation shall always be preceded by details of pharmacological
investigations
undertaken in laboratory animals and all relevant information observed during clinical studies in the target
animal.

3.

Toxicology

3.1.

Single-dose toxicity

Single-dose toxicity studies can be used to predict:

(cid:151) the possible effects of acute overdosage in the target species,

(cid:151) the possible effects of accidental administration to humans,

(cid:151) the doses which may usefully be employed in the repeat dose studies.

Single dose toxicity studies should reveal the acute toxic effects of the substance and the time course for their
onset and remission.

These studies should normally be carried out in at least two mammalian species. One mammalian species may
be replaced, if appropriate, by an animal species for which the medicinal product is intended. At least two
different routes of administration should normally be studied. One of these may be the same as, or similar to,
that proposed for the target species. If substantial exposure of the user of the medicinal product is anticipated,
for example by inhalation or dermal contact, these routes should be studied.

In order to reduce the number and suffering of the animals involved, new protocols for single dose toxicity
testing are continually being developed. Studies carried out in accordance with these new procedures when
properly validated will be accepted, as well as studies carried out in accordance with established internationally
recognized guidelines.

3.2.

Repeated-dose toxicity

Repeated-dose toxicity tests are intended to reveal any physiological and/or pathological changes induced by
repeated administration of the active substance or combination of active substances under examination, and to
determine how these changes are related to dosage.

In the case of substances or medicinal products intended solely for use in non food-producing animals, a
repeated dose toxicity study in one species of experimental animal will normally be sufficient. This study may be
replaced by a study conducted in the target animal. The frequency and route of administration, and the duration
of the study should be chosen having regard to the proposed conditions of clinical use. The investigator shall
give his reasons for the extent and duration of the trials and the dosages chosen.

In the case of substances or medicinal products intended for use in food producing animals, the study should be
conducted in at least two species, one of which should be a non-rodent. The investigator shall give his reasons
for the choice of species, having regard to the available knowledge of the metabolism of the product in animals
and man. The test substance shall be administered orally. The duration of the test shall be at least 90 days. The
investigator shall clearly state and give his reasons for the method and frequency of administration and the
length of the trials.

The maximum dose should normally be selected so as to bring harmful effects to light. The lowest dose level
should not produce any evidence of toxicity.

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Evaluation of
the toxic effects shall be based on observation of behaviour, growth, haematology and
tests, especially those relating to the excretory organs, and also on autopsy reports and
physiological
accompanying histological data. The choice and range of each group of tests depends on the species of animal
used and the state of scientific knowledge at the time.

In the case of new combinations of known substances which have been investigated in accordance with the
provisions of
the repeated-dose tests may, except where toxicity tests have demonstrated
potentiation or novel toxic effects, be suitably modified by the investigator, who shall submit his reasons for
such modifications.

this Directive,

3.3.

Tolerance in the target species

Details should be provided of any signs of intolerance which have been observed during studies conducted in
the target species in accordance with the requirements of Part 4, Chapter I, Section B. The studies concerned, the
dosages at which the intolerance occurred and the species and breeds concerned should be identified. Details of
any unexpected physiological changes should also be provided.

3.4.

Reproductive toxicity including teratogenicity

3.4.1. Study of the effects on reproduction

The purpose of this study is to identify possible impairment of male or female reproductive function or harmful
effects on progeny resulting from the administration of the medicinal products or substance under investigation.

In the case of substances or medicinal products intended for use in food-producing animals, the study of the
effects on reproduction shall be carried out in the form of a two-generation study on at least one species, usually
a rodent. The substance or product under investigation shall be administered to males and females at an
appropriate time prior to mating. Administration should continue until the weaning of the F2 generation. At
least three dose levels shall be used. The maximum dose should be selected so as to bring harmful effects to
light. The lowest dose level should not produce any evidence of toxicity.

Evaluation of the effects on reproduction shall be based upon fertility, pregnancy and maternal behaviour; the
suckling, growth and development of the F1 offspring from conception to maturity; the development of the F2
offspring to weaning.

3.4.2. Study of embryotoxic/fetotoxic effects including teratogenecity

In the case of substances or medicinal products intended for use in food producing animals, studies of
embryotoxic/fetotoxic effects, including teratogenicity, shall be carried out. These studies shall be carried out in
at least two mammalian species, usually a rodent and the rabbit. The details of the test (number of animals,
doses, time at which administered and criteria for the evaluation of results) shall depend on the state of scientific
knowledge at the time the application is lodged and the level of statistical significance which the results should
attain. The rodent study may be combined with the study of effects on reproductive function.

In the case of substances or medicinal products which are not intended for use in food producing animals, a
study of embryotoxic/fetotoxic effects, including teratogenicity, shall be required in at least one species, which
may be the target species, if the product is intended for use in animals which might be used for breeding.

3.5. Mutagenicity

Mutagenicity tests are intended to assess the potential of substances to cause transmissible changes in the genetic
material of cells.

Any new substance intended for use in veterinary medicinal products must be assessed for mutagenic properties.

The number and types of tests and the criteria for the evaluation of the results shall depend on the state of
scientific knowledge when the application is submitted.

3.6.

Carcinogenicity

Long term animal carcinogenicity studies will usually be required for substances to which human beings will be
exposed

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(cid:151) which have a close chemical analogy with known carcinogens,

(cid:151) which during mutagenicity testing produced results indicating a possibility of carcinogenic effects,

(cid:151) which have given rise to suspect signs during toxicity testing.

The state of scientific knowledge at the time the application is submitted shall be taken into account when
designing carcinogenicity studies and evaluating their results.

3.7.

Exceptions

Where a medicinal product is intended for topical use, systemic absorption shall be investigated in the target
species of animal. If it is proved that systemic absorption is negligible, the repeated dose toxicity tests, the tests
for reproductive toxicity and the carcinogenicity tests may be omitted, unless:

(cid:151) under the conditions of use laid down, oral ingestion of the medicinal product by the animal is to be

expected, or

(cid:151) the medicinal particular may enter

foodstuffs obtained from the

treated animal

(intramammary

preparations).

4.

Other requirements

4.1.

Immunotoxicity

Where the effects observed during repeated dose studies in animals include specific changes in lymphoid organ
weights and/or histology and changes in the cellularity of
lymphoid tissues, bone marrow or peripheral
leukocytes, the investigator shall consider the need for additional studies of the effects of the product on the
immune system.

The state of scientific knowledge at the time the application is submitted shall be taken into account when
designing such studies and evaluating their results.

4.2. Microbiological properties of residues

4.2.1. Potential effects on the human gut flora

The microbiological risk presented by residues of anti-microbial compounds for the human intestinal flora shall
be investigated in accordance with the state of scientific knowledge at the time the application is submitted.

4.2.2. Potential effects on the microorganisms used for industrial food processing

In certain cases, it may be necessary to carry out tests to determine whether residues cause difficulties affecting
technological processes in industrial foodstuff processing.

4.3. Observations in humans

Information shall be provided showing whether the constituents of the veterinary medicinal product are used as
medicinal products in human therapy; if this is so, a report should be made on all the effects observed (including
adverse reactions) in humans and on their cause, to the extent that they may be important for the assessment of
the veterinary medicinal product, where appropriate in the light of trial results of bibliographical documents;
where constituents of the veterinary medicinal products are themselves not used or are no longer used as
medicinal products in human therapy, the reasons should be stated.

5.

Ecotoxicity

5.1.

The purpose of the study of the ecotoxicity of a veterinary medicinal product is to assess the potential harmful
effects which the use of the product may cause to the environment and to identify any precautionary measures
which may be necessary to reduce such risks.

5.2. An assessment of ecotoxicity shall be compulsory for any application for marketing authorization for a

veterinary medicinal product other than applications submitted in accordance with Articles 12(3)(j) and 13(1).

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5.3.

This assessment shall normally be conducted in two phases.

In the first phase, the investigator shall assess the potential extent of exposure to the environment of the
product, its active substances or relevant metabolites, taking into account:

(cid:151) the target species, and the proposed pattern of use (for example, mass-medication or individual animal

medication),

(cid:151) the method of administration, in particular the likely extent to which the product will enter directly into

environmental systems,

(cid:151) the possible excretion of the product, its active substances or relevant metabolites into the environment by

treated animals; persistence in such excretia,

(cid:151) the disposal of unused or waste product.

5.4.

In a second phase, having regard to the extent of exposure of the product to the environment, and the available
information about the physical/chemical, pharmacological and/or toxicological properties of the compound
which has been obtained during the conduct of the other tests and trials required by this Directive, the
investigator shall then consider whether further specific investigation of the effects of the product on particular
eco-systems is necessary.

5.5. As appropriate, further investigation may be required of:

(cid:151) fate and behaviour in soil,

(cid:151) fate and behaviour in water and air,

(cid:151) effects on aquatic organisms,

(cid:151) effects on other non-target organisms.

These further investigations shall be carried out in accordance with the test protocols laid down in Annex V of
Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations and administrative
provisions relating to the classification, packaging and labelling of dangerous substances (1), or where an end
point
in accordance with other internationally recognized
protocols on the veterinary medicinal product and/or the active substance(s) and/or the excreted metabolites as
appropriate. The number and types of tests and the criteria for their evaluation shall depend upon the state of
scientific knowledge at the time the application is submitted.

is not adequately covered by these protocols,

C h a p t e r I I

Presentation of particulars and documents

As in any scientific work, the dossier of safety tests shall include the following:

(a) an introduction defining the subject, accompanied by any useful bibliographical references;

(b)

the detailed identification of the substance under review, including:

(cid:151) international non-proprietary name (INN),

(cid:151) International Union of Pure and Applied Chemistry Name (IUPAC),

(cid:151) Chemical Abstract Service (CAS) number,

(cid:151) therapeutical and pharmacological classification,

(cid:151) synonyms and abbreviations,

(cid:151) structural formula,

(cid:151) molecular formula,

(cid:151) molecular weight,

(cid:151) degree of impurity,

(cid:151) qualitative and quantitative composition of impurities,

(1) OJ 196, 16.8.1967, p. 1. Directive as last amended by Commission Directive 2000/33/EC (OJ L 136, 8.6.2000, p. 90).

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(cid:151) description of physical properties,

(cid:151) melting point,

(cid:151) boiling point,

(cid:151) vapour pressure,

(cid:151) solubility in water and organic solvents expressed in g/l, with indication of temperature,

(cid:151) density,

(cid:151) spectra of refraction, rotation, etc;

(c) a detailed experimental protocol giving the reasons for any omission of certain tests listed above, a description of
the methods, apparatus and materials used, details of the species, breed or strain of animals, where they were
obtained, their number and the conditions under which they were housed and fed, stating inter alia whether they
were free from specific pathogens (SPF);

(d) all the results obtained, whether favourable or unfavourable. The original data should be described in sufficient
detail to allow the results to be critically evaluated independently of their interpretation by the author. By way of
explanation, the results may be accompanied by illustrations;

(e) a statistical analysis of the results, where such is called for by the test programme, and variance within the data;

(f)

an objective discussion of the results obtained, leading to conclusions on the safety of the substance, on its safety
margin in the test animal and the target animal and its possible side-effects, on its fields of application, on its
active dose levels and any possible incompatibilities;

(g) a detailed description and a thorough discussion of the results of the study of the safety of residues in food, and its
relevance for the evaluation of potential risks presented by residues to humans. This discussion shall be followed
by proposals to ensure that any danger to man is eliminated by applying internationally recognized assessment
criteria, for example: no observed effect level in animals, proposals for a choice of safety factor and for acceptable
daily intake (ADI);

(h) a thorough discussion of any risks for persons preparing the medicinal product or administering it to animals,

followed by proposals for appropriate measures to reduce such risks;

(i)

(j)

a thorough discussion of the risks which use of the veterinary medicinal product under the practical conditions
proposed may represent for the environment followed by appropriate proposals to reduce such risks;

all information necessary to acquaint the clinician as fully as possible with the utility of the proposed product. The
discussion will be supplemented by suggestions as to side-effects and possible treatment for acute toxic reactions in
animals to which the product is to be administered;

(k) a concluding expert report which provides a detailed critical analysis of the information referred to above in the
light of the state of scientific knowledge at the time the application is submitted together with a detailed summary
of all the results of the relevant safety tests and precise bibliographical references.

B. RESIDUE TESTING

1.

Introduction

C h a p t e r I

Performance of tests

For the purposes of this Directive, (cid:145)residues(cid:146) means all active substances or metabolites thereof which remain in
meat or other foodstuffs produced from the animal to which the medicinal product in question has been
administered.

The purpose of studying residues is to determine whether, and if so under what conditions and to what extent,
residues persist in foodstuffs produced from treated animals and to ascertain the withdrawal periods to be adhered
to in order to obviate any hazard to human health and/or difficulties in the industrial processing of foodstuffs.

Assessment of the hazard due to residues entails establishing whether residues are present in the animals treated
under recommended conditions of use and investigating the effects of those residues.

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In the case of veterinary medicinal products
documentation shall show:

intended for use in food-producing animals,

the residue

1.

2.

3.

to what extent, and how long, do residues of the veterinary medicinal product or its metabolites persist in the
tissues of the treated animal or foodstuffs obtained therefrom;

that in order to prevent any risk to the health of the consumer of foodstuffs of treated animals, or difficulties
in the industrial processing of foodstuffs, it is possible to establish realistic withdrawal periods which can be
observed under practical farming conditions;

that practical analytical methods suitable for routine use are available to verify compliance with the
withdrawal period.

2. Metabolism and residue kinetics

2.1. Pharmacokinetics (absorption, distribution, biotransformation, excretion)

The purpose of pharmacokinetic studies with respect to residues of veterinary medicinal products is to evaluate
the absorption, distribution, biotransformation and excretion of the product in the target species.

The final product, or a formulation which is bioequivalent, shall be administered to the target species at the
maximum recommended dose.

Having regard to the method of administration, the extent of absorption of the medicinal product shall be fully
described. If it is demonstrated that systemic absorption of products for topical application is negligible, further
residue studies will not be required.

The distribution of the medicinal product in the target animal shall be described; the possibility of plasma protein
binding, or passage into milk or eggs and of the accumulation of lipophilic compounds shall be considered.

The pathways for the excretion of the product from the target animal shall be described. The major metabolites
shall be identified and characterised.

2.2. Depletion of residues

The purposes of these studies, which measure the rate at which residues deplete in the target animal after the last
administration of the medicinal product, is to permit the determination of withdrawal periods.

At varying times after the test animal has received the final dose of the medicinal product, the quantities of
residues present shall be determined by appropriate physical, chemical or biological methods; the technical
procedures and the reliability and sensitivity of the methods employed shall be specified.

3.

Routine analytical method for the detection of residues

Analytical procedures shall be proposed which can be carried out in the course of a routine examination and
which have a level of sensitivity such as to enable violations of legally permitted maximum residue limits to be
detected with certainty.

The analytical method proposed shall be described in detail. It shall be validated and shall be sufficiently rugged
for use under normal conditions of routine monitoring for residues.

The following characteristics shall be described:

(cid:151) specificity,

(cid:151) accuracy, including sensitivity,

(cid:151) precision,

(cid:151) limit of detection,

(cid:151) limit of quantitation,

(cid:151) practicability and applicability under normal laboratory conditions,

(cid:151) susceptibility to interference.

The suitability of the analytical method proposed shall be evaluated in the light of the state of scientific and
technical knowledge at the time the application is submitted.

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C h a p t e r I I

Presentation of particulars and documents

As in any scientific work, the dossier of residue tests shall include the following:

(a) an introduction defining the subject, accompanied by any useful bibliographical references;

(b) a detailed identification of the medicinal, including:

(cid:151) composition,

(cid:151) purity,

(cid:151) batch identification,

(cid:151) relationship to the final product,

(cid:151) specific activity and radio-purity of labelled substances,

(cid:151) position of labelled atoms in the molecule;

(c) a detailed experimental protocol giving the reasons for any omission of certain tests listed above, a description of
the methods, apparatus and materials used, details of the species, breed or strain of animals, where they were
obtained, their number and the conditions under which they were housed and fed;

(d) all the results obtained, whether favourable or unfavourable. The original data should be described in sufficient
detail to allow the results to be critically evaluated independently of their interpretation by the author. The results
may be accompanied by illustrations;

(e) a statistical analysis of the results, where such is called for by the test programme, and variance within the data;

(f)

an objective discussion of the results obtained, followed by proposals for maximum residue limits for the active
substances contained in the product, specifying the marker residue and target tissues concerned, and proposals
concerning the withdrawal periods necessary to ensure that no residues which might constitute a hazard for
consumers are present in foodstuffs obtained from treated animals;

(g) a concluding expert report which provides a detailed critical analysis of the information referred to above in the
light of the state of scientific knowledge at the time the application is submitted together with a detailed summary
of the results of the residue tests and precise bibliographical references.

PART 4

Pre-clinical and clinical testing

The particulars and documents which shall accompany applications for marketing authorizations pursuant to Articles
12(3)(j) and 13(1) shall be submitted in accordance with the provisions of this Part.

C h a p t e r I

Pre-clinical requirements

Pre-clinical studies are required to establish the pharmacological activity and the tolerance of the product.

A.

PHARMACOLOGY

A.1. Pharmacodynamics

The study of pharmacodynamics shall follow two distinct lines of approach:

First, the mechanism of action and the pharmacological effects on which the recommended application in practice is
based shall be adequately described. The results shall be expressed in quantitative terms (using, for example, dose-effect
curves, time-effect curves, etc.) and, wherever possible, in comparison with a substance the activity of which is well
known. Where a higher efficacy is being claimed for an active substance, the difference shall be demonstrated and
shown to be statistically significant.

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Secondly, the investigator shall give an overall pharmacological assessment of the active substance, with special
reference to the possibility of side-effects. In general, the main functions shall be investigated.

The investigator shall identify the effect of the route of administration, formulation, etc, on the pharmacological activity
of the active substance.

The investigations shall be intensified where the recommended dose approaches that
reactions.

liable to produce adverse

The experimental techniques, unless they are standard procedures, shall be described in such detail as to allow them to
be reproduced, and the investigator shall establish their validity. The experimental results shall be set out clearly and,
for certain types of tests, their statistical significance quoted.

Unless good reasons are given to the contrary, any quantitative modification of responses resulting from repeated
administration of the substance shall also be investigated.

Medicinal combinations may be prompted either on pharmacological grounds or by clinical indications. In the first
case, the pharmacodynamic and/or pharmacokinetic studies shall demonstrate those interactions which might make the
combination itself of value in clinical use.
In the second case, where scientific justification for the medicinal
combination is sought through clinical experimentation, the investigation shall determine whether the effects expected
from the combination can be demonstrated in animals and, at least, the importance of any adverse reactions shall be
checked. If a combination includes a novel active substance, the latter shall have been previously studied in depth.

A.2. Pharmacokinetics

Basic pharmacokinetic information concerning a new active substance is generally useful in the clinical context.

Pharmacokinetic objectives can be divided into two main areas:

(i) descriptive pharmacokinetics leading to the evaluation of basic parameters such as body clearance, volume(s) of

distribution, mean residence time, etc;

(ii) use of these parameters to investigate the relationships between dosage regimen, plasma and tissue concentration

and pharmacologic, therapeutic or toxic effects.

In target species, pharmacokinetic studies are, as a rule, necessary in order to employ drugs with the greatest possible
efficacy and safety. Such studies are especially useful to assist the clinician in establishing dosage regimens (route and
site of administration, dose, dosing interval, number of administrations, etc.) and to adopt dosage regimens according
to certain population variables (e.g. age, disease). Such studies can be more efficient in number of animals and generally
provide more information than classical dose titration studies.

In the case of new combinations of known substances which have been investigated in accordance with the provisions
of this Directive, pharmacokinetic studies of the fixed combination are not required if it can be justified that the
administration of the active substances as a fixed combination does not change their pharmacokinetic properties.

A.2.1. Bioavailability/bioequivalence

Appropriate bioavailability studies shall be undertaken to establish bioequivalence:

(cid:151) when comparing a reformulated medicinal product with the existing one,

(cid:151) when comparing a new method or route of administration with an established one,

(cid:151) in all cases referred to in Article 13(1).

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B. TOLERANCE IN THE TARGET SPECIES OF ANIMAL

The purpose of this study, which shall be carried out with all animal species for which the medicinal product is
intended, is to carry out in all such animal species local and general tolerance trials designed to establish a tolerated
dosage wide enough to allow an adequate safety margin and the clinical symptoms of
intolerance using the
recommended route or routes, in so far as this may be achieved by increasing the therapeutic dose and/or the duration
of treatment. The report on the trials shall contain as many details as possible of the expected pharmacological effects
and the adverse reactions; the latter shall be assessed with due regard to the fact that the animals used may be of very
high value.

The medicinal product shall be administered at least via the recommended route of administration.

C. RESISTANCE

Data on the emergence of resistant organisms are necessary in the case of medicinal products used for the prevention
or treatment of infectious diseases or parasitic infestations in animals.

C h a p t e r I I

Clinical requirements

1. General principles

The purposes of clinical trials are to demonstrate or substantiate the effect of the veterinary medicinal product after
administration of the recommended dosage, to specify its indications and contra-indications according to species,
age, breed and sex, its directions for use, any adverse reactions which it may have and its safety and tolerance
under normal conditions of use.

Unless justified, clinical trials shall be carried out with control animals (controlled clinical trials). The effect
obtained should be compared with a placebo or with absence of treatment and/or with the effect of an authorized
medicinal product known to be of therapeutic value. All the results obtained, whether positive or negative, shall be
reported.

The methods used to make the diagnosis shall be specified. The results shall be set out by making use of
quantitative or conventional clinical criteria. Adequate statistical methods shall be used and justified.

In the case of a veterinary medicinal product intended primarily for use as a performance enhancer, particular
attention shall be given to:

(cid:151) the yield of animal produce,

(cid:151) the quality of animal produce (organoleptic, nutritional, hygienic and technological qualities),

(cid:151) nutritional efficiency and growth of animal,

(cid:151) the general status of health of the animal.

Experimental data shall be confirmed by data obtained under practical field conditions.

in respect of particular therapeutic indications, the applicant can show that he is unable to provide

Where,
comprehensive data on therapeutic effect because:

(a)

the indications for which the medicinal product in question is intended are encountered so rarely that the
applicant cannot reasonably be expected to provide comprehensive evidence;

(b)

in the present state of scientific knowledge, comprehensive information cannot be provided;

the marketing authorization may only be granted subject to the following conditions:

(a)

the medicinal product in question is to be supplied on veterinary prescription only and may, in certain cases,
be administered only under strict veterinary supervision;

(b)

the package insert and any other information must draw the attention of the veterinary practitioner to the fact
that, in certain specified respects, the particulars available concerning the medicinal product in question are as
yet incomplete.

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2. Performance of trials

All veterinary clinical trials shall be conducted in accordance with a fully considered detailed trial protocol which
shall be recorded in writing prior to commencement of the trial. The welfare of the trial animals shall be subject to
veterinary supervision and shall be taken fully into consideration during the elaboration of any trial protocol and
throughout the conduct of the trial.

Pre-established systematic written procedures for the organization, conduct, data collection, documentation and
verification of clinical trials shall be required.

Before the commencement of any trial, the informed consent of the owner of the animals to be used in the trial
shall be obtained and documented.
the
consequences of participation in the trial for the subsequent disposal of treated animals or for the taking of
foodstuffs from treated animals. A copy of this notification, countersigned and dated by the animal owner, shall be
included in the trial documentation.

the animal owner shall be informed in writing of

In particular,

Unless the trial is conducted with a blind design, the provisions of Articles 58, 59 and 60 concerning the labelling
of veterinary medicinal products shall apply by analogy to the labelling of formulations intended for use in
veterinary clinical trials. In all cases, the words (cid:145)for veterinary clinical trial use only(cid:146) shall appear prominently and
indelibly upon the labelling.

C h a p t e r I I I

Particulars and documents

As in any scientific work, the dossier on efficacy shall include an introduction defining the subject accompanied by any
useful bibliographical documentation.

All pre-clinical and clinical documentation must be sufficiently detailed to enable an objective judgement to be made.
All studies and trials must be reported, whether favourable or unfavourable to the applicant.

1.

Records of pre-clinical observations

Wherever possible, particulars shall be given of the results of:

(a)

tests demonstrating pharmacological actions;

(b)

tests demonstrating the pharmacological mechanisms underlying the therapeutic effect;

(c)

tests demonstrating the main pharmacokinetic processes.

Should unexpected results occur during the course of the tests, these should be detailed.

Additionally the following particulars shall be provided in all pre-clinical studies:

(a) a summary;

(b) a detailed experimental protocol giving a description of the methods, apparatus and materials used, details
such as species, age, weight, sex, number, breed or strain of animals, identification of animals, dose, route
and schedule of administration;

(c) a statistical analysis of the results where relevant;

(d) an objective discussion of the results obtained,

leading to conclusions on the safety and efficacy of the

product.

Total or partial omission of these data must be explained.

2.1. Records of clinical observations

All the particulars shall be supplied by each of the investigators on individual record-sheets in the case of
individual treatment and collective record-sheets in the case of collective treatment.

The particulars supplied shall take the following form:

(a) name, address, function and qualifications of investigator in charge;

(b) place and date of treatment; name and address of owner of the animals;

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(c) details of the trial protocol giving a description of the methods used, including methods of randomization
and blinding, details such as the route of administration, schedule of administration, the dose, identification
of trial animals, species, breeds or strains, age, weight, sex, physiological status;

(d) method of rearing and feeding, stating the composition of the feed and the nature and quantity of any

additives contained in the feed;

(e) case history (as full as possible), occurrence and course of any inter-current diseases;

(f) diagnosis and means used to make it;

(g)

symptoms and severity of the disease, if possible according to conventional criteria;

(h)

the precise identification of the clinical trial formulation used in the trial;

(i) dosage of the medicinal product, method, route and frequency of administration and precautions, if any,

taken during administration (duration of injection, etc.);

(j)

duration of treatment and period of subsequent observation;

(k) all details concerning medicinal products (other than that under study) which have been administered during
the period of examination, either prior to or concurrently with the test product and, in the latter case, details
of the interactions observed;

(l)

all results of the clinical trials (including unfavourable or negative results) with a full statement of the clinical
observations and the results of the objective tests of activity (laboratory analyses, physiological tests), required
to evaluate the application; the techniques used must be specified, and the significance of any variations in
the results explained (e.g. variance in method, variance between individuals or the effects of the medication);
demonstration of the pharmacodynamic effect in animals shall not in itself suffice to justify conclusions
concerning any therapeutic effect;

(m) all particulars of any unintended effects, whether harmful or not, and of any measures taken in consequence;

the cause-and-effect relationship shall be investigated if possible;

(n) effect of animals’ performance (e.g. egg-laying, milk production and reproductive function);

(o) effects on the quality of foodstuffs obtained from treated animals, particularly in the case of medicinal

products intended for use as performance enhancers;

(p) a conclusion on each individual case or, where collective treatment is concerned, on each collective case.

Omission of one or more items (a) to (p) shall be justified.

The marketing authorization holder shall make all necessary arrangements to ensure that the original documents,
which formed the basis of the data supplied, are kept for at least five years after the veterinary medicinal product
is no longer authorized.

2.2. Summary and conclusions of clinical observations

In respect of each clinical trial, the clinical observations shall be summarized in a synopsis of the trials and the
results thereof, indicating in particular:

(a)

the number of controls, the number of animals treated either individually or collectively, with a breakdown
according to species, breed or strain, age and sex;

(b)

the number of animals withdrawn prematurely from the trials and the reasons for such withdrawal;

(c)

in the case of control animals, whether they have:

(cid:151) received no treatment;

(cid:151) received a placebo;

(cid:151) received another authorized medicinal product of known effect;

(cid:151) received the active substance under investigation in a different formulation or by a different route;

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(d)

the frequency of observed adverse reactions;

(e) observations as to the effect on performance (e.g. egg-laying, milk production, reproductive function and food

quality);

(f) details concerning test animals which may be at increased risk owing to their age, their mode of rearing or
feeding, or the purpose for which they are intended, or animals the physiological or pathological condition of
which requires special consideration;

(g) a statistical evaluation of the results, when this is called for by the test programme.

Finally, the investigator shall draw general conclusions from the experimental evidence, expressing his opinion on
the harmlessness of the medicinal product under the proposed conditions of use, its therapeutic effect and any
useful information relating to indications and contra-indications, dosage and average duration of treatment and
where appropriate, any interactions observed with other medicinal products or feed additives as well as any
special precautions to be taken during treatment and the clinical symptoms of overdosage.

In the case of fixed combination products, the investigator shall also draw conclusions concerning the safety and
the efficacy of the product when compared with the separate administration of the active substances involved.

3.

Concluding expert report

The concluding expert report shall provide a detailed critical analysis of all
the pre-clinical and clinical
documentation in the light of the state of scientific knowledge at the time the application is submitted together
with a detailed summary of the results of the tests and trials submitted and precise bibliographic references.

Requirements for immunological veterinary medicinal products

TITLE II

Without prejudice to the specific requirements laid down by Community legislation for the control and eradication of
animal desease, the following requirements shall apply to immunological veterinary medicinal products.

PART 5

Summary of the dossier

A.

ADMINISTRATIVE DATA

The immunological veterinary medicinal product which is the subject of the application shall be identified by name and
by name of the active substances, together with the strength and pharmaceutical form, the method and route of
administration, and a description of the final sales presentation of the product.

The name and address of the applicant shall be given, together with the name and address of the manufacturer and the
sites involved in the different stages of manufacture (including the manufacturer of the finished product and the
manufacturer(s) of the active substance(s)) and where relevant the name and address of the importer.

The applicant shall identify the number and titles of volumes of documentation submitted in support of the application
and indicate what samples, if any, are also provided.

Annexed to the administrative data shall be copies of a document showing that the manufacturer is authorized to
produce immunological veterinary medicinal products, as defined in Article 44 (with a brief description of
the
production site). Moreover, the list of organisms handled at the production site shall be given.

The applicant shall submit a list of countries in which authorization has been granted, copies of all the summaries of
product characteristics in accordance with Article 14 as approved by Member States and a list of countries in which an
application has been submitted.

B.

SUMMARY OF PRODUCT CHARACTERISTICS

The applicant shall propose a summary of the product characteristics, in accordance with Article 14.

In addition the applicant shall provide one or more specimens or mock-ups of
immunological veterinary medicinal product, together with a package insert, where one is required.

the sales presentation of

the

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C.

EXPERT REPORTS

In accordance with Article 15(2) and (3) expert reports must be provided on all aspects of the documentation.

Each expert report shall consist of a critical evaluation of the various tests and/or trials, which have been carried out in
accordance with this Directive, and bring out all the data relevant for evaluation. The expert shall give his opinion as to
whether sufficient guarantees have been provided as to the quality, safety and efficacy of the product concerned. A
factual summary is not sufficient.

All important data shall be summarized in an appendix to the expert report, whenever possible in tabular or graphic
form. The expert report and the summaries shall contain precise cross references to the information contained in the
main documentation.

Each expert report shall be prepared by a suitably qualified and experienced person. It shall be signed and dated by the
expert, and attached to the report shall be brief
training and
occupational experience of the expert. The professional relationship of the expert to the applicant shall be declared.

the educational background,

information about

Analytical (physico-chemical, biological or microbiological) tests of immunological veterinary medicinal
products

PART 6

test procedures used shall correspond to the state of scientific progress at

All
procedures; results of the validation studies shall be provided.

the time and shall be validated

All the test procedure(s) shall be described in sufficiently precise detail so as to be reproducible in control tests, carried
out at the request of the competent authority; any special apparatus and equipment which may be used shall be
described in adequate detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall be
supplemented,
if necessary, by the manufacturing method. In the case of test procedures included in the European
Pharmacopoeia or the pharmacopoeia of a Member State, this description may be replaced by a detailed reference to the
pharmacopoeia in question.

A. QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS

The particulars and documents which must accompany applications for marketing authorization, pursuant to Article
12(3)(c), shall be submitted in accordance with the following requirements.

1. Qualitative particulars

(cid:145)Qualitative particulars(cid:146) of all the constituents of the immunological veterinary medicinal product shall mean the
designation or description of:

(cid:151) the active substance(s),

(cid:151) the constituents of the adjuvants,

(cid:151) the constituent(s) of the excipients, whatever their nature or the quantity used,

including preservatives,

stabilisers, emulsifiers, colouring matter, flavouring, aromatic substances, markers, etc.,

(cid:151) the constituents of the pharmaceutical form administered to animals.

These particulars shall be supplemented by any relevant data concerning the container and, where appropriate, its
manner of closure, together with details of devices with which the immunological veterinary medicinal product
will be used or administered and which will be delivered with the medicinal product.

2.

The (cid:145)usual terminology(cid:146), to be used in describing the constituents of immunological veterinary medicinal products,
shall mean, notwithstanding the application of the other provisions of Article 12(3)(c):

(cid:151) in respect of substances which appear in the European Pharmacopoeia or,

in the national
pharmacopoeia of one of the Member States, the main title of the monograph in question, which will be
obligatory for all such substances, with reference to the pharmacopoeia concerned,

failing this,

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(cid:151) in respect of other substances, the international non-proprietary name recommended by the World Health
Organization, which may be accompanied by another non-proprietary name or, failing these, the exact
scientific designation; substances not having an international non-proprietary name or an exact scientific
designation shall be described by a statement of how and from what they were prepared, supplemented,
where appropriate, by any other relevant details,

(cid:151) in respect of colouring matter, designation by the (cid:145)E(cid:146) code assigned to them in Directive 78/25/EEC.

3. Quantitative particulars

In order to give the (cid:145)quantitative particulars(cid:146) of the active substances of an immunological veterinary medicinal
product, it is necessary to specify whenever possible the number of organisms, the specific protein content, the
mass, the number of International Units (IU) or units of biological activity, either per dosage-unit or volume, and
with regard to the adjuvant and to the constituents of the excipients, the mass or the volume of each of them,
with due allowance for the details provided in section B.

Where an International Unit of biological activity has been defined, this shall be used.

The units of biological activity for which no published data exist shall be expressed in such a way as to provide
unambiguous information on the activity of the ingredients, e.g. by stating the immunological effect on which the
method of determining the dose is based.

4.

Development pharmaceutics

An explanation shall be provided with regard to the composition, components and containers, supported by
scientific data on development pharmaceutics. The overage, with justification thereof, shall be stated. The efficacy
of any preservative system shall be demonstrated.

B.

DESCRIPTION OF MANUFACTURING METHOD OF THE FINISHED PRODUCT

The description of the manufacturing method accompanying the application for marketing authorization pursuant to
Article 12(3)(d), shall be drafted in such a way as to give an adequate description of the nature of the operations
employed.

For this purpose the description shall include at least:

(cid:151) the various stages of manufacture (including purification procedures) so that an assessment can be made of the
reproducibility of the manufacturing procedure and of the risks of adverse effects on the finished products, such as
microbiological contamination,

(cid:151) in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity and

consistency of each batch of the finished product,

(cid:151) mention of substances which cannot be recovered in the course of manufacture,

(cid:151) the details of the blending, with the quantitative particulars of all the substances used,

(cid:151) a statement of the stage of manufacture at which sampling is carried out for in-process control tests.

C.

PRODUCTION AND CONTROL OF STARTING MATERIALS

For the purposes of
the
immunological veterinary medicinal product. Culture media used for the production of the active substance are
considered as one single starting material.

this paragraph (cid:145)starting materials(cid:146) means all components used in the production of

In the case of:

(cid:151) an active substance not described in the European Pharmacopoeia or in the pharmacopoeia of a Member State,

or

(cid:151) an active substance described in the European Pharmacopoeia or in the pharmacopoeia of a Member State when
prepared by a method liable to leave impurities not mentioned in the pharmacopoeial monograph and for which
the monograph is inappropriate to adequately control its quality,

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which is manufactured by a person different from the applicant, the latter may arrange for the detailed description of
the manufacturing method, quality control during manufacture and process validation to be supplied directly to the
competent authorities by the manufacturer of the active substance. In this case, the manufacturer shall however provide
the applicant with all the data which may be necessary for the latter to take responsibility for the medicinal product.
The manufacturer shall confirm in writing to the applicant that he shall ensure batch-to-batch consistency and not
modify the manufacturing process or specifications without
informing the applicant. Documents and particulars
supporting the application for such a change shall be supplied to the competent authorities.

The particulars and documents accompanying the application for marketing authorization pursuant to Article 12(3)(i)
and (j) and Article 13(1) shall include the results of the tests relating to quality control of all the components used and
shall be submitted in accordance with the following provisions.

1.

Starting materials listed in pharmacopoeias

The monographs of the European Pharmacopoeia shall be applicable to all substances appearing in it.

In respect of other substances, each Member State may require observance of its own national pharmacopoeia
with regard to products manufactured in its territory.

Components fulfilling the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the
Member States shall be deemed to comply sufficiently with Article 12(3)(i). In this case the description of the
analytical methods may be replaced by a detailed reference to the pharmacopoeia in question.

Reference to pharmacopoeias of third countries may be permitted in cases where the substance is described
neither in the European Pharmacopoeia nor in the national pharmacopoeia concerned; in that case the monograph
shall be submitted, accompanied where necessary by a translation for which the applicant will be responsible.

Colouring matter shall, in all cases, satisfy the requirements of Council Directive 78/25/EEC.

The routine tests carried out on each batch of starting materials must be as stated in the application for
marketing authorization. If tests other than those mentioned in the pharmacopoeia are used, proof must be
supplied that the starting materials meet the quality requirements of that pharmacopoeia.

In cases where a specification or other provisions contained in a monograph of the European Pharmacopoeia or in
the national pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the
competent authorities may request more appropriate specifications
for marketing
authorization.

from the applicant

The competent authorities shall
inform the authorities responsible for the pharmacopoeia in question. The
applicant for marketing authorization shall provide the authorities of that pharmacopoeia with the details of the
alleged insufficiency and the additional specifications applied.

In cases where a starting material is described neither in the European Pharmacopoeia nor in the pharmacopoeia of
a Member State, compliance with the monograph of a third country pharmacopoeia can be accepted; in such
cases, the applicant shall submit a copy of the monograph accompanied where necessary by the validation of the
test procedures contained in the monograph and by a translation where appropriate. For active ingredients,
demonstration of the ability of the monograph adequately to control their quality shall be presented.

2.

Starting materials not listed in a pharmacopoeia

2.1.

Starting materials of biological origin

The description shall be given in the form of a monograph.

Whenever possible, vaccine production shall be based on a seed lot system and on established cell banks. For the
production of immunological veterinary medicinal products consisting of serums, the origin, general health and
immunological status of the producing animals shall be indicated; defined pools of source materials shall be used.

The origin and history of starting materials shall be described and documented. For genetically engineered
starting materials this information shall include details such as the description of the starting cells or strains, the
construction of the expression vector (name, origin, function of the replicon, promoter enhancer and other
regulator elements), control of the sequence of DNA or RNA effectively inserted, oligonucleotidic sequences of
plasmid vector in cells, plasmid used for cotransfection, added or deleted genes, biological properties of the final
construct and the genes expressed, copy number and genetic stability.

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Seed materials, including cell banks and raw serum for anti-serum production shall be tested for identity and
adventitious agents.

Information shall be provided on all substances of biological origin used at any stage in the manufacturing
procedure. The information shall include:

(cid:151) details of the source of the materials,

(cid:151) details of any processing, purification and inactivation applied, with data on the validation of these process

and in-process controls,

(cid:151) details of any tests for contamination carried out on each batch of the substance.

If the presence of adventitious agents is detected or suspected, the corresponding material shall be discarded or
used in very exceptional circumstances only when further processing of the product ensures their elimination
and/or inactivation; elimination and/or inactivation of such adventitious agents shall be demonstrated.

When cell banks are used, the cell characteristics shall be shown to have remained unchanged up to the highest
passage level used for the production.

For live attenuated vaccines, proof of the stability of the attenuation characteristics of the seed has to be given.

When required, samples of the biological starting material or reagents used in the testing procedures shall be
provided to enable the competent authority to arrange for check tests to be carried out.

2.2.

Starting materials of non-biological origin

The description shall be given in the form of a monograph under the following headings:

(cid:151) the name of the starting material meeting the requirements of point 2 of Section A shall be supplemented by

any trade or scientific synonyms,

(cid:151) the description of the starting material, set down in a form similar to that used in a descriptive item in the

European Pharmacopoeia,

(cid:151) the function of the starting material,

(cid:151) methods of identification,

(cid:151) purity shall be described in relation to the sum total of predictable impurities, especially those which may
have a harmful effect and, if necessary, those which, having regard to the combination of substances to
which the application refers, may adversely effect the stability of the medicinal product or distort analytical
results. A brief description shall be provided of the tests undertaken to establish the purity of each batch of
the starting material,

(cid:151) any special precautions which may be necessary during storage of the starting material and, if necessary, its

storage life shall be given.

D.

SPECIFIC MEASURES CONCERNING THE PREVENTION OF THE TRANSMISSION OF ANIMAL SPONGIFORM
ENCEPHALOPATHIES

The applicant must demonstrate that the veterinary medical product is manufactured in accordance with the Note for
Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via veterinary medicinal
products and its updates, published by the European Commission in Volume 7 of its publication (cid:145)The rules governing
medicinal products in the European Community(cid:146).

E.

CONTROL TESTS DURING PRODUCTION

1.

The particulars and documents accompanying an application for marketing authorization, pursuant to Article
12(3)(i) and (j) and Article 13(1), shall include particulars relating to the control tests which are carried out on
intermediate products with a view to verifying the consistency of the production process and the final product.

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2.

For inactivated or detoxified vaccines, inactivation or detoxification shall be tested during each production run
immediately after the inactivation or detoxification process.

F.

CONTROL TESTS ON THE FINISHED PRODUCT

The particulars and documents accompanying the application for marketing authorization pursuant to Article 12(3)(i)
and (j) and Article 13(1), shall include particulars relating to control tests on the finished product. Where appropriate
monographs exist,
if test procedures and limits other than those mentioned in the monographs of the European
Pharmacopoeia, or failing this, in the national pharmacopoeia of a Member State, are used, proof must be supplied that
the finished product would, if tested in accordance with those monographs, meet the quality requirements of that
pharmacopoeia for the pharmaceutical form concerned. The application for marketing authorization shall list those
tests which are carried out on representative samples of each batch of finished product. The frequency of the tests
which are not carried out on each batch shall be stated. Release limits shall be indicated.

1.

General characteristics of the finished product

Certain tests of the general characteristics of a product shall be included among the tests on the finished product,
even if they have been carried out in the course of the manufacturing process.

These tests shall, wherever applicable, relate to the control of average masses and maximum deviations, to
mechanical, physical, chemical or microbiological tests, physical characteristics such as density, pH, refractive
index, etc. For each of these characteristics, specifications, with appropriate confidence limits, shall be established
by the applicant in each particular case.

2.

Identification and assay of active substance(s)

For all tests, the description of the techniques for analyzing the finished product shall be set out in sufficiently
precise detail, so that they can be reproduced readily.

The assay of biological activity of the active substance(s) shall be carried out either in a representative sample
from the production batch or in a number of dosage-units analysed individually.

Where necessary, a specific test for identification shall also be carried out.

In certain exceptional cases where assay of active substances which are very numerous or present in very low
amounts would necessitate an intricate investigation difficult to carry out in respect of each production batch, the
assay of one or more active substances in the finished product may be omitted, on the express condition that
such assays are made at intermediate stages as late as possible in the production process. This relaxation may not
be extended to the characterization of the substances concerned. This simplified technique shall be supplemented
by a method of quantitative evaluation, enabling the competent authority to verify that the immunological
veterinary medicinal product is in accordance with its formula after it has been placed on the market.

3.

Identification and assay of adjuvants

In so far as testing procedures are available, the quantity and nature of the adjuvant and its components shall be
verified on the finished product.

4.

Identification and assay of excipient components

In so far as is necessary, the excipient(s) shall be subject at least to identification tests.

The test procedure proposed for identifying colouring matters must enable a verification to be made that such
matters are permitted under Directive 78/25/EEC.

An upper and lower limit test shall be obligatory in respect of preserving agents; an upper limit test for any
other excipient components liable to give rise to an adverse reaction shall be obligatory.

5.

Safety tests

Apart from the results of tests submitted in accordance with Part 7 of this Annex, particulars of safety tests shall
be submitted. These tests shall preferably be overdosage studies carried out in at least one of the most sensitive
target species and by at least the recommended route of administration posing the greatest risk.

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6.

Sterility and purity test

Appropriate tests to demonstrate the absence of contamination by adventitious agents or other substances shall
be carried out according to the nature of the immunological veterinary medicinal product, the method and the
conditions of manufacture.

7.

Inactivation

Where applicable, a test to verify inactivation shall be carried out on the product in the final container.

8.

Residual humidity

Each batch of lyophilised product shall be tested for residual humidity.

9.

Batch-to-batch consistency

In order to ensure that efficacy of
the product
is reproducible from batch to batch and to demonstrate
including appropriate
conformity with specifications, potency tests based upon in vitro or in vivo methods,
reference materials whenever available, shall be carried out on each final bulk or each batch of finished product,
with appropriate confidence limits;
in exceptional circumstances, potency testing may be carried out at an
intermediate stage, as late as possible in the production process.

G.

STABILITY TESTS

The particulars and documents accompanying the application for marketing authorization pursuant to Article 12(3)(f)
and (i) shall be submitted in accordance with the following requirements.

A description shall be given of the tests undertaken to support the shelf life proposed by the applicant. These tests shall
always be real-time studies; they shall be carried out on a sufficient number of batches produced according to the
described production process and on products stored in the final container(s); these tests include biological and
physico-chemical stability tests.

The conclusions shall contain the results of analyses,
conditions.

justifying the proposed shelf-life under all proposed storage

In the case of products administered in the feed, information shall also be given as necessary on the shelf-life of the
product, at the different stages of mixing, when mixed in accordance with the recommended instructions.

Where a finished product requires reconstitution prior to administration, details of the proposed shelf-life are required
for the product reconstituted as recommended. Data in support of the proposed shelf-life for the reconstituted product
shall be submitted.

PART 7

Safety testing

A.

INTRODUCTION

1.

2.

3.

The safety tests shall show the potential risks from the immunological veterinary medicinal product which may
occur under the proposed conditions of use in animals: these shall be evaluated in relation to the potential
benefits of the product.

Where immunological veterinary medicinal products consist of live organisms, especially those which could be
shed by vaccinated animals, the potential risk to unvaccinated animals of the same or of any other potentially
exposed species shall be evaluated.

The particulars and documents which shall accompany the application for marketing authorization pursuant to
Article 12(3)(j) and 13(1) shall be submitted in accordance with the requirements of section B.

Member States shall ensure that the laboratory tests are carried out in conformity with the principles of good
laboratory practice laid down in Council Directives 87/18/EEC and 88/320/EEC.

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B.

1.

2.

3.

C.

1.

GENERAL REQUIREMENTS

The safety tests shall be carried out in the target species.

The dose to be used shall be that quantity of the product to be recommended for use and containing the
maximum titre or potency for which the application is submitted.

The sample used for safety testing shall be taken from a batch or batches produced according to the
manufacturing process described in the application for marketing authorization.

LABORATORY TESTS

Safety of the administration of one dose

The immunological veterinary medicinal product shall be administered at the recommended dose and by each
recommended route of administration to animals of each species and category in which it is intended for use,
including animals of the minimum age of administration. The animals shall be observed and examined for signs
of systemic and local reactions. Where appropriate, these studies shall include detailed post-mortem macroscopic
and microscopic examinations of the injection site. Other objective criteria shall be recorded, such as rectal
temperature and performance measurements.

The animals shall be observed and examined until reactions may no longer be expected, but in all cases, the
observation and examination period shall be at least 14 days after administration.

2.

Safety of one administration of an overdose

An overdose of the immunological veterinary medicinal product shall be administered by each recommended
route of administration to animals of the most sensitive categories of the target species. The animals shall be
observed and examined for signs of systemic and local reactions. Other objective criteria shall be recorded, such
as rectal temperature and performance measurements.

The animals shall be observed and examined for at least 14 days after administration.

3.

Safety of the repeated administration of one dose

Repeated administration of one dose may be required to reveal any adverse effects
induced by such
administration. These tests shall be carried out on the most sensitive categories of the target species, using the
recommended route of administration.

The animals shall be observed and examined for at least 14 days after the last administration for signs of
systemic and local reactions. Other objective criteria shall be recorded, such as rectal
temperature and
performance measurements.

4.

Examination of reproductive performance

Examination of reproductive performance shall be considered when data suggest that the starting material from
risk factor. Reproductive performance of males and
which the product
non-pregnant and pregnant females shall be investigated with the recommended dose and by each of the
recommended routes of administration. In addition, harmful effects on the progeny, as well as teratogenic and
abortifacient effects, shall be investigated.

is derived may be a potential

These studies may form part of the safety studies described in paragraph 1.

5.

Examination of immunological functions

Where the immunological veterinary medicinal product might adversely affect the immune response of the
vaccinated animal or of its progeny, suitable tests on the immunological functions shall be carried out.

6.

Special requirements for live vaccines:

6.1.

Spread of the vaccine strain

Spread of the vaccine strain from vaccinated to unvaccinated target animals shall be investigated, using the
recommended route of administration most likely to result in the spread. Moreover, it may be necessary to
investigate the spread to non target species which could be highly susceptible to a live vaccine strain.

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6.2. Dissemination in the vaccinated animal

Faeces, urine, milk, eggs, oral, nasal and other secretions shall be tested for the presence of the organism.
Moreover, studies may be required of the dissemination of the vaccine strain in the body, with particular
attention being paid to the predilection sites for replication of the organism. In the case of live vaccines for well
established zoonotic diseases for food producing animals, these studies must be undertaken.

6.3. Reversion to virulence of attenuated vaccines

Reversion to virulence shall be investigated with material from the passage level which is least attenuated
between the master seed and the final product. The initial vaccination shall be carried out using the
recommended route of administration most likely to lead to reversion to virulence. At least five serial passages
through animals of the target species shall be undertaken. Where this is not technically possible due to failure of
the organism to replicate adequately, as many passages as possible shall be carried out in the target species. If
necessary, in vitro propagation of the organism may be carried out between passages in vivo. The passages shall be
undertaken by the route of administration most likely to lead to reversion to virulence.

6.4. Biological properties of the vaccine strain

Other tests may be necessary to determine as precisely as possible the intrinsic biological properties of the
vaccine strain (e.g. neurotropism).

6.5. Recombination or genomic reassortment of strains

The probability of recombination or genomic reassortment with field or other strains shall be discussed.

7.

Study of residues

For immunological veterinary medicinal products, it will normally not be necessary to undertake a study of
residues. However, where adjuvants and/or preservatives are used in the manufacture of
immunological
veterinary medicinal products, consideration shall be given to the possibility of any residue remaining in the
foodstuffs. If necessary, the effects of such residues shall be investigated. Moreover, in the case of live vaccines for
zoonotic diseases, the determination of residues at the injection site may be required in addition to the studies
described in paragraph 6.2.

A proposal for a withdrawal period shall be made and its adequacy shall be discussed in relation to any residue
studies which have been undertaken.

8.

Interactions

Any known interactions with other products shall be indicated.

D.

FIELD STUDIES

Unless justified, results from laboratory studies shall be supplemented with supportive data from field studies.

E.

ECOTOXICITY

The purpose of the study of the ecotoxicity of an immunological veterinary medicinal product is to assess the potential
harmful effects which the use of the product may cause to the environment and to identify any precautionary measures
which may be necessary to reduce such risks.

An assessment of ecotoxicity shall be compulsory for any application for marketing authorization for an
immunological veterinary medicinal product other than applications submitted in accordance with Article 12(3)(j) and
13(1).

This assessment shall normally be conducted in two phases.

The first phase of the assessment shall always be carried out: the investigator shall assess the potential extent of
exposure of the environment to the product, its active substances, or relevant metabolites, taking into account:

(cid:151) the target species and the proposed pattern of use (e.g. mass medication or individual animal medication),

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(cid:151) the method of administration,

in particular the likely extent

to which the product will enter directly into

environmental system,

(cid:151) the possible excretion of the product, its active substances or relevant metabolites into the environment by treated

animals, persistence in such excretia,

(cid:151) the disposal of unused or waste product.

Where the conclusions of the first phase indicate potential exposure of the environment to the product, the applicant
shall proceed to the second phase and evaluate the potential ecotoxicity of the product. For this purpose, he shall
consider the extent and duration of exposure of the environment to the product, and the information about the
physical/chemical, pharmacological and/or toxicological properties of the compound obtained during the conduct of
the other tests and trials required by this Directive. Where necessary, further investigations on the impact of the
product (soil, water, air, aquatic systems, non-target organisms) shall be carried out.

These further investigations shall be carried out in accordance with the test protocols laid down in Annex V to Council
Directive 67/548/EEC or where an end point is not adequately covered by these protocols, in accordance with other
internationally recognized protocols on the immunological veterinary medicinal product and/or the active substances
and/or the excreted metabolites as appropriate. The number and types of tests and the criteria for their evaluation shall
depend upon the state of scientific knowledge at the time the application is submitted.

PART 8

Efficacy trials

A.

INTRODUCTION

1.

2.

3.

4.

5.

B.

1.

2.

The purpose of the trials described in this Part is to demonstrate or to confirm the efficacy of the immunological
veterinary medicinal product. All claims made by the applicant with regard to the properties, effects and use of
the product, shall be fully supported by results of specific trials contained in the application for marketing
authorization.

The particulars and documents which shall accompany applications for marketing authorizations pursuant to
Article 12(3)(j) and 13(1) shall be submitted in accordance with the provisions below.

All veterinary clinical trials shall be conducted in accordance with a fully considered detailed trial protocol which
shall be recorded in writing prior to commencement of the trial. The welfare of the trial animals shall be subject
to veterinary supervision and shall be taken fully into consideration during the elaboration of any trial protocol
and throughout the conduct of the trial.

Pre-established systematic written procedures for the organization, conduct, data collection, documentation and
verification of clinical trials shall be required.

Before the commencement of any trial, the informed consent of the owner of the animals to be used in the trial
shall be obtained and documented.
the
consequences of participation in the trial for the subsequent disposal of treated animals or for the taking of
foodstuffs from treated animals. A copy of this notification, countersigned and dated by the animal owner, shall
be included in the trial documentation.

the animal owner shall be informed in writing of

In particular,

Unless the trial is conducted with a blind design, the provisions of Articles 58, 59 and 60 shall apply by analogy
to the labelling of formulations intended for use in veterinary clinical trials. In all cases, the words (cid:145)for veterinary
clinical trial use only(cid:146) shall appear prominently and indelibly upon the labelling.

GENERAL REQUIREMENTS

The choice of vaccine strains shall be justified on the basis of epizoological data.

Efficacy trials carried out in the laboratory shall be controlled trials, including untreated control animals.

In general, these trails shall be supported by trials carried out in field conditions, including untreated control
animals.

All trials shall be described in sufficiently precise details so as to be reproducible in control trials, carried out at
the request of the competent authorities. The investigator shall demonstrate the validity of all the techniques
involved. All results shall be presented as precisely as possible.

All results obtained, whether favourable or unfavourable, shall be reported.

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3.

4.

The efficacy of an immunological veterinary medicinal product shall be demonstrated for each category of each
species recommended for vaccination, by each recommended route of administration and using the proposed
schedule of administration. The influence of passively acquired and maternally derived antibodies on the efficacy
of a vaccine shall be adequately evaluated. Any claims regarding the onset and duration of protection shall be
supported by data from trials.

The efficacy of each of
the components of multivalent and combined immunological veterinary medicinal
products shall be demonstrated. If the product is recommended for administration in combination with or at the
same time as another veterinary medicinal product, they shall be shown to be compatible.

5. Whenever a product forms part of a vaccination scheme recommended by the applicant, the priming or booster

effect or the contribution of the product to the efficacy of the scheme as a whole shall be demonstrated.

6.

7.

8.

The dose to be used shall be that quantity of the product to be recommended for use and containing the
minimum titre or potency for which the application is submitted.

The samples used for efficacy trials shall be taken from a batch or batches produced according to the
manufacturing process described in the application for marketing authorization.

For diagnostic immunological veterinary medicinal products administered to animals, the applicant shall indicate
how reactions to the product are to be interpreted.

C.

LABORATORY TRIALS

1.

2.

In principle, demonstration of efficacy shall be undertaken under well controlled laboratory conditions by
challenge after administration of the immunological veterinary medicinal product to the target animal under the
recommended conditions of use. In so far as possible, the conditions under which the challenge is carried out
shall mimic the natural conditions for infection, for example with regard to the amount of challenge organism
and the route of administration of the challenge.

local/general classes of immunoglobulin) which is
If possible, the immune mechanism (cell-mediated/humoral,
initiated after the administration of the immunological veterinary medicinal product to target animals by the
recommended route of administration shall be specified and documented.

D.

FIELD TRIALS

1.

Unless justified, results from laboratory trials shall be supplemented with data from field trials.

2. Where laboratory trials cannot be supportive of efficacy, the performance of field trials alone may be acceptable.

Particulars and documents concerning safety testing and efficacy trials of immunological veterinary medicinal
products

PART 9

A.

INTRODUCTION

As in any scientific work, the dossier of safety and efficacy studies shall include an introduction defining the subject
and indicating the tests which have been carried out in compliance with Parts 7 and 8, as well as a summary, with
references to the published literature. Omission of any tests or trials listed in Parts 7 and 8 shall be indicated and
discussed.

B.

LABORATORY STUDIES

The following shall be provided for all studies:

1.

a summary;

2.

the name of the body having carried out the studies;

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3.

4.

5.

6.

7.

8.

9.

a detailed experimental protocol giving a description of the methods, apparatus and materials used, details such as
species, breed or strain of animals, categories of animals, where they were obtained, their identification and
number, the conditions under which they were housed and fed (stating inter alia whether they were free from any
specified pathogens and/or specified antibodies, the nature and quantity of any additives contained in the feed),
dose, route, schedule and dates of administration, a description of the statistical methods used;

in the case of control animals, whether they received a placebo or no treatment;

all general and individual observations and results obtained (with averages and standard deviations), whether
favourable or unfavourable. The data shall be described in sufficient detail to allow the results to be critically
evaluated independently of their interpretation by the author. The raw data shall be presented in tabular form. By
way of explanation and illustration,
recordings,
photomicrographs, etc.;

the results may be accompanied by reproductions of

the nature, frequency and duration of observed side-effects;

the number of animals withdrawn prematurely from the studies and reasons for such withdrawal;

a statistical analysis of the results, where such is called for by the test programme, and variance within the data;

occurrence and course of any intercurrent disease;

10.

all details concerning medicinal products (other than the product under study), the administration of which was
necessary during the course of the study;

11.

an objective discussion of the results obtained, leading to conclusions on the safety and efficacy of the product.

C.

FIELD STUDIES

Particulars concerning field studies shall be sufficiently detailed to enable an objective judgement to be made. They shall
include the following:

1.

2.

3.

4.

5.

6.

7.

8.

9.

a summary;

name, address, function and qualifications of the investigator in charge;

place and date of administration, name and address of the owner of the animal(s);

details of the trial protocol, giving a description of the methods, apparatus and materials used, details such as the
route of administration, the schedule of administration, the dose, the categories of animals, the duration of
observation, the serological response and other investigations carried out on the animals after administration;

in the case of control animals, whether they received a placebo or no treatment;

identification of the treated and control animals (collective or individual, as appropriate), such as species, breeds
or strains, age, weight, sex, physiological status;

a brief description of the method of rearing and feeding, stating the nature and quantity of any additives
contained in the feed;

all the particulars on observations, performances and results (with averages and standard deviation); individual
data shall be indicated when tests and measurements on individuals have been carried out;

all observations and results of the studies, whether favourable or unfavourable, with a full statement of the
observations and the results of the objective tests of activity required to evaluate the product; the techniques used
must be specified and the significance of any variations in the results explained;

10.

effect on the animals’ performances (e.g. egg laying, milk production, reproductive performance);

11.

the number of animals withdrawn prematurely from the studies and reasons for such withdrawal;

12.

the nature, frequency and duration of observed adverse reactions;

13. occurrence and course of any intercurrent disease;

28.11.2001

EN

Official Journal of the European Communities

L 311/59

14.

all details concerning medicinal products (other than the product under study) which have been administered
either prior to or concurrently with the test product or during the observation period; details of any interactions
observed;

15.

an objective discussion of the results obtained, leading to conclusions on the safety and efficacy of the product.

D.

GENERAL CONCLUSIONS

General conclusions on all results of tests and trials carried out in compliance with Parts 7 and 8 shall be given. They
shall contain an objective discussion of all the results obtained and lead to a conclusion on the safety and efficacy of
the immunological veterinary medicinal product.

E.

BIBLIOGRAPHICAL REFERENCES

The bibliographical references cited in the summary mentioned under Section A shall be listed in detail.

L 311/60

EN

Official Journal of the European Communities

28.11.2001

ANNEX II

PART A

Repealed Directives and their successive amendments

(referred to by Article 96)

Council Directive 81/851/EEC (OJ L 317, 6.11.1981, p. 1)

Council Directive 90/676/EEC (OJ L 373, 31.12.1990, p. 15)

Council Directive 90/677/EEC (OJ L 373, 31.12.1990, p. 26)

Council Directive 92/74/EEC (OJ L 297, 13.10.1992, p. 12)

Council Directive 93/40/EEC (OJ L 214, 24.8.1993, p. 31)

Commission Directive 2000/37/EC (OJ L 139, 10.6.2000, p. 25)

Council Directive 81/852/EEC (OJ L 317, 6.11.1981, p. 16)

Council Directive 87/20/EEC (OJ L 15, 17.1.1987, p. 34)

Council Directive 92/18/EEC (OJ L 97, 10.4.1992, p. 1)

Council Directive 93/40/EEC

Commission Directive 1999/104/EC (OJ L 3, 6.1.2000, p. 18)

PART B

Time-limits for transposition into national law

(referred to by Article 96)

Directive

Deadline for transposition

Directive 81/851/EEC

Directive 81/852/EEC

Directive 87/20/EEC

Directive 90/676/EEC

Directive 90/677/EEC

Directive 92/18/EEC

Directive 92/74/EEC

Directive 93/40/EEC

Directive 1999/104/EC

Directive 2000/37/EC

9 October 1983

9 October 1983

1 July 1987

1 January 1992

20 March 1993

1 April 1993

31 December 1993

1 January 1995

1 January 1998 (Art. 1.7)

1 January 2000

5 December 2001

This Directive

Dir. 65/65/EEC

Dir. 81/851/EEC

Dir. 81/852/EEC

Dir. 90/677/EEC

Dir. 92/74/EEC

ANNEX III

CORRELATION TABLE

Art. 1 points 1 and 2

Art. 1 points 1 and 2

Art. 1(1)

Art. 1 point 3

Art. 1 point 4

Art. 1(2), 2nd indent

Art. 1, point 3

Art. 1(1)

Art. 1 points 5 and 6

Art. 1(2), 3rd and 4th indents

Art. 1 point 7

Art. 1 point 8

Art. 1 point 9

Art. 1 points 10 to 16

Art. 1 point 17

Art. 1 point 18

Art. 1 point 19

Art. 2

Art. 3 point 1, 1st subparagraph

Art. 5, 3rd subparagraph, point 8

Art.42b, 1st subparagraph

Art. 50a(1), 2nd subparagraph

Art.16(1)

Art. 18(1), footnote

Art. 2(1)

Art. 2(2), 1st indent

Art. 1(2)

Art. 1

Art. 3 point 1, 2nd subparagraph

Art. 2(3)

Art. 3 point 2

Art. 3 points 3 and 4

Art. 3 point 5

Art. 3 point 6

Art. 4(1)

Art. 4(2)

Art. 5

Art. 1 points 4 and 5 and Art.
2(3)

Art. 1(1)

Art. 2(2), 3rd indent

Art. 1 point 4

Art. 3

Art. 4(1), 1st subparagraph

Art. 1(3)

Art. 1(4)

.

2
8
1
1
2
0
0
1

.

E
N

O

f
f
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i
a
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J
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a
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o
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t
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E
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a
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This Directive

Dir. 65/65/EEC

Dir. 81/851/EEC

Dir. 81/852/EEC

Dir. 90/677/EEC

Dir. 92/74/EEC

Art. 4(2), 1st subparagraph

Art. 4(1), 2nd subparagraph

Art. 4(1), 3rd subparagraph

Art. 4(3), 1st subparagraph

Art. 4(4), 1st and 2nd
subparagraphs

Art. 4(4), 3rd subparagraph

Art. 5, 1st subparagraph

Art. 5, 2nd subparagraph

Art. 5, 3rd subparagraph, points 1
to 9

Art. 1, 1st subparagraph

Art. 5, 3rd subparagraph, point
10, 1st subparagraph

Art. 5, 3rd subparagraph, points
11 to 14

Art. 5, 3rd subparagraph, point
10, 2nd subparagraph

Art. 5a

Art. 6

Art. 7

Art. 1, 2nd subparagraph

Art. 6

Art. 7

Art. 8

Art. 9

Art. 10(1) and (2), 1st and 2nd
subparagraphs

Art. 10(2), 3rd subparagraph

Art. 11

Art. 12(1)

Art. 12(2)

Art. 12(3)(a) to (i)

Art. 12(3)(j)

Art. 12(3)(k) to (n)

Art. 13(1)

Art. 13(2)

Art. 14

Art. 15(1)

Art. 15(2) and (3)

Art. 16

Art. 17(1)

Art. 17(2)

Art. 17(3)

Art. 18

Art. 19

Art. 20 first paragraph

Art. 2(1), 2nd subparagraph

Art. 6

Art. 7(1)

Art. 7(3)

Art. 4, 2nd subparagraph

Art. 8

Art. 9

Art. 2(3)

L

3
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1
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6
2

E
N

O

f
f
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i
a
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J
o
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a
l

o
f

t
h
e

E
u
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o
p
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a
n

C
o
m
m
u
n
i
t
i
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s

.

2
8
1
1
2
0
0
1

.

Art. 20 second paragraph

Art. 9

Art. 21

Art. 22

Art. 23

Art. 24

Art. 25

Art. 26(1) and (2)

Art. 26(3)

Art. 27(1)

Art. 27(2)

Art. 27(3)

Art. 27(4) and (5)

Art. 28

Art. 29

Art. 30

Art. 31(1)

Art. 31(2)

Art. 31(3)

Art. 32(1)

Art. 32(2)

Art. 32(3)

Art. 32(4)

Art. 33

Art. 34

Art. 35

Art. 36

Art. 37

Art. 8

Art. 8a

Art. 9

Art. 10

Art. 5b

Art. 12

Art. 15(2)

Art. 14(1), 1st subparagraph

Art. 14(1), 2nd subparagraph

Art. 14(2)

Art. 14(3) and (4)

Art. 15(1)

Art. 13

Art. 11

Art. 16(1)

Art. 16(2)

Art. 16(3)

Art. 17(3)

Art. 17(1)

Art. 17(2)

Art. 17(4)

Art. 18

Art. 19

Art. 20

Art. 21

Art. 22(1)

Art. 2

.

2
8
1
1
2
0
0
1

.

E
N

O

f
f
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a
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J
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a
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o
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t
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This Directive

Dir. 65/65/EEC

Dir. 81/851/EEC

Dir. 81/852/EEC

Dir. 90/677/EEC

Dir. 92/74/EEC

Art. 38

Art. 39

Art. 40

Art. 41

Art. 42

Art. 43

Art. 44

Art. 45

Art. 46

Art. 47

Art. 48

Art. 49

Art. 50

Art. 51

Art. 52

Art. 53

Art. 54

Art. 55(1)

Art. 55(2)

Art. 55(3)

Art. 56

Art. 57

Art. 58(1) to (3)

Art. 58(4)

Art. 59(1)

Art. 59(2)

Art. 22(2), (3) and (4)

Art. 23

Art. 23a

Art. 23b

Art. 23c

Art. 22(5)

Art. 24

Art. 25

Art. 26

Art. 28(1)

Art. 28(2)

Art. 28(3)

Art. 27

Art. 27a

Art. 29

Art. 31

Art. 32

Art. 30(1), 1st and 2nd
subparagraphs

Art. 30(1), 3rd subparagraph

Art. 30(2)

Art. 33

Art. 43

Art. 47

Art. 44

Art. 45

Art. 3

L

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J
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t
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a
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C
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s

.

2
8
1
1
2
0
0
1

.

Art. 59(3)

Art. 60

Art. 61(1)

Art. 61(2)

Art. 61(3)

Art. 62

Art. 63

Art. 64(1)

Art. 64(2)

Art. 65(1)

Art. 65(2), (3) and (4)

Art. 66

Art. 67

Art. 68

Art. 69

Art. 70

Art. 71

Art. 72

Art. 73

Art. 74

Art. 75

Art. 76

Art. 77(1)

Art. 77(2)

Art. 78

Art. 79

Art. 80(1)

Art. 47

Art. 46

Art. 48, 1st subparagraph

Art. 48, 2nd subparagraph

Art. 48, 3rd subparagraph

Art. 49, 1st subparagraph

Art. 50

Art. 50a(1), 1st and 3rd
subparagraphs

Art. 50a(2), (3) and (4)

Art. 50b

Art. 4(3), 3rd subparagraph

Art. 1(5)

Art. 50c

Art. 4(5)

Art. 42e

Art. 42a

Art. 42c

Art. 42d

Art. 42f

Art. 42g

Art. 42b

Art. 42h

Art. 42i

Art. 34, 1st and 2nd
subparagraphs

.

2
8
1
1
2
0
0
1

.

Art. 2(2)

Art. 7(2)

Art. 4

E
N

O

f
f
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a
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J
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n
a
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o
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t
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E
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This Directive

Dir. 65/65/EEC

Dir. 81/851/EEC

Dir. 81/852/EEC

Dir. 90/677/EEC

Dir. 92/74/EEC

Art. 80(2)

Art. 80(3)

Art. 81(1)

Art. 81(2)

Art. 82

Art. 83

Art. 84

Art. 85

Art. 86

Art. 87

Art. 88

Art. 89

Art. 90

Art. 91

Art. 92

Art. 93

Art. 94

Art. 95

Art. 96

Art. 97

Art. 98

Annex I

Annex II

Annex III

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

Art. 34, 3rd subparagraph

Art. 35

Art. 36

Art. 37

Art. 38

Art. 38a

Art. 42j

Art. 39

Art. 42

Art. 24a

Art. 40, 41 and 49, 2nd
subparagraph

Art. 4(2), 2nd subparagraph

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

Art. 2a

Art. 2b

(cid:151)

(cid:151)

(cid:151)

Annex

(cid:151)

(cid:151)

Art. 3(1)

Art. 3(2)

Art. 3(3)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

Art. 4, 1st subparagraph

Art. 5

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

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2
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.