Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use
Date: 2001-11-06
Institutions: Council of the European Union, European Parliament
Subjects: approximation of laws, legal code, medicinal product, pharmaceutical legislation, public health, single market

28.11.2001

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Official Journal of the European Communities

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DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

of 6 November 2001

on the Community code relating to medicinal products for human use

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)

by

laid

law,

down

regulation

laid down by

Council Directive 65/65/EEC of 26 January 1965 on the
approximation of provisions
law,
regulation or administrative action relating to medicinal
products (3), Council Directive 75/318/EEC of 20 May
1975 on the approximation of
the laws of Member
States relating to analytical, pharmaco-toxicological and
clinical standards and protocols in respect of the testing
of proprietary medicinal products (4), Council Directive
75/319/EEC of 20 May 1975 on the approximation of
provisions
or
administrative action relating to proprietary medicinal
products (5), Council Directive 89/342/EEC of 3 May
1989 extending the scope of Directives 65/65/EEC and
75/319/EEC and laying down additional provisions for
immunological medicinal
of
products
toxins or serums and allergens (6), Council
vaccines,
Directive 89/343/EEC of 3 May 1989 extending the
scope of Directives 65/65/EEC and 75/319/EEC and
laying
for
additional
radiopharmaceuticals (7), Council Directive 89/381/EEC
of 14 June 1989 extending the scope of Directives
65/65/EEC and 75/319/EEC on the approximation of
provisions
or
administrative action relating to medicinal products and
laying down special provisions for proprietary medicinal
products derived from human blood or human
plasma (8), Council Directive 92/25/EEC of 31 March

provisions

regulation

consisting

down

down

law,

laid

by

(1) OJ C 368, 20.12.1999, p. 3.
(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 22, 9.2.1965, p. 369/65. Directive as last amended by Directive

93/39/EEC (OJ L 214, 24.8.1993, p. 22).
(4) OJ L 147, 9.6.1975, p. 1. Directive as

last amended by

Commission Directive 1999/83/EC (OJ L 243, 15.9.1999, p. 9).

(5) OJ L 147, 9.6.1975, p. 13. Directive as

last amended by

Commission Directive 2000/38/EC (OJ L 139, 10.6.2000, p. 28).

(6) OJ L 142, 25.5.1989, p. 14.
(7) OJ L 142, 25.5.1989, p. 16.
(8) OJ L 181, 28.6.1989, p. 44.

for

human

use (9),

and on package

1992 on the wholesale distribution of medicinal
products
Council Directive
the
92/26/EEC of 31 March 1992 concerning
classification for the supply of medicinal products for
human use (10), Council Directive 92/27/EEC of 31
March 1992 on the labelling of medicinal products for
leaflets (11), Council
human use
Directive 92/28/EEC of 31 March 1992 on the
advertising of medicinal products for human use (12),
Council Directive 92/73/EEC of 22 September 1992
widening the
scope of Directives 65/65/EEC and
75/319/EEC on the approximation of provisions laid
down by law,
action
relating
and laying down
additional
homeopathic medicinal
on
products (13) have been frequently and substantially
amended. In the interests of clarity and rationality, the
said Directives
by
assembling them in a single text.

regulation or administrative

to medicinal products

provisions

therefore

codified

should

be

(2)

(3)

(4)

(5)

(6)

The essential aim of any rules governing the production,
distribution and use of medicinal products must be to
safeguard public health.

this objective must be attained by means
However,
which will not hinder
the
pharmaceutical industry or trade in medicinal products
within the Community.

the development of

by

between

disparities

Trade in medicinal products within the Community is
national
hindered
provisions, in particular between provisions relating to
medicinal
or
combinations of substances which are foods, animal
feeding-stuffs or toilet preparations), and such disparities
directly affect the functioning of the internal market.

substances

(excluding

products

certain

Such hindrances must accordingly be removed; whereas
this entails approximation of the relevant provisions.

In order to reduce the disparities which remain, rules
should be laid down on the control of medicinal
products and the duties incumbent upon the Member
States’ competent authorities should be specified with a
view to ensuring compliance with legal requirements.

(9) OJ L 113, 30.4.1992, p. 1.
(10) OJ L 113, 30.4.1992, p. 5.
(11) OJ L 113, 30.4.1992, p. 8.
(12) OJ L 113, 30.4.1992, p. 13.
(13) OJ L 297, 13.10.1992, p. 8.

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(7)

(8)

(9)

The concepts of harmfulness and therapeutic efficacy
can only be examined in relation to each other 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
marketing
a medicinal product
demonstrate that potential risks are outweighed by the
therapeutic efficacy of the product.

authorization for

Standards and protocols for the performance of tests
and trials on 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 trials,
the compilation of dossiers and the
examination of applications.

Experience has shown that it is advisable to stipulate
in which the results of
more precisely the cases
toxicological and pharmacological tests or clinical trials
do not have to be provided with a view to obtaining
a medicinal product which is
authorization for
essentially similar
to an authorized product, while
innovative firms are not placed at a
ensuring that
disadvantage.

(10) However,

there are reasons of public policy for not
conducting repetitive tests on humans or animals
without over-riding cause.

(11)

The adoption of the same standards and protocols by all
the Member States will enable the competent authorities
to arrive at their decisions on the basis of uniform tests
and by reference to uniform criteria and will therefore
help to avoid differences in evaluation.

(12) With the exception of those medicinal products which
are subject to the centralized 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 (1) a marketing authorization for a
medicinal product granted by a competent authority in
one Member State ought
to be recognized by the
competent authorities of the other Member States unless
there are serious grounds
the
authorization of the medicinal product concerned may
In the event of a
present a risk to public health.
disagreement between Member States about the quality,

supposing that

for

the safety or the efficacy of a medicinal product, a
scientific evaluation of the matter should be undertaken
according to a Community standard, leading to a single
decision on the area of disagreement binding on the
Member States concerned. Whereas this decision should
ensuring close
be adopted by a rapid procedure
cooperation between the Commission and the Member
States.

For this purpose, a Committee for Proprietary Medicinal
Products should be set up attached to the European
Agency for
the Evaluation of Medicinal Products
established in the abovementioned Regulation (EEC) No
2309/93.

This Directive represents an important step towards
achievement of the objective of the free movement of
medicinal products. Further measures may abolish any
remaining barriers to the free movement of proprietary
medicinal products will be necessary in the light of
experience gained, particularly in the abovementioned
Committee for Proprietary Medicinal Products.

during

effort
for

of
application

duplication
of

In order better to protect public health and avoid any
the
unnecessary
examination
a marketing
authorization for medicinal products, Member States
should systematically prepare assessment
in
respect of each medicinal product which is authorized
by them, and exchange the reports upon request.
Furthermore, a Member State should be able to suspend
the examination of an application for authorization to
place a 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.

reports

Following the establishment of
the internal market,
specific controls to guarantee the quality of 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.

to adopt

is necessary

for
It
immunological medicinal
homeopathic
medicinal products, radiopharmaceuticals, and medicinal
products based on human blood or human plasma.

specific provisions
products,

(13)

(14)

(15)

(16)

(17)

(18) Any rules governing radiopharmaceuticals must

take
into account
the provisions of Council Directive
84/466/Euratom of 3 September 1984 laying down
basic measures for the radiation protection of persons
treatment (2).
undergoing medical
Account should also be taken of Council Directive
80/836/Euratom of 15 July 1980 amending the
Directives laying down the basic safety standards for the
the general public and workers
health protection of

examination

or

(1) 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).

(2) OJ L 265, 5.10.1984, p. 1. Directive repealed with effect from 13
May 2000 by Directive 97/43/Euratom (OJ L 180, 9.7.1997, p.
22).

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the dangers of

ionizing radiation (1),

against
the
objective of which is to prevent the exposure of workers
or patients to excessive or unnecessarily high levels of
ionizing radiation, and in particular of Article 5c
thereof, which requires prior authorization for
the
addition of radioactive substances to medicinal products
as well as
such medicinal
the importation of
products.

for

In particular,

therapeutic effect.
those Member States
which have a homeopathic tradition 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 provided that they
notify them to the Commission.

(19)

(20)

plasma

the
The Community entirely supports the efforts of
Council of Europe to promote voluntary unpaid blood
and
self-sufficiency
to
throughout
the Community in the supply of blood
products, and to ensure respect for ethical principles in
trade in therapeutic substances of human origin.

donation

attain

The rules designed to guarantee the quality, safety and
efficacy of medicinal products derived from human
blood or human plasma must be applied in the same
manner to both public and private establishments, and
to blood and plasma imported from third countries.

(26)

(27)

(28)

(21) Having regard to the particular characteristics of these
homeopathic medicinal products, such as the very low
level of active principles they contain and the difficulty
of applying to them the conventional statistical methods
it is desirable to provide a
relating to clinical
special,
those
homeopathic medicinal products which are placed on
the market without
in a
pharmaceutical form and dosage which do not present a
risk for the patient.

simplified registration procedure

therapeutic

indications

trials,

for

(22)

(23)

(24)

(25)

The anthroposophic medicinal products described in an
official pharmacopoeia and prepared by a homeopathic
method are to be treated, as regards registration and
marketing
as
homeopathic medicinal products.

authorization,

same way

the

in

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

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

The usual rules governing the authorization to market
medicinal products should be applied to homeopathic
medicinal products placed
on the market with
therapeutic indications or in a form which may present
the desired
risks which must be balanced against

(1) OJ L 246, 17.9.1980, p. 1. Directive as amended by Directive
84/467/Euratom (OJ L 265, 5.10.1984, p. 4), repealed with effect
from 13 May 2000 by Directive 96/29/Euratom (OJ L 314,
4.12.1996, p. 20).

In order
to facilitate the movement of medicinal
products and to prevent the controls carried out in one
in another,
State
Member
minimum requirements
laid down for
manufacture and imports coming from third countries
and for the grant of the authorization relating thereto.

from being

should be

repeated

It should be ensured that,
in the Member States, the
supervision and control of the manufacture of medicinal
products
carried out by a person who fulfils
minimum conditions of qualification.

is

his

Before an authorization to market an immunological
medicinal product or derived from human blood or
human plasma can be granted, the manufacturer must
batch-to-batch
demonstrate
consistency. Before
a
medicinal product derived from human blood or human
the manufacturer must also
plasma can be granted,
demonstrate the absence of specific viral contamination,
to the extent that the state of technology permits.

attain
an authorization to market

ability

to

(29)

The conditions governing the supply of medicinal
products to the public should be harmonized.

(30)

(31)

(32)

In this connection persons moving around within the
Community have the right
to carry a reasonable
quantity of medicinal products lawfully obtained for
their personal use. It must also be possible for a person
established in one Member State to receive from another
Member State
a reasonable quantity of medicinal
products intended for his personal use.

are

the

In addition, by virtue of Regulation (EC) No 2309/93,
subject of
certain medicinal products
a
Community marketing authorization.
In this context,
the classification for the supply of medicinal products
covered by a Community marketing authorization needs
to be established. It is therefore important to set the
criteria on the basis of which Community decisions will
be taken.

the basic principles

therefore appropriate, as an initial
applicable

step,
to
It
is
harmonize
to the
classification for the supply of medicinal products in the
Community or in the Member State concerned, while
taking as
already
established on this subject by the Council of Europe as
well as the work of harmonization completed within the
framework of the United Nations, concerning narcotic
and psychotropic substances.

the principles

starting point

a

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(33)

The provisions dealing with the
classification of
medicinal products for the purpose of supply do not
infringe the national social security arrangements for
reimbursement or payment for medicinal products on
prescription.

(41)

(42)

(34) Many operations involving the wholesale distribution of
medicinal products for human use may cover several
Member States simultaneously.

The marketing of medicinal products whose labelling
and package leaflets comply with this Directive should
not be prohibited or impeded on grounds connected
with the labelling or package leaflet.

adopted pursuant

This Directive is without prejudice to the application of
measures
to Council Directive
84/450/EEC of 10 September 1984 relating to the
and
approximation
administrative
States
concerning misleading advertising (1).

regulations
the Member

the
provisions

laws,
of

of

(35)

It is necessary to exercise control over the entire chain
of distribution of medicinal products,
from their
manufacture or import into the Community through to
supply to the public, so as to guarantee that such
products are stored, transported and handled in suitable
conditions. The requirements which must be adopted
for
the
withdrawal of defective products from the market and
allow more effective efforts against counterfeit products.

this purpose will

considerably

facilitate

(36) Any person involved in the wholesale distribution of
medicinal products should be in possession of a special
authorization. Pharmacists and persons authorized to
supply medicinal products
to the public, and who
confine themselves to this activity, should be exempt
from obtaining this
is however
in order to control the complete chain of
necessary,
distribution of medicinal products, that pharmacists and
persons authorized to supply medicinal products to the
public keep records showing transactions in products
received.

authorization.

It

(37) Authorization must be subject

to certain essential
conditions and it is the responsibility of the Member
State concerned to ensure that such conditions are met;
whereas
recognize
authorizations granted by other Member States.

each Member

State must

(38)

Certain Member States impose on wholesalers who
supply medicinal products
to pharmacists and on
persons authorized to supply medicinal products to the
public certain public service obligations. Those Member
States must be able to continue to impose those
established within their
obligations on wholesalers
territory. They must also be able to impose them on
wholesalers in other Member States on condition that
they do not impose any obligation more stringent than
those which they impose on their own wholesalers and
provided that such obligations may be regarded as
warranted on grounds of public health protection and
are proportionate in relation to the objective of such
protection.

(39)

Rules should be laid down as to how the labelling and
package leaflets are to be presented.

(40)

The provisions governing the information supplied to
should provide a high degree of consumer
users
protection,
in order that medicinal products may be
used correctly on the basis of full and comprehensible
information.

(43) All Member States have
concerning the

adopted further
specific
measures
advertising of medicinal
products. There are disparities between these measures.
These disparities are likely to have an impact on the
functioning of
the internal market, since advertising
disseminated in one Member State is likely to have
effects in other Member States.

(44)

the pursuit of

Council Directive 89/552/EEC of 3 October 1989 on
the coordination of certain provisions laid down by law,
regulation or administrative action in Member States
television broadcasting
concerning
activities (2) prohibits
television advertising of
medicinal products which are available only on medical
prescription in the Member
State within whose
jurisdiction the television broadcaster is located. This
principle should be made of general application by
extending it to other media.

the

(45) Advertising

to

the

public,

general

of
non-prescription medicinal products, could affect public
health, were it
to be excessive and ill-considered.
Advertising of medicinal products to the general public,
where it is permitted, ought therefore to satisfy certain
essential criteria which ought to be defined.

even

(46)

(47)

Furthermore, distribution of samples free of charge to
the general public for promotional ends must be
prohibited.

The advertising of medicinal products
to persons
qualified to prescribe or supply them contributes to the
information available to such persons. Nevertheless, this
advertising should be subject to strict conditions and
effective monitoring, referring in particular to the work
carried out within the framework of
the Council of
Europe.

(48) Advertising of medicinal products should be subject to
effective, adequate monitoring. Reference in this regard
should be made to the monitoring mechanisms set up
by Directive 84/450/EEC.

(49) Medical sales representatives have an important role in
the promotion of medicinal products. Therefore, certain
obligations should be imposed upon them, in particular
the obligation to supply the person visited with a
summary of product characteristics.

(1) OJ L 250, 19.9.1984, p. 17. Directive as amended by Directive

97/55/EC (OJ L 290, 23.10.1997, p. 18).

(2) OJ L 298, 17.10.1989, p. 23. Directive as amended by Directive

97/36/EC (OJ L 202, 30.7.1997, p. 60).

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(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

Persons qualified to prescribe medicinal products must
be able to carry out these functions objectively without
being
financial
direct
inducements.

influenced

indirect

by

or

It should be possible within certain restrictive conditions
to provide samples of medicinal products free of charge
to persons qualified to prescribe or supply them so that
they can familiarize themselves with new products and
acquire experience in dealing with them.

Persons qualified to prescribe or
supply medicinal
products must have access to a neutral, objective source
of information about products available on the market.
Whereas it is nevertheless for the Member States to take
all measures necessary to this end, in the light of their
own particular situation.

imports
Each undertaking which manufactures or
medicinal products
should set up a mechanism to
ensure that all information supplied about a medicinal
product conforms with the approved conditions of use.

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

is necessary to ensure

it
systems

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

of

use

electronic

increasing

The
for
communication of information on adverse reactions to
medicinal products marketed in the Community is
intended to allow competent authorities to share the
information at the same time.

networks

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

centrally

systems

for

(58) Holders

of marketing

be
proactively responsible for on-going pharmacovigilance
of the medicinal products they place on the market.

authorisations

should

(59)

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).

(1) OJ L 184, 17.7.1999, p. 23.

(60)

(61)

The Commission should be empowered to adopt any
in order to take into
necessary changes to Annex I
account scientific and technical progress.

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.

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:

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

2. Medicinal product:

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

Any substance or combination of substances which may
be administered to human beings with a view to making
a medical diagnosis or
correcting or
modifying physiological
functions in human beings is
likewise considered a medicinal product.

to restoring,

3.

Substance:

Any matter irrespective of origin which may be:

(cid:151) human, e.g.

human blood and human blood products;

(cid:151) animal, e.g.

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

(cid:151) vegetable, e.g.

micro-organisms, plants, parts of plants, vegetable
secretions, extracts;

(cid:151) chemical, e.g.

elements, naturally occurring chemical materials and
chemical products obtained by chemical change or
synthesis.

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4.

Immunological medicinal product:

9.

Radionuclide precursor:

Any medicinal product consisting of vaccines,
serums or allergen products:

toxins,

Any other radionuclide produced for the radio-labelling of
another substance prior to administration.

(a) vaccines, toxins and serums shall cover in particular:

(i) agents used to produce active immunity, such as
cholera vaccine, BCG, polio vaccines, smallpox
vaccine;

(ii) agents used to diagnose the state of immunity,
including in particular tuberculin and tuberculin
PPD,
the Schick and Dick Tests,
brucellin;

toxins

for

10. Medicinal products derived from human blood or human

plasma:

Medicinal products based on blood constitutents which
private
are
prepared
establishments,
in
particular,
and
immunoglobulins of human origin.

industrially
public
such medicinal products

including,
factors

coagulating

albumin,

by

or

(iii) agents used to produce passive immunity, such as
globulin,

anti-smallpox

diphtheria
antilymphocytic globulin;

antitoxin,

11. Adverse reaction:

(b)

(cid:145)allergen product(cid:146) shall mean any medicinal product
which is intended to identify or induce a specific
acquired alteration in the immunological response to
an allergizing agent.

A response to a medicinal product which is noxious and
unintended and which occurs at doses normally used in
man for the prophylaxis, diagnosis or therapy of disease
or
the restoration, correction or modification of
physiological function.

for

5. Homeopathic medicinal product:

12. Serious adverse reaction:

product

prepared

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

adverse

reaction which

is
An
inpatient hospitalisation or
life-threatening,
prolongation
in
persistent or significant disability or incapacity, or is a
congenital anomaly/birth defect.

hospitalisation,

requires

existing

results

results

death,

of

in

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

13. Unexpected adverse reaction:

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

6.

Radiopharmaceutical:

Any medicinal product which, when ready for use,
contains one or more radionuclides (radioactive isotopes)
included for a medicinal purpose.

14. Periodic safety update reports:

The periodical reports containing the records referred to
in Article 104.

7.

Radionuclide generator:

15. Post-authorisation safety study:

Any system incorporating a fixed parent radionuclide
from which is produced a daughter radionuclide which is
to be obtained by elution or by any other method and
used in a radiopharmaceutical.

study or a clinical

A pharmacoepidemiological
trial
carried out in accordance with the terms of the marketing
authorisation, conducted with the aim of identifying or
quantifying a safety hazard relating to an authorised
medicinal product.

8.

Radionuclide kit:

16. Abuse of medicinal products:

Any preparation to be reconsitituted or combined with
radionuclides in the final
radiopharmaceutical, usually
prior to its administration.

sporadic,

Persistent or
excessive use of
medicinal products which is accompanied by harmful
physical or psychological effets.

intentional

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17. Wholesale distribution of medicinal products:

26. Package leaflet:

All activities consisting of procuring, holding, supplying
or exporting medicinal products, apart from supplying
medicinal products to the public. Such activities are
their depositories,
carried out with manufacturers or
importers,
or with
pharmacists and persons authorized or entitled to supply
medicinal products to the public in the Member State
concerned.

other wholesale

distributors

18. Public service obligation:

to guarantee
The obligation placed on wholesalers
permanently an adequate range of medicinal products to
meet the requirements of a specific geographical area and
to deliver the supplies requested within a very short time
over the whole of the area in question.

19. Medicinal Prescription:

Any medicinal prescription issued by a professional
person qualified to do so.

20. Name of the medicinal product:

The name given to a medicinal product, which may be
either an invented name or a common or scientific name,
together with a trade mark or
the
manufacturer; the invented name shall not be liable to
confusion with the common name.

the name of

21. Common name:

The international non-proprietary name recommended by
the World Health Organization, or, if one does not exist,
the usual common name.

22. Strength of the medicinal product:

content

The
expressed
active
quantitatively per dosage unit, per unit of volume or
weight according to the dosage form.

substances

the

of

23.

Immediate packaging:

A leaflet containing information for
accompanies the medicinal product.

the user which

27. Agency:

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

28. Risk to public health:

All risks with regard to the quality, safety and efficacy of
the medicinal product.

TITLE II

SCOPE

Article 2

The provisions of
this Directive shall apply to industrially
produced medicinal products for human use intended to be
placed on the market in Member States.

Article 3

This Directive shall not apply to:

1. Any medicinal product prepared in a pharmacy in
accordance with a medical prescription for an individual
patient (commonly known as the magistral formula).

2. Any medicinal product which is prepared in a pharmacy in
accordance with the prescriptions of a pharmacopoeia and
is intended to be supplied directly to the patients served by
the pharmacy in question (commonly known as the official
formula).

3. Medicinal products intended for research and development

trials.

4.

Intermediate products intended for further processing by
an authorized manufacturer.

The container or other form of packaging immediately in
contact with the medicinal product.

5. Any radionuclides in the form of sealed sources.

6. Whole blood, plasma or blood cells of human origin.

24. Outer packaging:

The packaging into which is placed the immediate
packaging.

25. Labelling:

Information on the immediate or outer packaging.

Article 4

Nothing in this Directive shall in any way derogate from
1.
the Community rules for the radiation protection of persons
undergoing medical examination or treatment, or from the
Community rules laying down the basic safety standards for
the health protection of the general public and workers against
the dangers of ionizing radiation.

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2.
This Directive shall be without prejudice to Council
Decision 86/346/EEC of 25 June 1986 accepting on behalf of
the Community the European Agreement on the Exchange of
Therapeutic Substances of Human Origin (1).

The provisions of

this Directive shall not affect

the
3.
powers of the Member States’ authorities either as regards the
setting of prices for medicinal products or their inclusion in
the scope of national health insurance schemes, on the basis of
health, economic and social conditions.

4.
This Directive shall not affect the application of national
legislation prohibiting or restricting the sale, supply or use of
medicinal products as contraceptives or abortifacients. The
legislation
Member States
concerned to the Commission.

shall communicate the national

Article 5

A Member State may, in accordance with legislation in force
and to fulfil special needs, exclude from the provisions of this
Directive medicinal products supplied in response to a bona
fide unsolicited order,
formulated in accordance with the
specifications of an authorized health care professional and for
use by his
individual patients on his direct personal
responsibility.

TITLE III

legislation,
health
radionuclide generators,
precursors in accordance with the manufacturer’s instructions.

to use such medicinal products in an approved
from authorized
exclusively
radionuclide
radionuclide kits or

establishment

care

Article 8

1.
In order to obtain an authorization to place a medicinal
product on the market regardless of the procedure established
by Regulation (EEC) No 2309/93, an application shall be made
to the competent authority of the Member State concerned.

A marketing authorization may only be granted to an

2.
applicant established in the Community.

The application shall be accompanied by the following
submitted in accordance with

3.
particulars and documents,
Annex I:

(a) Name or corporate name and permanent address of the
applicant and, where applicable, of the manufacturer.

(b) Name of the medicinal product.

(c) Qualitative

and

quantitative

the
constituents of the medicinal product in usual terminology,
but excluding empirical chemical formulae, with mention
of the international non-proprietary name recommended
by the World Health Organization where such name exists.

particulars

all

of

PLACING ON THE MARKET

(d) Description of the manufacturing method.

CHAPTER 1

reactions.

(e) Therapeutic indications, contra-indications and adverse

Marketing authorization

(f) Posology, pharmaceutical

form, method and route of

administration and expected shelf life.

Article 6

1.
No 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 an authorization has been
granted in accordance with Regulation (EEC) No 2309/93.

(g)

If applicable, reasons for any precautionary and safety
measures to be taken for the storage of
the medicinal
product, its administration to patients and for the disposal
together with an indication of any
of waste products,
potential risks presented by the medicinal product for the
environment.

The authorisation referred to in paragraph 1 shall also be
2.
required
kits,
radionuclide precursor radiopharmaceuticals and industrially
prepared radiopharmaceuticals.

radionuclide

radionuclide

generators,

for

(h) Description of

the control methods employed by the
manufacturer (qualitative and quantitative analysis of the
constituents and of the finished product, special tests, e.g.
sterility
the presence of pyrogenic
substances, the presence of heavy metals, stability tests,
biological and toxicity tests, controls carried out at an
intermediate stage of the manufacturing process).

tests,

tests

for

Article 7

(i) Results of:

A marketing authorization shall not be required for a
radiopharmaceutical prepared at the time of use by a person
or by an establishment authorized, according to national

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

(cid:151) toxicological and pharmacological tests,

(1) OJ L 207, 30.7.1986, p. 1.

(cid:151) clinical trials.

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(j) A summary, in accordance with Article 11, of the product
characteristics, one or more specimens or mock-ups of the
outer packaging and the immediate packaging of
the
medicinal product, together with a package leaflet.

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

(k) A document showing that the manufacturer is authorised

in his own country to produce medicinal products.

the summary of

(l) Copies of any authorisation obtained in another Member
State or in a third country to place the medicinal product
on the market, together with a list of those Member States
in which an application for authorisation submitted in
accordance with this Directive is under examination.
the product characteristics
Copies of
proposed by the applicant in accordance with Article 11
or approved by the competent authorities of the Member
State in accordance with Article 21. Copies of the package
leaflet proposed in accordance with Article 59 or approved
the Member State in
by the competent authorities of
accordance with Article 61. Details of any decision to
refuse authorization, whether in the Community or in a
third country, and the reasons for such a decision.

This information shall be updated on a regular basis.

Article 9

In addition to the requirements set out in Articles 8 and 10(1),
an application for authorization to market a radionuclide
generator shall also contain the following information and
particulars:

(b)

(cid:151) a general description of the system together with a detailed
description of the components of the system which may
affect the composition or quality of the daughter nucleid
preparation,

State

(iii) or that the 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
for which the
marketed in the Member
application is made. This period shall be extended to
10 years in the case of high-technology medicinal
products having been authorised according to the
procedure
laid down in Article 2(5) of Council
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
on 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.

However, where the medicinal product is intended for
a different
the other
therapeutic use from that of
medicinal products marketed or is to be administered
by different routes or in different doses, the results of
tests
appropriate toxicological and pharmacological
and/or of appropriate clinical trials must be provided.

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

the results of

it

(cid:151) qualitative and quantitative particulars of the eluate or the

sublimate.

Annex I shall apply by analogy where, pursuant to point
2.
(ii) of paragraph 1, (a), bibliographic references to published
data are submitted.

Article 10

1.
In derogation of Article 8(3)(i), and without prejudice to
the law relating to the protection of industrial and commercial
property:

Article 11

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

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

1.

Name of the medicinal product.

(i) either that the medicinal product is essentially similar
to a medicinal product authorized in the Member State
concerned by the application and that the holder of
the marketing authorization for the original medicinal
product
toxicological,
pharmacological and/or clinical references contained in
the file on the original medicinal product being used
for
the purpose of examining the application in
question;

consented

has

the

to

2.

Qualitative and quantitative composition in terms of the
the excipient,
active substances and constituents of
knowledge
proper
essential
of which
the medicinal product. The usual
administration of
common name or chemical description shall be used.

for

is

(1) OJ L 15, 17.1.1987, p. 38. Directive repealed by Directive

93/41/EEC (OJ L 214, 24.8.1993, p. 40).

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3.

4.

Pharmaceutical form.

Pharmacological properties and,
information
pharmacokinetic particulars.

useful

for

is

in so far as

this
purposes,

therapeutic

5.

Clinical particulars:

5.1.

therapeutic indications,

5.2.

contra-indications,

5.3.

adverse reactions (frequency and seriousness),

5.4.

for use

case of
and,
special precautions
special
products,
immunological medicinal
precautions
to be taken by persons handling such
products and administering them to patients, together
with any precautions to be taken by the patient,

in the
any

5.5. use during pregnancy and lactation,

5.6.

interaction with other medicaments and other forms of
interaction,

5.7. posology and method of administration for adults and,

where necessary, for children,

5.8. overdose (symptoms, emergency procedures, antidotes),

5.9.

special warnings,

5.10. effects on ability to drive and to use machines.

6.

Pharmaceutical particulars:

6.1. major incompatibilities,

6.2.

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

6.3.

special precautions for storage,

6.4. nature and contents of the immediate packaging,

6.5.

special precautions for disposal of unused medicinal
products or waste materials derived from such medicinal
products, if appropriate.

storage time during which any intermediate preparation
such as an eluate or the ready-to-use pharmaceutical will
conform with its specifications.

Article 12

take all appropriate measures to
1. Member States shall
ensure that
the documents and particulars listed in Article
8(3)(h) and (i), and Article 10(1)(a)(ii) are drawn up by experts
with the necessary technical or professional qualifications
before they are submitted to the competent authorities. These
documents and particulars shall be signed by the experts.

The duties of the experts according to their respective

2.
qualifications shall be:

(a)

to perform tasks falling within their respective disciplines
(analysis, pharmacology and similar experimental sciences,
clinical
trials) and to describe objectively the results
obtained (qualitatively and quantitatively);

(b) to describe their observations in accordance with Annex I,

and to state, in particular:

(cid:151) in the case of

the analyst, whether the medicinal
product is consistent with the declared composition,
giving any substantiation of
the control methods
employed by the manufacturer;

(cid:151) in the case of the pharmacologist or the specialist with
similar experimental competence, the toxicity of the
medicinal product and the pharmacological properties
observed;

(cid:151) in the case of the clinician, whether he has been able
to ascertain effects on persons
treated with the
medicinal product which correspond to the particulars
given by the applicant in accordance with Articles 8
and 10, whether the patient tolerates the medicinal
product well, the posology the clinician advises and
any contra-indications and adverse reactions;

(c) where applicable,

to state the grounds

for using the

bibliography mentioned in point (a)(ii) of Article 10(1).

3.
Detailed reports by the experts shall form part of the
particulars accompanying the application which the applicant
submits to the competent authorities.

7.

8.

9.

Name or corporate name and permanent address of the
marketing authorization holder.

For radiopharmaceuticals, full details of internal radiation
dosimetry.

CHAPTER 2

Specific provisions applicable to homeopathic medicinal
products

Article 13

For radiopharmaceuticals, additional detailed instructions
for extemporaneous preparation and quality control of
such preparation and, where appropriate, maximum

1. Member States shall ensure that homeopathic medicinal
products manufactured and placed on the market within the

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Community are registered or authorized in accordance with
Articles 14, 15 and 16, except where the products are covered
by a registration or authorization which was granted under
national law on or before 31 December 1993 (and whether or
not that registration or authorization has been renewed after
take due account of
that date). Each Member State shall
registrations and authorizations previously granted by another
Member State.

registration

2.
A Member State may refrain from establishing a special,
homeopathic
procedure
simplified
medicinal products referred to in Article 14. A Member State
shall inform the Commission accordingly. The Member State
concerned shall allow the use in its territory of homeopathic
in
medicinal products
accordance with Articles 14 and 15.

registered by other Member States

the

for

Article 14

Only homeopathic medicinal products which satisfy all
to a special,

the following conditions may be subject

1.
of
simplified registration procedure:

(cid:151) they are administered orally or externally,

(cid:151) no specific therapeutic indication appears on the labelling
of the 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
substances whose presence in an allopathic medicinal
product results in the obligation to submit a doctor’s
prescription.

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

2.
The criteria and rules of procedure provided for in
Article 4(4), Article 17(1) and Articles 22 to 26, 112, 116 and
simplified
125 shall
registration procedure for homeopathic medicinal products,
with the exception of the proof of therapeutic efficacy.

apply by analogy to the

special,

3.
The proof of therapeutic efficacy shall not be required
for homeopathic medicinal products registered in accordance
with paragraph 1 of
this Article, or, where appropriate,
admitted in accordance with Article 13(2).

Article 15

of medicinal products

An application for special, simplified registration may cover a
series
same
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
homeopathic nature, on the basis of
an adequate
bibliography,

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

file for each pharmaceutical
the method of dilution and

(cid:151) manufacturing authorization for

the medicinal product

concerned,

(cid:151) copies of any registrations or authorizations obtained for

the same medicinal product in other Member States,

(cid:151) one or more specimens or mock-ups of

the outer
packaging and the immediate packaging of the medicinal
products to be registered,

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

Article 16

Homeopathic medicinal products other

1.
than those
referred to in Article 14(1) shall be authorized and labelled in
accordance with Articles 8, 10 and 11.

2.
A Member State may introduce or retain in its territory
specific rules for the toxicological and pharmacological tests
and clinical trials of homeopathic medicinal products other
than those referred to in Article 14(1) in accordance with the
principles and characteristics of homeopathy as practised in
that Member State.

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

the Member State concerned shall notify the

Title IX shall apply to homeopathic medicinal products,

3.
with the exception of those referred to in Article 14(1).

CHAPTER 3

Procedures relevant to the marketing authorization

Article 17

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

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2. Where a Member State notes that an application for
authorization is already under active examination in another
Member State in respect of
the
Member State concerned may decide to suspend the detailed
examination of
the
assessment report prepared by the other Member State in
accordance with Article 21(4).

that medicinal product,

application in order

to await

the

The Member State concerned shall inform the other Member
State and the applicant of
its decision to suspend detailed
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 18

Where a Member State is informed in accordance with Article
8(3)(l) that another Member State has authorized a medicinal
product which is
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 21(4).

subject of

the

Within 90 days of the receipt of the assessment report, the
Member State concerned shall either recognize the decision of
the product
the first Member State and the summary of
characteristics as approved by it or, if it considers that there
are grounds
the
medicinal product concerned may present a risk to public
health, it shall apply the procedures set out in Articles 29 to
34.

the authorization of

supposing that

for

Article 20

Member States shall take all appropriate measures to ensure
that:

(a)

the competent authorities verify that manufacturers and
importers of medicinal products
coming from third
countries are able to carry out manufacture in compliance
with the particulars supplied pursuant to Article 8(3)(d),
and/or to carry out controls according to the methods
described in the particulars accompanying the application
in accordance with Article 8(3)(h);

(b) the competent authorities may allow manufacturers and
coming from third
importers of medicinal products
countries,
to have
in exceptional and justifiable cases,
certain stages of manufacture and/or certain of the controls
referred to in (a) carried out by third parties; in such cases,
the verifications by the competent authorities shall also be
made in the establishment designated.

Article 21

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

Article 19

In order to examine the application submitted in accordance
with Articles 8 and 10(1),
the
Member State:

the competent authority of

1. must verify whether the particulars submitted in support
of the application comply with the said Articles 8 and
10(1) and examine whether the conditions for issuing an
authorization to place medicinal products on the market
(marketing authorization) are complied with.

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

4.
The competent authorities shall draw up an assessment
report and comments on the dossier as regards the results of
the analytical and pharmacotoxicological tests and the clinical
trials of
the 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 medicinal product concerned.

its

2. may submit the medicinal product,

if need be,

its starting materials
and,
intermediate products or other
constituent materials, for testing by a State laboratory or
by a laboratory designated for that purpose in order to
employed by the
control methods
ensure
that
manufacturer
particulars
in
described
accompanying the application in accordance with Article
8(3)(h) are satisfactory.

and

the

the

3. may, where

the

require

applicant

appropriate,

to
supplement the particulars accompanying the application
in respect of the items listed in the Articles 8(3) and 10(1).
Where the competent authority avails itself of this option,
the time limits laid down in Article 17 shall be suspended
until such time as the supplementary information required
has been provided. Likewise,
these time limits shall be
suspended for
the time allowed the applicant, where
appropriate, for giving oral or written explanation.

Article 22

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

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

of authorization,

(cid:151) the notification of adverse reactions

to the medicinal

product.

These exceptional decisions may be adopted only for objective
and verifiable reasons and shall be based on one of the causes
referred to in Part 4 (G) of Annex I.

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Article 23

the authorization
After an authorization has been issued,
holder must,
in respect of the methods of manufacture and
control provided for in Article 8(3)(d) and (h), take account of
scientific and technical progress and introduce any changes
that may be required to enable the medicinal product to be
manufactured and checked by means of generally accepted
scientific methods.

Proprietary Medicinal Products, hereinafter referred to as (cid:145)the
Committee(cid:146), is hereby set up. The Committee shall be part of
the Agency.

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 this Directive.

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

to the approval of

the

The Committee

3.
Prodecure.

shall draw up its own Rules of

Article 24

Article 28

three months before

Authorization shall be valid for
five years and shall be
renewable for five-year periods, on application by the holder at
and after
least
a dossier
consideration by the
on
containing
data
in
pharmacovigilance and other
to the
monitoring of the medicinal product.

details
information relevant

expiry date
authority of
the

the
competent

particular

of

Article 25

Authorization shall not affect the civil and criminal liability of
the marketing
the manufacturer and, where applicable, of
authorization holder.

Article 26

The marketing
after
authorisation shall be
verification of the particulars and documents listed in Articles
8 and 10(1), it proves that:

refused if,

(a)

the medicinal product is harmful in the normal conditions
of use, or

(b) that its therapeutic efficacy is lacking or is insufficiently

substantiated by the applicant, or

(c)

that its qualitative and quantitative composition is not as
declared.

Authorisation shall
likewise be refused if the particulars and
documents submitted in support of the application do not
comply with Articles 8 and 10(1).

CHAPTER 4

Mutual recognition of authorizations

Article 27

1.
In order to facilitate the adoption of common decisions
by Member States on the authorization of medicinal products
on the basis of the scientific criteria of quality, safety and
efficacy, and to achieve thereby the free movement of
medicinal products within the Community, a Committee for

1.
Before submitting the application for recognition of a
marketing authorization, the holder of the authorization shall
inform the Member State which granted the authorization on
which the application is based (hereinafter (cid:145)reference Member
State(cid:146)), 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.

In addition the holder of the authorization shall request the
reference Member State to prepare an assessment report in
respect of the medicinal product concerned, or, if necessary, to
update any existing assessment report. That Member State shall
prepare the assessment report, or update it, within 90 days of
the receipt of the request.

At the same time as the application is submitted in accordance
with paragraph 2, the reference Member State 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
procedures 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 authorities of the Member State
or Member States concerned, together with the information
and particulars referred to in Articles 8, 10(1) and 11. 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 11 is identical to that accepted
by the reference Member State in accordance with Article 21.
Moreover, he shall certify that all the dossiers filed as part of
the procedure are identical.

The holder of

3.
authorization shall
the marketing
communicate 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 medicinal
product concerned, and shall indicate whether any application
for authorization is currently under consideration in any
Member State.

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4.
Save in the exceptional case provided for in Article
recognize the marketing
29(1), each Member State shall
authorization granted by the reference Member State within 90
days of receipt of the application and the assessment report. It
shall
inform the reference Member State which granted the
initial authorization, the other Member States concerned by
the application, the Agency, and the marketing authorization
holder.

Article 29

supposing that

the marketing authorization of

1. Where a Member State considers that there are grounds
for
the
medicinal product concerned may present a risk to public
health,
it shall forthwith inform the applicant, the reference
Member State which granted the initial authorization, any
other Member States concerned by the application and the
Agency. The Member State shall state its reasons in detail and
indicate what action may be necessary to correct any
shall
defect in the application.

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
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 28(4)
they shall forthwith refer the matter to the Agency with regard
to the Committee’s
the
procedure laid down in Article 32.

the application of

reference for

3. Within the time limit referred to in Article 28(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 28(2).

the applicant

shall

Article 31

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 32 before reaching a decision on a
request for a marketing authorization or on the suspension or
withdrawal of an authorization, or on any other variation to
terms of a marketing authorization which appears
the
in particular to take account of the information
necessary,
collected in accordance with Title IX.

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

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

Article 32

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 30 and 31, 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
for the
shall define their tasks and specify the time-limit
completion of these tasks.

to act as

Article 30

adopted divergent decisions

and Article 11 have been made

If several applications submitted in accordance with Articles 8,
10(1)
for marketing
authorization for a particular medicinal product, and Member
concerning the
States have
authorization of the medicinal product or its suspension or
withdrawal, a Member State, or
the
marketing authorization holder may refer the matter to the
Committee for application of
the procedure laid down in
Article 32.

the Commission, or

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,
where appropriate, shall inform the holder.

3.
In the cases referred to in Articles 29 and 30, before
issuing its opinion, the Committee shall provide the marketing
authorization holder with an opportunity to present written or
oral explanations.

case

In the
the marketing
referred to in Article 31,
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 Member State and the marketing authorization holder
shall
forward to the Committee all available information
relating to the matter in question.

The Agency shall

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

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(cid:151) the

application
authorization, or

does

not

satisfy

the

criteria

for

Article 34

(cid:151) the summary of the product characteristics proposed by
in accordance with Article 11 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
including
and effective use of
pharmacovigilance, or

the medicinal product

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

withdrawn.

Within 15 days of the receipt of the opinion, the marketing
authorization 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 consider whether its opinion
should be revised, and the 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 medicinal
product and stating the reasons for its conclusions.

In the event of an opinion in favour of granting or
maintaining an authorization to place the 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

to in Article 11;

(b) any conditions affecting the authorization within the

meaning of paragraph 4.

Article 33

Within 30 days of the 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
32(5)(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.

A final decision on the application shall be adopted in

1.
accordance with the procedure referred to in Article 121(2).

The rules of procedure of

2.
the Standing Committee
established by Article 121(1) shall be adjusted to take account
of
in accordance with this
Chapter.

the tasks incumbent upon it

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

33,
obtained in writing,

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

(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

the written
Where,
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 121(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
reported to the marketing authorization holder. The Member
States shall either grant or withdraw marketing 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 35

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 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.

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

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).

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These arrangements shall be adopted by the Commission in
the form of an implementing Regulation in accordance with
the procedure referred to in Article 121(2).

TITLE IV

MANUFACTURE AND IMPORTATION

In case of arbitration submitted to the Commission, the
2.
procedure laid down in Articles 32, 33 and 34 shall apply by
analogy to variations made to marketing authorizations.

Article 36

1. Where a Member State considers that the variation of a
marketing authorization which has been granted in accordance
with the provisions of
this Chapter or its suspension or
withdrawal is necessary for the protection of public health, the
Member State concerned shall forthwith refer the matter to the
Agency for the application of the procedures laid down in
Articles 32, 33 and 34.

2. Without prejudice to the provisions of Article 31,
in
exceptional cases, where urgent action is essential to protect
public health, until a definitive decision is adopted a Member
State may suspend the marketing and the use of the medicinal
product concerned on its
inform the
Commission and the other Member States no later than the
following working day of the reasons for its action.

territory.

shall

It

Article 40

1. Member States shall
take all appropriate measures to
ensure that the manufacture of the medicinal products within
their territory is subject to the holding of an authorization.
authorization
This manufacturing
required
shall
nothwithstanding that
the medicinal products manufactured
are intended for export.

be

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

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.

Authorization referred to in paragraph 1 shall also be
3.
imports coming from third countries into a
required for
Member
and Article 118 shall have
corresponding application to such imports as they have to
manufacture.

this Title

State;

Article 37

Article 41

Articles 35 and 36 shall apply by analogy to 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 38

The Agency shall publish an annual

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

In order
applicant shall meet at least the following requirements:

to obtain the manufacturing authorization,

the

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

they

are

and

suitable

sufficient

(b) have at his disposal, for the manufacture or import of the
technical
above,
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 medicinal products, in accordance with Article
20;

premises,

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.

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

person within the meaning of Article 48.

The applicant shall provide particulars in support of the above
in his application.

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

Article 39

The provisions referred to in Articles 27 to 34 shall not apply
to the homeopathic medicinal products referred to in Article
16(2).

Article 42

1.
The competent authority of the Member State shall issue
the manufacturing authorization only after having made sure
of the accuracy of the particulars supplied pursuant to Article
41, by means of an inquiry carried out by its agents.

2.
In order to ensure that the requirements referred to in
Article 41 are complied with, authorization may be made
conditional on the carrying out of certain obligations imposed
either when authorization is granted or at a later date.

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

Article 43

The Member States shall
take all appropriate measures to
ensure that the time taken for the procedure for granting the
manufacturing authorization does not exceed 90 days from the
day on which the competent authority receives the application.

Article 44

If the holder of the manufacturing authorization requests a
change in any of the particulars referred to in points (a) and
(b) of the first paragraph of Article 41, 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.

Article 45

further

applicant

The competent authority of the Member State may require
from the
information concerning the
particulars supplied pursuant to Article 41 and concerning the
qualified person referred to in Article 48; where the competent
authority concerned exercises this right, application of
the
time-limits referred to in Article 43 and 44 shall be suspended
until the additional data required have been supplied.

Article 46

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

(a)

to have at his disposal the services of staff who comply
with the legal requirements existing in the Member State
concerned both as regards manufacture and controls;

(b) to dispose of the authorized medicinal products only in
the Member States

accordance with the legislation of
concerned;

(c)

to give prior notice to the competent authority of any
changes he may wish to make to any of the particulars
supplied pursuant to Article 41; the competent authority
the
in any event, be immediately informed if
shall,
qualified person referred to in Article 48 is replaced
unexpectedly;

(d) to allow the agents of

the
Member State concerned access to his premises at any
time;

the competent authority of

to enable the qualified person referred to in Article 48 to
carry out his duties, for example by placing at his disposal
all the necessary facilities;

(e)

(f)

Article 47

The principles and guidelines of good manufacturing practices
for medicinal products referred to in Article 46(f) shall be
adopted in the form of a directive,
in accordance with the
procedure referred to in Article 121(2).

Detailed guidelines
in line with those principles will be
published by the Commission and revised necessary to take
account of technical and scientific progress.

Article 48

take all appropriate measures to
1. Member States shall
ensure that the holder of the manufacturing authorization has
permanently and continuously at his disposal the services of at
least one qualified person, in accordance with the conditions
laid down in Article 49, responsible in particular for carrying
out the duties specified in Article 51.

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

Article 49

the qualified person
1. Member States shall ensure that
referred to in Article 48 fulfils the minimum conditions of
qualification set out in paragraphs 2 and 3.

2.
A 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 study in one of the following scientific disciplines:
pharmacy, medicine,
chemistry,
veterinary medicine,
pharmaceutical chemistry and technology, biology.

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

theoretical and practical

Where two university courses or two courses recognized by
the State as equivalent co-exist in a Member State and where
one of these extends over four years and the other over three
years, the three-year course leading to a diploma, certificate or
other evidence of formal qualifications awarded on completion
of a university course or its recognized equivalent shall be
considered to fulfil the condition of duration referred to in the
second subparagraph in so far as the diplomas, 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 include theoretical and practical study bearing
upon at least the following basic subjects:

to comply with the principles and guidelines of good
manufacturing practice for medicinal products as
laid
down by Community law.

(cid:151) Applied physics

(cid:151) General and inorganic chemistry

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(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

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

Studies in these subjects should be so balanced as to enable the
person concerned to fulfil the obligations specified in Article
51.

following notification of
this directive in one or more
production
authorized
undertakings
supervision and/or qualitative and quantitative analysis of
active substances, and the necessary testing and checking
under the direct authority of the person referred to in Article
48 to ensure the quality of the medicinal products.

to manufacture:

If the person concerned has acquired the practical experience
referred to in the first subparagraph before 21 May 1965, a
further one year’s practical experience in accordance with the
conditions
subparagraph will be
required to be completed immediately before he engages in
such activities.

referred to in the first

Article 51

take all appropriate measures to
1. Member States shall
ensure that
the qualified person referred to in Article 48,
without prejudice to his relationship with the holder of the
manufacturing authorization, is responsible, in the context of
the procedures referred to in Article 52, for securing:

fulfil

In so far as certain diplomas, certificates or other evidence of
formal qualifications mentioned in the first subparagraph do
not
the
competent authority of the Member State shall ensure that the
person concerned provides evidence of adequate knowledge of
the subjects involved.

the criteria laid down in this paragraph,

at

least

The qualified person shall have
two years,

acquired practical
3.
experience over
in one or more
undertakings which are authorized to manufacture medicinal
products, 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
medicinal products.

(a)

(b)

in the case of medicinal products manufactured within the
Member States concerned, that each batch of medicinal
products
in
compliance with the laws in force in that Member State
and in accordance with the requirements of the marketing
authorization;

been manufactured

checked

and

has

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

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 50

1.
A person engaging in the activities of the person referred
to in Article 48 from the time of the application of Directive
75/319/EEC, in a Member State without complying with the
provisions of Article 49 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 48
in accordance with the laws of that State may (cid:151) if he began
his course prior to 21 May 1975 (cid:151) be considered as qualified
to carry out in that State the duties of the person referred to in
Article 48 provided that he has previously engaged in the
following activities for at least two years before 21 May 1985

The batches of medicinal products which have undergone such
controls in a Member State shall be exempt from the controls
if they are marketed in another Member State, accompanied by
the control reports signed by the qualified person.

2.
In the case of medicinal products imported from a third
country, where appropriate arrangements have been made by
the Community with the exporting country to ensure that the
manufacturer of the medicinal product applies standards of
good manufacturing practice at least equivalent to those laid
down by the Community, and to ensure that
the controls
subparagraph of
(b) of
referred to under point
paragraph 1 have been carried out in the exporting country,
the qualified person may be relieved of responsibility for
carrying out those controls.

the first

3.
In all cases and particularly where the medicinal products
are released for sale, the qualified person must certify in a
register or equivalent document provided for that purpose,
that each production batch satisfies the provisions of
this
Article; the said register or equivalent document must be kept

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up to date as operations are carried out and must remain at
the disposal of the agents of the competent authority for the
period specified in the provisions of
the Member State
concerned and in any event for at least five years.

Article 52

Member States shall ensure that the duties of qualified persons
referred to in Article 48 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 procedures against him for failure to fulfil his
obligations.

Article 53

The provisions of this Title shall also apply to homeopathic
medicinal products.

(g) a special warning,

if this is necessary for the medicinal

product;

(h) the expiry date in clear terms (month/year);

(i)

special storage precautions, if any;

(j)

special precautions
products or waste materials from medicinal products,
appropriate;

for disposal of unused medicinal
if

(k) the name and address of the holder of the authorization

for placing the medicinal product on the market;

(l)

the number of the authorization for placing the medicinal
product on the market;

(m) the manufacturer’s batch number;

(n)

in the case of self-medication, instructions on the use of
the medicinal products.

Article 55

TITLE V

LABELLING AND PACKAGE LEAFLET

1.
The particulars laid down in Articles 54 and 62 shall
appear on immediate packagings other than those referred to
in paragraphs 2 and 3.

Article 54

The following particulars shall appear on the outer packaging
of medicinal products or, where there is no outer packaging,
on the immediate packaging:

(a)

the medicinal product

the name of
followed by the
common name where the product contains only one active
substance and if its name is an invented name; where a
is available in several pharmaceutical
medicinal product
forms and/or several strengths, the pharmaceutical form
and/or the strength (baby, child or adult as appropriate)
must be included in the name of the medicinal product;

(b) a statement of the active substances expressed qualitatively
and quantitatively per dosage unit or according to the
form of administration for a given volume or weight, using
their common names;

The

following particulars at

2.
shall appear on
immediate packagings which take the form of blister packs
and are placed in an outer packaging that complies with the
requirements laid down in Articles 54 and 62.

least

(cid:151) the name of the medicinal product as laid down in Article

54(a),

(cid:151) the name of the holder of the authorization for placing the

product on the market,

(cid:151) the expiry date,

(cid:151) the batch number.

3.
The following particulars at least shall appear on small
immediate packaging units on which the particulars laid down
in Articles 54 and 62 cannot be displayed:

(cid:151) the name of the medicinal product and, if necessary, the

strength and the route of administration,

(c)

the pharmaceutical form and the contents by weight, by
volume or by number of doses of the product;

(cid:151) the method of administration,

(d) a list of

those excipients known to have a recognized
action or effect and included in the guidelines published
pursuant
is
injectable, or a topical or eye preparation, all excipients
must be stated;

to Article 65. However,

the product

if

(cid:151) the expiry date,

(cid:151) the batch number,

(cid:151) the contents by weight, by volume or by unit.

(e)

the method and, if necessary, the route of administration;

Article 56

(f) a special warning that

the medicinal product must be

stored out of reach of children;

The particulars referred to in Articles 54, 55 and 62 shall be
easily legible, clearly comprehensible and indelible.

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Article 57

(c)

list of information which is necessary before taking the
medicinal product:

Notwithstanding Article 60, Member States may require the
use of certain forms of
the medicinal product
labelling of
making it possible to ascertain:

(cid:151) the price of the medicinal product,

(cid:151) the

reimbursement

conditions

of

social

security

organizations,

(cid:151) contra-indications,

(cid:151) appropriate precautions for use,

(cid:151) forms of interaction with other medicinal products and

other forms of interaction

(e.g. alcohol, tobacco, foodstuffs) which may affect the
action of the medicinal product,

(cid:151) the legal status for supply to the patient,

in accordance

with Title VI,

(cid:151) special warnings;

(cid:151) identification and authenticity.

this list must:

Article 58

The inclusion in the packaging of all medicinal products of a
package leaflet shall be obligatory unless all the information
required by Articles 59 and 62 is directly conveyed on the
outer packaging or on the immediate packaging.

Article 59

1.
The package leaflet shall be drawn up in accordance with
the summary of the product characteristics; it shall include, in
the following order:

(a)

for the identification of the medicinal product:

(cid:151) the name of the medicinal product, followed by the
common name if the product contains only one active
substance and if its name is an invented name; where a
medicinal product is available in several pharmaceutical
the pharmaceutical
forms and/or
form and/or the strength (for example, baby, child,
adult) must be included in the name of the medicinal
product,

strengths,

several

(cid:151) a full statement of the active substances and excipients
expressed qualitatively and a statement of the active
substances
their
common names,
in the case of each presentation of
the medicinal product,

quantitatively,

expressed

using

(cid:151) the pharmaceutical form and the contents by weight,
by volume or by number of doses of the product, in
the case of each presentation of the product,

(cid:151) the pharmaco-therapeutic group, or type of activity in

terms easily comprehensible for the patient,

(cid:151) the name

and

the
authorization for placing the medicinal product on the
market and of the manufacturer;

the holder of

address of

(b) the therapeutic indications;

(cid:151) take into account the particular condition of certain
categories
or
(e.g.
breastfeeding women, the elderly, persons with specific
pathological conditions),

children, pregnant

users

of

(cid:151) mention, if appropriate, potential effects on the ability

to drive vehicles or to operate machinery,

(cid:151) detail

those

excipients,

knowledge of which is
the
important
medicinal product and included in the guidelines
published pursuant to Article 65;

the safe and effective use of

for

(d) the necessary and usual

instructions for proper use,

in

particular:

(cid:151) the dosage,

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

(cid:151) the frequency of administration, specifying if necessary,
the appropriate time at which the medicinal product
may or must be administered,

and, as appropriate, depending on the nature of
product:

the

(cid:151) the duration of treatment, where it should be limited,

(cid:151) the action to be taken in the case of an overdose (e.g.,

symptoms, emergency procedures),

(cid:151) the course of action to take when one or more doses

have not been taken,

(cid:151) indication,
effects;

if necessary, of

the risk of withdrawal

(e) a description of the undesirable effects which can occur
under normal use of
if
necessary, the action to be taken in such a case; the patient
any
invited
should

the medicinal product and,

communicate

expressly

be

to

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undesirable effect which is not mentioned in the leaflet to
his doctor or to his pharmacist;

Article 62

(f) a reference to the expiry date indicated on the label, with:

(cid:151) a warning against using the product after this date,

(cid:151) where appropriate, special storage precautions,

(cid:151) if necessary, a warning against certain visible signs of

deterioration;

(g) the date on which the package leaflet was last revised.

2.
Notwithstanding paragraph 1(b), the authority competent
may decide that certain therapeutic indications shall not be
mentioned in the package leaflet, where the dissemination of
such information might have serious disadvantages for the
patient.

Article 60

Member States may not prohibit or impede the placing on the
market of medicinal products within their territory on grounds
connected with labelling or the package leaflet where these
comply with the requirements of this Title.

Article 61

One or more specimens or mock-ups of

1.
the outer
packaging and the immediate packaging of a medicinal
together with the draft package leaflet, shall be
product,
authorizing
submitted to the
marketing when the marketing authorization is requested.

competent

authorities

for

The competent authority shall

2.
refuse the marketing
authorization if the labelling or the package leaflet do not
comply with the provisions of this Title or if they are not in
accordance with the particulars listed in the summary of
product characteristics.

3.
All proposed changes to an aspect of the labelling or the
package leaflet covered by this Title and not connected with
the summary of product characteristics shall be submitted to
the
the authorities competent
competent authorities have not opposed a proposed change
within 90 days following the introduction of the request, the
applicant may put the change into effect.

for authorizing marketing.

If

4.
The fact that the competent authority do not refuse a
marketing authorization pursuant to paragraph 2 or a change
to the labelling or the package leaflet pursuant to paragraph 3
does not alter the general legal liability of the manufacturer or
as appropriate the marketing authorization holder.

The outer packaging and the package leaflet may include
symbols or pictograms designed to clarify certain information
mentioned in Articles 54 and 59(1) and other information
compatible with the summary of the product characteristics
which is useful for health education, to the exclusion of any
element of a promotional nature.

Article 63

The particulars for labelling listed in Articles 54, 59 and
language or languages of the

1.
62 shall appear in the official
Member State where the product is placed on the market.

The first subparagraph shall not prevent these particulars from
languages, provided that the same
being indicated in several
particulars appear in all the languages used.

2.
The package leaflet must be written in clear and
understandable terms for the users and be clearly legible in the
official language or languages of the Member State where the
medicinal product is placed on the market.

The first subparagraph shall not prevent the package leaflet
being printed in several
languages, provided that the same
information is given in all the languages used.

for

specific medicinal products

competent authorities may exempt

labels and
The
3.
package leaflets
from the
obligation that certain particulars shall appear and that the
leaflet must be in the official
language or languages of the
Member State where the product is placed on the market,
when the product is not intended to be delivered to the patient
for self-administration.

Article 64

Where the provisions of this Title are not complied with, and
a notice served on the person concerned has remained without
effect, the competent authorities of the Member States may
suspend the marketing authorization, until the labelling and
the package leaflet of the medicinal product in question have
been made to comply with the requirements of this Title.

Article 65

As necessary,
concerning in particular:

the Commission shall publish guidelines

(cid:151) the formulation of certain special warnings for certain

categories of medicinal products,

(cid:151) the particular information needs relating to self-medication,

(cid:151) the legibility of particulars on the labelling and package

leaflet,

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(cid:151) methods

the
medicinal products,

for

identification and authentication of

Article 69

(cid:151) the list of excipients which must feature on the labelling of
medicinal products and the way these excipients must be
indicated.

These guidelines shall be adopted in the form of a Directive, in
accordance with the procedure referred to in Article 121(2).

Article 66

clear mention of

the words
1.
In addition to the
the labelling and, where
(cid:145)homeopathic medicinal product(cid:146),
appropriate,
for the medicinal products
referred to in Article 14(1) shall bear the following, and no
other, information:

the package insert

(cid:151) the scientific name of the stock or stocks followed by the
the

degree of dilution, making use of
pharmacopoeia used in accordance with Article 1(5),

the symbols of

1.
The outer carton and the container of medicinal products
containing radionuclides shall be labelled in accordance with
the regulations for the safe transport of radioactive materials
laid down by the International Atomic Energy Agency.
Moreover, the labelling shall comply with the provisions set
out in paragraphs 2 and 3.

(cid:151) name and address of the registration holder and, where

appropriate, of the manufacturer,

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

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

In addition,

The label on the shielding shall

include the particulars
2.
mentioned in Article 54.
the labelling on the
shielding shall explain in full, the codings used on the vial and
shall indicate, where necessary, for a given time and date, the
amount of radioactivity per dose or per vial and the number of
capsules, or,
the number of millilitres in the
container.

for liquids,

(cid:151) pharmaceutical form,

(cid:151) contents of the sales presentation,

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

3.

The vial shall be labelled with the following information:

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

(cid:151) manufacturer’s batch number,

(cid:151) the name or code of the medicinal product, including the

name or chemical symbol of the radionuclide,

(cid:151) registration number,

(cid:151) the batch identification and expiry date,

(cid:151) the international symbol for radioactivity,

(cid:151) the name of the manufacturer,

(cid:151) (cid:145)homeopathic medicinal
therapeutic indications(cid:146),

product without

approved

(cid:151) a warning advising the user to consult a doctor if the
symptoms persist during the use of the medicinal product.

(cid:151) the amount of radioactivity as specified in paragraph 2.

Notwithstanding paragraph 1, Member States may

2.
require the use of certain types of labelling in order to show:

Article 67

(cid:151) the price of the medicinal product,

that

shall

ensure

competent

authority
is

a detailed
The
instruction leaflet
enclosed with the packaging of
radiopharmaceuticals, radionuclide generators, radionuclide kits
or radionuclide precursors. The text of this leaflet shall be
established in accordance with the provisions of Article 59. In
addition, the leaflet shall include any precautions to be taken
by the user and the patient during the preparation and
administration
special
precautions for the disposal of the packaging and its unused
contents.

the medicinal

product

and

of

Article 68

prejudice

69,
provisions
the
Without
to
shall
in
homeopathic medicinal
products
accordance with the provisions of
this title and shall be
identified by a reference on their labels, in clear and legible
form, to their homeopathic nature.

of Article
be

labelled

(cid:151) the conditions for refunds by social security bodies.

TITLE VI

CLASSIFICATION OF MEDICINAL PRODUCTS

Article 70

1. When a marketing
granted,
competent authorities shall specify the classification of
medicinal product into:

authorization is

the
the

(cid:151) a medicinal product subject to medical prescription,

(cid:151) a medicinal product not subject to medical prescription.

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To this end, the criteria laid down in Article 71(1) shall apply.

2.
The competent authorities may fix sub-categories for
medicinal products which are available on medical prescription
only.
following
classification:

they shall

In that

to the

case,

refer

(a) medicinal products on renewable or non-renewable

medical prescription;

(b) medicinal products subject to special medical prescription;

(c) medicinal products on restricted medical prescription,

reserved for use in certain specialized areas.

Article 71

(cid:151) the medicinal product, because of

its pharmaceutical
characteristics or novelty or in the interests of public
health,
treatments which can only be
followed in a hospital environment,

is reserved for

(cid:151) the medicinal product

is used in the

treatment of
conditions which must be diagnosed in a hospital
environment or in institutions with adequate diagnostic
facilities, although administration and follow-up may be
carried out elsewhere, or

(cid:151) the medicinal product is intended for outpatients but its
use may produce very serious adverse reactions requiring a
prescription drawn up as required by a specialist and
special supervision throughout the treatment.

A competent

4.
paragraphs 1, 2 and 3 having regard to:

authority may waive

application of

1. Medicinal
prescription where they:

products

shall

be

subject

to medical

(a)

(cid:151) are likely to present a danger either directly or indirectly,
if utilized without medical

even when used correctly,
supervision, or

the maximum single dose, the maximum daily dose, the
strength,
certain types of
packaging; and/or

the pharmaceutical

form,

(cid:151) are frequently and to a very wide extent used incorrectly,
and as a result are likely to present a direct or indirect
danger to human health, or

(cid:151) contain substances or preparations thereof,

reactions of which require

the activity
further

and/or
adverse
investigation, or

(b) other circumstances of use which it has specified.

If a competent authority does not designate medicinal
5.
products into sub-categories referred to in Article 70(2),
it
shall nevertheless take into account the criteria referred to in
paragraphs 2 and 3 of this Article in determining whether any
medicinal product shall be classified as a prescription-only
medicine.

(cid:151) are normally prescribed by a doctor to be administered

parenterally.

Article 72

2. Where Member States provide for the sub-category of
medicinal products subject to special medical prescription, they
shall take account of the following factors:

Medicinal products not subject to prescription shall be those
which do not meet the criteria listed in Article 71.

(cid:151) the medicinal product contains, in a non-exempt quantity,
a substance classified as a narcotic or a psychotropic
substance within the meaning of
international
conventions
the United Nations
such as
in force,
Conventions of 1961 and 1971, or

the

(cid:151) the medicinal product

to
is likely,
present a substantial risk of medicinal abuse, to lead to
addiction or be misused for illegal purposes, or

incorrectly used,

if

Article 73

The competent authorities shall draw up a list of the medicinal
products subject, on their territory, to medical prescription,
specifying,
the category of classification. They
shall update this list annually.

if necessary,

(cid:151) the medicinal product contains a substance which, by
reason of its novelty or properties, could be considered as
belonging to the group envisaged in the second indent as a
precautionary measure.

3. Where Member States provide for the sub-category of
medicinal products subject to restricted prescription, they shall
take account of the following factors:

Article 74

On the occasion of the five-yearly renewal of the marketing
authorization or when new facts are brought to their notice,
the competent authorities shall examine and, as appropriate,
amend the classification of a medicinal product, by applying
the criteria listed in Article 71.

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Article 75

Each year, Member
to the
Commission and to the other Member States, the changes that
have been made to the list referred to in Article 73.

communicate

States

shall

TITLE VII

WHOLESALE DISTRIBUTION OF MEDICINAL PRODUCTS

Article 76

inform the Commission and the other Member State involved.
The latter shall take the measures necessary and shall inform
the Commission and the first Member State of the decisions
taken and the reasons for those decisions.

Article 78

shall ensure that

Member States
the
procedure for examining the application for the distribution
authorization does not exceed 90 days from the day on which
the competent authority of
the Member State concerned
receives the application.

the time taken for

Without prejudice to Article 6, Member States shall take all
appropriate action to ensure that only medicinal products in
respect of which a marketing authorization has been granted
in accordance with Community law are distributed on their
territory.

The competent authority may, if need be, require the applicant
to supply all necessary information concerning the conditions
of authorization. Where the authority exercises this option, the
period laid down in the first paragraph shall be suspended
until the requisite additional data have been supplied.

Article 77

Article 79

1. Member States shall
take all appropriate measures to
ensure that the wholesale distribution of medicinal products is
subject to the possession of an authorization to engage in
activity as a wholesaler in medicinal products, stating the place
for which it is valid.

In order to obtain the distribution authorization, applicants
must fulfil the following minimum requirements:

2. Where persons authorized or entitled to supply medicinal
products to the public may also, under national law, engage in
to the
wholesale business,
authorization provided for in paragraph 1.

shall be subject

such persons

3.
Possession of a manufacturing authorization shall include
authorization to distribute by wholesale the medicinal products
covered by that authorization. Possession of an authorization
to engage in activity as a wholesaler in medicinal products
shall not give dispensation from the obligation to possess a
to comply with the
manufacturing
the
even where
conditions
manufacturing or import business is secondary.

authorization and

set out

in that

respect,

At the request of the Commission or any Member State,
4.
information
Member States
concerning the individual authorizations which they have
granted under paragraph 1.

appropriate

supply all

shall

Checks on the persons authorized to engage in the
5.
activity of wholesaler in medicinal products and the inspection
of their premises, shall be carried out under the responsibility
of the Member State which granted the authorization.

The Member State which granted the authorization
6.
referred to in paragraph 1 shall suspend or
revoke that
authorization if the conditions of authorization cease to be
met. It shall forthwith inform the other Member States and the
Commission thereof.

Should a Member State consider that,

7.
in respect of a
person holding an authorization granted by another Member
State under the terms of paragraph 1,
the conditions of
authorization are not, or are no longer met, it shall forthwith

(a)

have

they must
suitable
installations and equipment,
conservation and distribution of the medicinal products;

premises,
to ensure proper

and
so as

adequate

(b) they must have staff, and in particular, a qualified person
designated as responsible, meeting the conditions provided
for by the legislation of the Member State concerned;

(c)

they must undertake to fulfil the obligations incumbent on
them under the terms of Article 80.

Article 80

Holders of
following minimum requirements:

the distribution authorization must

fulfil

the

(a)

they must make the premises, installations and equipment
referred to in Article 79(a) accessible at all times to the
persons responsible for inspecting them;

(b) they must obtain their supplies of medicinal products only
the
from persons who are themselves in possession of
distribution authorization or who are
from
obtaining such authorization under the terms of Article
77(3);

exempt

(c)

themselves

they must supply medicinal products only to persons who
are
distribution
possession
authorization or who are authorized or entitled to supply
medicinal products to the public in the Member State
concerned;

the

of

in

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(d) they must have an emergency plan which ensures effective
implementation of any recall from the market ordered by
the competent authorities or carried out in cooperation
with the manufacturer or marketing authorization holder
for the medicinal product concerned;

(e)

they must keep records either in the form of purchase/sales
invoices, or on computer, or in any other form, giving for
any
received or
transaction in medicinal products
dispatched at least the following information:

(cid:151) date,

(cid:151) name of the medicinal product,

(cid:151) quantity received or supplied,

(cid:151) name and address of

the supplier or consignee, as

appropriate;

(f)

they must keep the records referred to under (e) available
to the competent authorities, for inspection purposes, for a
period of five years;

products to the public are able to provide information that
makes it possible to trace the distribution path of every
medicinal product.

Article 83

The provisions of this Title shall not prevent the application of
more stringent requirements laid down by Member States in
respect of the wholesale distribution of:

(cid:151) narcotic or psychotropic substances within their territory,

(cid:151) medicinal products derived from blood,

(cid:151) immunological medicinal products,

(cid:151) radiopharmaceuticals.

Article 84

(g) they must comply with the principles and guidelines of
good distribution practice for medicinal products as laid
down in Article 84.

The Commission shall publish guidelines on good distribution
the Committee for
it shall consult
practice. To this end,
Proprietary Medicinal
Pharmaceutical
the
Products
Committee established by Council Decision 75/320/EEC (1).

and

Article 81

Article 85

supply of medicinal products

With regard to the
to
pharmacists and persons authorized or entitled to supply
medicinal products to the public, Member States shall not
impose upon the holder of a distribution authorization which
has been granted by another Member State, any obligation, in
particular public service obligations, more stringent than those
they
themselves
authorized to engage in equivalent activities.

impose on persons whom they have

The said obligations should, moreover, be justified, in keeping
with the Treaty, on grounds of public health protection and be
proportionate in relation to the objective of such protection.

Article 82

For all supplies of medicinal products to a person authorized
or entitled to supply medicinal products to the public in the
Member State concerned,
the authorized wholesaler must
enclose a document that makes it possible to ascertain:

(cid:151) the date,

(cid:151) the name and pharmaceutical

form of

the medicinal

product,

(cid:151) the quantity supplied,

The provisions of
this Title shall apply to homeopathic
medicinal products, with the exception of those referred to in
Article 14(1).

TITLE VIII

ADVERTISING

Article 86

For the purposes of this Title,

(cid:145)advertising of medicinal
1.
products(cid:146) shall include any form of door-to-door information,
canvassing activity or inducement designed to promote the
prescription,
consumption of medicinal
supply,
products; it shall include in particular:

sale or

(cid:151) the advertising of medicinal products to the general public,

(cid:151) advertising of medicinal products to persons qualified to

prescribe or supply them,

(cid:151) visits by medical sales representatives to persons qualified

to prescribe medicinal products,

(cid:151) the name and address of the supplier and consignor.

(cid:151) the supply of samples,

Member States shall take all appropriate measures to ensure
that persons authorized or entitled to supply medicinal

(1) OJ L 187, 9.6.1975, p. 23.

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(cid:151) the provision of

inducements

supply
medicinal products by the gift, offer or promise of any
benefit or bonus, whether in money or in kind, except
when their intrinsic value is minimal,

to prescribe or

(cid:151) sponsorship of promotional meetings attended by persons

qualified to prescribe or supply medicinal products,

(cid:151) sponsorship of scientific congresses attended by persons
qualified to prescribe or supply medicinal products and in
particular payment of their travelling and accommodation
expenses in connection therewith.

(cid:151) contain psychotropic or narcotic substances, such as the

United Nations Conventions of 1961 and 1971,

(cid:151) may not be advertised to the general public in accordance

with the second subparagraph of paragraph 2.

2. Medicinal products may be advertised to the general
public which, by virtue of their composition and purpose, are
intended and designed for use without the intervention of a
the
medical practitioner
prescription or monitoring of treatment, with the advice of the
pharmacist, if necessary.

for diagnostic purposes or

for

2.

The following are not covered by this Title:

Member States shall prohibit the mentioning in advertising to
the general public of therapeutic indications such as:

(cid:151) the labelling and the accompanying package leaflets, which

are subject to the provisions of Title V,

(cid:151) tuberculosis,

(cid:151) correspondence, possibly accompanied by material of a
non-promotional nature, needed to answer a specific
question about a particular medicinal product,

(cid:151) sexually transmitted diseases,

(cid:151) other serious infectious diseases,

for example,

(cid:151) factual, informative announcements and reference material
to pack changes, adverse-reaction
relating,
warnings as part of general drug precautions,
trade
catalogues and price lists, provided they include no
product claims,

(cid:151) cancer and other tumoral diseases,

(cid:151) chronic insomnia,

(cid:151) diabetes and other metabolic illnesses.

(cid:151) statements relating to human health or diseases, provided

there is no reference, even indirect, to medicinal products.

Article 87

shall prohibit any advertising of a
1. Member States
medicinal
a marketing
in
respect
authorization has not been granted in accordance with
Community law.

of which

product

2.
All parts of the advertising of a medicinal product must
comply with the particulars listed in the summary of product
characteristics.

3.

The advertising of a medicinal product:

3. Member States shall be able to ban, on their territory,
advertising to the general public of medicinal products the cost
of which may be reimbursed.

4.
The prohibition referred to in paragraph 1 shall not
apply to vaccination campaigns carried out by the industry
and approved by the competent authorities of the Member
States.

The prohibition referred to in paragraph 1 shall apply

5.
without prejudice to Article 14 of Directive 89/552/EEC.

6. Member States shall prohibit the direct distribution of
medicinal products
industry for
they may, however, authorize such
promotional purposes;
distribution in special cases for other purposes.

to the public by the

(cid:151) shall encourage the rational use of the medicinal product,
by presenting it objectively and without exaggerating its
properties,

Article 89

(cid:151) shall not be misleading.

Article 88

1. Member States
general public of medicinal products which:

shall prohibit

the advertising to the

1. Without prejudice to Article 88, all advertising to the
general public of a medicinal product shall:

(a) be set out in such a way that it is clear that the message is
an advertisement and that the product is clearly identified
as a medicinal product;

(b)

include the following minimum information:

(cid:151) are available on medical prescription only, in accordance

with Title VI,

(cid:151) the name of

the medicinal product, as well as the
common name if the medicinal product contains only
one active substance,

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(cid:151) the information necessary for correct use of

the

medicinal product,

(cid:151) an express,

legible invitation to read carefully the
instructions on the package leaflet or on the outer
packaging, as the case may be.

(k) uses, in improper, alarming or misleading terms, pictorial
representations of changes in the human body caused by
disease or injury, or of the action of a medicinal product
on the human body or parts thereof;

(l) mentions that the medicinal product has been granted a

marketing authorization.

2. Member States may decide that
the advertising of a
medicinal product to the general public may, notwithstanding
paragraph 1, include only the name of the medicinal product
if it is intended solely as a reminder.

Article 91

Article 90

The advertising of a medicinal product to the general public
shall not contain any material which:

(a) gives the impression that a medical consultation or surgical
in particular by offering a

operation is unnecessary,
diagnosis or by suggesting treatment by mail;

(b) suggests

that

the effects of

taking the medicine are
guaranteed, are unaccompanied by adverse reactions or are
better than, or equivalent to, those of another treatment or
medicinal product;

(c) suggests that the health of the subject can be enhanced by

taking the medicine;

(d) suggests that the health of the subject could be affected by
not taking the medicine; this prohibition shall not apply to
the vaccination campaigns referred to in Article 88(4);

(e)

is directed exclusively or principally at children;

(f)

a

to

recommendation

refers
health
professionals or persons who are neither of the foregoing
but who, because of their celebrity, could encourage the
consumption of medicinal products;

scientists,

by

(g) suggests that the medicinal product is a foodstuff, cosmetic

or other consumer product;

Any advertising of a medicinal product

1.
qualified to prescribe or supply such products shall include:

to persons

(cid:151) essential

information compatible with the summary of

product characteristics;

(cid:151) the supply classification of the medicinal product.

Member States may also require such advertising to include the
selling price or indicative price of the various presentations
and the conditions
security
bodies.

reimbursement by social

for

2. Member States may decide that
the advertising of a
medicinal product to persons qualified to prescribe or supply
such products may, notwithstanding paragraph 1, include only
the name of the medicinal product, if it is intended solely as a
reminder.

Article 92

1.
Any documentation relating to a medicinal product
which is transmitted as part of the promotion of that product
to persons qualified to prescribe or supply it shall include, as a
minimum, the particulars listed in Article 91(1) and shall state
the date on which it was drawn up or last revised.

All

2.
the information contained in the documentation
referred to in paragraph 1 shall be accurate, up-to-date,
verifiable and sufficiently complete to enable the recipient to
form his or her own opinion of the therapeutic value of the
medicinal product concerned.

3.
Quotations as well as tables and other illustrative matter
taken from medical journals or other scientific works for use
in the documentation referred to in paragraph 1 shall be
faithfully reproduced and the precise sources indicated.

(h) suggests

the safety or efficacy of
product is due to the fact that it is natural;

that

the medicinal

Article 93

(i) could, by a description or detailed representation of a case

history, lead to erroneous self-diagnosis;

(j)

in improper, alarming or misleading terms,

refers,
claims of recovery;

to

1. Medical sales representatives shall be given adequate
training by the firm which employs them and shall have
sufficient
to provide
information which is precise and as complete as possible about
the medicinal products which they promote.

knowledge

scientific

to be

able

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2.
During each visit, medical sales representatives shall give
the persons visited, or have available for them, summaries of
the product characteristics of each medicinal product
they
the Member State so
if the legislation of
present
together,
permits, with details of
for
and conditions
the price
reimbursement referred to in Article 91(1).

sales

representatives

3. Medical
to the
scientific service referred to in Article 98(1) any information
about the use of the medicinal products they advertise, with
particular reference to any adverse reactions reported to them
by the persons they visit.

transmit

shall

Article 94

1. Where medicinal products
are being promoted to
supply them, no gifts,
persons qualified to prescribe or
pecuniary advantages or benefits in kind may be supplied,
offered or promised to such persons unless
they are
inexpensive and relevant
to the practice of medicine or
pharmacy.

(c)

those supplying samples shall maintain an adequate system
of control and accountability;

(d) each sample

shall

be

identical with the

smallest

presentation on the market;

(e) each sample shall be marked (cid:145)free medical sample (cid:151) not
for sale(cid:146) or shall show some other wording having the
same meaning;

(f) each sample shall be accompanied by a copy of

the

summary of product characteristics;

(g) no samples of medicinal products containing psychotropic
or narcotic substances within the meaning of international
conventions, such as the United Nations Conventions of
1961 and 1971, may be supplied.

2. Member States may also place further restrictions on the
distribution of samples of certain medicinal products.

2.
Hospitality at sales promotion shall always be reasonable
in level and secondary to the main purpose of the meeting and
must not be extended to other than health professionals.

Article 97

Persons qualified to prescribe or

3.
supply medicinal
products shall not solicit or accept any inducement prohibited
under paragraph 1 or contrary to paragraph 2.

4.
Existing measures or trade practices in Member States
relating to prices, margins and discounts shall not be affected
by paragraphs 1, 2 and 3.

Article 95

The provisions of Article 94(1) shall not prevent hospitality
for purely
being offered, directly or
such hospitality shall
professional and scientific purposes;
always be reasonable in level and remain subordinate to the
main scientific objective of
it must not be
extended to persons other than health professionals.

indirectly, at events

the meeting;

Article 96

Free samples shall be provided on an exceptional basis
1.
only to persons qualified to prescribe them and on the
following conditions:

(a)

the number of samples for each medicinal product each
year on prescription shall be limited;

(b) any supply of samples shall be in response to a written
request, signed and dated, from the prescribing agent;

1. Member States shall ensure that there are adequate and
effective methods to monitor the advertising of medicinal
products. Such methods, which may be based on a system of
prior vetting, shall in any event include legal provisions under
which persons or organizations regarded under national law as
having a legitimate interest in prohibiting any advertisement
inconsistent with this Title, may take legal action against such
before
advertisement, or
an
to decide on
authority competent
administrative
complaints or to initiate appropriate legal proceedings.

such advertisement

either

bring

2.
Under the legal provisions referred to in paragraph 1,
Member States shall confer upon the courts or administrative
authorities powers enabling them, in cases where they deem
such measures to be necessary, taking into account all the
interests involved, and in particular the public interest:

(cid:151) to order the cessation of, or to institute appropriate legal
proceedings for an order for the cessation of, misleading
advertising, or

(cid:151) if misleading advertising has not yet been published but
publication is imminent, to order the prohibition of, or to
institute appropriate legal proceedings for an order for the
prohibition of, such publication,

even without proof of actual loss or damage or of intention or
negligence on the part of the advertiser.

3. Member States shall make provision for the measures
referred to in the second subparagraph to be taken under an
accelerated procedure, either with interim effect or with
definitive effect.

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It shall be for each Member State to decide which of the two
options set out in the first subparagraph to select.

in particular what penalties shall be imposed should the
provisions adopted in the execution of Title be infringed.

States may

4. Member
courts or
administrative authorities powers enabling them, with a view
to eliminating the continuing effects of misleading advertising
the cessation of which has been ordered by a final decision:

confer upon the

(cid:151) to require publication of that decision in full or in part and

in such form as they deem adequate,

(cid:151) to require in addition the publication of a corrective

statement.

5.
Paragraphs 1 to 4 shall not exclude the voluntary control
of advertising of medicinal products by self-regulatory bodies
and recourse to such bodies, if proceedings before such bodies
are possible in addition to the judicial or administrative
proceedings referred to in paragraph 1.

Article 98

The marketing authorization holder

1.
establish,
within his undertaking, a scientific service in charge of
information about the medicinal products which he places on
the market.

shall

2.

The marketing authorization holder shall:

(cid:151) keep available for, or communicate to, the authorities or
bodies responsible for monitoring advertising of medicinal
products, a sample of all advertisements emanating from
his undertaking together with a statement indicating the
persons
the method of
dissemination and the date of first dissemination,

to whom it

addressed,

is

(cid:151) ensure that advertising of medicinal products by his
undertaking conforms to the requirements of this Title,

(cid:151) verify that medical sales representatives employed by his
undertaking have been adequately trained and fulfill the
obligations imposed upon them by Article 93(2) and (3),

Article 100

Advertising of the homeopathic medicinal products referred to
in Article 13(2) and Article 14(1) shall be subject
to the
provisions of this Title with the exception of Article 87(1).

However, only the information specified in Article 69(1) may
be used in the advertising of such medicinal products.

Moreover, each Member State may prohibit in its territory any
advertising of the homeopathic medicinal products referred to
in Article 13(2) and Article 14(1).

TITLE IX

PHARMACOVIGILANCE

Article 101

The Member States shall
encourage doctors and other health care professionals
report
authorities.

take all appropriate measures to
to
competent

suspected

reactions

adverse

the

to

The Member States may impose specific requirements on
doctors and other health care professionals, in respect of the
reporting of suspected serious or unexpected adverse reactions,
in particular where such reporting is a condition of
the
marketing authorization.

Article 102

reactions

In order to ensure the adoption of appropriate regulatory
decisions concerning the medicinal products authorized within
the Community, having regard to information obtained about
to medicinal products under normal
adverse
conditions of use,
establish a
the Member States
pharmacovigilance system. This system shall be used to collect
information useful in the surveillance of medicinal products,
with particular reference to adverse reactions in human beings,
and to evaluate such information scientifically.

shall

(cid:151) supply the authorities or bodies responsible for monitoring
advertising of medicinal products with the information and
assistance they require to carry out their responsibilities,

Such information shall be collated with data on consumption
of medicinal products.

(cid:151) ensure that the decisions taken by the authorities or bodies
advertising of medicinal

responsible
products are immediately and fully complied with.

for monitoring

This
system shall also take into account any available
information on misuse and abuse of medicinal products which
may have an impact on the evaluation of their benefits and
risks.

Article 99

Article 103

Member States shall take the appropriate measures to ensure
that the provisions of this Title are applied and shall determine

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

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That qualified person shall be responsible for the following:

(a)

that

the establishment and maintenance of a system which
suspected adverse
ensures
information about all
reactions which are reported to the personnel of
the
company, and to medical representatives, is collected and
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 104, in such form as may be
laid down by those authorities,
in accordance with the
guidance referred to in Article 106(1);

(c) ensuring that any request from the competent authorities
information necessary for
for the provision of additional
the benefits and risks afforded by a
the evaluation of
medicinal product
and promptly,
including the provision of information about the volume
of
the medicinal product
concerned;

sales or prescriptions of

answered fully

is

(d) the provision to the competent authorities, of any other
information relevant to the evaluation of the benefits and
risks
including
a medicinal
appropriate
information on post-authorization safety
studies.

product,

afforded

by

Article 104

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

2.
The marketing authorization holder shall be required to
record and to report all suspected serious adverse reactions
which are brought
attention by a health care
professional
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.

to his

3.
The marketing authorization holder shall be required to
record and report all other suspected serious adverse reactions
the reporting criteria in accordance with the
which meet
guidance referred to in Article 106(1) of which he can
reasonably be expected to have knowledge 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.

4.
The marketing authorization holder shall ensure that all
suspected serious and unexpected adverse reactions occurring
in the territory of a third country and brought to his attention
by a health care professional are reported immediately in
accordance with the guidance referred to in Article 106(1), so
that they are available to the Agency and to the competent
authorities of the Member States where the medicinal product
is authorised, and in no case later than 15 calendar days
following the receipt of the information.

have benefited from the procedures of mutual recognition
foreseen in Articles 17 and 18 of this Directive, Article 28(4)
of this Directive, and medicinal products for which there has
been a referral to the procedures foreseen by Articles 32, 33
and 34 of this Directive, the marketing authorisation holder
shall additionally ensure that all suspected serious adverse
reactions occurring in the Community are reported in the
format and at
to be agreed with the reference
Member State, or a competent authority acting as the reference
Member State,
in such a way so as to be accessible to the
reference Member State.

intervals

6.
Unless other requirements have been laid down as a
condition of the granting of authorisation, or subsequently as
indicated in the guidance referred to in Article 106(1), records
of all adverse reactions shall be submitted to the 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 authorisation, annually for
the subsequent two years, and at the time of the first renewal.
Thereafter the periodic safety update reports shall be submitted
at
together with the application for
the authorisation. The periodic safety update
renewal of
reports shall include a scientific evaluation of the benefit and
risks afforded by the medicinal products.

five-yearly intervals

7.
Following the granting of a marketing authorisation, the
marketing authorisation holder may request the amendment of
the periods
referred to in this article according to the
procedure laid down by Commission Regulation (EC) No
541/95 (1).

Article 105

The Agency,

1.
in collaboration with the Member States
and the Commission shall set up a data-processing network to
facilitate
information
exchange of pharmacovigilance
regarding medicinal products marketed in the Community
intended to allow all competent authorities
to share the
information at the same time.

the

2. Making use of
the network foreseen in paragraph 1,
Member States shall ensure that reports of suspected serious
adverse reactions 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.

The Member States shall ensure that reports of suspected
3.
serious 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.

5.
In the case of medicinal products which have been
considered within the scope of Directive 87/22/EEC, or which

(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).

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Article 106

1.
In order to facilitate the exchange of information about
pharmacovigilance within the Community, the Commission, in
consultation with the Agency, Member States and interested
parties, shall draw up guidance on the collection, verification
including
and presentation of
of
technical
pharmacovigilance
with
internationally agreed formats and shall publish a reference to
an internationally agreed medical terminology.

reaction reports,
electronic
in

adverse
for

requirements

information

accordance

exchange

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 11 to 16 and the principles outlined in this
Title, the marketing authorisation holder and the competent
authorities shall refer to the guidance referred to in paragraph
1.

Article 107

1. Where, as a result of the evaluation of pharmacovigilance
data, a Member State considers that a marketing authorisation
should be suspended, withdrawn or varied in accordance with
the guidance referred to in Article 106(1),
it shall forthwith
inform the Agency,
the other Member States and the
marketing authorisation holder.

shall comprise those recommended by the Council of Europe
and the World Health Organization, particularly with reference
to the selection and testing of blood and plasma donors.

2. Member States shall
take the necessary measures to
ensure that human blood and human plasma donors and
donation centres are always clearly identifiable.

3.
All the safety guarantees referred to in paragraphs 1 and
2 must also be given by importers of human blood or human
plasma from third countries.

Article 110

Member States shall take the necessary measures to promote
Community self-sufficiency in human blood or human plasma.
For this purpose, they shall encourage the voluntary unpaid
donation of blood and plasma and shall take the necessary
measures to develop the production and use of products
derived from human blood or human plasma coming from
voluntary unpaid donations. They shall notify the Commission
of such measures.

TITLE XI

SUPERVISION AND SANCTIONS

Article 111

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

1.
The competent authority of the Member State concerned
shall ensure, by means of repeated inspections, that the legal
requirements governing medicinal products are complied with.

Article 108

Such inspections shall be carried out by officials representing
the competent authority who shall be empowered to:

amendments which may be necessary

Any
to update
provisions of Articles 101 to 107 to take account of scientific
and technical progress shall be adopted in accordance with the
procedure referred to in Article 121(2).

(a)

laboratories

inspect manufacturing or commercial establishments and
any
the
manufacturing authorization with the task of carrying out
checks pursuant to Article 20;

entrusted

holder

the

by

of

TITLE X

(b) take samples;

SPECIAL PROVISIONS ON MEDICINAL PRODUCTS DERIVED
FROM HUMAN BLOOD AND PLASMA

subject

(c) examine any documents relating to the object of

the
inspection,
in force in the
to the provisions
Member States on 21 May 1975 and which place
restrictions
the
these
descriptions of the method of preparation.

powers with

regard

on

to

Article 109

for

In respect of the use of human blood or human plasma
1.
the manufacture of medicinal
as a starting material
products, Member States shall take the necessary measures to
prevent the transmission of infectious diseases. In so far as this
is covered by the amendments referred to in Article 121(1), as
well as the application of the monographs of the European
Pharmacopoeia regarding blood and plasma, these measures

2. Member States shall take all appropriate steps to ensure
that the manufacturing processes used in the manufacture of
immunological products are properly validated and attain
batch-to-batch consistency.

3.
After every inspection as referred to in paragraph 1, the
officials representing the competent authority shall report on
whether the manufacturer complies with the principles and

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guidelines of good manufacturing practice laid down in Article
47. The content of such reports shall be communicated to the
manufacturer who has to undergo the inspection.

Article 112

and, where

Member States shall take all appropriate measures to ensure
that the holder of the marketing authorization for a medicinal
the
appropriate,
product
of
manufacturing authorization,
the controls
carried out on the medicinal product and/or the ingredients
and of the controls carried out at an intermediate stage of the
manufacturing process,
in accordance with the methods laid
down in Article 8(3)(h).

furnish proof of

holder

the

Article 113

For the purpose of implementing Article 112, Member States
may require manufacturers of
to
submit
the control
reports signed by the qualified person in accordance with
Article 51.

to a competent authority copies of all

immunological products

Article 114

1. Where it considers it necessary in the interests of public
health, a Member State may require the holder of an
authorization for marketing:

(cid:151) live vaccines,

(cid:151) immunological medicinal products used in the primary

immunization of infants or of other groups at risk,

(cid:151) immunological medicinal products used in public health

immunization programmes,

(cid:151) new immunological medicinal products or immunological
medicinal products manufactured using new or altered
kinds of technology or new for a particular manufacturer,
during a transitional period normally specified in the
marketing authorization,

to submit samples from each batch of the bulk and/or the
medicinal product for examination by a State laboratory or a
laboratory designated for that purpose before release on to the
market unless, in the case of a batch manufactured in another
Member State, the competent authority of that Member State
has previously examined the batch in question and declared it
to be in conformity with the approved specifications. Member
States shall ensure that any such examination is completed
within 60 days of the receipt of the samples.

in the interests of public health, the laws of a
2. Where,
the competent authorities may
Member State so provide,
require the marketing authorization holder
for medicinal
products derived from human blood or human plasma to
submit samples from each batch of
the bulk and/or the
medicinal product
for testing by a State laboratory or a
laboratory designated for that purpose before being released

into free circulation, unless
the competent authorities of
another Member State have previously examined the batch in
question and declared it to be in conformity with the approved
specifications. Member States
shall ensure that any such
examination is completed within 60 days of the receipt of the
samples.

Article 115

Member States shall take all necessary measures to ensure that
the manufacturing and purifying processes used in the
preparation of medicinal products derived from human blood
or human plasma are properly validated, attain batch-to-batch
consistency and guarantee, insofar as the state of technology
permits, the absence of specific viral contamination. To this
end manufacturers shall notify the competent authorities of the
method used to reduce or eliminate pathogenic viruses liable
to be transmitted by medicinal products derived from human
blood or human plasma. The competent authority may submit
samples of the bulk and/or the medicinal product for testing
by a State laboratory or a laboratory designated for that
purpose, either during the examination of
the application
pursuant to Article 19, or after a marketing authorization has
been granted.

Article 116

The competent authorities of the Member States shall suspend
or revoke an authorization to place a medicinal product on the
market where that product proves to be harmful in the normal
conditions of use, or where its therapeutic efficacy is lacking,
or where its qualitative and quantitative composition is not as
declared. Therapeutic efficacy is lacking when it is established
that therapeutic results cannot be obtained with the medicinal
product.

An authorization shall also be suspended or revoked where
the particulars supporting the application as provided for
in Articles 8, 10(1) and 11 are incorrect or have not been
amended in accordance with Article 23, or where the controls
referred to in Article 112 have not been carried out.

Article 117

Notwithstanding the measures provided for in Article
1.
take all appropriate measures to
116, Member States shall
ensure that
the medicinal product shall be
the supply of
prohibited and the medicinal product withdrawn from the
market if:

(a)

the medicinal product proves to be harmful under normal
conditions of use, or

(b)

it is lacking in therapeutic efficacy, or

(c)

its qualitative and quantitative composition is not as
declared, or

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(d) the controls on the medicinal product and/or on the
ingredients and the controls at an intermediate stage of the
manufacturing process have not been carried out or if
some other requirement or obligation relating to the grant
of the manufacturing authorization has not been fulfilled.

The competent authority may limit the prohibition to
from the market, to

2.
supply the product, or its withdrawal
those batches which are the subject of dispute.

The Standing Committee

3.
procedure.

shall

adopt

its

rules of

TITLE XIII

GENERAL PROVISIONS

Article 118

Article 122

The competent authority shall suspend or revoke the
1.
marketing authorization for a category of preparations or all
preparations where any one of the requirements laid down in
Article 41 is no longer met.

2.
In addition to the measures specified in Article 117, the
competent authority may suspend manufacture or imports of
medicinal products coming from third countries, or suspend or
revoke the manufacturing authorization for a category of
preparations or all preparations where Articles 42, 46, 51 and
112 are not complied with.

Article 119

The provisions of
medicinal products, subject to the provisions of Article 14(3).

this Title shall apply to homeopathic

TITLE XII

STANDING COMMITTEE

Article 120

Any changes which are necessary in order to adapt Annex I to
take account of scientific and technical progress shall be
adopted in accordance with the procedure referred to in
Article 121(2).

Article 121

The Commission shall be

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

referred to as

(hereinafter

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

Member States shall take all appropriate measures to ensure
that the competent authorities concerned communicate to each
other such information as is appropriate to guarantee that the
requirements
or
the manufacturing
marketing authorizations are fulfilled.

authorizations

for

shall

States

Upon reasoned request, Member
forthwith
communicate the reports referred to in Article 111(3) to the
If, after
competent authorities of another Member State.
considering the reports, the Member State receiving the reports
considers that it cannot accept the conclusions reached by the
competent authorities of the Member State in which the report
inform the competent authorities
was established,
concerned of its reasons and may request further information.
The Member States concerned shall use their best endeavours
to reach agreement.
serious
differences of opinion, the Commission shall be informed by
one of the Member States concerned.

in the case of

If necessary,

it shall

Article 123

all

the

shall

Each Member State

appropriate
take
1.
measures
to ensure that decisions authorizing marketing,
refusing or revoking a marketing authorization, cancelling a
revoking a marketing authorization,
decision refusing or
prohibiting supply, or withdrawing a product from the market,
together with the reasons on which such decisions are based,
are brought to the attention of the Agency forthwith.

2.
The marketing authorization holder shall be obliged to
notify the Member States concerned forthwith of any action
taken by him to suspend the marketing of a medicinal product
or to withdraw a medicinal product from the market, together
with the reasons for such action if the latter concerns the
efficacy of the 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 action taken pursuant to paragraphs 1 and 2 which may
the protection of public health in third countries is
affect
the World Health
to the attention of
forthwith brought
Organization, with a copy to the Agency.

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

in Article 5(6) of Decision

The Commission shall publish annually a list of

4.
medicinal products which are prohibited in the Community.

the

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Article 124

shall communicate to each other all

Member States
the
information necessary to guarantee the quality and safety of
homeopathic medicinal products manufactured and marketed
within the Community, and in particular the information
referred to in Articles 122 and 123.

Article 125

Every decision referred to in this Directive which is taken by
the competent authority of a Member State shall state in detail
the reasons on which it is based.

Such decision shall be notified to the party concerned, together
with information as to the redress available to him under the
laws in force and of the time-limit allowed for access to such
redress.

Marketing authorizations,
such
authorizations, shall be published by each Member State in the
appropriate official publication.

and decisions

to revoke

Article 126

An authorization to market a medicinal product shall not be
refused, suspended or revoked except on the grounds set out
in this Directive.

No decision concerning suspension of manufacture or of
from third
importation of medicinal products
countries, prohibition of
from the
market of a medicinal product may be taken except on the
grounds set out in Articles 117 and 118.

supply or withdrawal

coming

(b) for medicinal products intended for export which are
already authorized on their territory, they shall supply the
summary of
the product characteristics as approved in
accordance with Article 21.

2. When the manufacturer
in possession of a
marketing authorization he shall provide the authorities
responsible for establishing the certificate referred to in
paragraph 1, with a declaration explaining why no marketing
authorization is available.

is not

TITLE XIV

FINAL PROVISIONS

Article 128

Directives 65/65/EEC, 75/318/EEC, 75/319/EEC, 89/342/EEC,
89/343/EEC, 89/381/EEC, 92/25/EEC, 92/26/EEC, 92/27/EEC,
92/28/EEC and 92/73/EEC, amended by the Directives referred
to in Annex II, Part A, are repealed, without prejudice to the
obligations of the Member States concerning the time-limits
for implementation set out in Annex II, Part B.

References to the repealed Directives shall be construed as
references to this Directive and shall be read in accordance
with the correlation table in Annex III.

Article 129

This Directive shall enter into force on the twentieth day
following that of its publication in the Official Journal of the
European Communities.

Article 127

Article 130

This Directive is addressed to the Member States.

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

shall

is

(a)

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

Done at Brussels, 6 November 2001.

For the European Parliament

The President

N. FONTAINE

For the Council

The President

D. REYNDERS

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ANNEX I

ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS AND PROTOCOLS IN
RESPECT OF THE TESTING OF MEDICINAL PRODUCTS

INTRODUCTION

The particulars and documents accompanying an application for marketing authorization pursuant to Articles 8 and
10(1) shall be presented in four parts, in accordance with the requirements set out in this Annex and taking account of
the guidance published by the Commission in The rules governing medicinal products in the European Community,Volume II:
Notice to applicants for marketing authorizations for medicinal products for human use in the Member States of the European
Community.

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 medicinal products published by the Commission in The rules
governing medicinal products in the European Community, Volume III and its supplements: Guidelines on the quality, safety and
efficacy of medicinal products for human use.

All
information which is relevant to the evaluation of the medicinal product concerned shall be included in the
application, whether favourable or unfavourable to the product. In particular, all relevant details shall be given of any
incomplete or abandoned pharmacotoxicological or clinical test or trial relating to the medicinal product. Moreover, in
order to monitor the benefit/risk assessment after marketing authorization has been granted, any change to the data in
the dossier, any new information not in the original application and all pharmacovigilance reports, shall be submitted
to the competent authorities.

this Annex give the requirements for all categories of medicinal products;

The general sections of
they are
supplemented by sections containing additional special requirements for radiopharmaceuticals and for biological
medicinal products, such as immunological medicinal products derived from human blood or plasma. The additional
special requirements for biological medicinal products are also applicable to medicinal products obtained through
processes mentioned in Part A and the first indent of Part B of the Annex to Regulation (EEC) No 2309/93.

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

PART I

SUMMARY OF THE DOSSIER

A. Administrative data

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

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 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 the manufacturing authorization as defined in Article 40,
together with a list of countries in which authorization has been granted, copies of all the summaries of product
characteristics in accordance with Article 11 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 11.

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

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In addition the applicant shall provide samples or mock-ups of the packaging, labels and package leaflets for the
medicinal product concerned.

C. Expert reports

In accordance with Article 12(2), expert reports must be provided on the chemical, pharmaceutical and biological
documentation, the pharmacotoxicological documentation and the clinical documentation respectively.

The expert report shall consist of a critical evaluation of the quality of the medicinal product and the investigations
carried out on animals and human beings and bring out all the data relevant for evaluation. It shall be worded so
as to enable the reader to obtain a good understanding of the properties, quality, the proposed specifications and
control methods, the safety, the efficacy, the advantages and disadvantages of the medicinal product.

All important data shall be summarized in an appendix to the expert report, whenever possible including report
formats in tabular or in 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 information about the educational background, training and
professional experience of the expert. The professional relationship of the expert to the applicant shall be declared.

CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL TESTING OF MEDICINAL PRODUCTS

PART 2

All the 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
if necessary, by the manufacturing method. In the case of test procedures included in the European
supplemented,
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 point 3
of Article 8(3)(c) shall be submitted in accordance with the following requirements.

1.

Qualitative particulars

1.1.

(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, stabilizers, thickeners, emulsifiers, flavouring and aromatic substances, etc.,

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

the medicinal products (cid:151) capsules, gelatine capsules, rectal 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.

1.2.

In the context of a radiopharmaceutical kit, which is to be radiolabelled after supply by the manufacturer, the
active substance is considered to be that part of the formulation which is intended to carry or bind the
radionuclide. Details of the source of the radionuclide shall be stated. In addition, any compounds essential for the
radiolabelling shall be stated.

In a generator, both mother and daughter radionuclides are to be considered as active substances.

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2.

The (cid:145)usual
notwithstanding the application of the other provisions in Article 8(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,

(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 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.

it is necessary,
In order to give (cid:145)quantitative particulars(cid:146) of the active substances of the medicinal products,
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 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
unit container, taking into account the usable volume of the product, after reconstitution, where 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 designated 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.

3.4. For allergen products, the quantitative particulars shall be expressed by units of biological activity, except for well

defined allergen products for which the concentration may be expressed by mass/unit of volume.

3.5. The requirement to express the content of active substances in terms of the mass of active entities, as in point
3.3. above, may not apply to radiopharmaceuticals. For radionuclides, radioactivity shall be expressed in
becquerels at a given date and, if necessary, time with reference to time zone. The type of radiation shall be
indicated.

4.

Development pharmaceutics

4.1. An explanation should 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 during manufacture, with justification thereof, should be stated.

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

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4.2. For radiopharmaceuticals, this should include a consideration of chemical/radiochemical purity and its relationship

to biodistribution.

B. Description of manufacturing method

1.

The description of the manufacturing method accompanying the application for marketing authorization pursuant
to Article 8(3)(d), shall be drafted in such a way as to give an adequate synopsis of the nature of the operations
employed.

2.

C.

1.

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,

(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 medicinal products, details of the sterilization processes and/or aseptic procedures used.

For radiopharmaceutical kits, the description of the manufacturing method shall also include details of the
manufacture of the kit and details of its recommended final processing to produce the radioactive medicinal
product.

For radionuclides, the nuclear reactions involved shall be discussed.

Controls of starting materials

For the purposes of this section, (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,

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,

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
8(3)(h) and (i) and 10(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. S t a r t i n g m a t e r i a l s l i s t e d i n p h a r m a c o p o e i a s

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.

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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 8(3)(h). 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 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.

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. S t a r t i n g m a t e r i a l s n o t i n a p h a r m a c o p o e i a

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
appropriate;
it must be accompanied by an appropriate description of the method of synthesis. Where
substances can only be described by their manufacturing method, the description should be sufficiently
detailed to characterize a substance which is constant both in 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/human origin, a distinction must be made between the
case where multiple pharmacological effects render chemical, physical or biological control of the principal
constituents 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/human origin are used, measures to ensure freedom from potentially pathogenic

agents shall be described;

(g)

for radionuclides, the nature of the radionuclide, the identity of the isotope, likely impurities, the carrier, the
use and the specific activity shall be given;

(h) 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.

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1.3. P h y s i c o - c h e m i c a l c h a r a c t e r i s t i c s l i a b l e t o e f f e c t b i o - a v a i l a b i l i t y

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.

For biological medicinal products, such as immunological medicinal products and medicinal products derived
from human blood or plasma, the requirements of this paragraph shall apply.

For the purposes of this paragraph, starting materials shall mean any substance used in the manufacture of the
medicinal product; this includes the constituents of the medicinal product, and, if necessary, of its container, as
referred to in paragraph A, point 1 above, as well as source materials such as microorganisms, tissues of either
plant or animal origin, cells or fluids (including blood) of human or animal origin, and biotechnological cell
constructs. 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.

2.2. Seed materials, cell banks, pools of serum or plasma and other materials 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 correspondant material shall be used
only when further processing ensures their elimination and/or inactivation, and this shall be validated.

2.3. Whenever possible, vaccine production shall be based on a seed lot system and on established cell banks; for

serums, defined pools of starting materials shall be used.

For bacterial and viral vaccines, the characteristics of the infectious agent shall be demonstrated on the seed. In
addition, for live vaccines, the stability of the attenuation characteristics shall be demonstrated on the seed; if this
proof is not sufficient, the attenuation characteristics shall also be demonstrated at the production stage.

2.4. For allergen products, the specifications and control methods for the source materials shall be described in as

much detail as possible. The description shall include particulars concerning collection, pretreatment and storage.

2.5. For medicinal products derived from human blood or plasma, the origin and the criteria and procedures for

collection, transportation and storage of the source material shall be described and documented.

Defined pools of source material shall be used.

3.

For radiopharmaceuticals, starting materials include irradiation target materials.

D.

Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies

The applicant must demonstrate that the medicinal product is manufactured in accordance with the Note for
Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal
Products and its updates, published by the Commission in Volume 3 of its publication The rules governing medicinal
products in the European Community.

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

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E.

Control tests carried out at intermediate stages of the manufacturing process

1.

The particulars and documents accompanying an application for marketing authorization, pursuant to Article
8(3)(h) and (i) and Article 10, paragraph 1 of this Directive, 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
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 constituents subject to the same requirements as the
active substances).

for checking the conformity of

The same applies where the quality control of
particularly if the medicinal product is essentially defined by its method or preparation.

the finished product depends on in-process control

tests,

2.

For biological medicinal products, such as immunological medicinal products and medicinal products derived
from human blood or plasma, the procedures and the criteria of acceptability published as recommendations of
the WHO (Requirements for Biological Substances) shall serve as guidelines for all controls of production stages
which are not specified in the European Pharmacopoeia, or falling this, in the national pharmacopoeia of a Member
State.

For inactivated or detoxified vaccines, effective inactivation or detoxification shall be verified during each
production run, unless this control is dependent upon a test for which the availability of susceptible animals is
limited. In this case, the test shall be carried out until consistency of production and correlation with appropriate
in process controls have been established and thereafter compensated by appropriate in-process controls.

3.

For modified or adsorbed allergen products, the products shall be qualitatively and quantitatively characterized at
an intermediate stage, as late as possible in the manufacturing process.

F.

Control tests on the finished product

1.

For the control of the finished product, a batch of a medicinal 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
8(3)(h) and (i) and Article 10(1) of this Directive, 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 monographs for pharmaceutical forms,
immunosera, vaccines and radiopharmaceutical
preparations of the European Pharmacopoeia or failing that, of a Member State, shall be applicable to all products
defined therein. For all controls of biological medicinal products such as immunological medicinal products and
medicinal products derived from human blood or plasma which are not specified in the European Pharmacopoeia or
failing this, in the pharmacopoeia of a Member State, the procedures and the criteria of acceptability published as
recommendations in the WHO (Requirements for Biological Substances) shall serve as guidelines.

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 shall be supplied that the finished
that
product would,
pharmacopoeia for the pharmaceutical form concerned.

tested in accordance with those monographs, meet

the quality requirements of

if

1.1. G e n e r a l c h a r a c t e r i s t i c s o f t h e f i n i s h e d p r o d u c t

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.

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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.

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.

I d e n t i f i c a t i o n a n d a s s a y o f a c t i v e s u b s t a n c e ( s )

Identification and assay of the active substance(s) shall be carried out either in an average 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, if necessary, the toxico-pharmacological investigation of the changes that
this substance has undergone, and possibly the characterization and/or assay of the degradation products.

1.3.

I d e n t i f i c a t i o n a n d a s s a y o f e x c i p i e n t c o n s t i t u e n t s

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 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 constituent liable to affect adversely organic 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. S a f e t y t e s t s

1.

2.

from the pharmacotoxicological

Apart
tests submitted with the application for marketing authorization,
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.

For all controls of biological medicinal products, such as immunological medicinal products and medicinal
products derived from human blood or plasma, which are not specified in the European Pharmacopoeia, or failing
this, in the national pharmacopoeia of a Member State, the procedures and the criteria of acceptability published
as recommendations in the World Health Organization (Requirements for Biological Substances) shall serve as
guidelines.

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3.

For radiopharmaceuticals, radionuclidic purity, radiochemical purity and specific activity shall be described. For
content of radioactivity, the deviation from that stated on the label should not exceed – 10 %.

For generators, details on the testing for mother and daughter radionuclides are required. For generator-eluates,
tests for mother radionuclides and for other components of the generator system shall be provided.

the specifications of

For kits,
include tests on performance of products after
radiolabelling. Appropriate controls on radiochemical and radionuclidic purity of the radiolabelled compound
shall be included. Any material essential for radiolabelling shall be identified and assayed.

the finished product shall

G.

Stability tests

1.

The particulars and documents accompanying the application for marketing authorization pursuant to Article
8(3)(g) and (h) 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.

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 shelf-life under these
recommended storage conditions.

the finished product at

the end of

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.

2. Where for biological medicinal products, such as immunological medicinal products and medicinal products
derived from human blood or plasma, stability tests cannot be carried out on the finished products,
it is
acceptable to carry out stability indicating tests at an intermediate stage of production as late as possible in the
manufacturing process. In addition, there should be an evaluation of the stability of the finished product using
other secondary tests.

3.

For radiopharmaceuticals, information on stability shall be given for radionuclide generators, radionuclide kits and
radiolabelled products. The stability during use of radiopharmaceuticals in multi-dose vials shall be documented.

PART 3

TOXICOLOGICAL AND PHARMACOLOGICAL TESTS

I.

Introduction

1.

The particulars and documents accompanying the application for marketing authorization pursuant to Articles
8(3)(i) and 10(1) shall be given in accordance with the requirements below.

Member States shall ensure that the safety tests are carried out in conformity with the provisions relating to good
laboratory practice laid down by Council Directives 87/18/EEC (1) and 88/320/EEC (2).

The toxicological and pharmacological tests must show:

(a)

the potential toxicity of the product and any dangerous or undesirable toxic effects that may occur under the
proposed conditions of use in human beings; these should be evaluated in relation to the pathological
condition concerned;

(1) OJ L 15, 17.1.1987, p. 29.
(2) OJ L 145, 11.6.1988, p. 35. Directive as amended by Directive 90/18/EEC (OJ L 11, 13.1.1990, p. 37).

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(b)

the pharmacological properties of
in both qualitative and quantitative relationship to the
proposed use in human beings. All results must be reliable and of general applicability. Whenever
appropriate, mathematical and statistical procedures shall be used in designing the experimental methods and
in evaluating the results.

the product,

Additionally, it is necessary for clinicians to be given information about the therapeutic potential of the product.

2. Where a medicinal product is intended for topical use, systemic absorption must be investigated, due account also
being taken of the possible use of the product on broken skin and absorption through other relevant surfaces.
Only if it is proved that systemic absorption under these conditions is negligible may repeated dose systemic
toxicity tests, foetal toxicity tests and studies of reproductive function be omitted.

If, however, systemic absorption is demonstrated during therapeutic experimentation, toxicity tests shall be carried
out on animals, including where necessary, foetal toxicity tests.

In all cases, tests of local tolerance after repeated application shall be carried out with particular care and include
histological examinations; the possibility of sensitization shall be investigated and any carcinogenic potential
investigated in the cases referred to in Section II E of this Part.

3.

For biological medicinal products such as immunological medicinal products and medicinal products derived from
human blood or plasma, the requirements of this Part may have to be adapted for individual products; therefore
the testing programme carried out shall be justified by the applicant.

In establishing the testing programme, the following shall be taken into consideration:

(cid:151) all tests requiring repeated administration of the product shall be designed to take account of the possible

induction of, and interference by, antibodies;

(cid:151) examination of reproductive function, of embryo/foetal and perinatal toxicity, of mutagenic potential and of
carcinogenic potential shall be considered. Where components other than the active substance(s) are
incriminated, validation of their removal may replace the study.

4.

For radiopharmaceuticals, it is appreciated that toxicity may be associated with a radiation dose. In diagnosis, this
is a consequence of the use of radiopharmaceuticals; in therapy, it is the wanted property. The evaluation of
safety and efficacy of radiopharmaceuticals shall, therefore, address requirements for medicinal products and
radiation dosimetry aspects. Organ/tissue exposure to radiation shall be documented. Absorbed radiation dose
estimates shall be calculated according to a specified, internationally recognized system by a particular route of
administration.

5.

The toxicology and pharmacokinetics of an excipient used for the first time in the pharmaceutical field shall be
investigated.

6. Where there is a possibility of significant degradation during storage of the medicinal product, the toxicology of

degradation products must be considered.

II.

PERFORMANCE OF TESTS

A.

Toxicity

1.

Single dose toxicity

An acute test is a qualitative and quantitative study of the toxic reactions which may result from a single
administration of the active substance or substances contained in the medicinal product, in the proportions and
physico-chemical state in which they are present in the actual product.

The acute toxicity test must be carried out in two or more mammalian species of known strain unless a single
species can be justified. At least two different routes of administration shall normally be used, one being identical
with or similar to that proposed for use in human beings and the other ensuring systemic exposure to the
substance.

This study will cover the signs observed, including local reactions. The period during which the test animals are
observed shall be fixed by the investigator as being adequate to reveal tissue or organ damage or recovery, usually
for a period of 14 days but not less than 7 days, but without exposing the animals to prolonged suffering.

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Animals dying during the observation period should be subject to autopsy as also should all animals surviving to
the end of the observation period. Histopathological examinations should be considered on any organ showing
macroscopic changes at autopsy. The maximum amount of information should be obtained from the animals
used in the study.

The single dose toxicity tests should be conducted in such a way that signs of acute toxicity are revealed and the
mode of death assessed as far as reasonably possible.
the
approximate lethal dose and information on the dose effect relationship should be obtained, but a high level of
precision is not required.

In suitable species, a quantitative evaluation of

These studies may give some indication of the likely effects of acute overdosage in man and may be useful for the
design of toxicity studies requiring repeated dosing on the suitable animal species.

In the case of active substances in combination, the study must be carried out in such a way as to check whether
or not there is enhancement of toxicity or if novel toxic effects occur.

2.

Repeated dose toxicity (sub-acute or chronic toxicity)

Repeated dose toxicity tests are intended to reveal any physiological and/or anatomo-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.

it is desirable that two tests be performed: one short-term,

Generally,
lasting two to four weeks, the other
long-term. The duration of the latter shall depend on the conditions of clinical use. Its purpose shall be to
determine by experiment the non-toxic dose range of the product and normally it shall last three to six months.

In respect of medicinal products to be administered once only to humans, a single test lasting two to four weeks
shall be performed.

If however, having regard to the proposed duration of use in human beings, the investigator sees fit to carry out
experiments of greater or lesser duration than indicated above, he must give adequate reasons for doing so.

Reasons should also be given for the dosages chosen.

Repeated dose toxicity tests shall be carried out on two species of mammals one of which must be a non-rodent.
The choice of route(s) of administration employed shall depend on the intended therapeutic use and the
possibilities of systemic absorption. The method and frequency of dosage shall be clearly stated.

The maximum dose should be chosen so as to bring harmful effects to light. The lower doses will then enable the
animal’s tolerance of the product to be determined.

Wherever possible, and always in experiments on small rodents, the design of the experiment and the control
procedures must be suited to the scale of the problem being tackled and enable fiducial limits to be determined.

The evaluation of the toxic effects shall be based on observation of behaviour, growth, haematological and
tests, especially those relating to the excretory mechanism, and also on autopsy reports and
biochemical
accompanying histological data. The choice and range of each group of tests will depend on the species of animal
used and the state of scientific knowledge at the time.

In the case of new combinations of known substances that have been investigated in accordance with the
provisions of this Directive, the chronic long-term tests may, except where acute and sub-acute toxicity tests have
demonstrated potentiation or novel toxic effects, be suitably modified by the investigator who shall submit his
reasons for such modification.

B.

Examination of reproductive function

If the results of other tests reveal anything suggesting harmful effects on progeny or impairment of male or
female reproductive function, this shall be investigated by appropriate tests.

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C.

Embryo/foetal and perinatal toxicity

This investigation comprises a demonstration of the toxic and especially the teratogenic effects observed in the
issue of conception when the medicinal product under investigation has been administered to the female during
pregnancy.

Although up to the present these tests have had only a limited predictive value in regard to the application of the
results to human beings, they are thought to provide important information where the results show effects such
as resorptions and other anomalies.

Omission of these tests, either because the medicinal product will not normally be used by women capable of
child-bearing or for other reasons, must be adequately justified.

Embryo/foetal toxicity studies shall normally be conducted on two mammalian species, one of which should be
other than a rodent. Peri- and postnatal studies shall be conducted in at least one species. Where metabolism of a
medicinal product in a particular species is known to be similar to that in man, it is desirable to include this
species. Also, it is desirable that one of the species is the same as in the repeated dose toxicity studies.

The details of the test (number of animals, amounts administered, timing of administration and criteria for
evaluation of results) shall depend on the state of scientific knowledge at the time when the application is lodged,
and the level of statistical significance that the results must attain.

D. Mutagenic potential

The purpose of the study of mutagenic potential is to reveal the changes which a substance may cause in the
genetic material of
individuals or cells and which have the effect of making successors permanently and
hereditarily different from their predecessors. This study is obligatory for any new substance.

The number and types of results and the criteria for their evaluation shall depend on the state of scientific
knowledge at the time when the application is lodged.

E.

Carcinogenic potential

Tests to reveal carcinogenic effects shall normally be required:

(a)

in respect of substances having a close chemical analogy with known carcinogenic or cocarcinogenic
compounds;

(b)

in respect of substances which have given rise to suspicious changes during the long-term toxicological tests;

(c)

in respect of substances which have given rise to suspicious results in the mutagenic-potential tests or in
other short-term carcinogenicity tests.

Such tests may also be required in respect of substances to be included in medicinal products likely to be
administered regularly over a prolonged period of a patient’s life.

The state of scientific knowledge at the time when the application is lodged shall be taken into account when
determining the details of the tests.

F.

Pharmacodynamics

This heading covers the variations caused by the medicinal product in the functions of the physiological systems,
whether these functions are normal or experimentally modified.

This study shall follow two distinct lines of approach.

Firstly, the actions on which the recommended application in therapeutic practice is based shall be adequately
described. The results shall be expressed in quantitative terms using, (e.g. dose-effect curves, time-effect curves
etc.), and wherever possible, compared with data relating to a substance whose activity is known. Where a higher
therapeutic potency is being claimed for a substance, the difference shall be demonstrated and shown to be
statistically significant.

Secondly, the investigator shall provide a general pharmacological characterization of the substance, with special
reference to adverse reactions. In general, the main functions of the physiological systems should be investigated.
The depth of this investigation must be increased as the doses liable to produce adverse reactions approach those
producing the main effect for which the substance is being proposed.

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The experimental techniques, unless they are standard procedures, must be described in such detail as to allow
them to be reproduced, and the investigator must establish their validity. The experimental results shall be set out
clearly and, when relevant to the test, 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 be investigated.

Tests on combinations of active substances may be prompted either by pharmacological premisses or by
indications of therapeutic effect.

In the first case,
combination of value in therapeutic use.

the pharmacodynamic study shall demonstrate those interactions which might make the

through therapeutic
In the second case, where scientific justification for
experimentation, the investigation shall determine whether the effects expected from the combination can be
demonstrated in animals, and the importance of any collateral effects shall at least be investigated.

the combination is

sought

If a combination includes a novel active substance, the latter must previously have been studied in depth.

G.

Pharmacokinetics

Pharmacokinetics means the study of the fate of the active substance within the organism, and covers the study of
the absorption, distribution, biotransformation and excretion of the substance.

The study of these different phases may be carried out both by means of physical, chemical or biological
methods, and by observation of the actual pharmacodynamic activity of the substance itself.

Information on distribution and elimination (i.e. biotransformation and excretion) shall be necessary in all cases
where such data are indispensable to determine the dosage for humans, and in respect of chemotherapeutic
substances (antibiotics, etc.) and substances whose use depends on their non-pharmacodynamic effects (e.g.
numerous diagnostic agents, etc.).

Pharmacokinetic investigation of pharmacologically active substances is necessary.

In the case of new combinations of known substances which have been investigated in accordance with the
provisions of this Directive, pharmacokinetic studies may not be required, if the toxicity tests and therapeutic
experimentation justify their omission.

H.

Local tolerance

The purpose of local tolerance studies is to ascertain whether medicinal products (both active substances and
excipients) are tolerated at sites in the body which may come into contact with the medicinal product as a result
of
its administration in clinical use. The testing strategy shall be such that any mechanical effects of
administration or purely physico-chemical actions of the product can be distinguished from toxicological or
pharmacodynamic ones.

I. Well-established medicinal use

For the purpose of demonstrating, pursuant to Article 10(1)(a)(ii), that the component(s) of a medicinal product
have a well established use, with an acceptable level of safety, the following specific rules shall apply:

(a) Factors which have to be taken into account in order to establish a (cid:145)well established medicinal use(cid:146) of
components of medicinal products are the time over which a substance has been used, quantitative aspects of
the use of the substance, the degree of scientific interest in the use of the substance (reflected in the published
scientific literature) and the coherence of scientific assessments. Therefore different periods of time may be
necessary for establishing (cid:145)well established use(cid:146) of different substances. In any case, however, the period of
time required for establishing a (cid:145)well established medicinal use(cid:146) of a component of a medicinal product must
not be less than one decade from the first systematic and documented use of that substance as a medicinal
product in the Community.

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(b) The documentation submitted by the applicant should cover all aspects of the safety assessment and must
include or refer to a review of the relevant literature, taking into account pre- and postmarketing studies and
published scientific literature concerning experience in the form of epidemiological studies and in particular
of comparative epidemiological studies. All documentation, both favourable and unfavourable, should be
communicated.

(c) Particular attention must be paid to any missing information and justification must be given why

demonstration of an acceptable level of safety can be supported although some studies are lacking.

(d) The Expert report must explain the relevance of any data submitted which concern a product different from
intended for marketing. A judgment must be made whether the product studied can be
the product
considered as similar to the product which will be granted a marketing authorisation in spite of the existing
differences.

(e) Post-marketing experience with other products containing the same components is of particular importance

and applicants should put a special emphasis on this issue.

PART 4

CLINICAL DOCUMENTATION

The particulars and documents accompanying applications for marketing authorizations pursuant to Articles 8(3)(i) and
10(1) of this Directive shall be submitted in accordance with the provisions below.

A clinical trial is any systematic study of medicinal products in human subjects whether in patients or non-patient
volunteers in order to discover or verify the effects of and/or identify any adverse reaction to investigational products,
and/or study their absorption, distribution, metabolism and excretion in order to ascertain the efficacy and safety of the
products.

the application for marketing authorization shall be based on clinical

Evaluation of
including clinical
pharmacological trials designed to determine the efficacy and safety of the product under normal conditions of use,
having regard to the therapeutic indications for use in human beings. Therapeutic advantages must outweigh potential
risks.

trials

A. General requirements

The clinical particulars to be provided pursuant
to Articles 8(3)(i) and 10(1) must enable a sufficiently
well-founded and scientifically valid opinion to be formed as to whether the medicinal product satisfies the
criteria governing the granting of a marketing authorization. Consequently, an essential requirement is that the
results of all clinical trials should be communicated, both favourable and unfavourable.

Clinical trials must always be preceded by adequate pharmacological and toxicological tests, carried out on
animals in accordance with the requirements of Part 3 of this Annex. The investigator must acquaint himself with
the conclusions drawn from the pharmacological and toxicological studies and hence the applicant must provide
him at least with the investigator’s brochure, consisting of all the relevant information known prior to the onset
of a clinical trial
including chemical, pharmaceutical and biological data, toxicological, pharmacokinetic and
pharmacodynamic data in animals and the results of earlier clinical trials, with adequate data to justify the nature,
scale and duration of the proposed trial; the complete pharmacological and toxicological reports shall be provided
on request. For materials of human or animal origin, all available means shall be employed to ensure safety from
transmission of infectious agents prior to the commencement of the trial.

B.

Conduct of trials

1.

Good clinical practice

1.1. All phases of clinical

investigation,

including bioavailability and bioequivalence studies, shall be designed,

implemented and reported in accordance with good clinical practice.

1.2. All clinical trials shall be carried out in accordance with the ethical principles laid down in the current revision of
the Declaration of Helsinki. In principle, the freely given informed consent of each trial subject shall be obtained
and documented.

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The trial protocol (including statistical design), the technical application and documentation shall be submitted by
the sponsor and/or investigator for an opinion to the relevant ethics committee. The trials shall not begin before
the opinion of this committee has been received in writing.

1.3. Pre-established, systematic written procedures for the organization, conduct, data collection, documentation and

verification of clinical trials shall be required.

1.4.

In the case of radiopharmaceuticals, clinical trials shall be carried out under the responsibility of a medical doctor
authorized to use radionuclides for medical purposes.

2.

Archiving

The marketing authorization holder shall make arrangements for archiving of documentation.

(a) The investigator shall arrange for the retention of the patient identification codes for at least 15 years after

the completion or discontinuation of the trial.

(b) Patient files and other source data shall be kept for the maximum period of time permitted by the hospital,

institution or private practice.

(c) The sponsor or other owner of the data shall retain all other documentation pertaining to the trial as long as

the product is authorized. These procedures shall include:

(cid:151) the protocol including the rationale, objectives and statistical design and methodology of the trial, with
conditions under which it is performed and managed, and details of the investigational product, the
reference medicinal product and/or the placebo used,

(cid:151) standard operating procedures,

(cid:151) all written opinions on the protocol and procedures,

(cid:151) the investigator’s brochure,

(cid:151) case report forms on each trial subject,

(cid:151) final report,

(cid:151) audit certificate(s), if available.

(d) The final report shall be retained by the sponsor or subsequent owner, for five years after the medicinal

product is no longer authorized.

Any change of ownership of the data shall be documented.

All data and documents shall be made available if requested by relevant authorities.

C.

Presentation of results

1.

The particulars of each clinical trial must contain sufficient detail to allow an objective judgement to be made:

(cid:151) the protocol,

including the rationale, objectives and statistical design and methodology of the trial, with
conditions under which it is performed and managed, and details of the investigational medicinal product
used,

(cid:151) audit certificate(s), if available,

(cid:151) the list of investigator(s), and each investigator shall give his name, address, appointments, qualifications and
clinical duties, state where the trial was carried out and assemble the information in respect of each patient
individually, including case report forms on each trial subject,

(cid:151) final report signed by the investigator and for multicentre trials, by all the investigators or the coordinating

(principal) investigator.

2.

The particulars of clinical trials referred to above shall be forwarded to the competent authorities. However, in
agreement with the competent authorities,
information. Complete
documentation shall be provided forthwith upon request.

the applicant may omit part of

this

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3.

The clinical observations shall be summarized for each trial indicating:

(a)

the number and sex of patients treated;

(b)

the selection and age-distribution of the groups of patients being investigated and the comparative tests;

(c)

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

(d) where controlled trials were carried out under the above conditions, whether the control group:

(cid:151) received no treatment,

(cid:151) received a placebo,

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

(cid:151) received treatment other than therapy using medicinal products;

(e)

the frequency of observed adverse reactions;

(f) details concerning patients who may be at increased risk, e.g. elderly people, children, women during
pregnancy or menstruation, or whose physiological or pathological condition requires special consideration;

(g) parameters or evaluation criteria of efficacy and the results in terms of these parameters;

(h) a statistical evaluation of the results when this is called for by the design of the trials and the variable factors

involved.

4.

The investigator shall, in his conclusions on the experimental evidence, express an opinion on the safety of the
information relating to
product under normal conditions of use,
indications and contra-indications, dosage and average duration of treatment as well as any special precautions to
be taken during treatment and the clinical symptoms of overdosage. In reporting the results of a multi-centre
study, the principal investigator shall, in his conclusions, express an opinion on the safety and efficacy of the
investigational medicinal product on behalf of all centres.

its efficacy and any useful

its tolerance,

5.

In addition, the investigator shall always indicate his observations on:

(a) any signs of habituation, addiction or difficulty in weaning patients from the medicinal product;

(b) any interactions that have been observed with other medicinal products administered concomitantly;

(c)

the criteria determining exclusion of certain patients from the trials;

(d) any deaths which occurred during the trial or within the follow-up period.

6.

7.

Particulars concerning a new combination of medicinal substances must be identical to those required for new
medicinal products and must substantiate the safety and efficacy of the combination.

Total or partial omission of data must be explained. Should unexpected results occur during the course of the
trials, further preclinical toxicological and pharmacological tests must be undertaken and reviewed.

If the medicinal product is intended for long-term administration, particulars shall be given of any modification of
the pharmacological action following repeated administration, as well as the establishment of long-term dosage.

D.

Clinical pharmacology

1.

Pharmacodynamics

The pharmacodynamic action correlated to the efficacy shall be demonstrated including:

(cid:151) the dose-response relationship and its time course,

(cid:151) justification for the dosage and conditions of administration,

(cid:151) the mode of action, if possible.

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The pharmacodynamic action not related to efficacy shall be described.

The demonstration of pharmacodynamic effects in human beings shall not in itself be sufficient to justify
conclusions regarding any particular potential therapeutic effect.

2.

Pharmacokinetics

The following pharmacokinetic characteristics shall be described:

(cid:151) absorption (rate and extent),

(cid:151) distribution,

(cid:151) metabolism,

(cid:151) excretion.

Clinically significant features including the implication of the kinetic data for the dosage regimen especially for
patients at risk, and differences between man and animal species used in the preclinical studies, shall be described.

3.

Interactions

If the medicinal product is normally to be administered concomitantly with other medicinal products, particulars
shall be given of joint administration tests performed to demonstrate possible modification of the pharmacological
action.

If pharmacodynamic/pharmacokinetic interactions exist between the substance and other medical products or
substances like alcohol, caffeine, tobacco or nicotine, likely to be taken simultaneously, or if such interactions are
likely, they should be described and discussed; particularly from the point of view of clinical relevance and the
relationship to the statement concerning interactions in the summary of product characteristics presented in
accordance with Article 11 point 5.6.

E.

Bioavailability/bioequivalence

The assessment of bioavailability must be undertaken in all cases where it is necessary, e.g. where the therapeutic
dose is near the toxic dose or where the previous tests have revealed anomalies which may be related to
pharmacodynamic properties, such as variable absorption.

In addition, an assessment of bioavailability shall be undertaken where necessary to demonstrate bioequivalence
for the medicinal products referred to in Article 10(1)(a).

F.

Clinical efficacy and safety

1.

2.

In general, clinical trials shall be done as (cid:145)controlled clinical trials(cid:146) and if possible, randomized; any other design
shall be justified. The treatment of the control groups will vary from case to case and also will depend on ethical
considerations; thus it may, in some instances, be more pertinent to compare the efficacy of a new medicinal
product with that of an established medicinal product of proven therapeutic value rather than with the effect of a
placebo.

As far as possible, and particularly in trials where the effect of the product cannot be objectively measured, steps
shall be taken to avoid bias, including methods of randomization and blinding.

The protocol of the trial must include a thorough description of the statistical methods to be employed, the
number and reasons for inclusion of patients (including calculations of the power of the trial), the level of
significance to be used and a description of the statistical unit. Measures taken to avoid bias, particularly methods
of randomization, shall be documented. Inclusion of a large number of subjects in a trial must not be regarded as
an adequate substitute for a properly controlled trial.

3.

Clinical statements concerning the efficacy or safety of a medicinal product under normal conditions of use which
are not scientifically substantiated cannot be accepted as valid evidence.

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4.

5.

The value of data on the efficacy and safety of a medicinal product under normal conditions of use will be very
greatly enhanced if such data come from several competent investigators working independently.

For vaccines and serums, the immunological status and age of the trial population and the local epidemiology are
of critical importance and shall be monitored during the trial and fully described.

For live attenuated vaccines, clinical
the
immunizing agent from vaccinated to non-vaccinated subjects. If transmission is possible, the genotypic and
phenotypic stability of the immunizing agent shall be studied.

trials shall be so designed as to reveal potential

transmission of

For vaccines and allergen products, follow-up studies shall include appropriate immunological tests, and where
applicable, antibody assays.

6.

The pertinence of the different trials to the assessment of safety and the validity of methods of evaluation shall be
discussed in the expert report.

7.

All adverse events including abnormal laboratory values shall be presented individually and discussed, especially:

(cid:151) in terms of overall adverse experience, and

(cid:151) as a function of the nature, seriousness and causality of effects.

8.

A critical assessment of relative safety, taking into account adverse reactions, shall be made in relation to:

(cid:151) the disease to be treated,

(cid:151) other therapeutic approaches,

(cid:151) particular characteristics in sub-groups of patients,

(cid:151) preclinical data on toxicology and pharmacology.

9.

Recommendations shall be made for the conditions of use, with the intention of reducing the incidence of adverse
reactions.

G. Documentation for applications in exceptional circumstances

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

When,
comprehensive data on the efficacy and safety under normal conditions of use, because:

(cid:151) the indications for which the product in question is intended are encountered so rarely that the applicant

cannot reasonably be expected to provide comprehensive evidence, or

(cid:151) in the present state of scientific knowledge, comprehensive information cannot be provided, or

(cid:151) it would be contrary to generally accepted principles of medical ethics to collect such information,

marketing authorization may be granted on the following conditions:

(a)

the applicant completes on identified programme of studies within a time period specified by the competent
authority, the results of which shall form the basis of a reassessment of the benefit/risk profile,

(b)

(c)

the medicinal product in question may be supplied on medical prescription only and may in certain cases be
administered only under strict medical supervision, possibly in a hospital and for a radiopharmaceutical, by
an authorized person,

the package leaflet and any medical information shall draw the attention of the medical practitioner to the
fact that the particulars available concerning the medicinal product in question are as yet inadequate in
certain specified respects.

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H.

Post-marketing experience

1.

If the medicinal product is already authorized in other countries, information shall be given in respect of adverse
drug reactions of
the medicinal product concerned and medicinal products containing the same active
substance(s), in relation to the usage rates if possible. Information from worldwide studies relevant to the safety of
the medicinal product shall be included.

For this purpose, an adverse drug reaction is a reaction which is noxious and unintended and which occurs at
doses normally used in man for prophylaxis, diagnosis or therapy of disease or for the modification of
physiological function.

2.

information on the monitoring of vaccinated
In the case of vaccines already authorized in other countries,
subjects to evaluate the prevalence of the disease in question as compared to nonvaccinated subjects shall be
submitted, when available.

3.

For allergen products, response in periods of increased antigen exposure shall be identified.

I. Well-established medicinal use

For the purpose of demonstrating, pursuant to Article 10(1)(a)(ii), that the component(s) of a medicinal product
have a well established use, with recognised efficacy, the following specific rules shall apply:

(a) Factors which have to be taken into account in order to establish a (cid:145)well established medicinal use(cid:146) of
components of medicinal products are the time over which a substance has been used, quantitative aspects of
the use of the substance, the degree of scientific interest in the use of the substance (reflected in the published
scientific literature) and the coherence of scientific assessments. Therefore different periods of time may be
necessary for establishing (cid:145)well established use(cid:146) of different substances. In any case, however, the period of
time required for establishing a (cid:145)well established medicinal use(cid:146) of a component of a medicinal product must
not be less than one decade from the first systematic and documented use of that substance as a medicinal
product in the Community.

(b) The documentation submitted by the applicant should cover all aspects of the efficacy assessment and must
include or refer to a review of the relevant literature, taking into account pre- and postmarketing studies and
published scientific literature concerning experience in the form of epidemiological studies and in particular
of comparative epidemiological studies. All documentation, both favourable and unfavourable, should be
communicated.

(c) Particular attention must be paid to any missing information and justification must be given why

demonstration of efficacy can be supported although some studies are lacking.

(d) The Expert report must explain the relevance of any data submitted which concern a product different from
the product
intended for marketing. A judgment must be made whether the product studied can be
considered as similar to the product which will be granted a marketing authorisation in spite of the existing
differences.

(e) Post-marketing experience with other products containing the same components is of particular importance

and applicants should put a special emphasis on this issue.

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ANNEX II

PART A

Repealed Directives, with their successive amendments (referred to by Article 128)

Council Directive 65/65/EEC (OJ 22, 9. 2. 1965, p. 369/65)

Council Directive 66/454/EEC (OJ 144, 5. 8. 1966, p. 2658/66)

Council Directive 75/319/EEC (OJ L 147, 9. 6. 1975, p. 13)

Council Directive 83/570/EEC (OJ L 332, 28. 11. 1983, p. 1)

Council Directive 87/21/EEC (OJ L 15, 17. 1. 1987, p. 36)

Council Directive 89/341/EEC (OJ L 142, 25. 5. 1989, p. 11)

Council Directive 92/27/EEC (OJ L 113, 30. 4. 1992, p. 8)

Council Directive 93/39/EEC (OJ L 214, 24. 8. 1993, p. 22)

Council Directive 75/318/EEC (OJ L 147, 9. 6. 1975, p. 1)

Council Directive 83/570/EEC

Council Directive 87/19/EEC (OJ L 15, 17. 1. 1987, p. 31)

Council Directive 89/341/EEC

Commission Directive 91/507/EEC (OJ L 270, 26. 9. 1991, p. 32)

Council Directive 93/39/EEC

Commission Directive 1999/82/EC (OJ L 243, 15. 9. 1999, p. 7)

Commission Directive 1999/83/EC (OJ L 243, 15. 9. 1999, p. 9)

Council Directive 75/319/EEC

Council Directive 78/420/EEC (OJ L 123, 11. 5. 1978, p. 26)

Council Directive 83/570/EEC

Council Directive 89/341/EEC

Council Directive 92/27/EEC

Council Directive 93/39/EEC

Commission Directive 2000/38/EC (OJ L 139, 10. 6. 2000, p. 28)

Council Directive 89/342/EEC (OJ L 142, 25. 5. 1989, p. 14)

Council Directive 89/343/EEC (OJ L 142, 25. 5. 1989, p. 16)

Council Directive 89/381/EEC (OJ L 181, 28. 6. 1989, p. 44)

Council Directive 92/25/EEC (OJ L 113, 30. 4. 1992, p. 1)

Council Directive 92/26/EEC (OJ L 113, 30. 4. 1992, p. 5)

Council Directive 92/27/EEC

Council Directive 92/28/EEC (OJ L 113, 30. 4. 1992, p. 13)

Council Directive 92/73/EEC (OJ L 297, 13. 10. 1992, p. 8)

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Time-limits for transposition into national law (referred to by Article 128)

PART B

Directive

Deadline for transposition

Directive 65/65/EEC

Directive 66/454/EEC

Directive 75/318/EEC

Directive 75/319/EEC

Directive 78/420/EEC

Directive 83/570/EEC

Directive 87/19/EEC

Directive 87/21/EEC

Directive 89/341/EEC

Directive 89/342/EEC

Directive 89/343/EEC

Directive 89/381/EEC

Directive 91/507/EEC

Directive 92/25/EEC

Directive 92/26/EEC

Directive 92/27/EEC

Directive 92/28/EEC

Directive 92/73/EEC

Directive 93/39/EEC

Directive 1999/82/EC

Directive 1999/83/EC

Directive 2000/38/EC

31 December 1966

(cid:151)

21 November 1976

21 November 1976

(cid:151)

31 October 1985

1 July 1987

1 July 1987

1 January 1992 (1)

1 January 1992

1 January 1992

1 January 1992

1 January 1992

1 January 1992 (2)

1 January 1995 (3)

1 January 1993

1 January 1993

1 January 1993

1 January 1993

31 December 1993

1 January 1995 (4)

1 January 1998 (5)

1 January 2000

1 March 2000

5 December 2001

(1) Deadline for transposition applicable to Greece, Spain and Portugal.
(2) Except Section A, point 3.3 in Part II of the Annex.
(3) Deadline for transposition applicable to Section A, point 3.3 in Part II of the Annex.
(4) Except with regard to Article 1(6).
(5) Deadline for transposition applicable to Article 1(7).

This Dir.

65/65/EEC

75/318/EEC

75/319/EEC

89/342/EEC

89/343/EEC

89/381/EEC

92/25/EEC

92/26/EEC

92/27/EEC

92/28/EEC

92/73/EEC

Art. 1(1) to (3)

Art. 1(1) to (3)

ANNEX III

CORRELATION TABLE

Art. 1(4)

Art. 1(5)

Art. 1(6) to (9)

Art. 1(10)

Art. 1(11) to
(16)

Art. 1(17) and
(18)

Art. 1(19)

Art. 1(20) to
(26)

Art. 1(27)

Art. 1(28)

Art. 2

Art. 2(1)

Art. 3(1) and (2) Art. 1(4) and

(5)

Art 2(3), 1st
indent

Art. 3(3) and (4) Art.2(3), 2nd

and 3rd indents

Art. 3(5)

Art. 3(6)

Art. 4(1)

Art. 4(2)

Annex

Art. 1(1) and
(2)

Art. 1(2)

Art. 1(1)

Art. 1

Art. 29b, 1st
paragraph

Art. 8(1)

Art. 10(1)

Art. 1(2)

Art. 1(2), 2nd
sentence

Art. 1(2)

Art. 1(1)

Art. 1(3)

Art. 1(2)

Art. 1(3)

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Art. 4(3)

Art. 3, 2nd
subparagraph

Art. 4(4)

Art. 6

Art. 2(4)

Art. 3(1)

Art. 5

Art. 6(1)

Art. 6(2)

Art. 7

Art. 8(1) and (2) Art. 4(1) and

(2)

Art. 8(3)(a) to
(e)

Art. 4, 3rd
para., points 1
to 5

Art. 1, 1st
paragraph

Art. 8(3)(f) to (i) Art. 4, 3rd

para., points 6
to 8.1

Art. 8(3)(j) to (l) Art. 4, 3rd

para., points 9
to 11

Art. 9

Art. 10(1)

Art. 10(2)

Art. 4, 3rd
paragraph,
point 8.2

Art. 11, points
1 to 5.3

Art. 4a, points
1 to 5.3

Art. 11, point
5.4

Art. 4a, point
5.4

Art. 11, points
5.5 to 6.4

Art. 4a, points
5.5 to 6.4

Art. 11, point
6.5

Art. 4a, point
6.6

Art. 11, point 7 Art. 4a, point

6.5

Art. 11, points
8 to 9

Art. 12(1)

Art. 1, 2nd
paragraph

Art. 3

Art. 1

Art. 2, 1st
sentence

Art. 2, 2nd
sentence

Art. 3

Art. 4

.

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This Dir.

65/65/EEC

75/318/EEC

75/319/EEC

89/342/EEC

89/343/EEC

89/381/EEC

92/25/EEC

92/26/EEC

92/27/EEC

92/28/EEC

92/73/EEC

Art. 6(1) and (2)

Art. 7(1) and (4)

Art. 4, 2nd
paragraph

Art. 8

Art. 9

Art. 7

Art. 7a

Art. 4b

Art. 10(2)

Art. 9a

Art. 10(1)

Art. 9

Art. 5

Art. 12(2) and
(3)

Art. 13

Art. 14(1) and
(2)

Art. 14(3)

Art. 15

Art. 16

Art. 17

Art. 18

Art. 19

Art. 20

Art. 21

Art. 22

Art. 23

Art. 24

Art. 25

Art. 26

Art. 27

Art. 28(1)

Art. 28(2)

Art. 28(3)

Art. 28(4)

Art. 29

Art. 30

Art. 31

Art. 32

Art. 33

Art. 34

Art. 35

Art. 2

Art. 4

Art. 5

Art. 8

Art. 9(3)

Art. 9(1)

Art. 9(2)

Art. 9(4)

Art. 10

Art. 11

Art. 12

Art. 13

Art. 14(1)

Art. 14(2) to (4)

Art. 15

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Art. 15a

Art. 15b

Art. 15c

Art. 14(5)

Art. 16

Art. 17

Art. 18

Art. 20(1)

Art. 20(2)

Art. 20(3)

Art. 19

Art. 19a

Art. 21

Art. 23

Art. 24

Art. 22(1)

Art. 22(2)

Art. 25

Art. 36

Art. 37

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(1) and
(2)

Art. 51(3)

Art. 52

Art. 53

Art. 54

Art. 55

Art. 56

Art. 57

Art. 58

Art. 59

Art. 60

Art. 61

Art. 62

.

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5

Art. 3

Art. 2(1)

Art. 3

Art. 4(1)

Art. 5(2)

Art. 6

Art. 7(1) and
(2)

Art. 5(1) and
Art. 9

Art. 10(1) to (4)

Art. 2(2) and

Art. 7(3)

This Dir.

65/65/EEC

75/318/EEC

75/319/EEC

89/342/EEC

89/343/EEC

89/381/EEC

92/25/EEC

92/26/EEC

92/27/EEC

92/28/EEC

92/73/EEC

Art. 63(1)

Art. 63(2)

Art. 63(3)

Art. 64

Art. 65

Art. 66

Art. 67

Art. 68

Art. 69

Art. 70

Art. 71

Art. 72

Art. 73

Art. 74

Art. 75

Art. 76

Art. 77

Art. 78

Art. 79

Art. 80

Art. 81

Art. 82

Art. 83

Art. 84

Art. 85

Art. 86

Art. 87

Art. 88

Art. 5

Art. 6(1)

Art. 4(2)

Art. 8

Art. 10(5)

Art. 11(1)

Art. 12

Art. 2(2)

Art. 7(2) and (3)

Art. 2

Art. 3

Art. 4

Art. 5(1)

Art. 5(2)

Art. 6(2)

Art. 2

Art. 3

Art. 4(1)

Art. 5

Art. 6

Art. 7

Art. 8

Art. 9

Art. 10

Art. 9

Art. 1(3) and
(4)

Art. 2

Art. 3(1) to (6)

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Art. 4

Art. 5

Art. 6

Art. 7

Art. 8

Art. 9

Art. 10

Art. 11

Art. 12(1) and
(2)

Art. 12(4)

Art. 13

Art. 14

Art. 6(3)

Art. 89

Art. 90

Art. 91

Art. 92

Art. 93

Art. 94

Art. 95

Art. 96

Art. 97(1) to (4)

Art. 97(5)

Art. 98

Art. 99

Art. 100

Art. 101

Art. 102

Art. 103

Art. 104

Art. 105

Art. 106(1)

Art. 106(2)

Art. 107

Art. 108

Art. 109

Art. 110

Art. 111(1)

Art. 111(2)

Art. 111(3)

Art. 29e

Art. 29a

Art. 29c

Art. 29d

Art. 29f

Art. 29g

Art. 29b, 2nd
paragraph

Art. 29h

Art. 29i

Art. 26, 1st and
2nd paragraph

Art. 26, 3rd
paragraph

Art. 4(1)

Art. 3(1) to (3)

Art. 3(4)

.

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This Dir.

65/65/EEC

75/318/EEC

75/319/EEC

89/342/EEC

89/343/EEC

89/381/EEC

92/25/EEC

92/26/EEC

92/27/EEC

92/28/EEC

92/73/EEC

Art. 112

Art. 113

Art. 114(1)

Art. 114(2)

Art. 115

Art. 116

Art. 117

Art. 118

Art. 119

Art. 120

Art. 121

Art. 122

Art. 123

Art. 124

Art. 125

Art. 126, 1st
paragraph

Art. 126, 2nd
paragraph

Art. 127

Art. 128

Art. 129

Art. 130

Annex I

Annex II

Annex III

Art. 8

Art. 27

Art. 11

Art. 12

Art. 21

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

Art. 28

Art. 29

Art. 37a

Art. 30

Art. 33

Art. 31

Art. 32

Art. 28a

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

Art. 2a, 1st
paragraph

Art. 2b

(cid:151)

(cid:151)

(cid:151)

Annex

(cid:151)

(cid:151)

Art. 4(2)

Art. 4(3)

Art. 4(2)

Art. 4(3)

Art. 4(1)

Art. 4(2)

Art. 11(2)

Art. 12(3)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

Art. 4(1)

Art. 5

(cid:151)

(cid:151)

(cid:151)

(cid:151)

(cid:151)

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