COMMISSION OF THE EUROPEAN COMMUNITIES 
Proposal for a Brussels, 28.06.1999 
COM(1999)315 final 
99/0134 (COD) 
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE 
on the Community code relating to medicinal products for human use 
(codified version) 
(presented by the Commission) 

EXPLANATORY MEMORANDUM 
I. In the context of a people's Europe, the Commission attaches great importance to simplifying and clarifying Community 
law so as to make it clearer and more accessible to the ordinary citizen, thus giving him new opportunities and the chance 
t~ make use of the specific rights it gives him. 
This aim cannot be achieved so long as numerous provisions that have been amended several times, often quite 
substantially, remain scattered, so that they must be sought partly in the original instrument and partly in later amending 
ones. Considerable research work, comparing many· different instruments, is thus needed to identify the current rules. 
For this reason a codification of rules that have frequently been amended is also essential if Community law is to be clear 
and transparent. 
2. On 1 April 1987 the Commission therefore decided to instruct its stall· that all legislative measures should be codified 
after no more than ten amendments, stressing that this was a minimum requirement and that departments should 
endeavour to condify at even shorter intervals the texts for which they were responsible, to ensure that the Community 
rules were clear and readily understandable. 
3. The Conclusions of the Presider:tcY of the Edinourgh European Council (December J 992) confinned this, stressing the 
importance of legislative codification as it offers certainty as to the law applicable to a given matter at a given time. 
It must be undertaken in full compliance with the normal Community legislative procedure. 
Given that no changes of substance may be made to the instruments affected by legislative codification, Parliament, the 
Council and the Commission have agreed, by an interinstitutional agreement dated 20 December 1994, that an 
accelerated procedure may be used for the fast-track adoption of codification instruments. 
4. The purpose of this proposal I for legislative codification of Council Dir~ctives 65/65/EEC of 26 January 1965 on the 
approximation of provisions laid down by law, regulation or administrative · action relating to medicinal products; 
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; 75/319/EEC 
of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to 
proprietary medicinal products; 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 products consisting of vaccines, toxins 
or serums and allergens; 89/343/EEC of 3 May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and 
laying down additional provisions for radiophannaceuticals; 89/381/EEC of 14 June 1989 extending the scope of 
Directives 65/65/EEC and 75/319/EEC on the approximation of provisions laid down by law, regulation or 
administrative action relating to medicinal products and laying down special provisions for proprietary medicinal 
products derived from human blood or human plasma; 92/25/EEC of 31 March 1992 on the wholesale distribution of 
medicinal products for human use; 92/26/EEC of 31 March 1992 concerning the classification for the supply of 
medicinal products for human use; 92/27/EEC of 31 March 1992 on the labelling of medicinal products for human use 
and on package leaflets; 92/28/EEC of 31 March 1992 on the advertising of medicinal products for human use; and 
92/73/EEC of22 September 1992 widening the scope of Directives 65/65/EEC and 75/319/EEC on the approximation of 
provisions laid down by law, regulation or administrative action relating to medicinal products and laying down 
additional provisions on. homeopathic medicinal products, prepared ~y the Legal Service in conjunction with the 
Directorate-General Ill, is to undertake official codification of this type. The new directive will supersede the various 
directives incorporated in it2, their content is fully preserved, and they are brought together with only such formal 
amendments as are required by the codification exercise itself. 
4a In order to point out the satisfactory application of the codification of the Directive mentioned above, in order to take 
into account the fact that since the last Directive cited in point 4, the European Agency for the Evaluation of Medicinal 
Products has been established by Council Regulation (EEC) 2309/9~ of22 July 1993. 
2 In the same manner, in order to point out that this codification proposal concerning medicinal products for human use 
was created in parallel with the codification proposal for Directives relating to veterinary medicinal products. 
Entered in the legislative programme for 1998. 
See Annex 11, Part A of this Proposal. 
2 
5. This legislative codification proposal was drawn up on the basis of a preliminary consolidation, in all the official 
languages. The. instruments ~ending it, carried out by the Office for Official Publications of the European 
Communities, by means of the data-proeessing system referred to in the conclusions of the European Council meeting at 
Edinburgh. Although the articles have been given new numbers, the old numbering has been retained in the margin for 
ease of reference; the correlation between the old and new numbers is shown in a table set out in Annex Ill of the 
consolidated Directive. 
3 
Proposal for a 
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE .•• / ... /EC 
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 the Economic and Social Committee1 
Acting in accordance with the procedure laid down in Article 251 of the Treaty2, 
( 1) Whereas Council Directive 65/65/EEC of 26 January 1965 on the 
approximation of provisions laid down by law, regulation or administrative 
action relating to medicinal products3, .Council Directive 7 5/318/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 r~spect of the testing of proprietary medicinal products4, 
Council Directive 75/319/EEC of 20 May 1975 on the approximation of 
provisions laid down by law' regulation or administrative action relating 
to proprietary medicinal productsS, 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 
products consisting of vaccines, toxins or serums and allergens6, 
Council Directive 89/343/EEC of 3 May 1989 extending the scope of 
Directives 65/65/EEC and 
2 
3 
4 
5 
6 OJC 
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). 
OJ L 147, 9.6.1975, p. I. Directive as last amended by Directive 93/39/EEC. 
OJ L, 147, 9.6.1975, p. 13. Directive as last amended by Directive 93/39/EEC. 
OJ L 142, 25.5.1989, p. 14. 
4 
75/319/EEC and laying down additional provisions for 
radiophannaceuticals1, 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 laid down by law, regulation or administrative 
action relating to medicinal products and laying down special provisions for 
proprietary medicinal products derived from human blood or human plasma2, 
Council Directive 92125/EEC of 31 March 1992 on the 
wholesale distribution of medicinal products for human usel, 
Council Directive 92/26/EEC of 31 March t 992 concerning the 
classification for the supply of medicinal products for human usc4, 
· Council Directive 92/27/EEC of 31 March 1992 on the labelling of 
medicinal products for human use and on package leafletsS, 
Council Directive 92128/EEC of 3 f· March 1992 on the advertising of 
medicinal products for human use6, 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, regulation 
or administrative action relating to medicinal products and laying down 
additional provisions on homeopathic medicinal products 7 have been 
frequently and substantially amended; whereas, in the interests of clarity and 
rationality, the said Directives should therefore be codified by assembling 
them in a single text; 
(2) Whereas the essential aim of any rules governing the production, distribution 
and use of medicinal products must be to safeguard public health; 
(3) Whereas, however, this objective must be attained by means which will not 
hinder the development of the pharmaceutical industry or trade in medicinal 
products within the Community; 
I 
2 
3 
4 
s 
6 
7 OJ L 142, 2S.S.J989, p. 16. 
OJ L 181, 21.6.1989, p. 44. 
OJ L Jl3, 30.4.1992, p. I. 
01 L 113, 30.4.1992, p. S. 
OJ L 113, 30.4.1992, p. &. 
OJ L 113, 30.4.1992, p. 13. 
OJ L 297, 13.10.1992, p. 8. 
5 1. 89/341/EEC 
2. 65/65/EEC 
(4) Whereas trade in medicinal products within the Community is hindered by 
disparities between certain r:-ational provisions, in particular between 
provisions relating to medicinal products (excluding substances or 
combinations of substances which are foods, animal feeding-stuffs or toilet 
preparations); and whereas such disparities directly affect the functioning of 
the internal market; 
(5) Whereas such hindrances must accordingly be removed; whereas this entails 
approximation of the relevant provisions; 
( 6) Whereas 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; 
(7) Whereas 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; whereas the particulars and documents which 
. must accompany an application for marketing authorization for a medicinal 
product demonstrate that potential risks are outweighed by the therapeutic 
efficacy of the product; 
(8) Whereas 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; 
(9) Whereas experience has shown that it is advisable to stipulate more precisely 
the cases in which the results of toxicological and. pharmacological tests or 
clinical trials do not have to be provided with a view to obtaining 
authorization for a medicinal product which is essentially similar to an 
authorized product, w~ile ensuring that innovative firms are not placed at a 
disadvantage; 
6 3. 
4. 
2. 
7. 
3. 
2. 65/65/EEC 
(adapted) 
65/65/EEC 
75/319/EEC 
(adapted) 
75/318/EEC 
(adapted) 
75/318/EEC 
(ad~pted) 
87/21/EEC 
(adapted) 
( 1 0) Whereas, however, there are reasons of public policy for not conducting 
repetitive tests on humans or animals without over-riding cause; 
(ll)Whereas 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)Whereas, 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 for supposing that the authorization of the 
medicinal product concerned may present a risk to public health; whereas,· in 
the event of a disagreement between Member States about the quality, 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 be adopted by a rapid procedure 
ensuring close cooperation between the Commission and the Member States; 
( 13) Whereas, 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; 
(14)Whereas this Directive represents an important step towards achievement of 
the objective of the .free movement of medicinal products; whereas 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; 
(15) Whereas in order better to protect public health and avoid any unnecessary 
duplication of effort during the examination of application for a marketing 
authorization for medicinal products, Member States should systematically 
prepare assessment reports in respect of each medicinal product which is 
authorized by them, and exchange the reports upon request; whereas, 
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; 4. 
4. 
4. 
4. 
5. 
5. 
OJ L214, 24.8.1993, p. I; Regulation as amended by Commission Regulation (EC) No 649198 (OJ L 88, 24.3.1998, p. 7). 
7 87/21/EEC 
75/318/EEC 
93/39/EEC 
(adapted) 
75/319/EEC 
(adapted) 
75/319/EEC 
(adapted) 
93/39/EEC 
(adapted) 
(16)Whereas 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; 
(17)Whereas it is necessary to adopt specific provisions for immunological 
medicinal products, homeopathic medicinal products, radiopharmaceuticals, 
and medicinal products based on human blood or human plasma; 
(18)Whereas 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 
undergoing medical examination or treatment1; whereas 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 health protection of 
the general public and workers against the dangers of ionizing radiation2, 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 Se thereof, which requires prior authorization for the addition of 
radioactive substances to medicinal products as well as for the importation of 
such medicinal products; 
( 19) Whereas the Community entirely supports the efforts of the Council of 
Europe to promote voluntary unpaid blood and plasma donation to attain 
self-sufficiency throughout the Community in the supply of bl~od products, 
and to ensure respect for ethical principles in trade in therapeutic substances 
of human origin; 
(20)Whereas 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; 
(21) Whereas, 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 relating to clinical trials, it is desirable to provide a special, 
simplified registration procedure for those. homeopathic medicinal products 
which are placed on the market without therapeutic indications in a 
pharmaceutical fonn and dosage which do not present a risk for the patient; 
(22) Whereas the anthroposophic medicinal products described in an official 
pharmacopoeia and prepared by a homeopathic method are to be treated, as 
regards registration and marketing authorization, in the same way as 
homeopathic medicinal products; 6. 
8. 
7. 
5. 
6. 
10. 
4. 93/39/EEC 
75/319/EEC 
(adapted) 
89/343/EEC 
(adapted) 
89/381/EEC 
89/381/EEC 
92173/EEC 
(adapted) 
92173/EEC 
I 
2 OJ L 265, 5.10.1984, p. I; Directive repealed with effect from 13 May 2000 by Direc;tive 97/43/Euratom (OJ L 180, 9.7.1997, p. 22). 
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). 
8 
(23)Whereas 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; 
(24)Whereas 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 
~nd of good quality; 
(25) Whereas 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 fonn which may present risks 
which must be balanced against the desired therapeutic effect; whereas, in 
particular, 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, 
(26)Whereas in order to facilitate the movement of medicinal products and to 
prevent the controls carried out in one Member State from being repeated in 
-another, minimum requirements should be laid down for manufacture and 
imports coming from third countries and for the grant of the authorization 
relating thereto; 
(27)Whereas it should be ensured that, in the Member States, the supervision and 
control of the manufacture of medicinal products is carried out by a person 
who fulfils minimum conditions of qualification; · 
(28) Whereas, ·before an authorization to market an immunological medicinal 
· prod.uct or derived from human blood or human plasma can be granted, the 
manufacturer must demonstrate his ability to attain batch-to-batch 
consistency; whereas before and authorization to market a medicinal product 
derived from human blood or human plasma can be granted, the 
manufacturer must also demonstrate the absence of specific viral 
contamination, to the extent that the state of technology permits; 
9 8. 
9. 
6. 
7. 
5. 
+ 
7. 92173/EEC 
92/73/EEC 
92173/EEC 
75/319/EEC 
(adapted) . 
75/319/EEC 
(adapted) 
89/342/EEC 
(adapted) 
89/381/EEC 
(adapted) 
(29)Whereas the conditions governing the supply of medicinal products to the 
public should be harmonized; 
(30)Whereas 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; whereas 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; 
{3l)Whereas, in addition, by virtue of Regulation (EC) No 2309/93, certain 
medicinal products are the subject of a Community marketing authorization; 
whereas, in this context, the classification for the supply of medicinal 
products covered by a Community marketing authorization needs to be 
established; whereas it is therefore important to set the criteria on the basis of 
which Community decisions will be taken; 
(32) Whereas it is therefore appropriate, as an initial step, to harmonize the basic 
principles applicable to the classification for the supply of medicinal products 
. in the Community or in the Member State concerned, while taking as a 
starting point the principles 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; 
(33)Whereas the provisions dealing with the classification of medicinal products 
for the purpose of supply do not infringe the national social security 
arrangements for reimbursell)ent or payment for medicinal products on 
prescription; 
(34)Whereas many operations involving the wholesale distribution of medicinal 
products for human use may cover several Member States simultaneously; 
(35)Whereas 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; whereas 
the requirements which must be adopted for this purpose will considerably 
facilitate the withdrawal of defective products from the market and allow 
more effective efforts against counterfeit products; 
10 3. 
4: 
5. 
6. 
7. 
2. 
3. 92/26/EEC 
(adapted) 
92/26/EEC 
(adapted) 
92/26/EEC 
(adapted) 
92/26/EEC 
92/26/EEC 
(adapted) 
92/25/EEC 
(adapted) 
92/25/EEC 
.(36) Whereas any person involved in the wholesale distribution of medicinal 
products should be in possession of a special authorization; whereas 
pharmacists and persons authorized to supply medicinal products to the 
public, and who confine themselves to this activity, should be exempt from 
obtaining this authorization; whereas it is however necessary, in order to 
control the complete chain of distribution of medicinal products, that 
pharmacists and persons authorized to supply medicinal products to the 
public keep records showing transactions in products received; 
(3 7) Whereas 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 each Member State must recognize' 
authorizations granted by other Member States; 
(38)Whereas 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; whereas those 
Member States must be able to continue to impose those obligations on 
wholesalers established within their territory; whereas 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) Whereas rules . should be laid down as to how the labelling and package 
leaflets are to be presented; 
(40)Whereas the provisions governing the information supplied to users should 
provide a high degree of consumer protection, in order that medicinal 
products may be used correctly on the basis of full and comprehensible 
information; 
( 41) Whereas 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; 
(42)Whereas this Directive is without prejudice to the application of measures 
adopted pursuant to Council Directive 84/450/EEC of 10 September 1984 
relating to the approximation of the laws, regulations and administrative 
provisions ofthe Member States concerning misleading advertisingl; 
OJ L 250, 19.9.1984, p. 17. Directive as amended by Directive 97/55/EC (OJ L 290,23. 10. 1997, p. 18). 
11 4. 
5. 
6. 
2. 
+ 
3. 
5. 
6. 
I. 92/25/EEC 
(adapted) 
92/25/EEC 
92/25/EEC 
92/27/EEC 
(adapted) 
92/27/EEC 
92/27/EEC 
92/28/EEC 
(adapted) 
(43)Whereas all Member States have adopted further specific measures 
concerning the adve~ising of medicinal products; whereas there are 
disparities between these measures; whereas 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)Whereas 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 concerning the pursuit of television 
broadcasting activities1 prohibits the television advertising of medicinal 
products which are available only on medical prescription in the 
Member State within whose jurisdiction the television broadcaster is located; 
whereas this principle should be made of general application by extending it 
· to oth~r media; 
( 45) Whereas advertising to the general public, even of non-prescription 
medicinal products, could affect public health, were it to be excessive and ill­
considered; whereas advertising of medicinal products to the general public, 
where it is permitted, ought therefore to satisfy certain essential criteria 
which ought to be defined; 
( 46) Whereas, furthermore, distribution of samples free of charge to the general 
public for promotional ends must be prohibited; 
( 4 7) Whereas the advertising of medicinal products to persons qualified to 
prescribe or supply them contributes to the information available to such 
persons; whereas, 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) Whereas advertising of medicinal products should be subject to effective, 
adequate monitoring; whereas reference in this regard should b~ made to the 
monitoring mechanisms set up by Directive 84/450/EEC; 
(49)Whereas medical sales representatives have an important role in the 
promotion of medicinal products; whereas, therefore, certain obligations 
should be imposed upon them, in particular the obligation to supply the 
person visited with a summary of product characteristics; 
(50)Whereas persons qualified to prescribe medicinal products must be able to 
carry out these functions objectively without being influenced by direct or 
indirect financial inducements; 
(5I)Whereas 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; 
OJ L 298, 17.10.1989, p. 23; Directive as amended by Directive 97/36/EC (OJ L 202,30. 7. 1997, p. 60). 
12 2. 
3. 
4. 
5. 
6. 
!1. 
7. 
8. 
9. 92/28/EEC 
(adapted) 
92/28/EEC 
92/28/EEC 
92/28/EEC 
92/28/EEC 
92/28/EEC 
92/28/EEC 
92/28/EEC 
92/28/EEC 
(52)Whereas 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; 
(53)Whereas each undertaking which manufactures or imports medicinal 
products should set up a mechanism to ensure that all information supplied 
about a medicinal product conforms with the approved conditions of use; 
(54) Whereas it is desirable to regulate and improve the cooperation and exchange 
of information between Member States relating to the supervision of 
medicinal products and in particular the monitoring of adverse reactions 
under practical conditions of use through the national pharmacovigilance 
systems; 
(55)Whereas the Commission should be empowered to adopt any necessary 
changes to Annex I in order to take into account scientific and technical 
progress; 
(56)Whereas this Directive is without prejudice to the obligations of the 
Member States concerning the deadlines for transposition set out in Annex 11, 
Part B. 
HAVE ADOPTED THIS DIRECTIVE: 
13 10. 
12. 
7. 
8. 
+ 
6. 
+ 
6. 
+ 
8. 92/28/EEC 
92/28/EEC 
93/39/EEC 
(adapted) 
75/318/EEC 
(;ldapted) 
89/342/EEC 
(adapted) 
89/343/EEC 
(adapted) 
89/381/EEC 
(adapted) 
TITLE I 
DEFINITIONS 
Article 1 
For the purposes of this Directive, the following tenns shall bear the following 65/65/EEC 
meanings: Art. I (I) to (3) 
(adapted) 
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 to restoring, correcting or 
modifying physiological functions in human beings is likewise considered a 
medicinal product. 
3. Substance: 
Any matter irrespective of origin which may be: 
human, e.g. 
human blood and human blood products; 
animal, e.g. 
micro-organisms, whole animals, parts of organs, anima_l secretions, toxins, 
extracts, blood products; 
vegetable, e.g. 
micro-organisms, plants, parts of plants, vegetable secretions, extracts; 
chemical, e.g. 
elements, naturally occurring chemical materials and chemical products 
obtained by chemical change or synthesis. · 
14 
4. Immunological medicinal product: 
Any medicinal product consisting of vaccines, toxins, serums or allergen products: 
(a) vaccines, toxins and serums shall cover in particular: 89/342/EEC 
Art. I (1) 
(adapted) 
89/342/EEC 
Art. 1 (2), 2nd indent 
(i) agents used to produce active immunity, such as cholera vaccine, BCG, + 
polio vaccines, smallpox vaccine; 75/319/EEC 
(ii) agents used to diagnose the state of immunity, including in particular 
tuberculin and tuberculin PPD, toxins for the Schick and Dick Tests, 
brucellin; 
(iii) agents used to produce passive immunity, such as diphtheria antitoxin, 
anti-smallpox globulin, antilymphocytic globulin. Annex 
(b) "allergen product" shall mean any medicinal product which is intended to 89/342/EEC 
identify or induce a specific acquired alteration in the immunological response Art. 1 (2), 1st indent 
to an allergizing agent. (adapted) 
5. Homeopathic medicinal product: 92173/EEC 
Art. 1 
Any medicinal product prepared from products, substances or-compositions called (adapted) 
homeopathic stocks in accordance with a homeopathic manufacturing procedure 
described by the European Pharmacopoeia or, in absence thereof, by the 
pharmacopoeias currently used official~y in the Member States. 
A homeopathic medicinal product may also contain a number of principles. 
6. Radiopharmaceutical: 89/343/EEC 
Art. 1 (2) 
Any medicinal product which, when ready for use, contains one or more (adapted) 
radionuclides (radioactive isotopes) included for a medicinal purpose. 
7. Radionuclide generator: 
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. 
8. Radionuc/ide kit: 
Any preparation to be reconsitituted or combined with radionuclides in the final 
radiopharmaceutical, usually prior to its administration. 
9. Radionuclide precursor: 
Any other radionuclide produced for the radio-labelling of another substance prior 
to administration. 
15 
I 0. Medicinal products derived from human blood or human plasma: 89/381/EEC 
Art. I (I) 
Medicinal products based on blood constitutents which are prepared industrially by (adapted) 
public or prjvate establishments, such medicinal products including, in particular, 
albumin, coagulating factors and immunoglobulins of human origin. 
'11. Adverse reaction: . 75/319/EEC 
Art. 29b 
A reaction which is harmful and unintended and which occurs at doses normally (as amended by 
used in man for the prophylaxis, diagnosis or treatment. of disease or the 93/39/EEC Art. 3 (3)) 
modification of physiological function. 
12. Serious adverse reaction: 
An adverse reaction which is fatal, life-threatening, disabling, incapacitating, or 
which results in or prolongs hospitalization. 
13. Unexpected adverse reaction: 
An adverse reaction which is not mentioned in the summary of product 
characteristics. 
14. Serious unexpected adverse reaction: 
An adverse reaction which is both serious and unexpected. 
15. Wholesale distribution of medicinal products: 
All activities consisting of procuring, holding, supplying or exporting medicinal 
products, apart from supplying medicinal products to the public; such activities are 
carried out with manufacturers or their depositories, importers, . other wholesale 
distributors or with pharmacists and persons authorized to supply medicinal products· 
to the public in the Member State concerned. 
16. Public service obligation: 
The obligation placed on wholesalers to guarantee 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. · 
17. Medicinal Prescription: 92/25/EEC 
Art. 1 (2) 
92/26/EEC 
Art. J. (2), 2nd sentence 
Any medicinal prescription issued by a professional person qualified to. make such a (adapted) 
prescription. 
16 
18. 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 name of the 
manufacturer; the invented name shall not be liable to confusion with the common 
name. 
19. Common name: 
The international name recommended by the World Health Organization, or, if one 
does not exist, the usual common name . 
. 20. Strength of the medicinal product: 92/27/EEC 
Art. 1 (2) 
The content of the active substances expressed quantitatively per dosage unit, per (adapted) 
unit of volume or weight according to the dosage form. 
21. Immediate packaging: 
The container or other form of packaging immediately in contact with the medicinal 
product. 
22. Outer packaging: 
The packaging into which is placed the immediate packaging. 
23. Labelling: 
Information on the immediate or outer packaging. 
24. Package leaflet: 
A leaflet containing information for the user which accompanies the medicinal 
product. 
25. Agency: 
The European Agency for the Evaluation of Medicinal Products established by 
Regulation (EEC) No 2309/93. 
26. Risk to public health: 
All risks with regard to the ·quality, safety and efficacy of the medicinal product. 
. . . 
17 75/319/EEC 
Art. 8 (1) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 
75/319/EEC 
Art. 10 (1) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 
(2) TITLE 11 
SCOPE 
Article 2 
The. provisions of this Directive shall apply to medicinal products for human use 
intended to be placed on the market in Member States. 
Article 3 
This Directive shall not apply to: 
I. 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 s~rved 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; 
5. Any radionuclides in the form of sealed sources; 
6. Whole blood, plasma or blood cells of human origin. 
Article 4 65/65/EEC 
Art. 2 (I) 
(as amended by 
89/341/EEC Art. I (3)) 
(adapted) 
65/65/EEC 
Art. 1 (4) and (5) and 
Art. 2 (3), Ist'indent 
(as amended by 
89/34I/EEC Art. 1 (2) 
and (3)) 
(adapted) 
65/65/EEC 
Art. 2 (3), 2nd and 3rd 
indents 
(as amended by 
89/341/EEC Art. I (3)) 
(adapted) 
\ 
\ 
89/343/EEC 
Art. I (I) ' 
(adapted) 
189/381/EEC 
Art. 1 (2) 
I. Nothing in this Directive shall in any way derogate from the Community rules for the 89/343/EEC 
radiation protection of persons undergoing medical examination or treatment, or from Art. 1 (3) 
the Community rules laying down the basic safety standards for the health protection of 
the general public and ~orkers against the dangers of ionizing radiation. 
18 
2. This Directive shall be without prejudice to Council.Decision 86/346/EEC1• 
189/381/EEC 
Art. I (3) 
3. The provisions of this Directive shall not affect the powers of the Member States' 65/65/EEC 
authorities either as regards the setting of prices for medicinal products or their inclusion Art. 3, 2nd subparagraph 
in the scope of national health insurance schemes, on the basis of health, economic and (as amended by 
social conditions. 93/39/EEC Art. I (I)) 
4. This Directive shall not affect the application of national legislation prohibiting or 65/65/EEC 
restricting the sale, supply or use · of medicinal products as contraceptives or Art. 6 
abortifacients. The Member States shall communicate the national legislation concerned (as amended by 
to the Commission. 93/39/EEC Art. I (5)) 
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~ 
OJ L 207, 30.7.1986, p. I. 
19 65/65/EEC 
Art. 2 (4) 
(as amended by 
89/341/EEC Art. I (3)) 
(adapted) 
TITLE Ill 
PLACING ON THE MARKET 
Chapter 1 
Marketi~g authorization 
Article 6 
No medicinal product 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 
States in accordance with this Directive or an authorization has been granted in 
accordance with Regulation (EEC) No 2309/93. 
Article 7 .65/65/EEC 
Art. 3 (1) 
(as amended by 
93/39/EEC Art. 1 ( 1)) 
(adapted) 
A marketing authorization shall not be required for a radiopharmaceutical prepared at 89/343/EEC 
the time of use by a person or by an establishment authorized, according to national Art. 2, 2nd sentence 
legislation, to use such medicinal products in an approved health care establishment (adapted) 
exclusively from authorized radionuclide generators, radionuclide kits or radionuclide 
precursors in accordance with the manufacturer's instructions. 
Article 8 
I. In order to obtain an authorization to place a medicinal product on the market 65/65/EEC 
regardless of the procedure established by Regulation (EEC) No 2309/93, an application Art. 4 (1) 
shall be made to the competent authority of the Member State concerned. (adapted) 
2. A marketing authorization may only be granted to an applicant ·established in the 
Community .. 
20 65/65/EEC 
Art. 4 (2) 
(as amended by 
93/39/EEC Art. 1 (2)) 
(adapted) 
3. The application shall be accompanied by the. following particulars and documents, 65/65/EEC 
submitted in accordance with Annex 1: Art. 4, 3rd paragraph, 
points I to 5 
(a) Name or corporate name and permanent address of the applicant and, where (as amended by 
applicable, of the manufacturer: 89/341/EEC Art. 1 (1)) 
(adapted) 
(b) Name of th~ medicinal product. 
(c) Qualitative and quantitative particulars of all the constituents of the medicinal 
product in usual tenninology, but excluding empirical chemical formulae, with 
mention ofthe_intemational name 'recommended by the World Health Organization 
where such name exists. 
(d) Description of the manufacturing method. 
(e) · Therapeutic indications, contra-indications and adverse reactions. 
(t) Posology, pharmaceutical form, method and route of administration and expected 
shelf life. 
(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 of 
waste products, together with an indication of any potential risks presented by the 
medicinal product for the environment. 
(h) Description of the control methods employed by the manufacturer (qualitative and 
quantitative analysis of the constituents and Qf the finished product, special tests~ 
e.g. sterility tests, tests for the presence of pyrogenic su.bstances, the presence of 
heavy metals, stability tests, biological and toxicity tests, controls carried out at an 
intermediat~ stage of the manufacturing process). 
(i) Results of: . 
physico-chemical, biological or microbiological tests, 
toxicological and phartnacological tests, 
clinical trials. 
21 + 
75/318/EEC 
Art. i , 1st paragraph 
(adapted) 
65/65/EEC 
Art. 4, 3rd paragraph, 
point 6 
(as amended by 
93/39/EEC Art. 1 (3)) 
65/65/EEC 
Art. 4, 3rd paragraph, 
point 7 
(as amended by 
75/319/EEC Art. 35) 
(adapted) 
65/65/EEC 
Art. 4, 3rd paragraph, 
point 8.1 
·(as amended by 
87/21/EEC Art. 1 (1)) 
(j) A summary, in accordance with Article 11, of the product characteristics, one or 
more specimens or mock-ups of the sales presentation of the medicinal product, 
~ogether with a package leaflet. 
(k) A document showing that the manufacturer is authorised in his own country to 
produce medicinal.products. · 
(I) 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 e~amination. Copies of the summary of the product characteristics 
proposed by the applicant in accordance with Article 11 or approved by the 
competent authorities of the Member State in accordance with Article 21. C~pies of 
the package leaflet proposed. in accordance with Article 59 or approved by the 
competent authorities of the Member State in accor~ce 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 65/65/EEC 
Art. 4, 3rd paragraph, 
point 9 
(as amended by · 
83/570/EEC Art. 1 ( 1) 
(c) and 89/341/EEC 
Art. I (I)) 
(adapted) 
65/65/EEC 
Art. 4, 3rd paragraph, 
point 10 
(as amended by 
89/341 /EEC Art. 1 ( 1)) 
65/65/EEC 
Art. 4, 3rd paragraph, 
point 11 
(as amended by 
93/39/EEC Art. 1 (3)) 
(adapted) 
In addition to the requirements set out in Articles 8 and 10 (l ), an application for 89/343/EEC 
authorization to market a radionuclide generator shall also contain the following Art. 3 
information and particulars: (adapted) 
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, · 
qualitative and quantitative particulars of the eluate or the sublimate. 
22 
Article 10 
I. In derogation of Article 8 (3) (i), and without prejudice to the law relating to the 
protection of industrial and commercial property: 
(a) The applicant shall not be required to provide the results of toxicological and 
pharmacological tests or the results of clinical trials if he can demonstrate: 
(i) either that the medicinal product is essentially similar to a medicinal product 
authorized in the country concerned by the application and that the marketing 
authorization holder has consented to the toxicological, pharmacological and 
clinical references contained in the file on the original medicinal product being 
used for the purpose of examining the application in question; 
(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, with a detailed scientific bibliography; 
(iii) or that the proprietary medicinal product is essentially similar to a medicinal 
product which has been· authorized within the Community, in accordance with 
Community provisions in force, for not less than six years and is marketed in 
the Member St:tte for which the application is made; this period shall be 
extended to I 0 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 I 0 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 therapeutic use 
from that of the other medicinal products marketed or is to be administered by 
different routes or in different doses, the results of appropriate toxicological and 
pharmacological tests and of approp~iate clinical trials must _be provided. 
I OJ LIS, 17.1.1987, p. 38; Directive repealed by ~irective 93/41/EEC (OJ L 214, 24.8.~993, p. 40). 
23 65/65/EEC 
Art. 4, 3rd paragraph, 
point 8, 2nd 
subparagraph 
(as amended by 
87/21/EEC Art. 1 (I) and 
89/341/EEC Art. 1 (l)) 
(adapted). 
(b) In the case of new medicinal products containing known constituents not hitherto 
used in combination for the~peutic purposes, the results of toxicological and 
pharmacological tests and of clinical trials relating, to that combination must be 
provided, but it shall not . be· necessary to provide references relating ·to each 
individual constituent. · 65/65/EEC 
Art. 4, 3rd paragraph, 
point 8, 2nd 
subparagraph 
(as amended by 
87121/EEC Art. 1 (I) and 
89/341/EEC Art. I (I)) 
(adapted) 
2. Annex I shall apply by analogy where, pursuant to point (ii) of paragraph I, (a), 75/318/EEC 
bibliographic references to published data are submitted. Art. 1, 2nd paragraph 
(adapted) 
Article 11 
The summary of the product characteristics shall contain the following information: 65/65/EEC 
Art. 4a, points I to 5.4, 
·1. Name of the medicinal product. (as amended by 
83/570/EEC Art. 1 (2) 
2. Qualitative and quantitative composition in terms of the active substances and and 89/341/EEC · 
constituents of the excipient, knowledge of which is essential for, proper Art. I (I)) 
administration of the medicinal product; the usual common· name .or chemical (adapted) 
. descripti.on shall be used. 
3. Pharmaceutical form. 
4. Pharmacological properties and, in so far,as this information is useful for therapeutic 
purposes, pharmacokinetic particulars. 
5. Clinical particulars: 
5.1. 
5.2. 
5.3. 
5.4. 
5.5. 
5.6. 5.7. 
5.8. 
5.9. 
~.10. ·therapeut~c indications, 
contra-indications, 
adverse reactions (frequency and seriousness), 
special precautions for· use and, in the case of immunological medicinal 
products, any special precautions to be taken by persons handling such 
products and administering them to patients, together with any precautions 
to be taken by the patient, · · 
use during pregnancy and lactation, 
interaction with other medicaments and other forms of interaction, 
posology and method of administration for adults and, where necessary, for 
children, 
overdose (symptoms, emergency procedures, antidotes), 
special warnings, 
effects on ability to drive and to use machines. 
24 89/342/EEC 
Art.3 
(adapted) 
65/65/EEC 
Art. 4a, points 5.5 to 6.4 
(as amended by 
83/570/EEC, Art. 1 (2) 
and 89/341/EEC, 
Art. 1(1) 
(adapted) 
6. Pharmaceutical particulars: 
6.1. major incompatibi~ities, 
6.2. shelf life, when necessary after reconstitution of the 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; 
7. Name or corporate name and permanent address of the marketing authorization 
holder; 
8. For radiopharmaceuticals, fuU details of internal radiation dosimetry; 65/65/EEC 
Art. 4a (I) to ( 6), 
point6.4 
(as amended by 
83/570/EEC Art. I (2) 
and 89/341/EEC 
Art. I (1)) 
(adapted) 
65/65/EEC 
Art. 4a (6), point 6.6 
(as amended by 
89/341/EEC Art. 1 (4)) 
(adapted) 
65/65/EEC 
Art. 4a (6), point 6.5 
(as amended by 
83/570/EEC Art. 1 (2)) 
(adapted) 
9. For radiopharinaceuticals, additional detailed instructions for extemporaneous 89/343/EEC 
preparation and quality control of such preparation and, where appropriate, Art. 4 
maximum storage time during which any intermediate preparation such as an eluate (adapted) 
or the ready-to-use pharmaceutical will conform with its specifications. 
25 
Article 12 
1. Member States shall take all appropriate measures to ensure that the documents and 75/319/EEC 
particulars listed ifl Article 8 (3) (h) and (i), and Article 10 (1) are drawn up by experts Art. 1 
with the necessary technical or professional qualifications before they are submitted to (adapted) 
the competent authorities. These documents and ·particulars shall be signed by the 
experts. 
2. The duties of the experts according to their respective qualifications shall be: 7 5/319/EEC 
Art. 2 
(a) to perfoim tasks falling within their respective disciplines (analysis, pharmacology (adapted) 
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: . 
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; 
· in the· case of the pharmacologist or the specialist with similar experimental 
competence, the toxicity of the medicinal product and the pharmacological 
properties observed; · 
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 ·I 0, whether the patient 
tolerates the medicinal product w.ell, 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. 
26 
Chapter 2 
Specific provisions applicable to 
homeopathic medicinal products 
Article 13 
1. Member States shall ensure that homeopathic medicinal products manufactured and 92173/EEC 
placed on the market within the Community are registered or authorized in accordance Art. 6 (1) and (2) 
with Articles 14, 15 and 16. Each Member State shall take due account of registrations (adapted) 
and authorizations previously granted by another Member State. 
2. A Member State may refrain from establishing a special, simplified registration 
procedure for the homeopathic medicinal products referred to in Article 14. A Member 
State shall inform the Commission accord4tgly. The Member State concerned shall 
allow the use in its territory of homeopathic" medicinal products registered by other 
Member States in accordance with Articles 14 and 15. 
Article 14 
1. Only homeopathic medicinal products which satisfy all of the following conditions 92173/EEC 
m~y be subject to a special, simplified registration proced':lre: Art. 7 (I) and (4) 
(adapted) 
they are administered orally or externally, 
:-no specific therapeutic indication appears on the labelling of the medicinal product 
or in any information relating thereto, 
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 l/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 Articles 4 (4), 17, 18, 22 to 26, 
112, 116 and 127 shall apply by analogy to the special, simplified registration procedure 
for· homeopathic medicinal products, with the exception of the proof of therapeutic 
efficacy. 
27 
3. The proof of therapeutic efficacy shall not be required for homeopathic medicinal 92/73/EEC 
products registered in accordance with paragraph I of this Article, or, where appropriate, Art. 4, 2nd paragraph 
admitted in accordance with Article 13 (2). (adapted) 
Article 15 
An application for special, simplified registration may cover a series of medicinal 92173/EEC 
products derived from the same homeopathic stock or stocks~ The following documents Art. 8 
shall be included with the application in order to demonstrate, in particular, the (adapted) 
pharmaceutical quality and the batch-to-batch homogeneity of the produc~ concerned: 
scientific name or othername 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, 
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, 
manufacturing and control file for each pharmaceutical form and a description of the 
method of dilution and potentization, 
manufacturing authorization for the medicinal product concerned, 
copies of any registrations or authorizations obtained for the same medicinal product 
in other Member States, 
one or more specimens or mock-ups of the sales presentation of the medicinal 
products to be registered, 
data concerning the stability of the medicinal product. 
28 
Article 16 
I. Homeopathic medicinal products other than those referred ~o in Article 14 (I) shall be 92173/EEC 
authoriied in accordance witl_t Articles 8, I 0 (I) and 11. Art. 9 
(adapted) 
2. ·A Member State may introduce or retain in its territory specific rules for the· 
toxicological and phannacological tests and clinical trials of homeopathic medicinal 
products other than those referred to in Article 14 (I) in accordance with the principles 
and characteristics o(homeopathy as practised in that Member State. 
In this case, the Member State concerned shall notify the Commission of the specific 
rules in force. · 
29 
Chapter3 
Procedures relevant to the 
marketing authorization 
Article 17 
I. 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. 
2. Where a Member State notes that an applicatioQ for authorization is already under 
active examination in another Member State in respect of that medicinal product, the 
Member State concerned may decide to suspend the detailed examination of the 
application in order to await the assessment report prepared by the other Member State 
in accordance with Article 21 (4). 
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) (I) that another 
Member State· has authorized a medicinal pr~duct which is the subject of an application 
for authorization in the Member State concerned, that Member State shall forthwith 
request the authorities of the Member State which has granted the authorization to 
forward to it the assessment report referred to in Article 21 (4). 
Within 90 days of the receipt of the assessment report, the ·Member State concerned shall 
either recognize the decision of the first Member State and the summary of the product 
characteristics as approv~d by it or, if it considers that there are grounds for supposing 
that the authorization of the medicinal product concerned may present a risk to public 
health, it shall apply the procedures set out in Articles 29 to 34. 
30 65/65/EEC 
Art. 7 
(as amended by 
93/39/EEC Art. 1 (6)) 
(adapted) 
65/65/EEC 
Art. 7a 
(as amended by 
93/39/EEC Art. 1 (7)) 
(adapted) 
Article 19 
In order to examine the application submitted in accordance with Articles 8 and I 0 (I), 75/319/EEC 
the competent authority of the Member State: Art. 4 (a) 
(adapted) 
I. must verify whether the particulars submitted in support of the application comply 
with the said Article~ 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; 
2 .. may submit the medicinal product for testing by a State laboratory or by a laboratory 75/319/EEC 
designated for that purpose in order to ensure that the control methods employed by Art. 4 (b) 
the manufacturer and described in the particulars accompanying the application in (as amended by 
accordance with Article 8 (3) (h) are satisfactory; 89/341/EEC Art. 3 (1)) 
3. may, where appropriate, require the applicant to supplement the particulars 75/319/EEC 
accompanying the application in respect of the items listed in the Articles 8 (3) and Art. 4 (c) 
10 (1). Where the competent authority avails itself of this option, the time limits laid (adapted) 
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. 
31 
Article 20 
Member States shall take all appropriate measures to ensure that: 75/319/EEC 
Art. 5 
(a) the competent authorities verify that manufacturers and importers of medicinal (adapted) 
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 importers of medicinal 
products coming from third countries, in exceptional and justifiable cases, to have 
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 
I. When the marketing authorization is issued, the holder shall be infonned, by the 65/65/EEC 
competent authorities of the Member State concerned, of the summary of the product Art. 4b 
characteristics as approved by it. (as amended by 
93/39/EEC Art. 1 (4)) 
2. The. competent authorities shall take all necessary measures to ensure that the (adapted) 
i~formation given in the summary is in confonnity with that accepted when the 
marketing authorization is issued or subsequently. 
3. The competent authorities shall forward to the Agency a notification of the 
authorization, or a copy of this, together with the summary of the product characteristics. 
·4. The competent authorities ·shall draw up an assessment report and comments on the 
~ossier as regards the results of the analytical and phannacotoxicological 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. 
32 
Article 22 
In exceptional circumstances, and following consultation with the applicant, an 65/65/EEC 
authorization may be granted subject to certain specific obligations, including: Art. 10 (2) 
(as amended by 
the carrying out of further studies following the granting of authorization, 93/39/EEC Art. I (9)) 
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. 
Article 23 
After an authorization has been issued, the authorization 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. 
These changes shall be subject to the approval of the competent authority of the Member 
State concerned. 
Article 24 65/65/EEC 
Art. 9a 
(as amended by 
93/39/EEC Art. I (8)) 
(adapted) 
Authorization shall be valid for five years and shall be renewable for five-year periods, 65/65/EEC 
on application by the holder at least three months before the expiry date and after Art. I 0 (I) 
consideration by the competent authority of a dossier containing in particular details of (as amended by 
the data on pharmacovigilance and other information relevant to the monitoring of the 93/39/EEC Art. I (9)) 
medicinal product. 
Article 25 
Authorization shall not affect the civil and criminal liability of the manufacturer and, 65/65/EEC 
where applicable, of the marketing authorization holder. Art. 9 
(adapted) 
33 
(3} Article 26 
The marketing authorisation shall be refused if, after. verification of the particulars and 65/65/EEC 
documents listed in Articles 8 and 10 ( 1 ), it proves that: Art. 5 
(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 docume.nts submitted .in 
support of the application do not comply with Articles 8 and I 0 ( 1 ). 
34 (as amended by 
89/341/EEC Art. 1 (I)) 
(adapted) 
Chaptcr4 
Mutual recognition of authorizations 
Article 27 
1. In order to facilitate the adoption of common decisions by Member States on the 75/319/EEC 
authorization of medicinal products on the basis of the scientific criteria of quality, Art. 8 
safety and efficacy, and to achieve thereby the free movement of medicinal products (as amended by 
within the Community, a Committee for Proprietary Medicinal Products, hereinafter 93/39/EEC Art. 3 (1)) 
referred to as "the Committee", is hereby set up. The Committee shall be part of the (adapted) 
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. 
3. The Committee shall draw up its own Rules of Prodecure. 
Article 28 
1. Before submitting the application for recognition of a marketing authorization, the 75/319/EEC 
holder of the authorization shall infonn the Member State which ·granted the Art. 9 (3) 
~uthorization on which the application is based (hereinafter "referential Member State"), (as amended by 
that an application is to be made in accordance with this Directive and shall notify it of 93/39/EEC Art. 3 (I)) 
any additions to the original dossier; that Member State may require the applicant to (adapted) 
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 referential 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 
referential 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 75/319/EEC 
Chapter in one or more of the Member States of a marketing authorization issued by a Art. 9 ( 1) 
Member State, the holder of the authorization shall submit an application to the (as amended by 
competent authorities of the Member State or Member States conc~med, together with 93/39/EEC Art. 3 (1)) 
the information and particulars referred to in Articles 8, 10 (1) and 11. He shall testify (adapted) 
that the dossier is identical to that accepted by the referential Member S~te, 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 referential Member State in accordance 
with Article 21. Moreover, he shall certify that all the dossiers filed as part of the 
procedure are identical. 
35 
3. The holder of the marketing authorization shall communicate ·the application to the 
Agency, inform it ofthe Member States concerned and of the dates of submission of the 
application and send it a copy of the authorization granted by the referential Member 
State. He shall also send the Agency copies of any such authorization which may have 
been gr~ted 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. 
4. Save in the exceptional case provided for in Article 29(1 ), each Member State shall 
recognize the .marketing authorization granted by the referential Member State within 90 
days of receipt of the application and the assessment report. It shall inform the referential 
Member State which granted ·the initial authorization, the other Member States 
'concerned by the application, the Agency, and th~ marketing authorization holder 
Article 29 75/319/EEC 
Art. 9 (2) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 
75/319/EEC 
Art. 9 (4) 
(as amended by 
93/39/EEC Art. 3 (I)) 
(adapted) 
I. Where a Member State considers that there are grounds for supposing that the 75/3I9/EEC 
marketing authorization of the medicinal product concerned may present a risk to public Art. I 0 
health, it shall forthwith inform the applicant, the referential Member State which (as amended by 
granted the initial authorization, any other Member States concerned by the application 93/39/EEC Art. 3 (I)) 
and the Agency. The Member State shall s~te its reasons in detail and shall indicate (adapted) 
what action may be necessary to correct any defect in the application. 
2. All the Member States concerned shall use their best endeavours to reach agreement 
on the action to be taken iri 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 reference for the application of the procedure laid down in Article 32. 
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 to reach agreement and the reasons for their disagreement. The applicant shall be 
provided with a copy of this information. 
4. As soon as he is informed that the matter has been referred to the Committee, the 
applicant shall forthwith forward to the Committee a copy of the information and 
particulars referred.to in Article 28 (2).· 
36 
·Article 30 
-If several applications submitted in accordance with Articles 8, 10 (1) and Article 11 
have been made for marketing 'authorization for a particular medicinal product, and 
Member States have adopted divergent decisions concerning the authorization of the 
medicinal product or its suspension ()r withdrawal, a Member State, or the Commission, 
or the marketing authorisation holder may refer the matter to the Committee for 
application of the procedure laid down in Article 32. 
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. 
The Member State and the marketing authorization holder shall forward to the 
Committee all available information relating to the matter in question. 
Article 31 75/319/EEC 
Art. 11 
(as amended by_ 
93/39/EEC Art. 3 (1)) 
(adapted) 
The Member States or the Commission or the applicant or holder of the marketing 75/319/EEC 
authorization may, in specific cases where the interests of the Community are involved, Art. 12 
refer the matter to the Committee for the application of the· procedure laid down in (as amended by 
Article 32 before reaching a decision on~ request for a marketing authorization or on the 93/39/EEC Art. 3 (I)) 
suspension or withdrawal of an authorization, or on any other variation to the terms of a (adapted) 
marketing authorization which appears necessary, in particular to take -account of ~he 
. information 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. 
37 
Article 32 
· ·1. When reference is made to the procedure described in this Article, the Committee 75/319/EEC 
shall consider the matter concerned and issue a reasoned opinion within 90 days of the Art. 13 
date on which the matter was referred to it. (as amended by 
93/39/EEC_Art. 3 (I)) 
However, in cases submitted to the Committee in accordance with Articles 30 and 31, (adapted) · 
this period :"lay be extended by 90 days. 
In case of urgency, on a proposal from its Chairman, the Committee may agree to a 
shorter deadline. 
2. In order to consider the matter, the Committee may appoint one of its members to act 
as rapporteur. The Committee may also appoint individual experts to advise it on 
specific questions. When appointing experts, ihe Committee shall define their tasks and 
specify the time-limit for the completion of these ~ks. 
3. In the cases referred to in Articles 29 and 30, before issuing its opamon, the 
Committee shall provide the marketing authorization holder with an opportunity to 
present written or oral explanations. 
In the case referred to in Article 31, the marketing authorization holder may be asked to 
explain .himself o~lly 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. · 
38 
4. The Agency shall forthwith inform the marketing authorization holder where the 75/319/EEC 
opinion of the Committee is that: Art. 13 
the application does not satisfy the criteria for authorization, or 
the summary of the product characteristics proposed by the applicant in accordance 
with Article l1 should be amended, or 
the authorization should be granted subject to conditions, with regard to conditions 
considered essential for the safe and effective use of the medicinal product including 
pharmacovigilance, or 
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 affectin~ the authorization within the meaning of paragraph 4. 
39 (as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 
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 34 (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. 
The draft decision shall be forwarded to the Member States and the applicant. 
Article 34 75/319/EEC 
Art. 14 (1) 
(as amended by 
93/39/EEC Art. J (1)) 
(adapted) 
1. A final decision on the application shall be adopted in accordance with the procedure 7 5/319/EEC 
laid down in Article 124. Art. 14 (2) 
2. The rules of procedure of the Standing Committee established by Article 120 shall be 
adjusted to take account of the tasks incumbent upon it in accordance with this Chapter. 
These adjustments shall involve the following: 
except in cases referred to in the third paragraph of Article 33, the opinion of the 
Standing Committee shall be obtained in writing, 
each Member State is allowed at least 28 days to forward written observations on the 
draft decision to the Commission, 
each Member State is able to require in writing that the draft decision be discussed 
by th.e Standing Committee, giving its· reasons in detail. 
Where, in the opinion of the Commission, the written observations of a Member State 
raise important new questions of a scientific or technical nature which have not been 
addressed in the opinion of the Agency, the Chairman shall suspend the procedure and 
refer the application back to the Agency for further consideration. 
The provisions necessary for the implementation of this paragraph shall be adopted by 
the Commission in accordance with the procedure laid down in Article 122. 
3. A decision as 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 coritply with the decision within 30 days of 
its notification. They shall inform the Commission and the Agency thereof. 
40 (as amended by 
93/39/EEC Art. 3 (1)) 
75/319/EEC 
Art. 14 (3) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 
75/319/EEC 
Art. 14 (4) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 
Article 35 
l. Any application by the marketing authorization holder to vary a marketing 75/319/EEC 
authorimtion which has been granted in accordance with the provisions of this Chapter Art. 15 
· shall be submitted to all the Member States which have previously authorized the (as amended by 
medicinal product concerned. 93/39/EEC Art. 3 (I)) 
(adapted) 
The Commission shall~ in consultation with the Agency, adopt ·appropriate arrangements 
for the examination of variations to the terms of a marketing authorization. 
These arrangements shall include a notification system or administration procedures 
concerning minor variations and define precisely the concept of"a minor variation". 
These arrangements shall be adopted by the Commission in the form of an implementing 
Regulation in accordance with the procedure laid down in Article 122. 
2. The procedure laid down in Articles 32, 33 and 34 shall . apply by analogy to 
variations made to marketing authorizations for products. 
Article 36 
I. 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 products 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 territory. It shall inform the Commission and the other Member States 
no later tb~ the following working day of the reasons for its action. 
41 75/319/EEC 
Art. 15a 
(as amended by 
93/39/EEC Art. 3 (I)) 
(adapted) 
Article 37 
Articles 35 and 36 shall apply by analogy to medicinal products authorized by Member 75/319/EEC 
States following an opinion of the Committee given in accordance with Article 4 of Art. l5b 
Directive 87/22/EEC before l Janu_ary 1995. (as amended by 
93/39/EEC Art. 3 (I)) 
Article 38 
l. The Agency shall publish an annual report· on the operation of the procedures laid 75/319/EEC 
down in this Chapter and shall forward that report to the European Parliament and the Art.l5c 
Council for information. (as amended by 
93/39/EEC Art. 3 (I)) 
2. By I January 2001, the Commission shall publish a detailed review of the operation of 
the procedures laid down in this Chapter and shall propose any amendments which may 
be necessary to improve these procedures. 
_The Council shall decide, under the conditions provided for in the Treaty, on the 
Commission proposal within one year of its submission. 
Article 39 
The provisions referred to in Articles 27 to 34 shall not apply .to the homeopathic 
med~cinal products referred to in Article 16 (2). 
/ 
42 75/319/EEC 
Art. 14 (5) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 
TITLE IV 
MANUFACTURE AND IMPORTATION 
Article 40 
1. Member States shall take· all appropriate measures to ensure that the manufacture of 
~he medicinal products within their territory is subject to the holding of an authorization. 
This manufacturing authorization shall be required nothwithstanding th~t the medicinal 
products manufactured are intended for export. 75/319/EEC 
Art. 16 (1) 
(as amended by 
89/341/EEC Art. 3 (3)) 
(adapted) 
2. The authorization referred to in paragraph 1 shall be required for both total and partial 75/319/EEC 
manufacture, and for the various processes of dividing up, packaging or presentation. Art. 16 (2) and (3) 
(adapted) 
However, such authorization shall not be required for preparation, dividing up, changes 
in packaging or presentation where these processes are carried out, solely for retail 
supply, by phannaci~ts in dispensing pharmacies or by persons legally authorized in the 
Member States to carry out such processes. 
3. Authorization referred to in paragraph 1 shall also be required for imports coming 
from third countries into a Member State; this Title and Article 118 (I) shall have 
corresponding application to such imports as they have to manufacture. 
Article-41 
In order to obtain the manufacturing authorization, the applicant shall meet at least the 75/319/EEC 
following requirements: Art. 17 
(adapted) 
(a) specify the medicinal products and pharmaceutical fonns which are to be 
manufactured or imported and also the place where they are to be manufactured 
and/or controlled; 
(b) have at his disposal, for the manufacture or import of the above, suitable and 
sufficient premis~s, technical equipment and control facilities ·complying with the 
legal requirements which the Member State concerned lays down as regards both 
manufacture and control and the storage of medicinal products, in accordance with 
Article 20; · 
(c) have at his disposal the services of at least one qualified person within the meaning 
of Article 48. 
The appli~ant shall provide particulars in support of the above in his application. 
43 
Article 42 
1. The competent authority of the Member State shall issue the manufacturing · 75/319/EEC 
authorization only after having made sure of the accuracy of the particulars supplied Art. 18 
pursuant to Article 41, by means of an inquiry carried out by its a~ents. (adapted) 
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. 
3. The authorization shall apply only to the premises specified in the application and to 
the medicinal products and pharmace.-tical forms specified in that same application. 
Article 43 
The Member States shall take all appropriate measures to ensure that the time taken for 75/319/EEC 
the procedure for granting the manufacturing authorization does not exceed 90 days Art. 20 ( 1) 
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 75/319/EEC 
particulars referred to in the first paragraph of Article 41, the time taken for the Art. 20 (2) 
procedure relating to this request shall not exceed 30 days . .In exceptional cases this (adapted) 
period of time may be extended to 90 days. 
Article 45 
The competent authority of the Member State may require from the applicant further 75/319/EEC 
information concerning the particulars supplied pursuant to Article 41 and concerning Art. 20 (3) 
the qualified person referred to in Article 48; where the competent authority concerned (adapted) 
exercises this right, application of the time-limits referred to in Article 43 and 44 shall be 
suspended until the additiomd data required have been supplied. 
44 
Article 46 
The holder of a manufacturing authorization shall at least be obliged: 75/319/EEC 
Art. 19 (a) to (e) 
(a) to have at his disposal the services of staff who comply with the legal requirements (adapted) 
existing in the Member State concerned both as regards manufacture and controls; 
(b) to dispose of the authorized medicinal products only in . accordance with the 
legi~lation of the Member States 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 codtpetent authority 
shall, in any event, be immediately informed if the qualified person referred to in 
Article 48 is replaced unexpectedly; 
(d) to allow the agents of the competent authority of the Member State concerned access 
to his premises at any time; 
(e) to enable the qualified person referred to in Article 48 ~o carry out his duties, for 
example by placing at his disposal all the necessary facilities; 
(f) to comply with the principles and guidelines of good manufacturing practice for 75/319/EEC 
medicinal products as laid down by Community law. Art. 19 (f) 
Article 47 
The principles and guidelines of good manufacturing practices fo~ medicinal products 
referred to in Article 46 (f) shall be adopted in the form of a directive, in accordance 
with·the procedure laid down in Article 122. 
Detailed guidelines in line with those principles will be published by the Commission 
and revised as necessary to take account of technical and scientific progress. 
45 (as amended by 
89/341/EEC Art. 3 (4)) 
75/319/EEC 
Art. 19a 
(as amended by 
89/341/EEC Art. 3 (5)) 
(adapt~d) 
Article 48 
I. Member States shall take all approprjate measures to ensure that the holder of the 75/319/EEC 
manufacturing authorization .has permanently and continuously at his disposal the Art. 21 
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 th~ 
authorization may himself assume the responsibility referred to in paragraph I. 
Article 49 
1. Member· States shall ensure that the qualified person referred to in Article 48 fulfils 75/3 I 9/EEC 
the minimum conditio~s of qualification set out in paragraphs 2 and 3. Art. 23 
(adapted) 
2. A qualified person shall be in possession of a diploma, certificate or other evidence of 
formal qualificatioQs. awarded on completion of a university cou~se 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, veterinary medicine, chemistry, 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 theoretical and practical 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. 
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 c~mpletion of a university course or its recognJzed 
equivalent shall be considered to fulfil the condition of duration ref~rred to in the second 
subparagraph in so far as the dipl.omas, certificates or other evidence of formal 
qualifications awarded on completion of both courses are recognized as equivalent by 
the State in question. · 
46 
The course shall include theoretical and practical study bearing upon at least the 75/319/EEC 
following basic subjects: Art. 23 
(adapted) 
Applied physics 
General and inorganic chemistry 
Organic chemistry 
Analytical chemistry 
Pharmaceutical chemistry, including analysis of medicinal products 
General and applied biochemistry (medical) 
Physiology 
Microbiology 
Phannacology 
Pharmaceutical technology 
Toxicology 
Phannacognosy (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. 
In so far as certain diplomas, certificates or other evidence of fonnal qualifications 
mentioned in the first subparagraph do not fulfil the criteria laid down in this paragraph, 
the. competent authority of the Member State shall ensure that the person concerned 
provides evidence of adequate knowledge of the subjects involved. 
3. The qualified person shall have acquired practical experienc~ ~ver at least two years, 
. 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 
activ.e substances and of the testing and checking necessary to ensure the quality of · 
medicinal products. · 
The duration of practical experit?nce may be reduced by one year where a u~iversity 
course lasts for at least five years and by a year and a half where the course lasts for at 
least six years. 
47 
Article 50 
I. A person engaging in the activities of the person referred to in Article 48 from the 75/319/EEC 
time of the application of Directive 75/3 I 9/EEC, in a Member State without complying Art. 24 
with the provisions of Article 49 shall be eligible to continue to engage in those activities (adapted) 
in the State concerned. · 
2. The bolder of a diploma, certificate or other evid.ence of formal qualifications 
awarded on completion of a university course -or a course recognized as equivalent by 
the Member State concerned -in a scientific discipline allowing him to engage in the 
activities of the person referred to in Article 48r in accordance with the laws of that 'State 
may -if he began his course prior to 21 May 1975 -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 
following notification of this directive . in one or more undertakings authorized to 
manufacture: production supervision and/or qualitative and quantitative analysis of 
acti~e 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. 
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 referred to in the first subparagraph willl?e required to be 
completed immediately before he engages in such activities. 
48 
· Article 51 
I. Member States shall take all appropriate measures to ensure that the qualified person 75/319/EEC 
referred to in Article 48, without prejudice to his relationship with the holder of the Art. 22 (1); 1st and 2nd 
manufacturing authorization, is responsible, in the context of the procedures referred to subparagraphs 
in Article 52, for securing: (adapted) 
(a) in the case of medicinal products manufactured within the Member States 
concerned, that each batch of medicinal products has been manufactured and 
checked in compliance with the laws in force in that Member State and in 
accordance with the requirements of the marketing authorization; 
(b) in the case of medicinal products coming from third c_ountries, 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 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 75/319/EEC 
arrangements have been made by the Community with the exporting country to ensure Art. 22 (1}, 3rd 
that the manufacturer of the medicinal product applies standards of good manufacturing subparagraph 
practice at least equivalent to those laid down by the Community, and to ensure that the (as amended by 
controls referred to under point (b) of the first subparagraph of paragraph 1 have been 93/39/EEC Art. 3 (2)) 
carried out in the exporting country, the qualified person may be relieved of 
responsibility for _carrying out those controls. · 
3. In all cases and particularly where the medicinal products are released for sale, the 75/319/EEC 
qualified person must certify in a register or equivalent document provided for that Art. 22 (2) 
purpose, that each production batch satisfies the provisions of this Article; the said (adapted) 
register or equivalent document must be kept 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 7.5/319/EEC 
are fulfilled, either by means of appropriate administrative measures or by making such Art. 25 
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 apply to homeopathic medicinal products. 
49 92173/EEC 
Art. 3 
(adapted) 
(4) TITLE V 
LABELLING AND PACKAGE LEAFLET 
Article 54 
The following particulars shall appear on the outer packaging of medicinal products or, 92127/EEC 
where there is no outer packaging, on the immediate packaging: Art. 2 (1), points (a) to 
(n) 
(a) the name of the medicinal product followed by the common name where the product (adapted) 
contains only one active substance and if its ·name is a brand name; where a 
medicinal product is available in· several phiU'J1laceutical forms and/or several 
strengths, the phartnaceutical 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 u:nit or according to the form of administration for a given volume or weight, 
using their common names; 
(c) the pharmaceutical form ~d the contents by weight, by volume or by number of 
doses of the product; 
(d) a list of those excipients known to have a recognized action or effect and included in 
the guidelines. published pursuapt to Article 65. However, if the product is 
injectable, or a topical or eye preparation, all excipients must be stated; 
(e) the method and, if necessary, the route of administration; 
(t) a special warning that the medicinal product must be stored out of reach of children; 
(g) a spe,ial 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 for disposal of unused medicinal products or waste materials 
· from medicinal prQducts, if appropriate; · 
(k) the name and address of the holder of the authorization for placing the medicinal 
product on the market; 
(I) 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. 
so 
Article SS 
I. The particulars laid down in Articles 54 and 62 shall appear on immediate packagings 92/27/EEC 
other than those referred to in paragraphs 2 and 3. Art. 3 
2. The following particulars· at least 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. 
the name of the medicinal product as laid down in Article 54 (a), 
·the name of the holder of the authorization for placing the product on the market, 
the expiry date, 
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: 
the name of the medicinal product and, if necessary, the strength and the route of 
administration, 
the method of administration, 
the expiry date, 
the batch nu~ber, 
the contents by weight, by volume or by unit. 
Article 56 
The particulars referr~d to in Articles 54, 55 and 62 shall be easily legible, clearly 192/27 /EEC 
comprehensible and indelible. · Art. 4 ( 1) 
Article 57 
Notwithstanding Article 60, Member States may require the use of certain forms of 92/27 /EEC 
labelling of the medicinal product making it possible to ascertain: Art. 5 (2) 
(adapted) 
the price of the medicinal product, 
the reimbursement conditions of social security organizations, 
the legal status for supply to the patient, in accordance with Titl~ VI, 
· . identification and authenticity. 
51 
Article 58 
The inclusion in the packaging of all medicinal products of a package leaflet shall be 92/27/EEC 
obligatory unless all the information required by Articles 59 and 62 is directly conveyed Art. 6 
on the outer packaging or on the.immediate packaging (adapted) 
Article 59 
1. The package leaflet shall be drawn up in accordance with the summary of the product 92127/EEC 
characteri~tics; it shall include, in the following order: Art. 7 ( 1) 
(adapted) 
(a) for the identification of the medicinal product: 
the name of the medicinal product, followed by the common name if the 
product contains only one active substance and if its name is a brand name; 
where a medicinal product is available in several pharmaceutical forms and/or 
several strengths, the pharmaceutical form and/or the strength (for exaniple, 
baby, child, adult) must be included in the name of the medicinal product, 
a full statement of the active substance and excipients expressed qualitatively 
and a statement of the active substance expressed quantitatively, using their 
common names, in the case of each presentation of the medicinal product, 
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, 
the pharmaco-therapeutic group, or type of activity in terms easily 
comprehensible for the patient, 
the name and address of the holder of the authorization for placing the 
medicinal product on the market and of the manufacturer; 
(b) the therapeutic indications; 
52 
{c) a list of information which is necessary before taking the medicinal product: 
-contra-indications, 
-appropriate precautions for use, 
-forms of interaction with other medicinal products and other forms of 
interaction (for example, alcohol, tobacco, foodstuffs) which may affect the 
action of. the medicinal product, 
-special warnings; 
this list must: 
-take into account the particular condition of certain categories of users 
(e.g. children, pregnant or breastfeeding women, the elderly, persons with 
specific pathological conditions), 
-mention, if appropriate, potential effects on the ability to drive vehicles or to 
·operate machinery, 
detail those excipients, knowledge of which is important for the safe and 
effective use of the medicinal product and included in the guidelines published 
pursuant to Article 65; 
(d) the necessary and usual instructions for proper use, in particular: 
-the dosage, 
-the method and, if necessary, route of administration, 
-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 the product: 
-the duration of treatment, where it should be limited, 
-the action to be taken in the case of an overdose (e.g., symptoms, emergency 
procedures), 
-the course of action to take when one or ~ore doses have not been taken, · 
-indication, if necessary, of the risk of withdrawal effects; 
53 92/27/EEC 
Art. 7 (1) 
(adapted) 
(e) a description of the undesirable effects which can occur under normal use of th~ . 92/27/EEC 
medicinal product and, if necessary, the action to be taken in such a case; the Art. 7 ( 1) 
patient should be expressly invited to communicate any undesirable effect which is (adapted) 
not mentioned in the leaflet to his doctor or to his pharmacist; 
(f) a reference to the expiry date indicated on the label, with: 
- a warning again~t using the product after this date, 
-where appropriate, special storage precautions, 
-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 92127/EEC 
therapeutic indications shall not be mentioned . in the package leaflet, whe~ the Art. 7 (2) 
dissemination of such information might have serious disadvantages for the patient. (adapted) 
Article 60 
Member States may not prohibit or impede the placing on the market of medicinal 92127/EEC 
products within their territory on grounds connected with labelling or the package leaflet Art. 5 (I) and Art. 9 
where these comply with the ~equirements of this Title. (adapted) 
Article 61 
I. One or more specimens or mock-ups of the outer packaging and the immediate 92127/EEC 
packaging of a medicinal product, together with the draft package leaflet, shall be Art. I 0 (I) to ( 4) 
submitted to the authorities competent for authorizing marketing when the marketing (adapted) 
authorization is requested. 
2. The competent authority shall refuse the marketing authorization if the labelling or the 
package leaflet do riot 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 authorities competent for authorizing marketing. If the 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. 
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. 
54 
Article 62 
The outer packaging and the package leaflet may include symbols or pictograms 92127 /EEC 
designed to clarify certain information mentioned in Articles 54 and 59 (1) and other Art. 2 (2) and 
information compatible with the summary of the product characteristics which is useful Art. 7 (3) 
for health education, to the exclusion of any element of a promotional nature. (adapted) 
Article 63 
1. The particulars for labelling listed in Articles 54, 59 and 62 shall appear in the official 92/27/EEC 
language or languages of the Member State where the product is placed on the market. Art. 4 (2) 
(adapted) 
The first subparagraph shall not prevent these particulars from being indicated in several 
languages, provided that the same particulars appear in all the languages used. 
2. The package leaflet must be written in clear and understandabl~ terms for the us~rs 92/27/EEC 
and be clearly legible in the official language or languages of the Member State where Art. 8 
the medicinal product is placed on the market. (adapted) 
The fli'St subparagraph shall not prevent the package leaflet being printed in several 
languages, provided that the same information is given in all the languages used. 
3. The competent authorities may exempt labels and package leaflets for specific 92/27/EEC 
medicinal products from the obligation that c~rtain particulars shall appear and that the Art. 10 (5) 
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 92/27 /EEC 
person concerned has remained without effect, the competent authorities of the Art. 11 (1) 
Member States may suspend the marketing authorization, until the labelling and the (adapted) 
package leaflet of the medicinal product in question have been made to comply with the 
requirements of this Title. 
Article 65 
As necessary, the Commission shall publish guidelines concerning in particular: 92/27/EEC 
Art. 12 
the formulation of certain special warnings for certain categories of medicinal (adapted) 
products, 
the particular information needs relating to self-medication, 
the legibility of particulars on the labelling and package leaflet, 
methods for the identification and authentication of medicinal products, 
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 laid down in Article 122. 
55 
Article·66 
.I. The outer packaging and the container of medicinal products containing radionuclides 89/343/EEC 
shall be labelled in accordance with the regulations for the safe transport of radioactive Art. 5 
materials laid down by the International Atomic Energy Agency. Moreover, the labelling (adapted) 
shall comply with the provisions set out in paragraphs 2 and 3. 
· 2. The label on the shielding shall include the particulars mentioned in Article 54. In 
addition, 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, for liquids, the number 
of millilitres in the container; 
3. The vial shall be labelled with the following infonnation: 
the name or code of the medicinal product, including the name or chemical symbol 
of the radionuclide, 
the batch identification and expiry date, 
the international symbol for radioactivity, 
· the name of the manufacturer, 
the amount of radioactivity as specified in paragraph 2. 
Article 67 
The competent authority shall ensure that a detailed instruction leaflet is enclosed with 89/343/EEC 
the packaging of radiophannaceuticals, radionuclide generators, radionuclide kits or Art. 6 ( 1) 
radionuclide precursors. The text of this leaflet shall be established in accordance with (adapted) 
· 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 of the 
medicinal product and special precautions for the disposal of the packaging and its 
unused contents. 
56 
Article 68 
The homeopathic medicinal products shall be identified by a reference on their labels, in 92173/EEC 
clear and legible form, to their homeopathic nature. Art. 2 (2} 
(adapted) . 
Article69 
1. In addition to the clear mention of the words "homeopathic medicinal.product", the 92173/EEC 
labelling and, where appropriate, the package insert for the·medicinal products referred Art. 7 (2) and (3) 
to in Article 14 (1) shall bear the following, and no other, information: (adapted) 
the seientific name of the stock or stocks followed by the degree of dilution, making 
use of the symbols of the pharmacopoeia used in accordance with Article l (5), 
name and address of the registration holder and, where appropriate, . of the 
manufacturer, 
method of administration and, if necessary, route, 
expiry date, in clear terms (month, year}, 
pharmaceutical form, 
contents of the sales presentation, 
special storage precautions, if any, 
a special warning if necessary for the medicinal product, 
manufacturer's batch number, 
registration number, 
"homeopathic medicinal product without approved therapeutic indications", 
a warning advising the user to consult a doctor if the symptoms persist during ·the 
use of the medicinal product. 
2·. Notwithstanding paragraph I, Member States may require the use of certain typeS' of 
labelling in order to show: 
the pri~ of the medicinal product, 
.. the conditions for refunds by social security bodies. 
57 
TITLE VI 
CLASSIFICATION OF MEDICINAL PRODUCTS 
Article 70 
I. When a marketing authorization is granted, the competent authorities shall specify the 92/26/EEC 
classification of the medicinal product into: Art. 2 
a medicinal product subject to medical prescription, 
a medicinal product not subject to medical prescription. 
To this end, the criteria laid down in Article 71 (1) shall apply. 
2. The competent authorities may fix sub-categories for medici~al products which are 
available on. medical prescription only. In that case, they shall refer to the following 
classification: 
(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 
1. Medicinal products shall be subject to medical prescription where they: 92/26/EEC 
Art. 3 
are likely to present a danger either directly or indirectly, even when used correctly, (adapted) 
if utilized without medical supervision, or 
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 
contain substances or preparations thereof, the activity and/or adverse reactions of 
which require further investigation, or 
are normally prescribed by a doctor to be administered parenterally. 
58 
2. Where Member States provide for the sub-category of medicinal products subject to 92/26/EEC 
special medical prescription, they shall take account of the following factors: Art. 3 
(adapted) 
the medicinal product ·contains, in a non-exempt quantity, a substance .classified as a 
narcotic or a psychotropic substance within the meaning of the international 
conventions in force, such as the United Nations Conventions of 1961 and 1971, or 
the medicinal product is likely, if incorrectly used, to present a substantial risk of 
medicinal abuse, to lead to addiction or be misused for illegal purposes, or 
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: 
the medicinal product, because of its phannaceutical characteristics or novelty or in 
the interests of public health, is reserved for treatments which can only be followed 
in a hospital environment, · 
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 
the medicinal product is intended f~r 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. 
4. A competent authority may waive application of paragraphs 1, 2 and 3 having regard 
to: 
(a) the maximum single dose, the maximum daily dose, the strength, the phannaceutical 
form, certain types of packaging; and/or 
(b) other circumstances of use which it has specified. 
5. If a competent authority does not designate medicinal 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. 
59 
Article 72 
M~dicinal produc~ not subject to prescription shall be those which do not meet the 192/26/EEC 
criteria listed in Article 71. Art. 4 
Article 73 
The competent authorities shall draw up a list of the medicinal products subject, on their 92/26/EEC 
territory, to medical prescription, specifying, if necessary, the category of classification. Art. 5 (1) 
They shall update this list annually. 
Article 74 
On the occasion of the five-yearly renewal of the marketing authorization or when new 92/26/EEC 
facts are brought to their notice, the competent authorities shall examine and, as Art. 5 (2) 
appropriate, amend the classification of a medicinal product, by applying the criteria 
listed in Article 71. 
Article 75 
Each year, Member States shall communicate to the Commission and to the other 192/26/EEC · 
Member States, the changes that have been made to the list referred to in Article 73. Art. 6 (2) 
60 
TITLE VII 
WHOLESALE DISTRIBUTION OF 
MEDICINAL PRODUCTS 
Article 76 
.Without prejudice to Article 6, Member States shall take all appropriate action to ensure 92/25/EEC 
that only medicinal products in respect of which a marketing authorization has been Art. 2 
granted in accordance with Community law are distributed on their territory. 
Article 77 
I. Member States shall take all appropriate measures to ensure that the wholesale 92/25/EEC 
distribution of medicinal products is subject to· the possession of an authorization ~o Art. 3 
engage in activity as a wholesaler in medicinal products, stating the place for which it is (adapted) 
valid. . 
2. Where persons entitled to supply medicinal products to the public may also, under 
national. law, engage in wholesale business, such persons shall be subject to the 
authorization provid~d for in paragraph 1. 
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 giv.e 
dispensation from the obligation to possess a manufacturing authorization and to comply 
with the conditions set out in that respect, even where the manufacturing or import 
business is secondary. 
4. At the request of the Commission or any Member State, Member States shall supply 
all appropriate information concerning the individual authorizations which they have 
granted under paragraph 1. 
5. Checks on the persons authorized to engage in the 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. 
6. The Member State which granted the authorization 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. 
7. Should a Member State consider that, 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 inf~rm 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. 
61 
Article 78 
Member States shall ensure that the time taken for the procedure for examining the 92/25/EEC 
application for the distribution authorization does not exceed 90 days from the day on Art. 4 ( 1) 
which the comj>etent authority of the Member State c:;oncerned receives the application. (adapted) 
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 79 
In order to obtain the distribution authorization, applicants must fulfil the following 92/25/EEC 
minimum requirements: Art. 5 
(adapted) 
(a) they must have suitable and adequate premises, installations and equipment, so as to 
ensure proper conservation and distribution of the medicinal pro.ducts; 
(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 the distribution authorization must fulfil the · following minimum 92/25/EEC 
requireptents: Art. 6 
(adapted) 
(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 from persons who are 
themselves in possession of the distribution authorization or who are exempt from 
obta~.ing such authorization under the terms of Article 77 (3); 
(c) they must supply medicinal products only to persons who are themselves in 
possession of the distribution authorization or who are authorized or entitled to 
.supply medicinal products to the public in the Member State concerned; 
(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; 
62 
(e) they must keep records either ·in the form of purchase/sales invoices, or on 92/25/EEC 
computer, or in any other form, giving for any transaction in medicinal products Art. 6 
received or dispatched at least the following information: (adapted) 
date, 
name of the medicinal product, 
quantity received or supplied, 
name and address of the supplier or consignee, as appropriate; 
(f) they must keep the records referred to under (e) available to the competen~ 
authorities, for inspection purposes, for a period of five years; 
(g) they must comply with the principles and guidelines of good distribution practice for 
medicinal products as laid down in Article 84. 
Article 81 
With regard to the supply of medicinal products to pharmacists and persons authorized 92/25/EEC 
or entitled to supply medicinal prodUcts to the public, Member States shall not impose Art. 7 
upon the holder of a distribution authorization which has been granted by ·another (adapted) 
Member State,· any obligation, in particular public service obligations, more stringent 
than those they impose on persons whom they have themselves authorized to engage in 
equivalent activities. 
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 92/25/EEC 
medicinal products to the public in the Member State concerned, the authorized Art. 8 
wholesaler must enclose a document that makes it possible to ascertain: 
the date, 
the name and pharmaceutical form of the medicinal product, 
the quantity supplied, · 
the name and address of the supplier and consignor. 
Member States shall take all appropriate measures to ensure that persons authorized or 
entitled to supply medicinal products to the. public are able to provide information that 
makes it possible to trace the distribution path of every medicinal product. 
63 
Article 83 
The provisions of this Title shall not prevent the application of more stringent 92/25/EEC 
requirements laid down by Member States in respect of the wholesale distribution of: Art. 9 
(adapted) 
narcotic or psychotropic substances within their territory, 
medicinal products d~rived from blood, 
immunological medicinal products, 
radiopharmaceuticals. 
Article 84 
The Commission shall publish guidelines on good distribution practice. To this end, it 92/25/EEC 
shall consult the Committee for Proprietary Medicinal Products and the Pharmaceutical Art. 10 
Committee established by Council Decision 75/320/EECl. (adapted) 
Article 85 
Member States shall,· in special cases, authorize the direct distribution of medicinal 92/28/EEC 
products to the public, by the industry for promotional purposes. Art. 3 (6), 2nd sentence 
(adapted) 
OJ L 147, 9.6.1975, p. 23. 
64 
TITLE VIII 
ADVERTISING 
Article 86 
I. For the purposes of this Title, "advertising of medicinal products" shall include any 92/28/EEC 
form of door-to-door information, canvassing activity or inducement designed to Art. 1 (3) and (4) 
promote the prescription, supply, sale or consumption of medicinal products; it shall 
include in particular: 
the advertising of medicinal products to the general public, 
advertising of medicinal products to persons qualified to prescribe or supply them, 
visits by medical sales representatives to persons qualified to prescribe medicinal 
products, 
the supply of samples, 
the provision of inducements to prescribe or 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, 
sponsorship of promotional meetings attended by persons qualified to prescribe or 
supply medicinal products, 
sponsorship of scientific congresses attended by persons qualified to prescribe or 
supply medicinal products and in particular payment of their travelling and 
~ccommodation expenses in connection therewith. 
2. The following are not covered by this Title: 
the labelling and the accompanying package leaflets, which are subject to the 
provisions of Title V; 
correspondence, possibly accompanied by material of a non-promotional nature, 
needed to answer a specific question about a particular medicinal product; 
factual, informative announcements and reference material relating, for example, to 
pack changes, adverse-reaction warnings as part of general drug precautions, trade 
catalogues and price lists, provided they include no product claims; 
statements relating to human health or diseases, provided there is no reference, even 
indirect, to medicinal products. 
65 
(5) Article 87 
I. Member States shall prohibit any advertising of a medicinal product in respect of 92/28/EEC 
which· a marketing authorization has not been granted in accordance with Community Art. 2 
law. 
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: 
shall encourage the rational use of the medicinal product, by presenting it 
objectively and without exaggerating its properties, 
shall not be misleading. 
Article 88 
I. Member States shall prohibit the advertising to the general public of medicinal 92/28/EEC 
products which: Art. 3 (I) to (6), 1st 
are available on medical prescription only, in accordance with Title VI, 
contain psychotropic or narcotic substances, such as the United Nations Conventions 
of 1961 and 1971, · 
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 invervention of 
a medical practitioner for diagnostic purposes or for the prescription or monitoring of 
treatment, with the advice of the phamiacist, if necessary. 
Member States shall prohibit the mentioning in advertising to the general public of 
therapeutic indications such as: 
tuberculosis, 
sexually transmitted diseases, 
other serious infectious diseases, 
cancer and other tumoral diseases, 
chronic insomnia, 
diabetes and other metabolic ilinesses. 
66 sentence 
(adapted) 
3. Member States shall be able to ban, on their territory, advertising to the general public 92/28/EEC 
of medicinal products the cost of which may be reimbursed. Art. 3 ( 1) to ( 6) 
1st sentence 
4. The prohibition referred to in paragraph 1 shall not apply to vaccination campaigns (adapted) 
carried out by the industry and approved by the competent authorities of the -Member 
States. 
5. The prohibition referred to in paragraph 1 shall apply without prejudice to Article 14 
of Directive 89/552/EEC. 
6. Member States shall prohibit the direct distribution of medicinal products to the public 
by the industry for promotional purposes. 
Article 89 
1. Without prejudice to Article 88, all advertising to the general public of a medicinal 92/28/EEC . 
product shall: Art. 4 
(adapted) 
(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 minim.um information: 
the name of the medicinal product, as well as the common name if the 
medicinal product contains only one active substance, 
the information necessary for correct use of the medicinal product, 
an express, legible invitation to read carefully the instructions on ~he package 
leafle~ or on the outer packaging, as the case may be. 
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. 
67 
Article 90 
The advertising of a medicinal product to the general public shall not contain any 92/28/EEC 
material which: Art. 5 
(adapted) 
(a) gives the impression that a medical consultation or surgical operation is 
unnecessary, in particular by offering a 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 ~he 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) refers to a recommendation by scientists, health professionals or persons who are 
neither of the foregoing but who, because of their celebrity, could encourage the 
consumption of medicinal products; 
(g) suggests that the medicinal product is a foodstuff, cosmetic or other consumer 
product; 
(h) suggests that the safety or efficacy of the medicinal product is due to the fact that it 
is natural; · 
(i) could, by a description or detailed representation of a case history, lead to erroneous 
self-diagnosis; 
G) refers, in improper, alarming or misleading terms, to cli;iims of recovery; 
(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; 
(I) mentions that the medicinal product has been granted a marketing authorization. 
68 
Article 91 
I. Any advertising of a medicinal product to persons qualified to prescribe or supply 92/28/EEC 
such products shall include: Art. 6 
essential infonnation compatible with the summary of product characteristics; 
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 for reimbursement by 
social security bodies. 
2. Member States may decide that the advertising of a medicinal product to persons 
qualified to prescribe or supply such products may, notwithstanding paragraph l, 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 92/28/EEC 
promotion of that product to persons qualified to prescribe or supply it shall include, as a Art. 7 
minimum, the particulars listed in Article 91 (1) and shall state the date on which it was 
drawn up or last revised. 
2. All the infonnation contained in the documentation referred to in paragraph I shall be 
accurate, up-to-date, verifiable and sufficiently complete to enable the recipient to fonn 
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 doctunentation referred to in paragraph I shall be 
faithfully reproduced and the precise sources indicated. 
69 
Article 93 
1. Medical . sales representatives shall be given adequate training by the firm which 92128/EEC 
employs them and shall have sufficient scientific knowledge to be able to provide Art. 8 
information which is precise and as complete as possible about the medicinal products 
which they promote. 
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 present together, if the legislation of the Member State so permits, with details of 
the price and conditions for reimbursement referred to in Article 91 ( 1 ). 
3. Medical sales representatives shall transmit 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. 
Article 94 
1. Where medicinal products are being promoted to persons qualified to prescribe or 92/28/EEC 
supply them, no gifts, pecuniary advantages or benefits in kind may be supplied, offered Art. 9 
or promised to such persons unless they are inexpensive and relevant to the practice of (adapted) 
medicine or pharmacy. 
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. 
3. Persons qualified to prescribe or 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 being offered,. directly or 92/28/EEC 
indirectly, at events for purely professional and scientific purposes; such hospitality shall Art. 10 
always be reasonable in level and remain subordinate to the main scientific objective of 
the meeting; it must not be extended to persons other than health professionals. 
70 
Article 96 
I. Free samples shall be provided on an exceptional basis only to persons qualified to 92/28/EEC 
prescribe them and on the following conditions: Art. 11 
(adapted) 
(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; 
(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 "free medical sample-not for sale" 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. 
Article 97 
1. Member States shall ensure that there are adequate and effective methods to monitor 92/28/EEC 
the advertising of medicinal products. Such methods, which may be based on a system Art. 12 (1) and (2) 
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 
advertisement, or bring such advertisement before an adm!nistrative authority competent 
either to decide on complaints or to initiate appropriate legal proceedings. 
71 
2. Under the legal provisions referred to in paragraph I, Member States shall confer 92/28/EEC 
upon the courts or administrative authorities powers enabling them, in cases where they Art. 12 (1) and (2) 
deem such measures to be necessary, taking into account all the interests involved, and (adapted) 
in particular the pub~ic interest: 
to order the cessation of, or to institute appropriate legal proceedings for an order for 
the cessation of, misleading advertising, 
or 
· if misleading advertising has not yet been published but publication is imminent, to 
or~er 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 defmitive effect. · 
It shall be for each Member State to decide which of the two options set out in the first 
subparagraph to select.. 
4. Member . States may confer upon the 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: · 
to require publication of that decision in full or in part and in such form as they 
deem adequate~ 
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 92/28/EEC 
products by self-regulatory bodies and recourse to such bodies, if proceedings before Art. 12 (4) 
such bodies are possible in addition to the judicial or administrative proceedings referred (adapted) 
to in paragraph 1. 
72 
Article 98 
1. The marketing authorization holder shall establish, within his undertaking, a scientific 92/28/EEC 
service in charge of information about the medicinal products which he places on the Art. 13 
market. (adapted) 
2. The marketing authorization holder shall: 
keep available for, or communicate to, the authorities or bodies responsible for 
monitoring advertising of medicinal products, a sample of aJI advertisements 
emanating from his undertaking together with a statement indicating the persons to 
whom it is addressed, the method of dissemination and the ·date of first 
disse~ination, 
ensure that advertising of medicinal products by his undertaking conforms to the 
requirements of this Title, 
verify that medical sales representatives employed by his undertaking have been 
adequately trained and fulfill the obligations imposed upon them by Article 93 (2) 
~d (3), 
supply the authorities or bodies responsible for monitoring advertising of medicinal 
products with the information and assistance they require to carry out their 
responsibilities, 
ensure that the decisions taken by the authorities or bodies responsible for 
monitoring'advertising of medicinal products are immediately and fully complied 
with. 
Article 99 
Member States shall take the appropriate measures to ensure that the provisions of this 92/28/EEC 
Title are applied and shall determine in particular what penalties shall be imposed should Art. 14 
the provisions adopted in the execution of Title be infringed. (adapted) 
Article 100 
Advertising of the homeopathic medicinal products referred to in Article 13 (2) and 92173/EEC 
Article 14 (I) shall be subject to the provisions of this Title with the exception of Art. 6 (3) 
Article 87 (1). 
However, only the information specified in Article 69 (I) 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). 
73 
TITLE IX 
PHARMACOVIGILANCE 
Article 101 
The Member States shall take all appropriate measures to encourage doctors and other 75/319/EEC 
health care professionals to report suspected adverse reactions to the competent Art. 29e 
authorities. (as amended by 
93/39/EEC Art. 3 (3)) . 
The Member States may impose specific requirements on medical practitioners, in (adapted) 
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 
In order to ensure the adoption of appropriate regulatory decisions concerning the 75/319/EEC 
medicinal products authorized within the Community, having regard to information Art. 29a 
obtained al>out adverse reactions to medicinal products under normal conditions of use, (as amended by 
the Member States shall establish a pharmacovigilance system. This system shall be used 93/39/EEC Art. 3 (3)) 
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. 
_Such information shall be collated with data on consumption of medicinal products. 
This system shall also collate information on frequently observed misuse and serious 
abuse of medicinal products. 
74 
Article 103 
The marketing authorization holder shall have permanently and continuously at his 
disposal an appropriately qualified person responsible for pharmacovigilance. 
That qualified person shall be responsible for the following: 
(a) the establishment and maintenance of a system which ensures that information about 
all suspected adverse reactions which are reported to the personnel of the company, 
and to medical representatives, is collected and collated at a single point within the 
Community; 
(b) the preparation for the competent authorities of the reports referred to in Article I 04, 
in such form as may be laid down by those authorities, in accordance with the 
relevant national or Community guidelines; 
(c) ensuring that any request from the competent authorities for the prov1s1on . of 
additional information necessary for the evaluation of the benefits and risks afforded 
by a medicinal product is answered fully and promptly, including the provision of 
information about the volume of sales or prescriptions of the medicinal product 
concerned. 
Article 104 
I. The marketing authorization holder shall be required to record and to report all 
suspected serious adverse reactions which are brought to his attention by a health care 
professional to the competent authorities immediately, and in any case within 15 days of 
their receipt at the latest. 
2. The marketing authorization holder shall be required to maintain detailed records of 
all other suspected adverse reactions which are reported to him by a health care 
professional. 
Unless other requirements have been laid down as a condition of the granting of 
authorization, these records shall be submitted to the competent authorities immediately 
upon request or at least every six months during the first two years following 
authorization, and once a year for the following three years. Thereafter, th~ records shall 
be submitted at five-yearly intervals together with the application for renewal of the 
authorization, or immediately upon request. These records shall· be accompanied by a 
scientific evaluation. 
75 75/31.9/EEC 
Art. 29c 
(as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 
75/319/EEC 
Art. 29d 
(as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 
Article 105 
The Member States shall ensure that reports of suspected serious adverse reactions are 75/319/EEC 
immediately brought to the attention of the Agency and the marketing authorization Art. 29f 
hold~r, and in any case within 15 days of their notification, at the latest. (as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 
Article 106 
In order to facilitate the exchange of information about pharmacovigilarice within the 
Community, the Commission, in consultation with the Agency, Member States and 
interested parties, shall draw up guidance on the collection, verification and presentation 
of adverse reaction reports. 
This guidance shall take account of international harmonization work carried out with 
regard to terminology and classification in the field of pharmacovigilance. 
Article 107 75/319/EEC 
Art. 29g 
(as amended by 
93/39/EEC Art. 3 (3)) 
Where, as a result of the evaluation of adverse reaction reports, a Member State 75/319/EEC 
considers that a marketing authorization should be varied, suspended or withdrawn, it Art. 29h 
shall forthwith inform the Agency and the marketing authorization holder. (as amended by 
93/39/EEC Art. 3 (3)) 
In case of urg~ncy,. the competent authority concerned may suspend the marketing of a (adapted) 
medicinal product, provided the Agency is informed ·at the late~t on the following 
working day. 
Article 108 
Any amendments which may be necessary to update provisions of Articles 10 1 to I 07 to 7 5/319/EEC 
take account of scientific and technical progress shall be adopted in accordance with the Art. 29i 
procedure laid down in Article 122. (as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 
76 
TITLE X 
SPECIAL PROVISIONS ON MEDICINAL PRODUCTS DERIVED FROM 
HUMAN BLOOD AND PLASMA 
Article 109 
1. In respect of the use of human blood or human plasma as a starting material for the 89/381/EEC 
manufacture of medicinal products, Member States shall take the necessary measures to Art. 3 (1), (2) and (3) 
prevent the transmission of infectious diseases. In so far as this is covered by the (~dapted) 
amendments referred to in Article 121, as well as the application of the monographs of 
the European Pharmacopoeia regarding blood and . plasma, these measures 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 I 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 89/381/EEC 
self-sufficiency in human blood or human plasma. For this purpose, they shall encourage Art. 3 (4) 
the voluntary unpaid donation of blood and plasma and shall take the necessary (adapted) 
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. 
77 
TITLE XI 
SUPERVISION AND SANCTIONS 
Article 111 
I. The competent authority of the Member State concerned shall ensure, by means of 75/319/EEC 
.repeated inspections, that the legal requirements governing medicinal products are Art. 26, 1st paragraph 
complied with. (as amended by 
89/341/EEC Art. 3 (6)) 
Such inspections shall be carried out by officials representing the competent authority 75/319/EEC 
who shall be empowered to: Art. 26 (2) 
(adapted) 
(a) inspect manufacturing or commercial establishments and any laboratories entrusted 
by ·the holder of the manufacturing authorization with the task of carrying out 
checks pursuant to Article 20; 
(b) take samples; 
(c) examine any documents relating to the object of the inspection, subject to the 
provisions in force in the Member States on 21 May 1975 and which place 
restrictions on these powers with regard ·to the descriptions of the method of 
preparation. 
2. Member States shall. take all appropriate steps to ensure that the manufacturing 89/342/EEC 
processes used in the manufacture of immunological products are properly validated and Art. 4 ( 1) 
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 guidelines of good manufacturing practice laid down in Article 4 7. The 
content of such reports shall be communicated to the manufacturer who has to undergo 
the inspection. 
Article 112 
Member States shall take all appropriate measures to ensure that the person responsible 
for marketing a medicinal product and, where appropriate, the holder of the 
manufacturing authoriza~ion, furnish proof of the controls carried out on the medicinal 
product and/or the ingredi~nts 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). 
78 75/319/EEC 
Art. 26, 3rd paragraph 
(as amended by 
89/341/EEC Art. 3 (6)) 
(adapted) 
65/65/EEC 
Art. 8 
+ 
75/319/EEC 
Art. 27 
(adapted) 
Article 113 
"For the purpose of implementing Article 112, Member States may require manufacturers 89/342/EEC 
of immunological products to submit to a competent authority copies of all the control Art. 4 (2) 
reports signed by the qualified person in accordance with Article 51. + 
Article 114 
I. Where it considers it necessary in the interests of public health, a Member State may 
require the holder of an authorization for marketing: 
live vaccines, 
immunological medicinal products used in the primary immunization of infants or of 
other groups at risk, 
immunological medicinal products used in public health immunization programmes, 
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 examiniation is completed within 60 days of the receipt 
of the samples. 89/381/EEC 
Art. 4 (2) 
89/342/EEC 
Art. 4 (3) 
(adapted) 
2. Where, in the interests of public health, the laws of a Member State so provide, the 89/381/EEC 
competent authorities may require the marketing authorization holder for medicinal Art. 4 (3) 
products derived from human blood or human plasma to submit samples from each (adapted) 
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. 
79 
Article 115 
·Member States shall take all necessary measures to ensure that the manufacturing and 89/381/EEC 
. purifying processes used in the preparation of medicinal products derived from human Art. 4 ( 1) 
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 65/65/EEC 
to place a medicinal product on the market where that product proves to be harmful in Art. 11, 1st paragraph 
the normal conditions of use, or where its therapeutic efficacy is lacking, or where its (as amended by 
qualitative and quantitative composition is not as declared. Therapeutic efficacy is 89/341/EEC Art. 1 (1 )) 
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 65/65/EEC 
application as provided for in Articles 8, 10 (1) and 11 are incorrect or have not been . Art. 11, 2nd paragraph 
amended in accordance with Article 23. (as amended by 
· 83/570/EEC Art. 1 (6)) 
80 
Article 117 
I. Notwithstanding the measures provided for in Article 116, Member States shall take 75/319/EEC 
all appropriate measures to ensure that the supply of the medicinal product shall be Art. 28 
prohibited and the medicinal product withdrawn from the market if: (adapted) 
(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 
(d) the controls on the m~dicinal 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. 
2. The competent authority may limit the prohibition to supply the product, or its 
withdrawal from the market, to those batches which are the subject of dispute. 
Article 118 
1. The competent authority shall suspend or revoke the marketing authorization for a 75/319/EEC 
category of preparations or all preparations where any one of the requirements laid down Art. 29 
in Article 41 is no longer met. (adapted) 
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 ofthis Title shall apply to homeopathic medicinal products. 
81 92173/EEC 
Art. 4 (1) 
(adapted) 
(6) TITLE XII 
STANDING COMMITTEE 
Article 120 
1. A Standing Committee on Medicinal Products for Human Use on the Adaptation to 75/318/EEC 
Technical Progress of the Directives on the Removal ofTechni~al Barriers to trade in the Art. 2b 
Medicinal Products Sector, hereinafter called "the Standing Committee", is hereby set (adapted) 
up; it shall consist of representatives of the Member States with a representative of the 
Commission as chainnan. . 
2. The Standing Co!'lmittee shall adopt its own rules of procedure. 
Article 121 
Any changes which are necessary in order to adapt Annex I to take account of scientific 7 5/3I8/EEC 
and technical progress shall be adopted in accordance with the procedure laid down in Art. 2a, I st paragraph 
Article 122. (as amended by 
87/19/EEC Art. I (I)) 
(adapted) 
82 
Article 122 
Where the procedure laid down in this Article is to be followed, the Commission shall be 75/319/EEC 
assisted by the Standing Committee. Art. 37a 
(as amended by 
The representative of the Commission shall submit to the Standing Committee a draft of 93/39/EEC Art. 3 (4)) 
the measures to be taken. The Standing Committee shall deliver its opinion on the draft (adapted) 
within a time limit which the Chairman may lay down according to the urgency of the 
matter. The opinion shall be delivered by the majority laid down in Article 205 (2) of the 
Treaty in the case of decisions which the Council is required to adopt on a proposal from 
the Commission. The votes of the representatives of the Member States within the 
Standing Committee shall be weighted in the manner set out in that Article. The 
Chairman shall not vote. 
The Commission shall adopt the measures envisaged if they are in accordance with the 
opinion of the Standing Committee. 
If the measures envisaged are not in accordance with the opinion of the Standing 
Committee, or if no opinion is delivered, the Commission shall, without delay, submit to 
the Council a proposal relating to the measures to be taken. The Council shall act by a 
qualified majority. 
If on the expiry of a period of three months from the date of referral to the Council, the 
Council has not acted, the proposed measures shall be adopted by the Commission. 
Article 123 
Where the procedure laid down in this Article is to be followed, the Commission shall be 75/319/EEC 
assisted by the Standing Committee. Art. 3 7b 
(as amended by 
The representative of the Commission shall submit to the Standing Committee a draft of 93/39/EEC Art. 3 (4)) 
the measures to be taken. The Standing Committee shall deliver its opinion on the draft (adapted) 
within a time limit which the Chairman may lay down according to the urgency of the 
matter. The opinion shall be delivered by the majority laid down in Article 205 (2) of the 
Treaty in the case of decisions which the Council is required to adopt on a proposal from 
the Commission. The votes of the representatives of the Member States within the 
Standing Committee shall be weighted in the manner set out in that Article. The 
Chairman shall not vote. 
The Commission shall adopt the measures envisaged if they are in accordance with the 
opinion of the Standing Committee. 
If the. measures envisaged are not in accordance with the opinion of the Standing 
Committee, or if no opinion is delivered, the Commission shall, without delay, submit to 
the Council a proposal relating to the measures to be taken. The Council shall act by a 
qualified majority. 
If on the expiry of a period of three months from the date of referral to the Council, the 
Council has not acted, the proposed measures shall be adopted by the Commission, save 
where the Council has decided against the said measures by a simple majority. · 
83 
TITLE XIII 
GENERAL PROVISIONS 
. Article 124 
Member States shall take all appropriate measures to ensure that the competent 75/319/EEC 
authorities concerned communicate to each other such information as is appropriate to Art. 30, 1st paragraph 
guarantee that the requirements for the manufacturing authorizations or marketing (adapted) 
authorizations are fulfilled. 
Upon reasoned request, Member States shall forthwith communicate the reports referred 75/319/EEC 
to in Article Ill (3) to the competent authorities of another Member State. If, after Art. 30, 2nd paragraph 
considering the reports, the Member State receiving the reports considers that it cannot (as amended by 
accept the conclusions reached by the competent authorities of the Member State in 89/341/EEC Art. 3 (8)) 
which the report was established, it shall inform the competent authorities concerned of 
its reasons and may request further information. The Member States concerned shall use 
their best endeavours to reach agreement. If necessary, in the case of serious differences 
of opinion, the Commission shall be informed by one of the Member States concerned. 
Article 125 
1. Each Member State shall take all the appropriate measures to ensure that decisions 75/319/EEC 
authorizing marketing, refusing or revoking a marketing authorization, cancelling a Art. 33 (1) 
decision refusing or revoking a marketing authorization, prohibiting supply, or (adapted) 
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 75/319/EEC 
concerned forthwith of any action taken by him to suspend the marketing of a medicinal Art. 33 (2) to (4) 
product or to withdraw a medicinal product from the market, together with the reasons (as amended by 
for such action if the latter concerns the efficacy of the medicinal product or the 89/341/EEC Art. 3 (9)) 
protection of public health. Member States shall ensure that this information is brought (adapted) 
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 affect the protection of public health in third countries 
is forthwith brought to the attention of the World Health Organization, with a copy to the 
Agency. 
4. The Commission shall publish annually a list of the medicinal products which are 
prohibited in the Community. 
84 
Article 126 
Member States shall communicate to each other all the information necessary to 92173/EEC 
guarantee the quality and safety of homeopathic medicinal products manufactured and Art. 5 
marketed within the Community, and in particular the information referred to in 
Articles 124 and 125. 
Article 127 
Every decision referred to in this Directive which is taken by the competent authority of 65/65/EEEC 
a Member State shall state in detail the reasons on which it is based. Art. 12 
(adapted) 
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 75/319/EEC 
access to such redress. Art. 31 
(adapted) 
Marketing authorizations, and decisions to revoke such authorizations, shall be 
published by each Member State in the appropriate official publication. 
85 + 
92/25/EEC 
Art. 4 (2) 
(adapted) 
+ 
92/27/EEC 
Art. 11 (2) 
(adapted) 
+ 
92/28/EEC 
Art. 12 (3) 
(adapted) 
Article 128 
An authorization to market a medicinal product shall not be refused, suspended or 165/65/EEC 
revoked except on the grounds set out in this Directive. Art. 21 
No decision concerning suspension of manufacture or of importation of medicinal 75/319/EEC 
products coming from third countries, prohibition of supply or withdrawal from the Art. 32 
market of a medicinal product may be taken except on the ground set out in Articles 117 (adapted) 
and 118. · 
Article 129 
I. 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 is in 
possession of the manufacturing authorization. When issuing such certificates 
Member. States shall comply with the following conditions: 
(a) they shall have regard to the prevailing administrative arrangements of the World 
Health Organi7.ation; 
(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 is not in possession of a marketing authorization he shall 
provide the authorities responsible for establishing the certificate referred to . in 
paragraph I, with a declaration explaining why no marketing authorization is available. 
86 75/319/EEC 
Art. 28a 
(as amended by 
89/341/EEC Art. 3 (7)) 
(adapted) 
TITLE XIV 
FINAL PROVISIONS 
Article.130 
Directives 65/65/EEC, . 75/318/EEC, 75/319/EEC, 89/342/EEC, 89/343/EEC, 
89/381/EEC, 92/25/EEC, 92126/EEC, 92/27/EEC, 92/28/EEC and 92/73/EEC, amended 
by the Directives referred to in Annex 11, Part A, are repealed, without prejudice to the 
obligations ~f the Member States concerning the time-limits for implementation set out 
in Annex 11, 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 Ill. 
Article 131 
This Directive shall enter into force on 1 January 2000. 
Article 132 
This Directive is addressed to the Member States. 
Done at Brussels, 
For the European Parliament For the Council 
The President The President 
87 
ANNEX I 
ANALYTICAL, PHARMACOTOXICOLOGICAL 
AND CLINICAL STANDARDS AND PROTOCOLS IN 
RESPECT OF THE TESTING OF 
MEDICINAL PRODUCTS 
INTRODUCTION 75/318/EEC 
Annex 
The particulars and documents accompanying an application for marketing authorization (as amended by 
pursuant to Articles 8 and 10 (1) shall be presented in four parts, in accordance with the 91/507/EEC Art. 1) 
requirements set out in this Annex and taking account of the guidance published by the (adapted) 
Commission in The rules governing medicinal products in the European Community, 
Volume 2: Notice to applicants for marketing authorizations/or 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 3 and its supplements: Guidelines on the 
quality, safety and efficacy of medicinal products for human use. 
All infonnation 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 
phannacotoxicological 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 infonnation not in the 
original application and all pharmacovigilance reports, shall be submitted to the 
competent authorities. 
The general sections of this Annex give the requirements for all categories of medicinal 
products; 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 pl~ma. The additional special 
requirements for biological medicinal products are also applicable to medicinal products 
obtained through processes mentioned in the first indent of 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 • 
OJ L 358, 18.12.1986, p. I. 
88 
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 phannaceutical fonn, the method 
of administration, the strength and the fmal 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 
defmed 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. 
In addition the applicant shall provide samples or mock-ups of the packaging, labels and 
package leaflets for the medicinal product concerned. 
89 75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art. 1) 
(adapted} 
C. Expert reports 75/318/EEC 
Annex 
In accordance with Article 12 (2), expert reports must be provided on the chemical, (as amended by 
phannaceutical and biological documentation, the phannacotoxicological documentation 91/507/EEC Art. 1) 
and the clinical documentation respectively. (adapted) 
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. 
90 
PART2 
CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL TESTING OF 
MEDICINAL PRODUCTS 
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 supplemented, if necessary, by the manufacturing method. In the case of test 
procedures included in the European Pharmacopoeia or the pharmacopoeia of a 
Member State, this description may be replaced by a detailed reference to the 
pharmacopoeia in question. 
A. Qualitative and quantitative particulars of the constituents 
The particulars and documents which must accompany· applications for marketing 
auth~rization, pursuant to point 3 of Article 8 (3) (c) shall be submitted in accordance 
with the following requirements. 
I. Qualitative partiCulars 
1.1. "Qualitative particulars" of all the constituents of the medicinal product shall mean 
the designation or description of: 
the active substance(s), 
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., 
the constituents, intended to be ingested or otherwise administered ,to the patient, of 
the outer covering· of the medicinal products -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. 
91 75/318/EEC 
Annex 
(as amended by 
911507/EEC Art. 1) 
(adapted) 
1.2. In the context of a radiopharmaceutical kit, which is to be radio labelled after supply 
by the manufacturer, the active substance is considered to be that part of the fonnulation 
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 ~.aughter radionuclides are to be considered as active 
substances. 
2. The ''usual tenninology", to be used in describing the constituents of medicinal 
products, shall mean, notwithstanding the application of the other provisions in Article 8 
(3) (c): 
in respect of substances which appear in the European Pharmacopoeia or, failing 
this, 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, 
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, 
in respect of colouring matter, designation by the "E" code assigned to them in 
Council ·Directive 78/25/EEC of 12 December 1977 on the approximation of the 
rules of the Member States concerning the colouring matters authorized for use in 
medicinal products 1 • 
. 3. Quantitative particulars 
3.1. In order to give "quantitative particulars" of the active substances of t~e medicinal 
products, it is necessary, depending on the pharmaceutical fonn 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 defmed 
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 
defmed, the units of biological activity shall be expressed in such a way as to provide 
unambiguous infonnation on the activity of the substances. 
Whenever possible, biological activity per units of mass shall be indicated. 
OJ L 11, 14.1.1978, p. 18. Directive as last amended by the Act of Accession of Spain and Portugal. 
92 75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art. 1) 
(adapted) 
This information shall be supplemented: 75/318/EEC 
Annex 
in respect of injectable preparations, by the mass or units of biological activity of (as amended by 
each active substance in the unit container, taking into account the usable volume of 91/507/EEC Art. 1) 
the product, after reconstitution, where appropriate, (adapted) 
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, 
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 immunological medicinal products, the quantitative particulars shall be 
expressed by units of biological activity, except for well defined immunoligical 
medicinal 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 arid 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. 
4.2. For radiopharmaceuticals, this should include a consideration of 
chemical/radiochemical purity and its relationship to biodistribution. 
93 
75/318/EEC 
B. Description of manufacturing method Annex 
(as amended by 
1. The description of the manufacturing method accompanying. the application for 911507 /EEC Art 1) 
marketing authorization pursuant to point 4 of Article 8 (3) (d), shall be drafted in such a (adapted) 
way ·as to give an adequate synopsis of the nature of the operations employed. 
For this purpose it shall include at least: 
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, 
in the case of continuous ma~ufacture, full details concerning precautions taken to 
ensure the homogeneity of the finished product, 
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 b'e 
made of any substances that may disappear in the course of manufacture; any 
overage shall be indicated and justified, 
:-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, 
experimental studies validating the manufacturing process, where a non-standard 
method of manufacture is used or where it is critical for the product, 
for sterile medicinal products, details of the sterilization processes ~d/or aseptic 
procedures used. 
2. 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. 
C. Controls of starting materials 
1. For the purposes of this section, "starting materials" shall mean all the constituents of 
the medicinal product and, if necessary, of its container, as referred to in Section A, 
point I~ above. 
94 
In the case of: 
an active substance not described in the European Pharmacopoeia or in the 
pharmacopoeia of a Member State, or 
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 pharmacopoeia} 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. Starting materials listed in pharmacopoeias 
The monographs of the European Pharmacopoeia shall be applicable to all substances 
appearing in it. 
-In respect of other substances, each Member State may require observance of its own 
national pharmacopoeia with regard to products manufactured in its territory. 
Constituents fulfilling- the requirements of the European Pharmacopoeia or the 
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with 
Article 8 (3) (h). In this case the description of the analytical methods may be replaced 
by a detailed reference to the pharmacopoeia in question. 
95 75/318/EEC 
·Annex 
(as amended by 
91/507/EEC Art. 1) 
(adapted) 
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 
mor~ appropriate spe_cifications 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. Starting materials not in a pharmacopoeia 
Constituents which are not given in any pharmacopoeia shall be described in the form of 
a monograph under the following headings: · 
(a) The name of the substance, meeting the requirements of Section A, point 2, shall be 
supplemented by any trade or scientific synonyms; 
(b) the definition of the substance, set down in a form similar to that used in the 
European Pharmacopoeia, shall be accompanied by any necessary explanatory 
evidence, especially concerning the molecular structure where 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; 
96 75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art. I) 
(adapted) 
(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 ~ase 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. 
1.3. Physico-chemical characteristics liable to effect bio-availabi/ity 
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 tbe active . 
substances if the bio-availability of the medicinal product depends on them: 
crystalline form and solubility coefficients, 
particle size, where appropriate after pulverization, 
state of solvation, 
oiVwater 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. 
The competent authorities may also request the pK and pH values if they think this infonnation is essential. 
97 75/318/EEC 
Annex 
(as amended by 
911507/EEC Art. I) 
(adapted) 
(7) For the purposes of this paragraph, starting materials shall mean any substance used in 75/318/EEC 
the manufacture of the medicinal product; this includes the constituents of the medicinal Annex 
product, and, if necessary, of its container, as referred to in paragraph A, point I above, (as amended by 
as well as source materials such as microorganisms, tissues of either plant or animal 91/507/EEC Art. I) 
origin, cells or fluids (including blood) of human or animal origin, and biotechnological (adapted) 
cell constructs. The origin and history of starting materials shall be described and 
documented. 
The description of the starting material shall 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. 
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 proc~ssing 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 immunological medicinal 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. 
98 
D. Control tests carried out at intermediate stages of the manufacturing process 7 5/318/EEC 
Annex 
I. The particulars and documents accompanying an application for marketing (as amended by 
authorization, pursuant to Article 8 (3) (h) and (i) and Article IO, paragraph I of this 911507/EEC Art. 1) 
Directive, shall include particulars relating to the product control tests that may be (adapted) 
carried out at an intermediate stage of the manufacturing process, with a view to 
ensuring the consistency of the technical characteristics and the production process. 
These tests are essential for checking the conformity of the medicinal product with the 
formula when, exceptionally, an applicant proposes an analytical method for testing the 
finished product which does not include the assay of all the active substances (or of all 
the excipient constituents subject to the same requirements as the active substances). 
The same applies where the quality control of the finished product depends on in­
process control tests, particularly if the medicinal product is essentially defined by its 
method or preparation. 
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 immunological medicinal products, the products shall be 
qualitatively and quantitatively characterized at an intermediate stage, as late as possible 
in the manufacturing process. 
E. Control tests on the finished product 
1. For the control of the fmished 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. 
99 
The application for marketing authorization shall list those tests which are carried out 75/318/EEC 
routinely on each batch of finished product. The frequency of the tests which are not Annex 
carried out routinely shall be stated. Release Jjmits shall be indicated. (as amended by 
91/507/EEC Art. I) 
The particulars and documents accompanying the application for marketing (adapted) 
authorization pursuant to Article 8 (3) (b) and (i) and Article 10 (I) 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 proqucts 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 product would, if tested in 
accordance with those monographs, meet the quality requirements of that 
pharmacopoeia for ~e pharmaceutical form concerned. 
1.1. General characteristics of the finished product 
Certain tests of the general characteristics of a product shall alway~ be included among 
the tests on the finished product. These tests shall, wherever applicable, relate to the 
control of average masses and maximum deviations, to mechanical, physical or 
microbiological tests, organoleptic characteristics, physical characteristics such as 
density, pH, refractive index, etc. For each of these characteristics, standards and 
tolerance limits shall be specified by the applicant in each particular case. 
The conditions of the tests, where appropriate, the equipment/apparatus employed and 
the standards shall be described in precise details whenever they are not given in the 
European Pharmacopoeia or the pharmacopoeia of the Member States; the same shall 
apply in cases where the methods prescribed by such pharmacopoeias are not applicable. 
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 conc~rned consider this 
necessary. 
100 
1.2. JdenJijication and assay of active substan~e(s) 75/318/EEC 
Annex 
Identification and assay of the active substance(s) shall be carried out either in an (as amended by 
average representative sample from the production batch or in a number of dosage-units 91/507/EEC Art. I) 
analysed individually. (adapted) 
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 01:1 the finished product shall include, where appropriate, the chemical 
and, if necessary, the toxico-pharmacological ~nvestigation of the changes that this 
substance has undergone, and possibly the characterization and/or assay of the 
degradation products. 
1.3. Identification and assay of excipient constituents 
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. 
A~ 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. 
101 
1.4. Safety tests 75/318/EEC 
Annex 
Apart from the phannacotoxicological tests submitted with the application for marketing (as amended by 
authorization, particulars of safety tests, such as sterility, bacterial endotoxin, 91/507/EEC Art. I} 
pyrogenicity and local tolerance in animals shall be included in the analytical particulars (adapted) 
wherever such tests must be undertaken as a mauer of routine in order to verify the 
quality of the product 
2. 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 ~riteria of acceptability published as 
recommendations in the World Health Organization (Requirements for Biological 
Substances) shall serve as guidelines. 
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 s\lall be provided. 
For kits, the specifications of the finished product shall 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. 
F. Stability tests 
I. 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 
mus~ declare these and indicate characterization methods and test procedures. 
The conclusions shall contain the results of analyses, justifying the proposed shelf life 
under the recommended storage conditions and the specifications of the finished product 
· at the end of the shelf-life under these recommended storage conditions. 
102 
The maximum acceptable level of degradation products at the end of shelf-life shall be 75/318/EEC 
'indicated. Annex 
(as amended by 
A study of the interaction between product and container shall be submitted wherever 91/507 /EEC Art. I) 
the risk of such interaction is regarded as possible, especially where injectable (adapted) 
prep~ations 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 radiophannaceuticals, information on stability shall be given for radionuclide 
generators, radionuclide kits and . radio labelled products. The stability during use of 
radiophannaceuticals in multi-dose vials shall be documented. 
103 
PART3 
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/EECI and 88/320/EEC2. 
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; 
(b) the pharmacological properties of the product, in both qualitative and quantitative 
relationship to th'e ptoposed 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. 
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, reabsorption 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, reabsorption 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 11 E of this Part. 
I 
2 OJ LIS, 17.1.1987, p. 29. 
OJ L 145, 11.6.1988, p. 35; .Directive as amended by Direc:tive 90/18/EEC (OJ L 11, 13.l.l990, p. 37). 
104 75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art. 1) 
(adapted) 
3. For biological medicinal products such as immunological medicinal products and 75/318/EEC 
medicinal products derived from human blood or plasma, the requirements of this Part Annex 
may have to be adapted for individual products; therefore the testing programme carried (as amended by 
. out shall be justified by the applicant. 9 11507/EEC Art. I) 
(adapted) 
In establishing the testing programme, the following shall be taken into consideration: 
all tests requiring repeated administration of the product shall be designed to take 
account of the possible induction of, and interference by, antibodies; 
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 radiophannaceuticals; 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 cal~ulated 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. 
11. Performance of tests 
A. Toxicity 
I. 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. 
I05 
This study will cover the signs observed, including local reactions. The period during 7 5/318/EEC · 
which the test animals are observed shall be fixed by the investigator as being adequate Annex 
tc;l reveal tissue or organ d8:ffiage or recovery, usually for a period of 14 days but not less (as amended by 
than 7 days, but without exposing the animals to prolonged suffering. Animals dying 91/507/EEC Art. 1) 
during the observation period should be subject to autopsy as also should all animals (adapted) 
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. In 
suitable species, a quantitative evaluation of the approximate lethal dose and information 
on the dose effect relationship should be obtained, but a high level of precision is not 
requ~red. 
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. 
Generally, it is desirable that two tests be performed: one short-term, 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 forthe dosages chosen. 
106 
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 ba8ed on observation of behaviour, growth, 
haematological and biochemical tests, especially those relating to the excretory 
mechanism, and also on autopsy reports and accompanying histological data. The choice 
and range of each group of tests will depend on the speci~s of animal used and the· state 
of scientific knowledge at the time. 
·Jn 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 ~is 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 rep~oductive function, this shall be investigated by 
appropriate tests. 
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 ad!Dinistered 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, eith~r because the medicinal product will not normally be used 
by women capable of child-bearing or for other reasons, must be adequately justified. 
107 75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art. I) 
(adapted) 
Embryo/foetal toxicity studies shall normally be conducted on two mammalian species, 75/318/EEC 
one of which should be other than a rodent. Peri-and postnatal studies shall be Annex 
conducted in at least one species. Where metabolism of a medicinal product in a (as amended by 
particular species is known to be similar to that in man, it is desirable to include this 91/507 /EEC Art. 1) 
species. Also, it is desirable that one of the species is the same as in the repeated dose (adapted) 
~oxicity 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 
stati~tical 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 
predec~ssors. 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 w:hen 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 aprolonged 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. 
108 
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 experim.entally 
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, (for example, 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. 
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, the pharmacodynamic study shall demonstrate those interactions which 
might make the combination of value in therapeutic use. 
In the second case, where scientific justification for the combination is sought through 
therapeutic 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. 
If a combination includes a novel active substance, the latter must previously have been 
studied in depth. 
109 75/318/EEC 
Annex 
(as amended by 
911507/EEC Art. I) · 
(adapted) 
G. Pharmacokinetics 75/318/EEC 
Annex 
PharmacokineticS means the study of the fate of the active substance within the (as amended by 
organism, and covers the study of the absorption, distribution, biotransformation and 91/507 /EEC Art. 1) 
excretion of the substance. (adapted) 
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 ofpharmacologically 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. 
110 
PART 4 75/318/EEC 
Annex 
CLINICAL DOCUMENTATION (as amended by 
91/507/EEC Art. I) 
The particulars and documents accompanying applications for marketing authorizations (adapted) 
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. 
Evaluation of the application for marketing authorization shall be based on clinical trials 
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. 
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. 
Ill 
B. Conduct of trials 75/318/EEC 
Annex 
l. Good clinical practice (as·amcndcd by 
91/507/EEC Art. 1) 
1.1. All phases of clinic~) investigation, including bioavailability and bioequivalence (adapted) 
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. 
The trial protocol (including statistical design), the technical application and 
documentation shall be submitted by the sponsof 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-estab~ished, 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: 
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, 
standard operating procedures, 
all written opinions on the protocol and procedures, 
112 
the investigator's brochure, 
case report forms on each trial subject, 
final report, 
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 
I. The particulars of each clinical trial must contain sufficient detail to allow an 
objective judgement to be made: 
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, 
audit certificate(s), if available, 
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, 
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, the applicant may 
omit part of this information. Complete documentation shall be provided forthwith upon 
request. 
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; 
113 75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art. I) 
(adapted) 
(8) (c) the number of patients withdrawn prematurely from the trials and the reasons for 75/318/EEC 
such withdrawal; Annex 
(as amended by 
(d). where controlled trials were carried out under the above conditions, whether the 91~507/EECArt. I) 
control group: (adapted) 
received no treatment, 
received a placebo, 
received another medicinal product of known effect, 
received treatment other than therapy using medicinal products; 
(e) th~ 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 product under normal conditions of use, its tolerance, its 
efficacy and any useful information relating to 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. 
5. In addition, the investigator shall always indicate· his observations on: 
(a) ~Y 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) ~y deaths whi~h occurred during the trial or within the follow-up period. 
6. 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. 
114 
.... 7. Total or partial omission of data must be explained. Should unexpected results occur 75/318/EEC 
during the course of the trials, further preclinical toxicological and pharmacological tests Annex 
must be undertaken and reviewed. (as amended by 
91/507/EEC Art. 1) 
If the medicinal product is intended for long-tenn administration, particulars shall be (adapted) 
given of any modification of the pharmacological action following repeated 
administration, as well as tbe establishment of long-tenn dosage. 
D. Clinical pharmacology 
I. Pharmacodynamics · 
The pharmacodynamic action correlated to the efficacy shall be demonstrated including: 
ihe dose-response relationship and its time course, 
justification for the dosage and conditions of administration, 
the mode of action, if possible. 
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 phannacokinetic characteristics shall be described: 
absorption (rate and extent), 
distribution, 
metabolism, 
. 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 . 
115 
3./nteractions 75/3I8/EEC 
Annex 
If the medicinal product is ·normally to be administered concomitantly with other (as amended by 
medicinal products, particulars shall be given of joint administration tests performed to 911507 /EEC Art. I)· 
demonstrate possible modification of the pharmacological action. (adapted) 
If pharmacodynamic/pharmacokinetic interactions exist between the substance and other 
medical products or substances like alcohoJ, 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 w.ith 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 (I) (a). 
F. C~inical efficacy and safety 
I. In g~neral, clinical trials shall· be done as "controlled clinical trials" and if possible, 
randomized; any other design shall be justified. The treat.ment of the control groups will 
vary from ca8e 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 medic~nal 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. 
2. 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. 
116 
3. Clinical statements concerning the efficacy or safety of a medicinal product under 75/318/EEC 
normal conditions of use which are not scientifically substantiated cannot be accepted as Annex 
valid evidence. (as· amended by 
91 /507/EEC Art. 1) 
4. The value of data on the efficacy and safety. of a medicinal product under normal (adapted) · 
conditions of use will be very greatly enhanced if such data come from several 
competent investigators working independently. 
5. 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 ~e trial 
and fully described. 
For live attenuated vaccines, clinical trials shall be so designed as to reveal potential 
transmission of 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. 
For vaccines and immunological medicinal 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 
indiviilually -and discussed, ~specially: 
in terms of overall adverse experience and 
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:· 
the disease to be treated, 
other therapeutic approaches, 
particular characteristics in sub-groups of patients, 
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. 
117 
G. Documentation for applications in ex~eptional circumstances 75/318/EEC 
Annex 
'When, in respect of particular therapeutic indications, the applicant can show that he is {as amended by 
unable to provide comprehensive data on the efficacy and safety under normal 91/507/EEC Art. I) 
conditions of use, because: {adapted) 
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 
in the present state of scientific knowledge, comprehensive information cannot be 
provided, or 
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) 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 radiophannaceutical, by an authorized person, 
(c) 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. 
H. Post-marketing experience 
I. 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. worldw.ide studies relevant to the safety of the medicinal 
product shall be included. 
118 
For this purpose, an adverse drug reaction is a reaction which is noxious and unintended 75/318/EEC 
and which occurs at doses normally used in.man for prophylaxis, diagnosis or therapy of Annex 
disease or for the modification of physiological function. (as amended by 
91/507/EEC Art. 1) 
2. In the case of vaccines already authorized in other countries, information on the (adapted) 
monitoring of vacc~nated subjects to evaluate the prevalence of the disease in question as 
compared to non vaccinated subjects shall be submitted, .when availa~le. 
3. For immunological medicinal products, response in periods of increased antigen. 
exposure shall be identified. 
119 
ANNEXII 
Part A 
Repealed Directives, with their successive amendments 
(referred to by Article 130) 
Council Directive 65/65/EEC (OJ 22, 9. 2. 1965, p. 369) 
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 87121/EEC (OJ L 15, 17. I. 1987, p. 36) 
Council Directive 89/341/EEC (OJ L 142,25. 5. 1989, p. 11) 
Council Directive 92127/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 
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 92127/EEC 
Council Directive 93/39/EEC 
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 92127/EEC . 
Council Directive 92/28/EEC (OJ L 113, 30. 4. 1992, p. 13) 
Council Directive 92173/EEC (OJ L 297, 13. 10. 1992, p. 8) 
. 120 
PartB 
Deadlines for transposition into national law 
(referred to by ~rticle 130) 
Directive 
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 92127/EEC 
Directive 92/28/EEC 
Directive 92173/EEC 
Directive 93/39/EEC 
2 
3 
4 
s Deadline for transposition applicab~e to Greece, Spain and Portupl. 
Except Section A. point 3.3 in Part U of the Aanex. 
Deadline for transposition applicable to Section A. point 3.3 in Part U of the Annex. 
Except with reprd to Article I (6). 
Deadline for transposition applic:able to Article I (7). Deadline for transposition 
31 December 1966 
---
21 November 1976 
21 November 1976 
--
31 October 1985 
l July 1~87 
1 July 1987. 
1 January 19921 
1. January 1992 
1 January 1992 
1 January 1992 
1 January 1992 
1 January 19922 
1 January 19953 
1 January 1993 
1 January 1993 
I January 1993 
1 January 1993 
31 December 1995 
I January 19954 
I January 19985 
ThisDir. 65/65/EEC 75/318/EEC 75/319/EEC 
Art. 1 (1) to Art. 1 (I) to 
(3) (3) 
Art. 1 (4) Annex 
Art. 1 (S) 
Art. 1 (6) to 
(9) 
Art. 1 (10) 
Art. 1 (11) to Art. 29b 
(14) 
Art. 1 (IS) 
and (16) 
Art. 1 (17) 
Art. 1 (18) to 
(24) 
Art. 1 (25) .Art. 8 (1) 
Art. 1 (26) Art. 10 (1) 
Art.2 Art. 2 (1) 
Art. 3 (1) Art. 1 (4) 
and (2) and (S) 
Art 2 (3), 1st 
indent 
Art. 3 (3) Art.2 (3), 
and (4) 2nd and 3rd 
indents 
Art. 3 (5) 
Art. 3 (6) 89/342/EEC 
Art. 1 (1) 
and(2) ANNEX Ill 
CORRELATION TABLE 
89/343/EEC 89/381/EEC 
Art. 1 (2) 
Art. 1 (1) 
Art. 1 (1) 
Art. 1 (2) 
122 92/25/EEC 
Art. 1 (2) 92/26/EEC 92127/EEC 92128/EEC 92/73/EEC 
Art. 1 
. 
Art. 1 (2), 
2nd 
sentence 
Art. 1 (2) 
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 92173/EEC 
Art. 4 (1) Art. 1 (3) 
Art. 4 (2) Art. 1 (3) 
Art. 4 (3) Art.3,2nd 
sub paragraph 
Art. 4 (4) Art.6 
Art. 5 Art. 2 (4) 
Art.6 Art. 3 (l) 
Art. 7 Art. 2, I 
I 
2nd sentence 
Art. 8 (1) and (2) Art. 4.(1) and (2) 
Art. 8 (3) (a) to (e) Art. 4, 3rd paragraph, Art. 1 (l) 
points 1 to 5 
Art. 8 (3) (f) to (i) Art. 4, 3rd paragraph, 
points 6 to 8.1 
Art. 8 (3) G) to (I) Art. 4, 3rd paragraph, . 
points 9 to 11 
Art.9 Art.3 
Art. 10 (l) Art. 4, 3rd paragraph, 
point 8.2 
Art. 10.(2) Art. 1, 
2nd paragraph 
Art. 11 , points 1 to Art. 4a, points 1 to 
5.3 5.3 ' 
Art. 11, point 5.4 Art. 4a, point 5.4 Art.3 
Art. 11, points 5.5 Art. 4a, points 5.5 
to6.4 to6.4 
Art. 11, point 6.5 Art. 4a, point 6.6 
Art. 11, point 7 Art. 4a, point 6.5 
Art. 11, points 8 Art. 4 
to 9 
Art. 12 (l) Art. 1 
Art. 12 (2) and (3) Art.2 
Art.13 Art. 6 (I) 
and (2) 
---
123 
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Art. 14 (1) Art. 7 (1) and 
and (2) (4) 
Art. 14 (3) Art. 4, 
2nd paragraph 
Art. 15 Art.8 
Art. 16 Art.9 
Art. 17 Art. 7 
Art. 18 Art. 7a 
Art. 19 Art.4 
Art. 20 Art.S 
Art. 21 Art. 4b 
Art.22 Art. 10 (2) 
Art.23 Art. 9a : 
Art.24 Art. 10 (I) 
Art.25 Art.9 
Art.26 Art. s 
Art. 27 . Art. 8 
Art. 28 (1) Art. 9 (3) 
Art. 28 (2) Art. 9 (1) 
Art. 28 (3) Art. 9 (2) 
Art. 28 (4) Art. 9 (4) 
Art. 29 Art. 10 '" 
Art. 30 Art.ll 
Art. 31 Art. 12 
Art.32 Art. 13 
Art. 33 Art. 14 (I) 
~ 
124 
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Art.34 Art. 14 (2) to 
(4) 
Art. 35 Art. IS · 
Art.36 Art. 1Sa 
Art.37 Art. 1Sb 
Art.38 Art. 1Sc 
Art. 39 Art. 14 (S) 
Art. 40 Art. 16 
Art. 41 Art. 17 
Art. 42 Art. 18 
Art.43 Art. 20 (1) 
Art. 44 Art. 20 (2) 
Art. 4S Art. 20 (3) 
Art. 46 Art. 19 
Art.47 Art. 19a 
Art.48 Art.21 
Art. 49 . Art.23 
Art. so Art.24 
Art. 51 (1) Art. 22 (1) 
and (2) 
Art. S1 (3) Art. 22 (2) 
Art. 52 Art.2S 
Art.S3 Art~3 
Art.S4 Art. 2 (1) 
Art. SS Art.3 
125 
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Art. 56 Art. 4 (1) 
Art. 51 Art. 5 (2) 
Art. 58 Art.6 
Art. 59 Art. 7 (1) and 
(2) 
Art. 60 Art. 5 (1) and 
Art.9 
Art. 61 Art. 10 (1) to 
(4) 
Art. 62 Art. 2 (2) and 
·Art. 7 (3) 
Art. 63"(1) Art. 4 (2) 
.Art. 63 (2) Art.8 
Art. 63 (3) . Art. 10 (5) 
Art. 64 Art. 11 (1) 
Art. 65 Art. 12 
Art. 66 . Art. 5 
Art. 67 Art. 6 (1) 
Art.68 Art:2 (2) 
Art. 69 Art. 7 (2) i 
and (3) 
Art. 70 Art.2 
Art. 71 Art.3 
Art. 72 Art.4 
Art. 73 Art. S (I) 
Art. 74 Art. 5 (2) 
126 
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Art. 75 Art. 6 (2) 
Art. 76 Art.2 
Art. 77 Art.3 
Art. 78 Art. 4 (1) 
Art. 79 Art. 5 
Art.80 Art.6 
Art.81 Art. 7 
Art.82 Art.8 
Art.83 Art.9 
Art.84 Art. 10 
Art.85 Art. 3 (6), 
2nd sentence 
Art. 86 Art. 1 (3) 
and (4) 
Art.87 Art. 2 
Art.88 Art. 3 (1) to 
I (6), 1st 
sentence 
I 
Art.89 Art.4 
Art.90 Art.5 
Art.91 Art.6 
Art.92 Art. 7 
Art.93 Art.8 
Art.94 Art.9 
Art. 95 Art. 10 
,Art. 9~ Art.ll 
127 
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Art. 97 (1) Art. 12 (1) 
to (4) and (2) 
Art. 97 (5) / Art. 12 (4) 
Art.98 Art. 13 
Art99 Art. 14 
Art. 100 Art. 6 (3) 
Art. 101 Art.29e 
Art. 102 Art.29a 
Art. 103 Art.29c 
Art. 104 Art. 29d I 
Art. 105 Art.29f 
' 
Art. 106 Art.29g 
Art. 107 Art.29h 
Art. 108 Art. 29i 
Art. 109 Art.3 
Art.llO Art. 3 (4) 
Art. 111 (I) Art. 26, 1st 
and 2nd 
paragraph 
Art. 111 (2) Art. 4 (I) 
Art. 111 (3) Art. 26, 3rd 
paragraph 
Art. 112 Art. 8 Art.27 
Art.113 Art. 4 (2) Art. 4 (2) 
Art. 114 (1) Art. 4 (3) 
Art. 114 (2) Art. 4 (3) 
Art. 115 Art. 4 (1) 
Art. 116 Art. 11 
Art. 117 Art.28 
128 
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Art.ll8 Art.29 
Art.ll9 Art. 4 (1) 
Art. 120 Art.2b 
Art. 121 Art. 2a (1) 
Art. 122 Art. 37a 
Art. 123 Art.37b 
Art. 124 Art.30 
Art. 125 Art. 33 
Art. 126 Art.5 
Art. 127 Art. 12 Art. 31 . Art. 4 (2) Art. 11 (2) Art. 12 (3) 
Art. 128, Art. 21 
I st paragraph 
Art. 128, Art. 32 
2nd paragraph 
Art. 129 Art.28a 
Art. 130 - - - - -- - - - - - I 
Art. 131 . - - - - - - - - - - -I 
Art. 132 - - - - - ---. - - -
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 8.9/342/EEC 89/343/EEC 89/381/EEC 92125/EEC 92126/EEC 92/27/EEC 92128/EEC 92n3/EEC 
Annex I Annex 
Annexll - - - - - - - - - - -
-Annex Ill - - - -- - - - - - -
129 . 

ISSN 0254-1475 
COM(1999) 315 final 
DOCUMENTS 
EN 05 15 02 01 
Catalogue number : CB-C0-99-320-EN-C 
Office for Official Publications of the European Communities 
L-2985 Luxembourg