COMMISSION OF THE EUROPEAN COMMUNITIES 
Proposal for a Brussels, 08.09.1999 
COM( 1999) 213 final 
99/0180 (COD) 
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE 
on the Community code relating to veterinary medicinal products 
. (codified version) 
(presented by the Commission) 
COMMISSION OF THE EUROPEAN COMMUNITIES 
Proposal for a Brussels, 08.09.1999 
COM( 1999) 213 final 
99/0180 (COD) 
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE 
on the Community code relating to veterinary medicinal products 
. (codified version) 
(presented by the Commission) 

. EXPLANATORYMEMORANDUM 
1. In the co~tcXt 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 citUcn, thus. giving him new 
opportunities and the chance to make use of the specific rights it gives him. · 
This aim cannot be achieved so long as numerous provisiQDS that have been amended several tilnes, 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 staff that all legislative measures should be ~ after no more than ten amendments, stressing that this was a minimum requirement and that 
departments should endeavour to condify at even sboncr intervals the texts for which they were responsible, to 
ensure that the Community rules were clear and readily understandable. 
3. The Conclusions of the Presidency of the Edinburgh European Council (December 1992) 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 nonnal Community legislative procedure. 
Given that no changes of substance may be made to the instruments affected by legislatjve 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 proposalU> for legislative codification of Council Directives 81/8S 1/EEC of 
28 September 1981 on the approximation of the laws of the Member States relating to veterinazy medicinal 
products; 81/8S2/EEC of 28 September 1981 on the approximation of the laws of the Member States relating 
to analytical, pharmaco-toxicological and clinical standards and protocols in respect ofthe testing of veterinary 
medicinal products; 90/677/EEC of 13 December 1990 extending the scope of Directive Sf/851/EEC on the 
approximation of the laws of the Member States relating to veterinary medicinal products and laying down 
additional provisions for immunological veterinary medicinal products; 92/74/EEC of 22 September 1992 . 
widening the scope of Directive 8118S 1/EEC on the approximation of provisions laid down by law, regulation 
or administrative action relating to veterinary medicinal products and laying down additional provisions on 
homeopathic veterinary medicinal products, is to undertake official codification of this type. The new directive 
will supersede the various directives incorporated in it(2), their content is fully preserve~ and they are brought 
together with onlv such fonnal amendments as are required b;.· 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) 2309/93 of22 July 1993. 
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. 
S. This legislative codification proposal was drawn up on the basis of a prelimina.rv consolidation. in all the 
official languages. The instruments amending it, carried out by the Office for Official Publications of the 
European Communities, by means of the data-processing SVstcm 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 case of reference; the correlation between the old and new numbers is shown in 
a table set out in Annex lll of the consolidated Directive. · 
(1) Enta'Cd in the legislative programme for 1998. 
en Sec Annex n, Part A of this Proposal. 
2 
Proposal for a 
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE 
of ••• 
oa tbe Coblbluility code relatiDg to. 
veterillary medicblal products 
, THE EUROPEAN PARLIAMENT AND THE CQUNC~ 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 Committee«n. 
Acting in accordance with the procedure laid down in Article 25 1 of the Treaty<l>, 
(1) Whereas Council Directive 81/851/EEC of 28 September 1981 on the 
approximation of the laws of the Member States relating to veterinary 
medicinal products0l, Council Directive 81/852/EEC of 28 September 1981 
on the approximation of the laws of the Member States relating· to analytical, 
pharmaco-toxicological and clinical standards and protocols in respect of the 
testing of veterinary medicinal products<•>, Council Directive 90/677/EEC of 
13 December 1990 extending the scope of Directive 81/85 1/EEC on the 
approximation of the laws · of the Member States relating to veterinarY 
medicm.l products and laying down additional provisions for immunological 
veterinary medicinal prod~S). and Council Directive 92174/EEC of 
22 September 1992 widening the .scope of Directive 81/851/EEC on the 
approximation of provisions laid down by law, regulation or administrative 
action relating to veterinary medicinal products and laying down additional 
provisions on homeopathic veterinary medicinal products(l) 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; 
U> OJ C 
(2) 
P> OJ L 317, 6.11.1981, p. 1. Din:ctive as last amended by Dilutive 93/40/EEC (OJ L 214, 24 .. 8.1993, p. 31). 
<•> OJ L 317, 6.11.1981, p. 16. Directive as last amended by Directive 93/40/EEC. 
<5> OJ L 373, 31.12. 990, p. 26. 
<6> OJ L 297, 13.10.1992, p. 12. 
3 
(2) Whereas the primmy purpose of any rules for the production and distribution 1. 811851/.£EC 
· of vetefin:uY medicinal products must be the ~guarding of public health; 
(3) Whereas, however, this objective must be achieved bY means which will not 2. 81/851/EEC 
hinder the development of indusby and trade in medicinal products within the 
Co~unity; 
( 4) Whereas, in so far as the Member States already have certain provisions laid 3. 811851/EEC 
down by law, regulation or administrative action governing veterinary 
medicinal products, such provisions differ in essential principles; whereas this (adapted) 
results in the hindering of trade in medicinal-products within the Community, 
thereby directly affecting the fimctioning of the intemal market;· 
(5) Whereas such hindrances must, accordingly, be removed; whereas this entails 
approximation of the ~Ievant provisions; 4. 81/851/EEC 
( 6) Whereas it is necessary from the ~int of view of pu_blic health and the free 
movement of veterinary medicinal products for the competent authorities to 3. 90/676/EEC 
have at their disposal all useful information on authorized veterinary 
medicinal products in the form of approved summaries of the characteristics 
of products; 
(7) Whereas, with the exception of those medicinal products which are subject to ' the centralized Community authorization procedure established by Council 3. 93/40/EEC 
Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community (adapted) 
procedures for the authorization and supervision of medicinal products for 
human and veterinary use and establishing a Emopean Agency for the 
Evaluation of Medicinal Products«1), a marketing authorization in one Member 
State ought to be recognized by the competent authority of the other Member 
States unless there are serious grounds for supposing that the authorization of 
the veterinary medicinal product concerned may present a risk to human or 
animal health, or to the environment; 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, lead 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; 
(8) Whereas, for this purpose, a Committee for Veterinary Medicinal Products 
should be set up in accordance with the EW'Opean Agency for the 
Evaluation of Medicinal Products laid down in the aforementioned Regulation 10. 81/851/EEC 
(EEC) No 2309/93. (adapted) 
U> OJ L 214, 24.8.1993. p. 1; Regulation as IIDCDded by Commission Regulation (EC) No 649198 (OJ L 81, 24.3.1998, p. 7). 
4 
-(9): Wheioas this Directive is only one stage in the achievement. of ihe ahn of 11. 
freedom. of movement of vete,riDar)r medicinal products; wh~, however, 
for tbiS purj)ose, new .measures will prove necessary, in the light of experience 
· gained • especially within the CoiDD)ittee for ·veterinary Medicinal Products • 
· for the· removal of the remaining barriers ~ freedom of movement; 
(lO)Whereas medicated feedingstuffs do not come within the scope of this 6. 
·Directive; whereas, however, it is necessary~ for ~th public health· and 
. economic reasons, to prohibit the use of unauthorized medicinal. products in 
the manufacture of medicated feedingstuffs; 
.(ll)Whereas the concepts of harmfulness and therapeutic efficacy can be 7. 
· examined only in relation to one another and have only a relative significance, 
depending on the progress of scientific knowledge and the use for which the 
medicinal product is intended; whereas the partic:ulars and documents which 
must accompany an application for marketing authorization must demOilStrate 
that potential hazards are outweighed by the benefits due to efficacy; 
I 
(12)Whereas marketing authorization should be refused where a medicinal 7. 
product lacks therapeutic effect or where there is insufficient proof of such 
effect; whereas the concept of therapeutic effect must be understood as being 
the effect promised by the manufacturers; 
(13)Wbereas such marketing authorization should cilso be refused where the 8. 
withdrawal period indicated is not long enough to eHminate health hazards 
arising from residues; 
(14)Whereas, before an authorization to market an .immunological veterinary 5. 
medicinal product can be granted, the manufacturer must demonstrate his 
ability to attain batch-to-batch consistency; 
(IS)Wbereas the competent authorities should also be empowered to prohibit the ,. 6. 
use of an immunological veterinary medicinal· product when the 
immunological responses of the treated animal will interfere with a national or 
Community programme for the diagnosis, eradication or control of animal 
disease; 
( 16) Whereas it is desirable in the first instance to provide users of homeopathic 7. 
medicinal products with a very clear indication of their homeopathic character 
and with sufficient guarantees of their quality and saf~ty; 
(17)Whereas the rules relating to the manufiscture, control and inspection of 8. 
homeopathic veterinaey medicinal. products must be harmonized to permit the 
circulation throughout the Community of medicinal products which are safe 
. and of good quality; 
s 811851/EEC 
(adapted) . 
.81/851/EEC 
811852/EEC 
(adapted} 
811851/EEC 
(adapted) 
81/851/EEC 
{adapted) 
90/677/EEC 
90/677/EEC 
92174/EEC 
92174/EEC 
(li)Wbereas, having.regard to· the particill8r characteristics.ofthese·hm;neopadiic 9. 
veterinary medicinal products, such as the very low level of active principles 
they comain·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 traditional homeopathic medicinal 
products which are placed on ·the market without ·therapeutic .indications in a 
phalmaceutical form and dosage which do not present a risk for the animal; 
( 19)Whereas the usual· rules governing the authorization to market_ veteriDary 11. 
·. medicinal ·prOducts must be applied to homeopathi<;. veteriDary medicinal 
productS · marketed with therapeutic indications or in. a form which may 
. present risks which must be balanced against the desired therapeutic effect; 
whereas· Member States should ·be able to apply particular rules for· the 
evaluation of the results of tests and trials intended to establish the safety and 
efficacy of these medicinal products for pet animals and exotic species, 
· provided that they notify them to the Commission; 
(20)Whereas in order to better protect human and animal health and avoid any 4. 
unnecessary duplication of effort during the examination of application for a 
marketiDg authorization, Member :States should systematically prepare 
assessment reports in respect of each veterinary medicinal product which is 
authorized by them, and exchange the reports upOn request; whereas, 
furthermore, a Member State should be able to suspend the examination of an 
. application for authorization to place a veterinary medicinal product on the 
market which is currently under active consideration in another Member State 
with a view to recognizing the decision reached by the latter Member State; 
(21 )Whereas, in order to facilitate the movement of veterinary medicinal products 12 
and to prevent the checks canied out in one Member· State from being 
repeated in another, harmonised requirements for manufacture and imports 
from third countries,. and the grant of corresponding authorization, should be 
applied to veterinary medicinal products, 
(22)Whereas the quality of veterinary medicinal products manufactured within the 7. 
Community should be guaranteed by requiring compliance with the principles 
of good manufacturing practice for medicinal products irrespective of the 
final destination of the medicinal products; 
(23)Whereas measures should also be taken to ensure that distributors of 10. 
veterinary medicinal products are authorized by MCJQber States and maintain 
adequate records; 
6 92!14/EEC 
(adapted) 
92n4/EEC 
(adapted) 
93/40/EEC 
(adapted) 
811851/EEC 
(adapted) 
90/676/EEC 
(adapted) 
90/676/EEC 
(24)Whereas standards and.protocols for. the perfouliance of tests on veterinary 3. 
· medicioal.produds ·arc an e1fective meaos of control of these products and, 
hence, of protecting public health and can facilitate the moveme.ot of these + 
productS by laying down WUform rules applicable to tests and the compilation 
of dossiers,·allowing the competent authorities to·anive .at their decisions on 4. 
the basis of UDifom tests and by reference to uniform criteria, and therefore 
helping to obviate diff~ces in evaluatioD; 
(2S)Whereas it is advisable to stipulate more precisely the cases in which the 
results pfpharmacological and toxicological tests or clinical trials do not have 6. 
to. be provided with . a view to obtaining authorization for a. veterinary 
mediciDal product which is essentially similar to an innovative product, while 
ensuring that innovative forms are not placed at a disadvantage; whereas, 
however, there are reasons of public policy for not repeating tests carried out 
on aliimals without overiding cause; 
(26)Whereas following the establishment of the mtemal market, specific controls. s. 
to guarantee the quality of veterinary medicinal products imported from third 
countrieS can be waived only if appropriate arrangements have been made by 
the Community to ensure that the necessary controls are tarried out in th,e 
exporting COtmtry; 
(27)Whereas it is desirable to codify and improve ·the· cooperation and 6. 
exchange of information between Member States relating to the 
surveillance o( veterinary medicinal· products and in particular the monitoring 
of adverse reactions under practical conditious of use through the natio!W 
phannacovigilance systems; 
(28)Whereas in order to improve the protection of public health, .it is necessary to 7. 
specify that foodstuffs for human consumption may not be taken from animals 
which have been used in clinical trials of veterinary medicinal products unless 
a· maximum residue limit has b~ laid down for residues of the veterinary 
medicinal product concerned in accordance with the provisions of Cotmcil· . 
IU:gulation (EEC) No 2377/90. of 26 June 1990 laying down a Community 
prOcedme for the establishment of maximum residue limits of veterinary 
medicinal products in foodstuffs of animal originU);; 
(29) Whereas the Commission should be empowered to adopt the 7. 
necessary changes laid down in Annex I in order to adapt to scientific and 
technical progress; . · 
(30) Whereas, this Directive is without prejudice to the obligations of the 
Member States concerning the deadlines for transposition set out in Annex Il, 
PartB; · 
HAVE ADOPTED THIS DIRECTIVE: 811852/EEC 
(adapted) 
90/676/EEC 
93/40/EEC 
93/40/EEC 
93/40/EEC 
90/677/EEC 
(adapted) 
(I) OJ L 224, 18.1.1990, p.· 1; RCgu1alioa u·llst acadcd by Cm~mission Rcpllticm (EC) No 1958198 (OJ L 2S4, 
16.9.1998, p. 7). 
7 
. tTI'i.J:'I 
DEFINITIONS 
Article 1 
For the pm-poses of this Directive, the following terms sbaU bear the following meanings: 65/65/EEC 
Art. 1 (1) and (2) 
1. .Propriet'al'y medicinal product: (adapted) 
Any ready-prepared medicinal product placed on the market under a special name 
·and m a special pack. . . 
2. Veterinluy medicinlll product: 81/851/EEC 
Art. 1 (1) 
Ally substance or combination of substances _presented for treating or preventing (adapted) 
. disease in animals. 
Ally substance or combination of substances which may be administered to animals 
with a view to making a medical diagnosis or to restoring, correcting or modifying 
physiological functions in animals is likewise considered a veterinary medicinal 
product. 
3. Ready-made veterinary medicina~ product 
shall mean any veterinary medicinal product prepared· in advance which does not 
comply with the definition of proprietary medicinal products and which is marketed 
in a pharmaceutical form which may be used without further processing. · 
4. Substance: 
Any matter iiTespective of origin which may be: 
.. human, e.g. human blood and human blood products; 
-animal, . e.g. micro-organisms, whole animals, parts of organs, animal secretions,· 
toxins, extracts, blood products; 
8 81/851/EEC 
Art. 1 (2), 2nd indent 
65/65/EEC 
Art. 1 (3) 
81/851/EEC 
Art. 1 (1) 
(adapted) 
• vegetable~ e.g. micro-orpnisms, plants, ·parts of plams, vegetable secretions, ~; . . 
• chemical, e.g. elements, naturally occurring chemical materials and chemiall. 
products .obtained by chemical change or synthesis. 65165/EEC, 
Art. 1 (3) 
81/85 1/EEC . 
Art. 1 (1) 
(adapted) 
. 5. Pr.,mi% for medicatedftedingstuffs 81185 1/EEC 
Art. 1 (2), 3rd and 
Any veterinary medicinal product pRpared in advance with a view to the subsequent 4th indents 
manufacture of medicated feedingstuffs, 
6. Medicatedfeedinptuffs. 
Any mixture of a veterinary medicinal product or products and feed or feeds which is 
ready prepared ·for marketing and intended to be fed to animals without further 
processing. because of its curative or preventive properti~s or other properties as a 
medicinal product covered by point 2. 
7. Immunological veteri1U11')' medicinal product 
A veterinary medicinal product administered to animals in order to produce active or 
passive immunity or to diagnose the ~ of immunity. 
8. J!omeopathic veterinary medicinal product 
Any veterinary medicinal product prepared from products, substances or 
compositions called homeopathic stocks in accordance with a homeopathic 
manufacturing procedure described by the EW'Opean Pharmacopoeia or, in the 
absence thereof: by the pharmacopoeias CUil'ently used officially in the 
Member States. 
A homeopathic veterinary · medicinal product may also contain a number of 
principles. 90/677/EEC 
Art. I (2) 
92n4/EEC 
Art. I 
9. Withdrawal period . 81/851/EEC 
Art. 5, 3rd paragraph, (8) 
Period between the last administration of the veterinary medicinal product to animals (as amended by 
under normal conditions of use and the production of foodstuffs from such animals, 90/676/EEC Art. 1 (5)) 
in order to ensure that such foodstuffs do not contain residues in quantities in excess (adapted) 
of the maximum limits laid down in applying Regulation (EEC) No 2377/90. 
9 
·1 0. Adverse l'eaction · 81/SS 1/EEC · 
Art.42b 
A reaction which is harmfUl and uninteJided and which occurs at doses normally used (as amended by 
in animals for the prophylaxis, diagnosis or .1J'eatment of disease or the modification 93/40/EEC Art 1 (12)) 
of physiological function. 
11. Serious adverse reaction 
An adverse reaction which is fatal, life-threatening lesion-producing, disabling, 
incapacitating, or which results in permanent or prolonged symptoms in the animals 
treated. 
12. Unexpected adverse reaction 
An adverse reaction which is not mentioned in the summary of the product 
characteristics. 
13. Serious unexpected aiherse reaction 
An adverse reaction which is both serious and unexpected. 
14 .. Wholesale dealing in veterinary medicinal products 
Any activity which includes the purchase, sale, import, export, or any other 
commerCial transaction in veterinary medicinal products, whether or not for profit, 
exceptfor. · 
-the supply by a manufacturer of veterinary medicinal products manufactured by 
himself, 
-retail supplies of veterinary medicinal products by persons entitled to caiTY out 
such supplies in accordance with Article 66. 
15. Agency 
EW'opean Agency for the evaluation of medicinal products set up by Regulation 
(EEC) No 2309/93. 
16. Risk to human or animal health or the environment 
Any risk referring to the quality, safety and efficacy of the veterinary medicinal 
product. 
10 811851/EEC 
Art. SOa (1 ), 2nd 
subparagraph 
(as amended by 
90/676/EEC Art. 1 (27)) 
(adapted) 
811851/EEC 
Art. 16 (1), 
(as amended by 
93/40/EEC Art. 1 (10)) 
(adapted) 
811851/EEC 
Art. 18 ( 1 ), footnote 
(as (lmended by 
93/~0/EEC Art. 1 ( 1 0)) 
(adapted) 
,Artiele2 · 
The provisions of this Directive shall·apply to veterinacy medicinal products 
. . . I 
Artiele3 
This Directive sball not apply to: . 
1. Medicated feedingstuffs set out in Council Directive 90/167/EECO,; 811851/EEC 
Art..2.(1) 
(adapted) 
81/851/EEC 
Art 2 (2), 1st indent · 
(adapted) 
However, ·medicated feedingstuffs may. be prepared only from pre-mixes which have 81/851/EEC 
been authorized Under this Directive; Art. 2 (3) 
(adapted) 
2. inactivated immunological veterinary medicinal products which are manufactured 90/677/EEC 
from pathogens obtained from an animal or aDimals from a hc;>lding and used for the Art 1 (3) 
treatment oftbat animal or the animals of that holding in the same locality; (adapted) 
3. Any medicinal product prepared in a pharmacy in accordince with a prescription for 
an individual animal (commonly known as the magistral formula); 65/65/EEC 
Art. 1, points 4 and S 
(as amended by 
89/341/EEC Art. 1 (2)) 
(adapted) 
4. Any medicinal product· prepared in a pharmacy in accordance with the 81/851/EC 
prescriptions of a pbannacopoeia and is intended to be supplied directly to the. Art. 1 (1) 
end-user (commonly known as the official formula); · (adapted) 
5. Veterinary medicinal products based on radio-active isotopes; 
1811851/EEC 
Art. 2 (2), 3rd inden~ 
6. Any additives covered by Council Directive 70/524/EEC'l•, where they are 8 1/851/EEC 
incoiP.Orated in animal feedingstuffs and supplementary animal feedingstuffs in .Art. 1 ( 4) 
accordance with that Directive. (adapted) 
(I) OJ L 92. 7. 4.1990, p. 42. 
C:Z) OJ L 270, 14.12.1970, p. 1~ DileciM as 1.st IIDCDdcd by CommissiaD DiJective 98119/EC (OJ L 96,28.3.1998, p. 39). 
11 
Artide4 
1. Member States ~Y. provicSe that t;his Directive shall not apply to non-ictivated 90/677/EEC 
immunological veteJjnarymedicinal products manufactured from. pathogens obtained· Art. 1· (4) 
from an animal or animals from a holdhlg and used for ·tbe treatment of that animal (adapted) 
of that holdiDg in the same IQCality. 
2. Member States may permit exemptions on their tenitory in respect of. veterinaJy 81/85 1/EEC . 
medicinal products intended solely for aquarilDD ·fish, cage birds, hommg pigeons, An. 3 
terrarilDD animals and small rodents, from tbe provisions in Articles 5, 7 and · 8, 
provided that such producEs do not' contain substances the use of which requires 
veterinary control and that all possible measures have been taken to prevent 
unauthorized use of the product$ for ~ther animals. 
TITLE m 
MARKETIN'G 
Chapter 1 
· Marketing ·authorization 
Article 5 
No veterinary medicinal product may be placed on the market of a Member State unless a 
marketing authorization has been issued by the competent authorities of that Member 
State in accordailce with this Directive or a marketing authorization has been granted in 
accordance with Regulation (EEC) No 2309/93. · 
Article 6 
. . . 
In order that a veterinary medicinal product may be the subject of a marketing 
authorization for the pU;fpOse of administering it to food-producing animals, the active 
substances which it contains must be shown in Annexes I, ll or m of Regulation (EEC) 
No2377/90. 
Article 7 
Where the health situation so requires, a Member State may authorize the marketing or 
administration to animals of veterinary medicinal products which have been authorized 
by another Member State in accordance with this Directive. 
12 811851/EEC 
An. 4 (1), 1st 
sub paragraph 
(as amended by 
93/40/EEC Art. 1 (1 l' 
(adapted) 
81/851/EEC 
Art. 4 (2), 1st 
subparagraph 
(as 'amended by 
90/676/EEC Art. 1 (4)) 
(adapted) 
81/851/EEC· 
Art. 4 (1 ), 2nd 
sub paragraph 
(as amended by 
90/676/EEC Art. 1 (4)) 
(adapted) 
Article 8 
In. the· event .of serious disease epidemic, Member States may provisionally allow the use · 811851/EEC · 
of immunological veterinary mediciDal products without the authorization for placing on Art. 4 (1), 3rd 
the market, in ·the . absence of ·a suitable mediciDal product and after informing the subparagraph 
Commission of the detailed conditions of use. · (as amended by 
90/676/EEC Art. 1 (4)) 
(adapted) 
Article 9 
No veterinary medicinal product may be administered to animals unless the marketing 
authorization has been issued, except for the tests of veterinary medicinal products 
referred to in Article 12 (3) (j) which bave been accepted by the competent national 
authorities, following notification or authorization, in accordance with the national rules 
in force. 
Article 10 
1. Where there is no authorized medicinal product for a condition, Member States may 
exceptionally, in particular in order to avoid causing unacceptable suffering to the 
animals concerned, pemut the administration by a veterinarian or under his/her direct 
personal responsibility to an animal·or to a small number of animals on a particular 
holding: 
(a) of a veterinaty medicinal product authorized in the Member State cOncerned under 
this Directive or under Regulation (EEC) No 2309/93 for use in another animal 
species, or f~r another condition in the same species; or 
(b) if there is no product as referred to in point (a), of a medicinal product authorized for 
use in the Member State concerned in human beings in accordance with Directive 
[65/65/EEC] or under Regulation (EEC) No 2309!93; or 
(c) if there is no product as referred to in point (b) and within the limits of the law of the 
Member State concern~ of a ·veterinary . medicinal product prepared 
extemporaneously by a person authorized to do so under national legislation in 
accordance with the terms of a veterinary prescription. 
For the purposes of this paragraph, the phrase 'an animal or a small number of 
animals on a particular holding' also covers pets, and shall be interpreted more 
flexibly for minor or exotic animal species which do not produce food. 
13 81/SS I !EEC . 
Art. 4 (3), 1st 
subparagraph 
(as amended by 
90/676/EEC Art. 1 (4)) 
_(adapted) 
81/851/EEC 
An. 4 (4), 1st and 2nd 
subparagraphs 
(as amended by 
90/676/EEC Art. 1 (4)) 
(adapted) 
2. The Provisions of paragraph 1 shall apply provided tbat the inediciDal product, where 
_administ.ered to food-producing animals, contains only substances to be found in a 
veterinary medicinal product· authorized for such animals in the Member State 
concerned and that in the case of food·produ~ing animals the veterinarian 
responsible ·specifies an appropriate withdrawal period-to eDS1U'e that food produced 
from the treated animals does not contain residues harmfUl to consumers. 
Unless the medicinal. product used indicates -a withdrawal period for the species 
concerned, the specified withdrawal period sball not be less than: · 
7.days 
7days 
28 days 
500 degree· days eggs, 
milk, 
meat fr'Qm'poultry and mammals including fat and oftal, 
meat from fish. 811851/EEC . 
Art. 4 (4), 1st and 2nd 
subparagraphs 
(as amended by 
90/676/EEC Art. I_ (4)) 
(adapted) 
With· regard to homeopathic veterinary medicinal products -in which the level· of 92174/EEC 
·active principles is equal to or less than one part per million, the withdrawal period Art. 2 (1), 2nd 
referred to in the first and second subparagraphs is reduced to zero. subparagraph 
Artiele 11 
The veterinarian shall keep adequate records of the date of examination of the animals, 
· details of the owner, the number of animals treated, the diagnosis, the medicinal products 
prescrib~ the dosages administered, the duration of treatment and the withdrawal 
periods recommended, and make these records available for inspection by the competent 
authorities for a period of at least three years. This requirement may be extended by the 
Member States to food-producing animals. 
Artiele 12 
1. For the pmposes of obtaining an authorization for placing on the market irrespective 
ofthe procedure established by Regulation (EEC) No 2309/93, an application shall 
be lodged by the competent authority of the Member State concerned. 
2. A marketing authorization may only be granted to an applicant established in -the 
Community. 
14 (adapted) 
811851/EEC 
Art. 4 (4), 3rd 
subparagraph 
(as amended by 
90/676EEC Art I ( 4)) 
(adapted) 
81/851/EEC 
Art. 5, 1st subparagraph, 
(as amended by 
90/676/EEC Art. I (5)) 
(adapted) 
81/851/EEC 
Art. 5, 2nd subparagraph 
(as amended by · 
93/4~/EEC Art. 1 (3)) 
(adapted) 
· 3. 1be following partiCulars ·and documents shall be appeDded tO the;application· in 
~e with Almu 1:. -
(a) name or business name and permanent a&tress or registered place of business of the 
~.responsible for placiDg. the product on the market and, if different,. of the 
IDID1Ificturer or manufacturers ·involved and of the sites ofmanufilculre; '81/851/E2C . 
Art. s, 3rd subparagraph, 
points 1 to 9 
(as amended by 
99/676/EEC Art. 1 (5)) 
(adapted) 
· (b) name of the veterinary medicinal prodUct (brand name, non-proprietary ~e;· with + 
or without a trademark, or· name of the II1IIWfacturer or scientific name or formula, 
with or without a tradeirwk, or the name of the manufacturer); · · · 81/852/EEC 
Art. 1 t 1st paragraph 
(c) qualitative and quantitative particulars of all the constituents of the veterinary (adapted) 
medicinal product, using the ·usua1 terminology, but not empirical chemical formulae 
.· lnd giving the intemational non-proprietary name recommended by the World 
Health OrpnilJltiozi. where such a name exists; 
(d) description of the method of~; . 
·(e) therapeutic indications, contra-indications and adverse reactions; 
. (f) clOsaae for the various species of animal for which the veterinary medicinal product 
. is intended, its pharmaceutical form, method and route of administration and 
proP,sed shelf life; · 
(g) if applicable, explanations of the precautiomuy and safety measures to be taken when 
the product is stored, when it is administered to animals and when waste therefrom is 
disposed of, together with an indication of any potential risks the medicinai product 
might pose to tbe environment and the health of humans, animals or plants;. 
(h) indication of the withdrawal period. Where necessary, the applicant shall propose 
ind justify a tolerance level for residues which may be accepted in foodstuffs without 
risk for the conslimer, together with routine analysis methods which could be used by 
the cOmpetent authorities to trace residues; 
(i) description of the control testing methods employed by the manufacturer (qualitative 
and quantitative analysis of the co~tuents and the finished product, specific tests 
e.g. sterility tests, test for the presence of pyrogens, for the presence of heavy metals, 
stability tests, biological and toxicity tests, tests on intermediate products); 
IS 
(j) results of. 
-physico-chemical, biological or microbioiogical tests, 
• toxicological and pharmacological tests, 
cliJrlcal trials. 
(k) a summary in accordance with Article 14 of the product characteristics, one or more 
specimens or mock-ups of the sales presentation of the veterinary medicinal product 
together with the package insert; 
0) a document showing that the manufacturer is authorized in his own country to 
~uce veterinary medicinal products; 
. (m) copies of any marketing authorization obtained in another Member State or in a third. 
country for the relevant veterinary medicinal product, together with a list of:those 
Member States in which an application for authorization submitted in accordance 
with this Directive is under examination. Copies of the summary of the product 
characteristics proposed by the applicant in accordance with Article 14 -or approved 
by the competent authority of the Member. State in accordance with Article 25 and 
copies of the package insert proposed, details of any decision to refuse authorization, 
whether in the Community or a third country and the reasons for that deeision. 
This information shall be updated on a regular basis; 
(n) in the case ·of medicinal products containing new active substances which are not 
mentioned in Annex I, D or m to Regulation (EEC) No 2377/90, a copy of the 
documents submitted to the Commission in accordance with Annex V to that 
Regulation. 
16 81/SSl/EEC 
.Art. s, ~rd paragraph, 
point 10, 1st . 
. subparagraph 
(as amended by . 
90/61~<?Art. 1 (5)) 
81/851/EEC 
Art.· 5, 3rd paragraph, 
points 11 and 12 
(as amended by 
90/676/EEC Art. 1 (S)) 
(adapted) 
81/851/EEC 
Art. 5, 3rd paragraph, 
point 13 
(as amended.by 
93/40/EEC Art. 1 (4)) 
(adapted) 
81/851/EEC 
Art. 5, 3rd paragraph, 
point 14 
(as amended by 
90/676/EEC Art. l (5)) 
(adapted) 
Artldell 
1. By way. of derogation from point 0) of Article 12 (3), and without prejudice to ·the 
law relating to the protection of industrial and commercial property: 
(a) the applicant sball not· be required to provide the results of toxicological and 
pharmaco!ogical tests and clinical trials if he can demonstrate: 
(i) either that the v~terinaly medicinal product is essentially similar to a medicinal 
product authorized in the Member State concerned by the application and that 
~e mark~ting authorization · holder · has agreed that the toxicological, 
pharmacological and clinical ~ferences contained in :the file on the original 
veterinary ·medicinal product may be used for the purpose of examining the 
'application·in question; 
(ii) or that the constituent or constituents of the veterinary medicinal product have a 
well-established medicinal use, with recognized efficacy'· and also an acceptable 
level of safety, with detailed references to the scientific literature; 
(iii) or that the veterinary medicinal product is essentially similar to a medicinal 
product which has been authorized . within the Community, in accordance with 
Community provisions in force; for not less than six years and is marketed in the 
Member State for which the application is made; this period shall be extended to 
10 years in the case of high-technology having been authorized in pursuance of 
the procedwe established by Article 2 (5) of Council Directive 87122/EE01• • 
Furthermore, a Member State may also .extend this period to 10 years by a single 
Decision covering all the medicinal products marketed in its territory where it 
considers this necessary in the interest of public health. Member States are at 
liberty not to apply the six-year period beyond the date of expiry of a patent 
· protecting the origibal medicinal product. 
(b) in the. case of new veterinary medicinal products containing known constituents not 
hitherto used in combination for therapeutic 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 the relevant documentation for each 
individual constituent. 81/851/EEC 
Art. S, 3rd paragraph, 
point 10, 2nd. 
subparagraph . 
(as amended by 
90/676/EEC Art. 1 (S)) 
(adapted) 
2. Annex I shall apply in like manner where, pursuant to point (aXii) of paragraph. I, 81/852/EEC 
references to published data are submitted. Art. 1, 2nd paragraph 
(adapted) 
U> OJ LIS, 17.1.1987, p. 38, DiRctivc repealed by Direclive 93/41/EEC (OJ L 214, 24.8.1993, p. 40). 
17 
Article 14 .· 
The summary of the product characteristics shall contain the following information: 
1. Name of the veterinary medicinal products; 
2. Qualitative and ciwmtitative composition in terms of the active substances and 
constituents of the excipient, knowledge of which is essential ·for . proper 
~on of the medicinal product; the inter.nltional non-proprietary names 
recommended bY the World Health Organi~tion shall be used, where such names 
exist, or failing this, the usual non-proprietary name o~ chez;nical ~ption; 
3. Pharmaceutical form; 
4. Pharmacological properties and, in so far as this information . is useful for the 
therapeutic purposes, pharmacokirietic particulars; 
·5. · clinical particulars; 
5.1 target species, 
5.2 indications for use, specifying the target species, 
5.3 contra-indications, 
S.4 undesirable e~ects (frequency and seriousness), 
5.5 special precautions for use, 
5.6 use during pregnancy and lactation, 
5.7 interaction with other medicaments and other forms of interaction, 
S.8 posology Jnd method of administration, 
S.9 overdose (symptoms, emergency procedures, antidotes) (if necessary), 
S.I 0 special warnings for each target species, 
5.11 withdrawal periods, 
S.I2 special precautions to be taken by the per59n administering the medicinal 
product to animals; 
18 81/851/EEC 
Art. Sa 
· {as amended by~ 
90/676/EEC Art. 1 (6)) 
(adapted) 
6 .. · Pharmaceutical particulars: 
6.1 major in~mpatibllities, 
6.2 shelf life; when neceSSII'Y- after reconstitution of the medicinal product or when 
· the container is opened for the first time, · 
6.3 special precautions for storage, 
6.4 na11u'e and contents of container, 
6.5 special precautions for the disposal of unused medicinal product or waste 
· materials if any· · ' 
' t . • 
7. Name or corporate name and address or registered place of business of the . 
. authoriZation holder. · 
Article 15 81/851/EEC 
Art Sa 
(as amended by 
90/676/EEC Art 1 (6)) 
(adapted) 
1. Member States shall make all necessary arrangements to eDSW'e ~ the documents 81/85 1/EEC 
an~ particulars listed in Article 12 (3) {h), (i), 0) and Article 13 (1) are drafted by Art. 6 
experts with the requisite technical or professional qualifications before being 
submitted to the competent authorities. 
These documents and particulars shall be signed by the experts in question. 
2. According to their particular qualifications, the role ofthe experts shall be: 811851/EEC 
An. 7 (1), (2) and (3), 1st 
(a) to carry out such work as falls within their particular discipline (analysis, subparagraph 
pharmacology and similar experimental sciences,. clinical trials)-and to describe (adapted) 
objectively the results obtained in both quantitative and qualitative terms; 
(b) to describe their findings in accordance with Annex I and in particular to state: 
(i) in the case of analysts, whether the medicinal product conforms with the stated 
composition, providing any reasons for the control testing methods which the 
manufacturer is·to use; 
19 
(ii) in the ease of pharmacologists and appropriately qualified specialists: 81/85 1/EEC · 
Art. ,.(1), (2) and (3), 1st 
• the toxicity of the medicinal product and the pharmacological pro~ subparagraph 
observed, · (adapted) 
-whether, after administration of the veterinary medicinal product under 
normal conditions of use and observance Qf ~e recommended withdrawal 
. period, foodstuffs obtained from the treated animals contain residues wliich 
might constitute a health hazard to the consumer; · 
. (iii) in the case of clinicians, whether they have .found in animals treated with the 
medicinal product effects corresponding to the information furnished by the 
manufacturer pursuant to Articles 12 and .13 (1 ), whether the medicinal product 
is well tolerated,. what dosage they recommend and what are the contra­
indications and adverse reactions, if any; 
(c) to give reasons for the use of the references to published data referred to in 
point (a) (ii) of Article 13(1). 
3. The experts' detailed reports shall form part of the documentation which the 
applicant shall lodge with the competent authorities. A brief curriculum vitae of the 
expert shall be appended to each report. 
20 81/851/EEC 
Art. 7 (3), 2nd 
subparagraph 
(as amended by 
90/676/EEC An. I (8)) 
·· Chapter2 
· Particular provisions applicable to · 
homeopathic veterin81)' medi~al pro~ucts 
Artiele 16 
1. Member States · shall eDSW'e that homeopathic veterinary ·medicinal products 92f14/EEC 
manufactured· and marketed Within the ·Community are registered or authorized ~ Art. 6 
·accordance with the provisions of Articles 17 (1) and (2), 18 ~d ·J9. Each Member (adapted) 
State shall take due account of registrations and ·authorizations previously granted by 
another Member State. · · · 
2. A• Member State may refrain from establishing a special, simplified registration 
procedure for the homeopathic veterinary mediciDal products referred to in 
Article 17 ( 1) and (2). A Member State applying this provision shall inform the 
Commission accordingly. The Member State concerned shall, by 31 December 1995 
at the latest, allow. use in its tenitory of homeopathic veterinary medicinal products 
registered .by other Member States in accordance with Article 17 (I) and (2) and 
Article 18. 
Artielel7 
"1. Only homeopathic veterinary medicinal products which satisfy all of the following 92174/EEC 
conditions may be subject to a special, simplified registration procedure: Art. 7 ( 1) 
(adapted) 
they are. intended for administration to pet animals or exotic species which are . 
. non food-producing, 
they are administered by a route described in the European Pharmacopoeia or, 
in absence thereot by the pharmacopoeias cwrently used officially in the 
Member States, 
no specific therapeutic indication appears on the labelling of the ·veterinary 
medicinal product or in any information relating thereto, 
there is a sufficient degree of dilution to guarantee the safety of the medicinal 
product; in p~icular, the medicinal product may not contain either more than 
one part per 10 000 of the mother tincture or more than 1/1 OOth of the smallest 
dose used in allopathy with regard to active principles whose presence in an 
allopathic medicinal product results in the obligation to submit a veterinary 
prescription. 
At the time of registration, Member States shall determine the classification for the 
dispensing of the medicinal product. 
2. The criteria and rules of procedure provided for in Chapter 3 shall apply by analogy 92174/EEC 
to the special, simplified registration procedure for homeopthaic veterinary medicinal Art. 7 (3) 
products laid down in paragraph 1, with the exception of the proof of therapeutic (adapted) 
effect. 
21 
3. . The proof of therapeutic effect · sb8u not. be require. d for homeopathic. veteriDary J92fl. 4/EEC · . 
medicinal products registered in accordance with paragraph 1. of this Article or,. Art. 4, 2nd subparagraph 
where appropriate, admitted in accordance~ ~cle 16 (2). . (adapted) 
Article 18 
~ special, simplified application for registration may cover a series of medicinal products 92174/EEC · 
derived from the same homeopathic stock or stocks. The following document sbal1 be Art. 8 
included with the application in order to demonsttate, in particular, the pharmaceutical (adapted) 
quality and the batch-to-batch homogeneity of the products concerned: · 
scientific name or. other name given in a pharmacopoeia of the homeopathic stock or 
stocks, tOgether with a statement of the various routes. of administration, 
pharmaceutical forms and degree of dilution to be registered, 
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; in the case of homeopathic veterinary m~cinal products containing 
biological substances, a description of the measures taken to ensure the abSence of 
pathogens; 
manufacturing and control file for each pharmaceutical form and a description of the 
method of dilution and ~tentiation, 
manufacturing authorization for the medicinal products concerned, 
-· copies of any registrations or authorizations obtained for the same medicinal 
products in other Member States, 
one or more specimens or mock-ups of the sales presentation of the medicinial 
products to be registered, · 
data concerning the stability of the medicinal product 
22 
Artiele 19 
1. 'Homeopathic veteriDary products other than those referred to in Article 17 (1) shin 92174/EEC 
be authorized in KCOrdance with the provisions of Articles 12 and 13 and Chapter 3. Art. 9 
(adapted) 
2~ A Member State may introduce or retain in itS territoty specific rules for the 
phartnatological and toxicological tests and clinical trials of homeopathic veterinary 
medicinal products intended .for pet animals and exotic species which are non foocJ .. 
producing other tban those referred to in Article 17 (1), in accordance with the 
principles and characteristics of homeopathy as practised· in that Member State. 
In this case, the Member State concerned sball notify the Commission of the specific 
~esinf~. - · 
Ardele20 
This Chapter shall not apply to immunological veterinary medicinal products. 
23 92174/EEC 
Art. 2 (3) 
(adapted) 
Chapter~ 
· Procedure for marketing authorization· 
. . . 
Artide21 
1. Member States shall take all appropriate measures to ·ensure that the procedure for 
granting an authorizatiOn to place a veterinary medicinal product on the market· is 
completed within 210 days of the submis~ion of a valid. application. · 
2. Where a Member State notes that an application for authorization submitted is 
already under active examination in another Member State in respect of that 
·veterinary medicin81 prod~ the Member State concerned may decide to .suspend 
. the detailed examination of the application in order to await the assessment report 
prepared by the other Member State in accordance with Article 25 (4) . 
. The Member State concerned shall inform the other Member 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. · 
Artide22 
Where a Member State is informed in accordance with Article 12 (3) (m), that another 
Member State has authorized a veterinary medicinal product which is the subject of an 
application for authorization in the Member State con~ed, that Member State shall 
forthwith request the authorities of the Member State which has granted the authorization 
to forward to it the assessment report referred to in Article 25 (4). 
Within 90 days of 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 approved by it or, if it considers that there are groun~ for supposing 
that the authorization of the veterinary medicinal product concerned may present a risk to 
human or animal health or the environment, it shall apply the procedures set out in 
Articles 19 and 33 to 38. 
24 81/851/EEC 
Art. 8 
(as amended by .. 
93140/EEC Art. 1 (6)) 
(adapted) 
81/851/EEC 
Art.8a 
(as amended by 
93/40/EEC Art. 1 (7)) 
(adapted) 
Article 23 
In order to examine the application submitted pursuant to Articles 12 and 13 (l), the 81/85.1/EEC 
competent authority of the Member States: · Art. 9 (I) 
(adapted) 
1. sball check that the documentation submitted m support of the appliCation' complies 
with Articles 12 and 13 (l) and, on the basis :of the reports drawn up by the experts 
puisuant to Article 15. (2) and (3), ascertain whether the conditions for the issue of 
the marketing authorizatiC?n have been fulfilled; · 
2. may· submit the medicinal product, its raw materials and if necessary intermediate 
products or other constituent materials .for testing by a State laboratory or by a· 
laboratory designated for that pmpose, in order to ensure that the testing methodS 
employed by the manufacturer and described in the application documents, in 
accordance with Article 12 (3) (i), are satisfactory; · · 
3. may, where appropriate, require the applicant to provide further information as 
regards the items listed in Articles 12 ~ 13 (1). Where the competent' authorities 
take this course of action, the time-limits specified in -Article 21 shall be suspended 
until the further data required have been provided. Similarly, these time-limits shall 
be suspended for any period which the applicant may be given to provide oral or 
written explanatioas; 
4. may require the applicant to submit substances in the quantities necessary to 
verify the analytical detection method proposed by the applicant in accordance with 
Article 12 (3) (h) and to put it into effect as part of routine checks to reveal the 
presence of residues of the veterinary ·medicinal products concerned. 811851/EEC 
Art. 9 (2) 
(as amended by 
90/676/EEC Art.' 1 (9)) 
(adapted) 
81/851/EEC 
Art. 9 {3) 
(adapted) 
81/851/EEC 
Art. 9 (4) 
(as amended by 
90/676/EEC An. I (10)) 
(adapted) 
Article%4 
Member States shall take all appropriate measures to ensure that:. 
(a) the _competent authorities ascertain that the manufacturers and importers of veterinary 
medicinal products from third countries are able tO manufacture them in compliance. 
with the details. supplied pursuant to Article ·12 (3) (d), and/or· to carry out control 
tests· in accordance with the methods described in the application docwnents under 
Article 12 (3) (i); 
(b) the competent authorities may authorize manufacturers and importers of veterinary 
medicinal-products from third countries, where cin:umstances so justify, to ·have 
certain stages of manufacture and/or certain of the control tests,.referred to in (a) 
carried out by third parties; in such cases, checks by the competent authorities shall 
also be carried out in the establishments concerned. 
Article-25 
1. Wh~ the marketing authorization is issued, the holder shall be informed by the 
competent authorities of the Member State concerned, of the summary of the product 
characteristics as approved by it 
2. The competent authorities shall take all necessary measures to ensure tbat the 
information given· in the summary is in conformity with that accepted when the 
marketing authorization is issued or subsequently. 
3. The competent authorities shall forward to the Agency a copy of the authorization 
together with the summary of the product characteristics .. 
4. The competent authorities Shall draw up an assessment report and comments on the 
dossier as regards the results of the analytical and pharmacotoxicological tests and 
the clinical trials of the veterinary medicinal product concerned. The assessment 
report shall be updated whenever new information becomes available which is of 
importance for the evaluation of the quality, safety or efficacy of the veterinary 
medicinal product concerned. 
26 811851/EEC 
Art. 10 
811851/EEC 
Art. Sb 
(as amended by 
93/40/EEC Art. 1 (5)) 
(adapted) 
Articlel6 
1. The ·marketing authorization may require the holder to indicate on the container 81/85 1/EEC 
and/or the outer wrapping ~ the package insert, where the Jauer iS required, other Art. 12 
particulars essential for safety or health protection, including any special prCcautions (adapted) 
relating to use and any other Warnings . resultiDg from the clinical and 
pharmacological trials prescnDed in Articles 12 (3) (j) and 13 (1) or from experience 
gained during the use of the veterinary medicinal product once it has been marketed. 
2. The authorization may also require the inclusion of a tracer substance in the 
veterinary medicinal product.. 
3. In exceptional circumstances,. an4 following consultation with the applicant, an 81/851/EEC 
authorization may be granted subject to certain specific obligations, and subject to Art. 15 (2) 
annual review, including: {as amended by 
93/40/EEC Art. 1 (9)) 
-the carrying out of tbrther ~es following the granting of authorization, 
-the notification of adverse ·rea~ons to the veterinary medicinal product. 
These exceptional decisions may only be adopted for objective and verifiable 
reasons. 
Article 27 
1. After a marketing authorization has been issued, the holder must, in respect of the 
manufacturing methods and control methods provided for in Article 12 (3) (d) and 
(i), take account of scientific and technical progress and intrOduce any changes that 
may be required to enable tbat veterinary 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. 
2. Upon request from the competent authority, the marketing authorization holder shall 
also review the analytical detection methods provided for in Article 12 (3) (h) and 
propose any changes w~ch may be necessary ·to take account of scientific and 
technical progress. 
3. The marketing authorization holder shall ford.twith inform the competent authority of 
any new. information which might entail the amendment of the particulars and 
documents referred to in Articles 12 and 13 (I) or of the approved summary of the 
product characteristics. ID particular, he shall forthwith inform the competent 
authority of any prohibition or restriction imposed by the competent authority of any 
country in which the veterinary medicinal product is marketed and of any. serious 
unexpected adverse effect occurring in the animals concerned or hlUilaD beings. 
27 811851/EEC 
Art. 14 (1), 1st 
sub paragraph 
(as amended by 
93/40/EEC Art. 1 (8)) 
(adapted) 
81/851/EEC 
Art. 14 (1), 2nd 
subparagraph and (2) 
(as amended by 
90/676/EEC Art. I (11)) 
(adapted) 
4. The~ authorization ~der ~.be~ tO maintain records of all ,81/851/EEC. 
adverse reictions observed in animals or human beings. The records ·so estabisbed Art. 14 (3) and ( 4} 
sbal1 be kept at least five 'years and shall be made available_ to the competent (u amended by 
authorities upon request. · 90/676/EEC Art. 1 (11)} 
(adapted) 
S. The marketing . authorization holder sball immediately infonn the conlpetent 
authoriti~, with a view to ~orization, of any alteration he proposes to make to the 
particulars and documents refemd to.~ Articles 12 and 13 (1). · 
Article 28 · 
Authorization shall be valid for five years and shall be renewable for five-year periods, 81185 1/EEC 
on application by the holder at. least three months before the expiry date and after An. 15 (1) 
consideration .of a dossier updating ~e infonDation previously submitted. (as amended by 
93/40/EEC Art. 1 (9)) 
Article 29 
The granting of authorization shall not diminish the general legal liability of the 81185 1/EEC 
manufacturer and, where appropriate, of the authorization holder. Art. .13 
(adapted) 
Article 30 
The marketing authorization shall be withheld if examination . of the documents and. 81185 1/EEC 
particulars listed in Articles 12 and 13 (1) establishes that: Art. 11 
(adapted) 
(a) the veterinary medical product is harmfUl under the conditions of use stated .at the 
time of application for authorization; or 
(b) has no therapeutic effect or the applicant has not provided sufficient proof of such 
effect as regards the species of animal which is to be tr~d; or 
(c) its qualitative or quantitative composition is not as stated; or 
(d) the withdrawal period recommended by the applicant is not long enough to ensure 
that foodstuffs obtained from the treated animal do not contain residues which might 
constitute a health hazard to the consumer, or is insufficiently substantiated; or 
(e) the veterinary medicinal product is offered for sale for a use prohibited under other 
community provisions; or · · 
(f) a veterinary medicinal product presents a risk for the protection of public health, 
consumer or animal·health. 
Authorization shall also be withheld . if the application documents submitted to· the 
competent authorities do not comply with Articles 12, 13 (1) and 15. 
Chapter4 
·Mutual reeopition of authorizations 
Artlcl~31' 
1. In order to facilitate the adoption of common decisions by Member States on the 
authorization.ofveterinary·medicinal products on the basis of the scientific criteria of 
quality, safety and efficacy, and to achieve thereby the free .movement of veterinary 
medicinal products .within the Community, a Committee for Veteriiwy Medicinal 
Products, hereinafter referred to as "the Committee", is hereby set up. The 
Committee shall be part oftb.e Agency. 
2~ In addition to the other responsibilities conferred upon it by Community law, the 
Committee shall examine -.ny question relating to the granting, variation, suspension 
or withdrawal of marketing authorization which is submitted to it in accordance with 
the provisions of this Directive. It shall also examine any question relating to tests of 
veterinary medicinal products. · 
3. The Committee shall adopt its own rules of procedure. 
Artide32 81/851/EEC 
Art. 16 (1) 
(as amended by 
93/40/EEC Art. i (l 0)) 
(adapted) 
81/851/EEC 
Art. 16.(2) 
(as amended by 
93/40/EEC Art. 1 (10)) 
+ 
81/852/EEC 
Art. 2 
(adapted) 
81/851/EEC 
Art. 16 (3) 
(as amended by 
93/40/EEC Art. I (lO)J 
1. Before submitting an application for mutual recognition of marketing authorizations, 81/851/EEC 
the holder of the authorization shall inform the Member State which granted Art. 17 (3) 
the authorization on which the application is based (hereinafter: the referential (as amended by 
Member State) that an application is to be made in accordance with this Directive 93/40/EEC Art. I (10)) 
and shall notify it of any additions to the original dossier; that Member State may (adapted) 
require the applicant to provide it with all the particulars and documents necessary to 
enable it to check that the dossiers filed are identical. 
" In addition, the holder of the authorization shall request the referential Member State 
which granted the initial authorization to prepare an assessment report in respect of 
the veterinary medicinal product concerned, or, if necessary, to update it. That 
Member State shall prepare it within 90 days of receipt of the request 
At the same time as the application is submitted in accordance with paragraph 2 the 
referential Member Sate which granted the initial authorization shall forward the 
assessment report to the Member State or Member States concerned by the 
application. 
29 
2. In order to obtain the recognition according to the procedure laid· down in this 81/85 1/EEC 
Chapter in one or·more of the Member StateS of a marketing authorization issued by. Art. 17 (0 and (2) 
· . a Member State, the holder. of_ the authorization sbal1 submit an application to the (as amended by . · 
competent authority .of the Member State. or Member States concerned, together with 93/40/EEC Art. 1 (1 0)) 
the information- and pani~ refemd to in Articles 12, 13 (1) and 14. He sball (adapted) · 
testify tbat the dossier is identical to that accepted by the referential Member State,. 
or . sball identify any ~ons or amendments it may ·contain. In the latter case, 
he shall certify that the summary of the product characteristics proposed by him in 
accordance with Article · 14 is identical to that accepted by the referential 
Member State. Moreover, he shall certify that all the dossiers tiled as part o.f this 
procedure are identical. · 
3; The holder of the marketing authorization shall transmit 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 ~ send the Agency copies of any such authorization which 
may have been granted by the other Member States in respect of the veterinary 
medicinal product concerned, and shall · ~dicate whether any application for 
authorization is currently under consideration in any Member State. 
4. Save in the exceptional case provided for in Article 33 (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, the other Member States concerned by the application, the 
Agency, and the authorization bolder for placing the product on the market 
Article33 811851/EEC 
Art. 17 (4) 
(as amended by 
93/40/EEC Art. 1 (1 0)) 
(adapted) 
1. Where a Member State considers that there are grounds for supposing that the 811851/EEC 
. marketing authorization of the veterinary medicinal product concerned may present a Art. 18 
risk to human or animal health or the environment, it sb8n forthwith inform the (as amended by 
applicant, the referential Member State, any other Member States concerned py the 93/40/EEC Art. 1 (1 0)) 
application and the Agency. The Member State shall state its reason in detail and (adapted) 
shall indicate what action may be necessary to correct any defect in the application. 
2. All the Member States concerned shall use their best endeavoms to reach agreement 
on ·the action to be taken in respect of the application. They shall ptovide 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 tQ in Article 32 (4) they shall forthwith refer the matter to the Agency, 
according to the reference to the Committee, for the application of the procedure laid 
down in Article 36. , 
3·. Wif:hin the time-limit referred to in Article 32 ( 4 ), the Member States concerned shall 
provide the Committee with a detailed statement of the matters on which they have 
been unable 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 32 (2). 
30 
Article34 
If several applications submitted in accordance with Articles 12, ·13 (1 ).and 14 have been 81/85 1/EEC 
made for marketing authonz.tion for a particular veterinary medicinal .product and Art. 19 
Member States have adopted divergent ~isious concerning the authorization of that (as amended by 
veterinary medicinal prod~ or suspension or withc;trawar· of that authorimtion, a 93/40/EEC Art 1 (10)) 
Member· State, or the Commissi~ or the marketing authorization holder may refer the (adapted) 
matter to the Committee for application ofthe p~ wd down in Article 36. . 
The Member State concerned, the marketing authorization holder or the Commission 
shall clearly identify the question which is referred to the Committee for .consideration 
and, if appropriate, shall inform the aforemention~d holder thereof. 
The Member States and the marketing authorization holder shall forward to the 
Committee all available information relating to the matter in question. 
Article35 
The Member States or the Commission or the applicant or holder of the marketing 81/851/EEC 
authorization may, in specific cases where the interests of the Community are involved, Art 20 
refer the matter to the Committee for the application of the procedure laid down in. (as amended by 
Article 36 before reaching &·decision on a request for a marketing authorization or on the 93/40/EEC Art. 1 (10)) 
suspension or withdrawal of an authorization, or on any other variations to the terms of a· (adapted) 
marketing authorization which appears necessary, in particular to take account of the 
information collected in accordance with Title vn. 
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 holder shall forward to the Committee all available 
information relating to the matter in question. 
31 
Artiele36 
1. When ~ference is pwie to the procedure described in this Article, the Committee 
sbal1 consider the matter concerned. and issue a reasoned· opinion within. 90 days of 
the date on which the matter was referred to it 
However, in cases submitted to the Committee in accofdance with Articles 34 and 
35, this period may be extended l>Y 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. ad 
as rapporteur. The Committee may also appoint individual experts to advise it on 
specific questions. When appointing experts, the Committee shall define their tasks 
and specify the time-limit for the completion of these tasks. 
3. In the cases ·referred to in Articles 33 and 34, before issuing its opinion, the 
Committee shall provide the· marketing authorization holder with an opportunity to 
present written or oral explanations. 
In the case referred to in Article 35, the marketing authorization holder may be asked 
to explain himself orally or. in writing. 
If it considers it appropriate, the Committe.e may invite any other person to provide 
infonnation 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. 
32 81/851/EEC 
Art. 21 
(as amended by 
93/40/EEC Art. 1 (10)) 
(adapted) 
4. , ·The ApDty sball forlhwith inform the marketiDg authorization holder where the 
· opinion oflhe Committee is that: 
the ippUcation does not ~fy the criteria for authorization, or. 
the summary of the product characteristics· proposed by the applicant in 
iccordance with Article 14 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 ·veterinary 
medicinal product including pharmBcovigilance, or · 
a marketing authorimtion should be suspended, ~ed or withdrawn. 
Within 15 days of the receipt of the opinion, the holder may notify the Agency in 
writing of his intention to appeal. In that case, he sball 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. 
S. 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 th~ assessment of the veterinary medicinal 
product and the reasons for its conclusions. 
In the event of an opinion in favo\D" of granting or maintaining an authorization to 
place the veterinary medicinal product concerned on the market, the following 
documents shall be annexed to the opinion: 
(a) a draft summary of the product characteristics, as referred to in Article 14; where 
necessary this will reflect differences in the veterinary conditions pertaining in 
the Member States.· 
(b) any conditions affecting the authorization within the meaning of paragraph 4. · 
33 811851/EEC 
Art. 21 . 
(as amended·by 
93/40/EBC Art. 1 ( 1 0)) 
{adapted). 
Artlcle3'7 
Within 30 days of receipt of the opinion, the Commission shall prepare a ~ of the · 811851/EEC 
decision to be~ in respect ofth~ application, taldng into ·account Community law. Art. 22 (1) 
(as amended by 
·In the event of a draft decision which enVisages the granting of marketing authorization,. 93/~0/EEC Art 1 (1 0)) 
the documents referred to in Article 36 (5), 2nd mbparagraph, (a) and (b) shall be 
annexed. 
Where, exceptionally, the draft decision is not in accordance with the opinion of the 
Agency, the Conimission sball· also apnex a detailed explanation of the reasons for the 
differences. · 
The draft decision sbal1 be foovard~ to. the Member States and the applicant. 
Artiele38 
1. A final decision on the application sball bf: adopted in accordance with the procedure 
laid down in Article 91. 
2. The rules of procedure of the Standing Committee set up by Article 88 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 37, 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 of the Commission, 
each Member State is able to require in writing that the draft decision be 
discussed by the 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 sball 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 90. 
3. A decision as referred to in paragraph 1 shall be addressed to the Member States 
concerned by the matter and communicated to the marketing authorization holder. 
The Member States shall either grant or withdraw marketing authorization, or vary 
the terms of a marketing authorization as necessary to comply With the decision 
within 30 days of its notification. They shall inform the Commission and the Agency 
thereof. . 
34 81/851/EEC 
Art. 22 (2), (3) and (4) 
(as amended by 
93/40/EEC Art 1 (1 0)) 
·(adapted) 
Artide39 
. 1.' Any application.· by' the. marketing authorization holdei to varY a malteting 
autborization Which bas been granted in accordance with the provisions of this 
Chapter shall be submitted to all thf.' Member States which have previously 
authorized the veterinary medicinal product concerned. 
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 ~ce with the-procedure laid down in Article 89. · 
2. The procedure laid down in Articles 36, 37 and 38 shall apply by analogy to 
· variations made to marketing authorizations for products. 
Article 40 81/851/EEC 
Art. 2~ 
(as amended by 
93/40/EEC Art. 1 ( 1 0)) 
(adapted) 
1. Where a Member State .considers that the variation of the terms of a marketing 81/851/EEC 
authorization which has been granted in accordance with the provisions of this Art. 23a 
Chapter or its suspension or withdrawal is necessary for the protection of human or (as amended by 
aitimai health or the environment, the Member State concerned shall forthwith 93/40/EEC Art. 1 (10)) 
refer the matter to the Agency for the application of the procedures laid down in (adapted) 
Articles 36, 37 and 38. 
2. Without prejudice to the provisions of Article 35, in exceptional cases, where mgent 
action is essential to protect human or animal health or the environment, until a 
definitive decision is adopted, a Member State may suspend the marketing and the 
use of the veterinary medicinal product concerned on its territory. It shall inform the 
Commission and the other Member States no later than the following working day of 
the reasons for its action. · 
3S 
Artide41 
Articles 39 and 40 shall apply by analogy tO veteriiwy medicinal productS authorized by 81/851/BEC 
Member States following an opinion of the Committee given in accordance with Article 4 Art. 23b 
of Directive 87f22/EEC before 1 January·t995. · · (as amended by 
93/40/EEC Art. 1 (1 0)) 
Artide4l 
1. The Agency shall publish. an annual repOrt on the operation of the procedures laid· 81/85 1/EEC 
doWn in this Chapter and sba1l forward it to the European P.-liament and the Art. 23c 
Council for information. · (as amended by 
93/40/EEC Art. 1 (1 0)) 
2. By 1 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. 
·Artiele43 
The provisions of Articles 31 to 38 shall not apply to homeopathic veterinary medicinal 
products referred to in Article 19 (2). 
36 81/851/EEC 
Art. 22 {5) 
{as amended by 
93/40/EEC Art. 1 (10)) 
(adapted) 
TITLE IV 
MANUFACTURE AND IMPORTS 
Article 44 
1. · Member Swes shall take all appropriate measures. to ensure that the manufacture of 
veteJinary medicinal products in their tenitory is subject. to the holding of an 
authorization. This manufacturing authorization shall likewise be required for 
veterinary medicinal products intended for export. 
. . ' ·811851/EEC 
Art. 24 (1) 
(as amended by 
90/676/EEC Art..l (14)) 
(adapted) 
2. The authorizatiOn refened to in paragraph 1 sball·be requirCd both for total and 81/851/EEC 
partial manufacture _and for the various ·processes of dividing up, packaging or· Art. 24 (2) and (3), 1st 
· presentation. subparagraph 
(adapted) 
However, sueh authorization shall not be rCqu.ired for preparation, dividing up, 
changes in packaging or presentation where these processes are ~ed out solely for 
the dispensing of retail supply by pharmacists ·in dispensing pharmacies or by 
persons legally authorized in the Member States to c:any out such processes. 
3. The authorization referred to in paragraph l shall also be required for imports from 
third countries into a Member State; this Title and Article 83 shall apply to such 
' impons in the same way as to manufacture. 
Member States shall take all appropriate measures to ensure that veterinary 
medicinal products brought. into their territory from a third country and destined for 
another Member State are accompanied by a copy of the authorization refemd to in 
paragraph 1. 
Article45 811851/EEC 
Art. 24 (3), 2nd 
subparagraph 
(as amended by 
90/676/EEC Art. 1 (15)) 
In order to obtain the manufacturing authorization, the applicant shall meet at least the 81/85 1/EEC 
following requirements: Art. 25 
(adapted) 
(a) he shall specify the veterinary medicinal products and pharmaceutical forms which 
are to be manufactured or imported and also the place where they are to be 
manufactured and/or controlled; 
(b) he shall have at his disposal, for the manufacture or impon of the above, suitable and 
sufficient premises, technical equipment and control. facilities .complying with the 
legal requirements which the Member State concerned lays down· as regards both 
manufacture and control and the storage of products, in accordance with Article 24; 
(c) he shall have at his disposal the services of at least one qualified person within the 
meaning of Article 52. 
The applicant shall provide particulars in his application to establish his compliance with 
the above requirements. 
37 
Article46 
1. The compdent authority 9f the Member ·State sbalf not issue the manufaCuuing 81/85 llEEC 
authorization until. it ~ established the accuracy of the particulars supplied pursuant · Art. 26 
to Article 45 by means of an inquiry carried out by its representatives. . (adapted) 
2. In order to ensure that the requirements referred tO in Article 45 ·are complied with, 
authorization may be made ·conditional on the ful1ilment ~f certain obligations 
imposed either when authorizatio~ is granted or at a later date. 
3. The authorization shall apply only to the premises specified in the application and to 
the veterinary medicinal products and pharmaceutical forms Specified in that 
application. · · 
Article 47 
The Member States shall take all appropriate measures to ensure that the time taken for 81185 1/EEC 
the procedure for granting the manufacturing authorization does not exceed 90 days from An. 28 (1) 
the day on which the competent authority receives the application. (adapted) 
ArticleU 
If th~ holder of the manufacturing authorization requests a change in any of the 81/85 1/EEC 
particulars referred to in Article 45 (1) (a) and (b), the time taken for the procedure An. 28 (2) 
relating to this request shall not exceed 30 days. In exceptional cases, this period of time (adapted) 
may be extended to 90 days. 
Article 49 
The competent authority of the Member States may require from the applicant further 81/851/EEC 
information concerning both the particulars supplied pursuant· to Article 45 and the Art. 28 (3) 
qualified person referred to in Article 52; where the competent authority concerned (adapted) 
exercises this right, application of the time-limits referred to in Articles 47 and 48 shall 
be suspended until the additional data required have been supplied. 
38 
Artlde50 . 
· The ~~of a m""nfacturing aUthorization shall at least be obliged to: 81/85 1/BEC· 
Art. 27 (a) to (e) 
. (a) -have at his disposal the services of Staff complying with the legal requireDients (adapted) 
existing in the Member State concerned as iegards ~th manufacture and controls; 
· (b) dispOse of tbe. authorized veterinary medicinal products only in accordance with the 
legislation of the Member States conceme!i; 
(c) give prior notice to the competent authority of any changes which he may wish to 
make to any of the particulars supplied pursuant to Article 45; the competent' 
·authority shall, in any event, be immediately informed if the qualified person referred 
to m Article 52 is replaced unexpectedly; 
(d) . allow the representatives of the competent authority of the Member State concerned 
access to his premises at any time; · 
(e) enable ·the qualified person referred to in Article 52 to carry out hiS duties, 
particularly by placing at.bis disposal all the necessary facilities. 
(t) comply with the principles and the guidelines of good manufacturing practice for 811851/EEC 
medicinal products laid down by Community law; Art. 27 (t) ~d (g) 
(as amended by 
(g) keep detailed records of all veterinary medicinal products supplied by him, including 90/676/EEC An. 1 (17)) 
samples, in accordance ·with the laws of the countries of destination. The following 
information at least sbaU be recorded in respect of each transaction, whether or not it 
i$ made for payment: 
-date, 
-name of the veterinary medicinal product, 
quantity supplied, 
• name and address of the recipient, 
batch number. 
These records shall be available for inspection by the competent authorities for a period 
of .at least three years. 
Article 51 
The principles and guidelines. of good manufacturing practice for veterinary meqicinal 
products referred to in Article SO (f) shall be adopted in the form of a Directive addr~sed 
to the Member States in accordance with the procechu'e laid down in Article 90. 
Detailed guidelines shall be published by the Commission and revised as appropriate to 
take account of scientific and teclmical progress. 
39 811851/EEC 
Art. 27a 
(as amended by 
90/676/EEC An. 1 {18)) 
(adapted) 
Artlde52 
1. Member States sbal1 take all appropriate measures to ensure tbat. the holder of the 81/851/EEC 
manufacturing authorization has permanently and continuo~ly at his disposal the Art. 29 
services of·at least one qualiDed person who 1Wfils the conditions laid down in (adapted) 
Article 53 and is responsible, in particular, for carrying out· the duties specified in 
Article SS. · 
2. If he personally fulfils the conditions laid down in· Article 53, the holder of the 
authorization may himself assume the responsibility referred to in paragraph 1. 
Article 53 
1. Member States shall ensme tbat the qualified person referred to in Article 52 fulfils 81/851/EEC 
the minimum conditions of qualification set oUt in paragraphs 2 and 3. Art. 31 · 
(adapted) 
2. The qualified person shall be . in possession of a diploma, certificate or other 
evidence· of formal qualifications awarded on completion of a university course of 
study, or a course recognized as equivalent by the· Member 'State concerned, 
extending over a period of at least four years of theoretical and practical study in one 
of the following scientific disciplines: pharmacy, medicine, veterinary science, 
chemistry, pharmaceutical chemistry and technology, biology. 
However, the minimum duration of the university course may be three and a half 
years where the coW'Se is followed by a period of theoretical and practical training of 
at least one year and includes a training period of at least six months in a pharmacy 
open to the public, corroborated by an examination at university level, 
Where two university or recognized equivalent courses co-exist in a. Member State 
and where one of these extends over four ,years and the other over three years, the 
diploma, certificate or, other evidence of formal qualifications awarded on 
completion of the three-year university course or its recognized equivalent shall be 
-considered to fulfil the condition ·of duration referred to in the first subparagraph.in 
so far as the diplomas, certificates or other evidence of formal qualifications awarded 
on completion of both courses are recognized as equivalent by the State in question. 
40 
The course shall include theoretic81 and practical tuition bearing upon at least the 8118SliEEC 
foubwing basic subjects: · . · Art. 31 
experim.emal physics, 
general andjnorpaic chemistry, 
organic chemistry, 
-"analytical chemistry, 
pbannaceutical chemistry, including analysis of medicinal products, 
general and applied biochemistry (medical) , 
physiology, 
microbiology, 
pharmacology, 
phar.maceutical technology, 
toxicology, 
pharmacognosy (study of the composition and effects of the active principles of 
natural substances of plant and animal origin). 
Tuition in these subjects should be so balanced as to enable the person concerned to 
fulfil the obligations specified in Article SS. 
In so far as certain diplomas, certificates or other evidence of formal qualifications 
mentioned in this paragraph do not fulfil the criteria laid down above, the competent 
authority of the Member State shall ensure that the person concerned provides 
evidence that he has, in the subjects involved, the knowledge required for the 
man~ and control of veterinary medicinal Products. 
3. The qualified person shall have acquired practical experience over~ least two years, 
in one or more undertakings which are authorized manufacturers, in the activities of. 
qualitative analysis of medicinal products, of quantitative analysis of active 
substances and of the testing and checking necessary to ensure the quality of 
veterinary medicinal products. 
The duration of practical experience may be reduced by one year where a university 
course lasts for at least five years and by a year and a half where the course lasts for 
at least six years. 
41 (adapted) 
Artide54 
1. A person engaging m the activities of the person referred to in Article 52 from the 81185 1/EEC 
time of the application of Directive 81/85 1/EEC, but not complyiDg with the.· An. 32 
provisions of Article 53 shall·})e eligJ.ole to continue to engage in those activities in (~ted) 
the State concerned. · 
2. The · bolder of a diploma, certificate or other evidence of formal qualifications 
· awarded on completion of a university course • or a course recognized as equi~ent 
by the Member State concerned • in a scientific discipline allowing him to engage. in 
,.. · the. activities of the person referred tO in Article 52. in accordance with the laws of 
that State may -if be began his course prior to 9 October _1981 • be conSidered as 
qualified to cany out in that State. the duties of the person referred to in Article· 52, 
provided that be has previouSly engaged in the following activities for· at least two 
years before before 9 October 1991 . in ·one or more 1mdertakings authorized ·to 
manufactlue: production supervision .and/or qualitative and quantitative analysis of 
active substances, and the neceSS81)' testing and checking under the direct authority 
of a person as refemd to in Article 52 to ensure the quality of veterinary medicinal' 
products. 
If the person concerned has acquired the practical experience referred to in the first 
subparagraph before 9 October 1971, a further one year's practical experience in 
accordance with the Conditions referred to . in the first subparagraph shall · be 
completed by him immediately before be engages in such activities. 
42 
ArtltleSS 
l. · Member States shall take all appropriate measures to ensure that the qualified ~n 81/85 1/EEC 
·referred to in Article 52 is, without prejudice to his relati~ with the holder of Art. 30 (1), 1st and 2nd 
the manufacturing authorizatiOD, . ~ible, in the context of the. procedures subparagraphs . 
referred to in Article 56, for ·ensuring that: · (adapted) . 
(a) in the case of veterinary medicinal products manufactured within the Member 
State concerned, each batch of veterinary medicinal ·products has been 
manufactured and checked in·compliance with the laws in force in that Member 
State and in accordance with the requirements of the marketing .authorization; 
(b) in the case of veterinary medicinal prOducts coming from third countries, each 
production batch imported has undergone in the importing Member State a full 
qualitative 8D8lys~, a quantitative analysis. of at least all. the active substances 
and all the other tests or checks necessary to ensure the quality of veterinary 
medicinal products in accordance \\ith the ~ments of the marketing 
authorization. 
Batches of veterinary medicinal products which have undergone such controls in a 
Member State shall be exempt from the above controls if they are marketed in 
another Member State, accompanied by the control reports signed by the qualified 
person. 
2. In the case of veterinary medicinal products imported from a third country, where 81/851/EEC 
appropriate arrangements have been made by the Community with the exporting Art. 30 (I), 3rd 
country to ensure that the manufacturer of the veterinary medicinal product applies subparagraph 
standards of good manufacturing practice at least .equivalent to those laid down by (as amended by 
the Community and to ensure that the controls referred to under point (b) of the first 93/40/EEC Art. 1 (11)) 
subparagraph of paragraph 1 have been carried out in the exporting country, the 
qualified person may be relieved of responsibilil:}' for carrying out those controls. 
3. In all cases, and particularly where the veterinary medicinal products are released for 81/851/EEC 
sale, the qualified person shall certify, in a register or equivalent document provided Art. 30 (2) 
for the purpose, that each production batch satisfies the provisions of this Article; the 
said register or equivalent document shall be kept up to date as operations are. carried 
out and shall remain at the disposal of the representatives of the competent authority 
for the period specified in the provisions of the Member State concerned an~ in any 
event, for at least five years. 
Article 56 
Member States shall ensure that the obligations of qualified persons referred to in Article 81/85 1/EEC 
52 are fulfilled, either by means of appropriate administrative measures or by making Art. 33 
such persons subject to a professional code of conduct. 
Member States may provide for the temporary suspension of such a person upon the 
commencement of administrative or disciplinary proceedings against him for failure to 
fulfil his obligations. -
·Article 57 
The provisions of this Title shall apply to homeopathic veterinary medicinal products. 
43 92n4/EEC 
Art.3· 
(adapted) 
. TITLEV 
LABELLING AND PACKAGE INSERT 
Artiele58 
l. The following information, which shall conform with the particulars and documents 81/85 1/EEC 
provided pursuant to Articles 12 and 13 (1) and be .approved by the competent Art. 43 (1) 
· authorities, shall · appear in legible characters on containers and outer packages of 
medicinal products: · 
(a) Name of the veterinary medicinal product, which may be a brand name or a non­
proprietary name accompanied by a trade mark or the name of the manufacturer, or a 
scientific name or foimula, with or without , a trade mark, or the name of the 
manu1Dcturer. 
Where the special name of a medicinal product· containing only one active substance 
is a brand name, this name must be . accompanied in legible characters by the 
international non·propriety name recommended by the World Health Organization, 
where such name exists or, where no such name exists, by the usual non-proprietary 
name. 
(b) A statement of the active substances expressed qualitatively and quantitatively per 
dosage unit or according to the form of administration for a particular volume or 
weight, using the international non-proprietary names recommended by the World 
Health Organization, where such names exist or, where no such names exist, the 
usual non-proprietary names. 
(c) Manufacturer's batch number; 
(d) Marketing authorization number; 
(e) Name or corporate name and permanent address or registered place of business of 
the marketing authorization holder and of the manufacturer, if different; 
(f) The species of animal for which the veterinary medicinal pro9uct is intended; the 
method and route of administration; 
(g) The withdrawal period, even if nil, in the case of veterinary medicinal products 
administered to food-producing animals; 
(b) Expiry date, in plain language; 
(i) Special storage precautions, if any; 81/851/EEC 
Art. 43 (1), points 1 and 
2 (as amended by 
90/676/EEC Arl1 (23)) 
.(adapted) 
81/851/EEC 
Art. 43 (1 ), points 3 to 6 
(adapted) 
81/851/EEC 
Art. 43 (1), points 7 
and8 
(as amended by 
90/676/EEC Art. 1 (23)) 
(adapted) 
81/851/EEC 
Art. 43 (1), point 9 
811851/EEC 
(j) Special precautions for disposal of unused medicinal products or waste material from Art. 43 (1 ), point 9a 
medicinal products, if any; (as amended by 
90/676/EEC Art. 1 (23)) 
(adapted) 
·44 
(k) Particulars ~to be indicated pursuant to Article 26_ {1), if ~y; 
(I) The wOrds "For animal ~ent only". 81/8$1/BEC 
Art. 43 {1), points 10 
andll 
2. lbe.pharmaceutical·form and the contents by weight, volume or num~ of dose-81/851/EEC 
. units need only be shown on the outer package. Art. 42 (2) and (3) 
(adapted) 
3. The provisions of Pan 1, A of Almex I, in so far as they concern the qualitative and 
quantitative composition of veteriruuy medicinal prpducts in respeCt of active 
. substances, shall apply to the particulars provided for in paragraph 1 (b) .. 
4. · The pam_'culars mentioned in paragraph 1 (f) to (1) shall appear on the outer package 181/851/EEC 
and on the container of:the medicinal products in the language or languages of the Art. 47 
country in which they. are placed on the market (adapted) 
Article 59 
1. As regards ampoules, the paniculars listed in the first paragraph of Article SS (1) 81/851/EEC 
shall be given on the outer package.· On the containers, .however, only the following Art. 44 
particulars shall be necessary: · (adapted) · 
.. name of veterinary medicinal product, 
• quantity of the.active substances, 
-routeof~o~ 
.. manufacturer's batch number, 
-date of expiry, 
• the words 'For aniinal treatment only'. 
2. As regards small single-dose containers, other than ampoules, on which it is 811851/EEC 
impossible to give the particulars mentioned in paragraph 1, the requirements of Art. 45 
Article 58 (1),·(~) and (3}, shall apply only to the outer package. 
3. The particulars mentioned in the third and sixth indents of paragraph I shall appear 81/85 1/EEC 
on the outer package and on the container of the medicinal products in the language Art. 47 
or languages of the country in which they are placed on the market 
Article 60 
Where there is no outer package, all the particulars which Should feature on such a 81/85 1/EEC 
package pursuant to the Articles 58 and 59 shall be shown on the container. Art. 46 
(adapted) 
Artide61 . 
. 1. ·The inclusion of a package insert in. the packaging of veterinary medicinal prOducts 81/85 1/EEC 
shall be obligatory unless all the information required by this Article can be Art 48 (1) 
conveyed .on the CODtainer and the eXtemal packaging M~ States shall take all (as amended by 
appropriate measures to ensure that the insert relates solely to the veterinary 90/676/EEC An. 1 (24)) 
mediciDal product with which it is included. The .insen shall be in the· official 
langUage or languages of the fdember State in. which the medicinal product is 
marketed. 
2. The package insert shall contain at least the following information, which· shall 81185 1/EEC 
conform to the particulars and documents provided pursuant to Art;icles .12 and Art. 48 (2) (a) to (d) 
· 13 (1) and be approved by the competent authorities: · · (adapted) 
{a) name or corporate name and permanent address or registered place of business 
of the marketing authorization holder and ofthe·manufacturer, if different; 
(b) name of the veterinary. medicinal product and a statement of its active substances 
expressed qualitatively and quantitatively; 
The international non-proprietary names recommended by the World Trade 
Organization shall be used wherever they exist; · 
(c) the therapeutic indications; 
(d) contra-indications and adverse reactions in so far as these particulars are 
necessary for the use of the veterinary medicinal product; 
(e) the species of animal for which the veterinary medicinal product is intended, the 
dosage for each species, the method and route of administration and advice on 
correct administration, if necessary; 
(f) the withdrawal period, even if this is nil, in the case of veterinary medicinal 
· products administered to food-producing animals; 
(g) special storage precautions, if any; 
(h) particulars required to be indicated pW'Suant to Article 26 (1), if any. 
(i) special precB:Utions for the disposal of unused medicinal products or waste 
materials from medicinal products, if any; 81/851/EEC 
Art. 48 (2) (e) 
(as amended by 
90/676/EEC An. 1 (25) 
(a)) 
81/851/EEC 
Art. 48 (2) (t) and (g) 
81/851/EEC 
Art-48 {2) (h) 
(as amended by 
90/676/EEC An. 1 (25) 
(b)). 
3. The particulars referred to in paragraph 2 shall appear in the language or languages 81185 1/EEC 
of the counny in which the produa is marketed. The other infonnation shall be Art. 48 (3) 
clearly separate from such particulars. (adapted) 
46 
Article 62 
Where tbe ps:ovisiollS of this Title are not observed and a formal notice addressed to the . 81/IS li£EC 
person conceriaed bas been ineffectual, tbe competent authorities of the Member States Art. 49, 1st paraaraph 
may suspend or withdraw lll81'ketinl authorization 
Artide63 
The requirements of Member states· concerning conditions of supply to the public, the 81/851/EEC 
marldQg of prices on medicinal products for veterinary use and industrial property rights Art. SO 
. shall not be affe~ by the provisions of this Title. 
Artlcle.64 
1. Without prejudice . to paralraph 2, the homeopathic veterinary products shall be 92174/EEC 
identified by the inclusion on their labels, in clearly legible form, of the words Art. 2 (2) 
'homeopathic m.ediciDal· product for veterinary use'. (adapted) 
2. In addition to the clear mention of the words 'homeopathic veterinary medicinal 92174/EEC 
product without approved therapeutic indications', the labelling and, where Art 7 (2) 
appropriate, package insert for the homeopathic veterinary medicinal products (adapted) 
referred to in Article 17 (1) ·shall bear the following information and no other 
information: 
• the scientific name of the stock or stocks followed by the degree of dilution, 
using the symbols of the pharmacopoeia used in accordance with point 8 of 
Article 1, 
-name and address of the marketing authorization holder and, where appropriate, 
of the manufacturer, 
method of administration and, if necessary, route, 
expiry date, in clear terms (month, year), 
pharmaceutical ~orm, 
contents of the sales presentation, 
special storage precautions, if any, 
-target species, 
a. special warning if necessary for the medicinal product, 
·-manufacturer's batch number, 
-registration number. 
47 
TITLE VI 
POSSESSION~ WHOLESALE DISTRIBUTION 
AND DISPENSIN'G OF VETERINARY MEDICIN'AL PRODUCTS 
Article 65 
1. Member States shall take all appropriate measures to ensure that wholesale 
distribution of ·veterinary medicinal products is subject to the holding of an 
authorization. and to ensme that the time taken for the procedure for granting this 
authorization does not exceed 90 days from the date on which the competent 
authority receives the application. · 
Member States may also exclude supplies of small q~tities of veterinary medicinal 
products from one retailer to another. 
2. · In order to obtain the authorization for· distribution, the applicant shall have at his 
disposal technically competent staff and suitable and sufficient premises comp}ying 
with the requirements laid down in the Member State concerned as regards the 
storage and handling of veterinary medicinal products. 
3. The holder of the authorization for distribution shall be required to keep detailed 
records. The following minimum· information shall be recorded in respect of each 
incoming or outgoing transaction: · 
(a) date; 
(b) precise identity of the veterinary medicinal prod~ct; 
(c) manufacturer's batch number,; 
(d) quantity received or supplied; 
(e) name and address ofthe supplier or recipient. 
At least once a year a detailed audit shall be carried out to compare incoming and 
outgoing medicinal supplies with supplies currently held in stock, any discrepancies 
being recorded. 
These records shall be available for inspection by the competem authorities for· a 
period of at least three years. 
4. Member States shall take all appropriate measures to ensure that wholesalers supply 
veterinary medicinal products only to persons permitted to carry out retail activities 
in accordance with Article 66, or to other persons who are lawfully permitted to 
receive veterinary medicinal products from wholesalers. 
48 81/851/EEC 
Art. 50a (1), 1st 
subparagraph· 
(as amended by 
90/676/EEC Art. 1 (27)) 
(adapted) 
81/851/EEC 
Art. 50a (1), 3rd 
subparagraph and {2), {3) 
and{4) · 
(as amended by 
90/676/BEC Art. 1 (27)) 
·(adapted) 
Article 66 
1. Member States shall take all appropriate measures to ensure that the retail supply of 
veterinary medicinal products is conducted only by persons who are permitted to 
c1rry out such operations by the legislation of the Member State concerned. 
2. Any· person permitted under paragraph 1 to sell veterinary medicinal products shall 
be required to keep detailed records. The following information shall be recorded in 
~.of each incoming or outgoing transaction: · 
(a) date; · 
(b) precise identity of the veterinary medicinal product; 
(c) manufacturer's batch number; 
(d) quantity received or supplied; 
(e) name and address of the supplier or recipient; 
(f) where relevant, name and address of the prescribing veterinarian and a copy of 
the prescription. 
At least once a year a detailed audit shall be carried out, and incoming and outgoing 
veterinary medicinal products shall be reconciled with products currently held in 
stock, any discrepancies Qc:ing recorded. 
These records shall be available for inspection by the competent authorities for a 
period of three years. 
3. Member States may limit the number of detailed documenting requirements referred 
to in paragraph 2. However, these requirements shall always be applied in case of 
veterinary medicinal products which are intended for administration to food­
producing animals and which are available only on veterinary prescription or in 
respect of which a withdrawal period must be observed. 
4. Not later that I January 1992, Member States shall communicate to the Commission 
a list of the veterinary medicinal products which are available without prescription. 
After having taken note of the communication from the Member States, the 
Commission shall examine whether suitable measures should be proposed for 
drawing up a Community list of such medlcinal products. 
49 81/851/EEC 
Art. SOb 
(as amended by 
90/676/EEC Art. 1 (27)) 
(adapted) 
Artide67 
Without prejudice· to stricter Community or national rules relating to dispensing 
veterinary medicinal products and to protect human and animal health,. a prescription 
shall be required' for dispensing to the public the following veterinary medicinal products; 
(a) those'products subject to official restrictions on supply or use, s~ch as: 
. . 
the restrictions resulting from the implementation of the relevant United Nations 
conventions on narcotic and psychotropic sub~ces, · 
the restrictions on the use of veterinary medicmai products resulting from 
Community law; 
(b) those products in respect of which special precautions must be taken by the 
veterinarian in order to avoid any unnecessary risk to: 
the target species, 
the person administering the products to the animal, 
the consumer of foodstuffs obtained from the treated animal, 
the environment; 
(c) those products intended for treatments or pathological processes which require a 
precise prior diagnosis or the use of which may cause effects which impede or 
interfere with subsequent diagnostic or therape~c measures; 
(d) magistral fonnulae intended for animals. 
In addition, a prescription shall be required for new veterinary medicinal products 
containing an active substance which has been authorized for use in a veterinary 
medicinal product for less than five years unless, having regard to the· information and 
particulars provided by the applicant, or experience acquired. in the practical use of the 
veterinary medicinal product, the competent authorities are satisfied that none of the 
criteria referred to in (a) to (d) of the first paragraph apply. 
so 811851/EEC 
Art. 4 (3), 3rd 
subparagraph 
(as amen~ by 
90/676/EEC Art. I (4)) 
(adapted) 
Article 68 
:1. -··Member.· States shaii · take ail measures necessazy · to ensure· that only pei-sons 
empowered UJider their national legislation ·in for~· possess or have under their 
control v~.medicina1 products or substances which may be .used as veterinary. 
medicinal products that have anabolic, anti-infectious, anti-parasitic; anti­
inflammatoty, honnoJ.ial ~r psychotropic properties~ 
2. .Member States. shall main~ a register. of manufacturers and dealers permitted· to 
be· in possession . Of· active .substances ·which may be used in the manufacture of 
-veterinary ·medicinal products having the ·properties referred ·to in ·paragraph 1. 
Such persons must jnaintain detailed records of all deaHn~ in subStances which may 
be used in the manufacture. of veterinary medicinal products and keep these records 
' available for inspection by the competent authorities for a period of at least 
three years. 
3. Any amendments to be made to the list of substances referred to in paragraph 1 shall 
be adopted in accordance with the procedure refetred to in Article 90. 
Article 69 
Member States shall ensure that the owners or keepers of food-producing animals can 
provide proof of purchase, possession and administration of veterinary medicinal 
products containing the substances set out in Article 68; Member States may extend the 
scope of this obligation to other veterinary medicinal products. 
In particular, Member States may require the maintenance of a record giving at least the 
following information: 
(a) date; 
· (b) name of the veterinary medicinal product; 
(c) quantity; 
(d) name and address of the supplier of the medicinal product; 
(e) identification of the animals treated. 
Sl 81/851/EEC 
Art. 1 (5) 
(as amended by 
90/676/EEC An. I (1 )) 
(adapted): 
811851/EEC 
Art. 50c 
(as amended by 
90/676/EEC Art. 1 (27)) 
(adapted) 
Artide70 · 
Nothwithstand.ing Articles 9 and 67, Member States shall ensure that veterinarians 81/851/EEC 
providing services in another Member State can take with them and adm.inister to animals Art. 4 (S) 
~ quantities of ready-made veterinary medicinal products not exceeding daily (as.amended by 
requirements. other than im.nlunological veterinary medicinal products which are not 90/676/EEC Art. I (4)) 
authorized for use in the M~ber State in which the ser;vlces are provided (hereinafter: (~pted) 
host Member State), providing that the ·foll9wing conditions ~ satisfied: · · · 
(a) the authorization to place the product on the market provided for in .Articles S, 7 and 
8 has been issued by the competent authorities of th~ Member State in which the 
veterinarian is established; · 
(b) the veterinary medicinal products are transported by the veterinarian in the Original 
manufacturer's packaging; · 
(c) the veterinary medicinal products intended for administration to food-producing 
animals have the same qualitative and quantitative composition in terms of active 
substances as the medicinal products authorized in accordance with Articles s, 7 and 
8 in the host Member State; 
(d) the veterinarian providing services in another Member Stite acquaiiJ.ts himself with 
the good veterinary practices applied in that Member State and ensures that the 
. Withdrawal period specified on the labelling of the veterinary medicinal product 
concerned is complied with, unless he could reasonably be expected to know that a 
longer withdrawal period should be specified to comply with these good veterinary 
practices; 
(e) the veterinarian shall not furnish any veterinary medicinal product to the owner or 
keeper of the animals treated in the host Member State unless this is permissible on 
the basis of the rules of the host Member State; in this case he shall, however, supply 
only in relation to animals under his care and only the minimmn quantities of · 
veterinary medicinal product necessary to complete the treatment of animals 
concerned on that occasion; 
(f) the veterinarian shall be required to keep detailed records of the animals treated, the 
diagnosis, the veterinary medicinal products administered, the dosage arlminist~ 
the dmation of treatment and the withdrawal period applied. These records shall be 
available for inspection by the competent authorities of the host Member State for a 
period of at least three years; 
(g) the overall range and quantity of veterinary medicinal products canied by the 
veterinarian shall not exceed that generally . required for the daily needs of good 
veterinary practice. 
52 
Artiele71 
1. · In th~ absence· of ·speCific CommunitY legislation concerning · the use of 90/677/EEC 
iliunuoologicai veteimary mediciDal products for the eradication or cOntrOl of animal Art. 4· 
disease, a Members-. ·may, in ~rdance with its national legislation, prohlbit the (adapted) 
·man~, import, ·posstsion, sale, supply and/or use of immunological veterinary 
medicinal Proctucts on the whole or part of its territorY if it is established tbat: ·· 
(a) the administration of the product . to axUmalS Will ·interfere ·With ihe . 
. implementation of a uationai programme for the ciiaSnosis, control or eradiction 
of: aniJDal· ·disease, .. or will cause difficulties in certifying the ·absence · of. 
Contamination in. live animals or in foodstuffs or other products obtaip.ed from 
treated anjfnals; 
(b) the disease to ·which the product is intended to confer immunity is largely absent 
from the territoty in question. 
2. The competerit authorities of the Member States shall inform the Commission of all 
instances in which the provisions of paragraph 1 are applied. 
S3 
TITLE VU 
PHARMACOVIGILANCE. 
Article 72 
Member States ·shall take aii apprQpriate measures ·to ·encourage the reporting to the 
c~ authorities of Suspected .. adverse reactions to the veterinmy mediciDal 
products.. . 
Artie~73 Si/851/EEC 
.Art.42e 
(as amended by 
93/40/EEC Art. l {12)) 
(idapted) 
in order to ensure the adoption of appropriate regulatory decisions concerning the 81/85 1/EEC 
veterinary medicinal products authorized· withiD the Commui'lity, having regard to Art. 42a · 
information obtained ab9ut suspected adverse.· r:eacuons to medicinal products under '(as amended by 
normal conditions of use, the Mem~ States ·shall establish a pharmacovigilance system. 93/40/EEC J_\rt. 1 (12)) 
This system shall be used to collect information useful in the surveillance of veterinmy. 
medicinal products, with particular reference to adverse reactions in animals, and to 
evaluate such information scientifically. · 
Such information shall be collated with data on consumption of veterinary medicinal 
products. 
This system shall also collate information on frequently observed misuse and serious 
abuse of veterinmy medicinal products. 
Article 74 
The marketing authorization· holder shall have permanently and continuously at his 
disposal an appropriately qualified person responsible for pharmacovigilance. 
That qualified person shall be responsible for the follo~g: 
(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, 
including its representatives, is collected and collated at a single point; 
(b) the preparation for the competent authorities of the reports referred to in Article 75, 
in such form as may be laid down by those authorities, . in accordance with the 
relevant national or Community guidelines; 
(c) ensuring that lilY request from the competent authorities for the provision of 
additional information necessary for the evaluation of the benefits and risks afforded 
by a veterinary medicinal product is answered fully and promptly, including the 
provision of information about the volume of sales or prescriptions of the veterinary 
medicinal product concerned 81/851/EEC 
Art. 42c 
(as amended by 
93/40/EEC Art. I (12)) 
(adapted) 
Articl~ 75 
· 1. The marketing aUthorization holder sball be required to record and to report all 
· suspected. serious . ad~ ·.reactions which are· brought ~ his. attention _to ·the 
competent authoritieS immediately, .and in any case~ 15 days. of~eir·i'eceipt at 
. the~ . . 
2. . The marketing aluthorization holder. shall be Rquired to maintain detailed records of 
: all other suspected adverse reactions which are reported to him. · 
Unless _other requirements·· have been laid down as a condition of the granting of 
authorizatioli. ~ese records .. shall be subuiitted to the competeat authorities 
immec:Uare~ upon request or at· least every six months during the fiist' two years 
following authorization, and once a year for ·the following three years. Thereafter, the 
records· sball be· submitted at five-yearly intervals together with the application for 
renewal of the authorization, or ~ediateJY upon request. These records shall be 
accompanied by a scientific evaluation. · 
Article 76 
Member States shall ensure that reports of suspected serious adverse reactions are 
immediately brought to the attention of the Agency and the marketing authorization 
holder, and in any case within 15 days of their notification, at the latest. 
Article 77 8~/851/EEC. 
Art.42d 
{is amended by 
93/40/EEC Art. 1 (12)) 
(adapted) . 
811851/EEC 
Art.42f 
(as amended by 
93/40/EEC Art. 1 (12)) 
(adapted) 
In order to facilitate the exchange of information about pharmacovigilancc; within the 81/851/EEC 
Community, the Commission, in consultation with the Agency, Member States and An. 42g 
interested parties, shall draw up guidance on the collection, verification and presentation (as amended by 
of adverse reaction reports. 93/40/EEC Art. 1 (12)) 
This guidance shall take account of international harmonization work carried out with 
regard to terminology and classification in the field of pharmacovigilance when use of 
such worlc can be made in the field of the vet&mnaly medicinal product concerned. 
ss 
Article 78 
·.1 ~ WbCre as~a reSUlt. ·of the evaluation Qf adverse reaction Je.Potts a c:Ompetem authority m a ··Member State. cousiders .that a ID8Iketii1g. authorization should be Wrled, 
suspended ,br withdra~ · it shall -forthwith infOrm the .Agency and the ~ 
authOrization holder. 
2. In case of urgency,. the toulpetcnt authority ·of a M* State concerned may 
suspend the ID8Iketii1g of. a. veterinary medicinal product,. provided the Agency is 
informed no later than on the first following working day. · 
Article 79 ·si!Bsi!EEc . 
Arl42h 
(as amended by ·. · 
93/40/EEC Art. 1 (12)) 
(adapted) . 
Any amendments which may be necessary to update the provisions of Articles 72 to 78 to 81/85 I !EEC 
take account of scientific and technical progress shall be· adopted in accordance witb.the An. 42i · · 
procedure laid down in Article 90. (as amended by 
93/40/EEC Art. 1 (12)) 
(adapted) 
S6 
TITLEVlll 
SUPERVISION AND SANCTIONS 
Article 80 
L The _co.tDpetent authority ~f the Member State concerned shall ensure by means of 81/851/EEC 
repeated inspection that the legal requirements relating to veterinary medicinal M 34, 1st subparagraph 
products are complied:with. · · (as amended by 
90/676/EEC Art. 1 {19)) 
SuCh inspections sball'be cmied out by authorized representatives of the competent 81185 1/EEC 
authoritywho·sballbe empowered to: Art 34, 2nd 
subparagrapb 
(a) inspect manufacturing or trading estabbsbments and any laboratories entrusted (adapted) 
by the holder of the manufacturing authorization,. with the task of carrying out 
control tests pursuant to Article 24; 
(b) take samples; 
(c) examine any documents relating to the object of the inspection, subject to current 
provisions in the Member States from 9 October 1981 which place restrictions 
on these powers with regard to the description of the manufacturing method. 
2. Member States shall take all appropriate measures to ensure that the manufacturing 90/677/EEC 
processess used in the manufacture of immunologi~ veterinary medicinal products Art 3 (1) 
are completely validated and batch-to-batch consistency ·is ensured. (adapted) 
3. The officials representing the competent authority shall report after each of the 
inspections mentioned in the first paragraph on whether the manufacturer complies 
with !he principles and guidelines of good manufacturing practice referred to in 
Article 5 I. The inspected manufacturer shall be informed of the content of such 
reports. 
Article 81 811851/EEC 
Art. 34, 3rd 
subparagrapb 
(as amended by 
90/676/EEC Art. 1 (19)) 
1. Member States shall take all appropriate measures to ensure that the marketing 81185 I !EEC 
authorization holder and, where appropriate, the holder of the manufacturing Art. 35 
authorization fwnish proof of the control tests carried out on the veterinary medicaf (adapted) 
product and/or on the constituents and intermediate products of the manufacturing 
process, in accordance with the methods laid down for the purposes cf marketing 
authorization. 
,, 
2. ·For the puqJOses of_implementing paragraph 1, .Membrer States ·may reqUire the. 90/671tEEC 
marketing authorization holder for mmiunologiCal veterlnary medicinal· products to Art. 3 (2) 
. sobmit to .. the competeilt authorities copies of ·all the control reports signed by the .(adapted) 
."qualified person m accOrdance with Article 55. 
The·~etiug ~rizatioil holder for immlDlological veterinary medicinal proaucts 
_ shall ensure that an ad~ ·number _of representative samples. of eaA;h batch of 
veterimuy medical products is held in stock. at least up to the expiry date, and 
provide samples promptly to the competent authorities on request 
Article 82 
1; Where it considers it necessary, . a Metn:ber State may require the marketing 90/677/EEC 
authorization holder for immunological products to submit samples from the batches Art. 3 (3) 
of tbe bulk and/or medical product for examination by a State laboratory or .an (adapted) 
approved laboratory before entry into circulation. 
In the case of a batch manufactured in another Member State, examined by ·the 
competent authority of another Member State and declared to be in conformity with 
national specifications, such a control may be canied out only after the control 
reports of the batch in question have been examined, after the Commission has been 
informed, and where the difference in veterinary conditions between the two Member 
States concerned justifies it. 
2. Except where the Commission has been informed that a long period is necessary to 
complete the analyses, Member States sball ensure that any such examination is 
completed within 60 days of receipt of the samples. The marketing authorization 
holder shall be notified of the results of the examination within the same time-limit. 
3. Before 1 January 1992, the Member States shall notify the Commission of the 
immunological veterinary medicinal products subject to compulsory· official control 
before being placed on the market. 
ss 
.. ·.~~83··. 
-The Competem auth~rities of the Member States shall suspend or ~draw marketing '81/85 1/EEC 
~orization wh~ 1i is clea;r tbat: · · · ' · Art. 36 
(adapted). 
· (a) 1he ~·medicinal product proves to .be harmful .pnder the -conditions of use 
stated at the time of appli~on for authorization or ~bsequently; 
(b) the veteriDaJy medicinal product does not have any therapeutic effect on the specieS 
of animal for which the .treatment ~ intended; 
(e) its qualitative and quantitative eomposition is not as stated; 
(d) the recommended withdrawal period is inadequate to ensure that foodstuffS obtained 
from the treated animal do not contain residues which might constitute a health 
hazard to the consumer; · · 
(e) the veterinary medicinal product is offered for sale for a use which is prohibited by 
other community provisions. 
However, pending Community rules, the competent authorities may refuse to grant 
authorization for a veterinary medicinal product where such action is necessary for 
tbe protection of public, consumer or animal health; 
(f) the information given in the application documents pursuant to Article 12, 13 (1) and 
27 is incomct; ' 
(g) the control tests referred to in Article 81 (I) have ~ot been carried out; 
(h) the obligation referred to in Article 26 (2) has not been twfilled. 
Authorization may also be suspended, or withdrawn where it is established that: 
(a) the particulars supporting the aPPlication, as provided for in Articles 12 and 13 (1), 
have not been amended in accordance with Article 27 (I), 
. (b) any new information as referred to in paragraph 3 of Article 27 has not been (adapted) 
communicated to the competent authorities. 
S9 
Artide~ 
1. Witholl_t prejudice .to. Article 83,.Member States ·shall take. all necessary measures to 811851/EEC. 
ensure tbat supply of a veterinary medicinal product is prohibited: and ·that die Art.·37 {1) 
tnediciDal ~ ~ed is withdrawn form the market, where: 
(a) it is clear that the veteiiQary medicinal product is harmful under the conditions of 
1ase stated ait the time of the application for authorization or subsequently, 
. pursumit to Article 27 (5); · · · · 
{b) the. veterinary medicinal product has DO therapeutic effect. OD the species of 
animal for which the treatment was intended; 
(c). the qualitative and quantitative composition of the veterinaJy medicinal product 
is not as stated; · 
(d) the rKOmmended withdrawal ·period is· inadequate to ensure that 'foodstuffs 
obtained from the treated animal do not contain residues which might constitute 
a health hazard to the consumer; 
(e) the control tests referred to in Article 81 (1) have not been canied out, or any (adapted) 
other requirement or obligation relating to the grant of the manufacturing 
authorization referred to in Article 44 (I) has not been complied with. 
2. . The competent authority may. confine the prohibition on supply and withdrawal from 
the market solely to the contested production batches. 
Article 85 
I. The competent authority of a Member State shall suspend or withdraw the 81/851/EEC 
manufacturing authorization for a category of preparations or for all preparations if Art. 38 
any of the requirements laid down in Article 45 are no longer met. (adapted) 
2. The competent authority of a Member State may, -in addition to the measures 
provided for in Article 84, either suspend manufacture or im~ of veterinary 
medicinal products from third countries or suspend or withdraw the manufacturing 
authorization for a category of preparations or for all preparations in the event of 
non-compliance with the provisions regarding manufacture or imports from third 
countries. 
Article 86 
The provisions of this Title shall apply to homeopathic veterinary medicinal products. 
Artide 87 
Member States shall. take appropriate measures to encourage veterinarians and other 
professionals concerned to report to the competent authorities any adverse reaction of 
veterinary medicinal products. · 
60 92n4/EEC 
Art. 4 (1) 
(adapted) 
81/851/EEC 
Art. 38a 
(as amended by 
90/676/EEC Art. 1 (20)) 
. (adapted) 
.TITLE IX 
STANDING .coMMITrEE 
Ai1ide88 
1. A Standing Committee on Veterinary Medicinal Pl-oducts for the Adaptation to 
Technical Progress of the Directives on the Removal of Technical Baniers to Trade 
in ·the Veterinary Medicinal Products. Sector, hereinafter called "the Standing 
Committee", is hereby set up; it sba1l consist of representatives of the Member States 
with a ~tative of the Commission a.S· Chairman. 
2. The Standing Committee shall.adopt its own rules of procedure. 
Article 89 
Any changes which are necessary in order to adapt Annex I to take account of scientific 
·and technical progress sball be adopted in accordance with the procedure laid down in 
Article 90. 
61 811852/EEC 
Art. 2b . 
(as amended by . 
87/20/EEC Art. 1 (1)) 
(as amended by 
93/40/EEC Art. 2) 
. (adapted) 
81/852/EEC 
Art. 2a 
(as amended 87/20/EEC 
Art. 1 (1)) 
(adapted) 
Article9.0 
Where the procedure laid down in thiS Article. is ~.be followed the Commission shall be 
. assisted by _the Standing ~mmi~. . · · 
the rePresentative -of the·.Commissio~ shall submit to the Standing Committee a draft of. 
the IPeasures to be taken. The StandiJig Committee sbal~ deliver its opinion on the draft 
within a time-limit which the 'Chairman may lay down _according ~-the· urgency of the 
matter. The opinion shall be delivered by the majority laid do~ in Article 205 (2) of the 
Treaty in the case of decisions which the Council is required to adopt on .a proposal froiJl 
the Conu:nission. The votes of the representatives .of the Member States .within the 
Standing Committee: shall be ·weighted in the manner set out in that Anicle. 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 ~lating 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 91 
Where the procedure laid down in this Article is to be followed the Commission shall be 
assisted by the Standing Committee. 
The representative of the Commission shall submit to the Standing Committee a draft of 
the measures to be taken. The Standing Committee shall deliver its opinion on the draft 
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. 
62 sv~silEEc 
Art. 42j 
(as· amelided by 
93/40/EEC Art. 1 {13)) 
(adapted) 
81/851/EEC 
Art.42k 
(as amended by 
93/40/EEC Art. 1 (13)) 
(adapted) 
TITLEX. · 
. G~ PROy.ISIONS 
Article9l 
Member States ·shall take all measures necessary. to ensure that the competent authorities 81/85 I !EEC 
COii~ communicate .. the appropriate· information to each other, in particular regarding . Art. 39 
complian~· with the rCquin:uients adopted for manufacturing authorization, . or for (as amended by 
. authorization to place J)roducts on·the mlrket.· · 90/676/EEC Art: 1 (21)) 
·' (adapted) 
Upon reasoned request, Member States ·shall forthwith communicate the reports referred 
to iD the third ~h of Article 80 (3) to the competent authorities of another Member 
State. If; after. CODSideriDg .the ~ the Member State receiving the repons considers 
that it caDDot acc:ept the conclusions reached by the competent authority of the Member 
State. in which the report was established, it sball inform the competent authorities 
concemed of i1s reasons ·and may request further information. The Member States -
concerned shall attempt to reach agreement If necessary, in the event of serious 
differences of opinion, one of the M~bcr States concerned shall inform the 
Commission. 
Artiele 93 
I. Each Member State shall take all appropriate measW'eS to ensure that the Agency is 81/85 1/EEC 
informed immediately of. decisions granting marketing authorization .and of all Art. 42 
decisions refusing or withdrawing marketing authorization, cancelling a decision (as amended by 
refusing or withdrawing marketing authorization, prohibiting supply or withdrawing 90/676/EEC Art. 1 (22)) 
a product from the market, together with the reasons on which such decisions are (adapted) 
based. 
2. The marketing authorization holder shall be obliged to notify the Member States 
forthwith of any action taken by him to suspend the marketing of a veterinary 
medicinal prOduct or to withdraw a product from the market, together with the 
reasons for such action if it concerns the effectiveness of the veterinary medicinal 
product or the protection of public health. Member States shall ensure that this 
information is brought to the attention of the Agency. 
3. Member States shall ensure that appropriate information about actions tiken pursuant 
to paragraphs 1 and 2 which may affect the protection of health in third countries is 
forthwith brought to the attention of the relevant international organizations, with a 
copy to the Agency. · 
Artiele 94 
Member States shall communicate to eaeh other. all the information necessary to 92!74/EEC 
guarantee the quality and safety· of homeopathic veterinary medicinal products Art. 5 
manufactured and marketed within the Community, and in particular the information 
referred to in Articles 92 and 93. 
63. 
~de95 
1. · At the mp.aest of rhe DlallU&cturer or exporteJ: of veterinarY blediciDBI produ~ or 
the ~orities of an Importing third country, Member. States shall certify ·that such 
marDJfacturer is in possession of the manUfacturing authOrization. When issuing such. 
certificates, ~einber States shall comp~ with the _following conditio~~$: 
(a) ·they shall have regard to the prevailing administrative arrangements of the 
World Health Organization; · 
(b) for veterinary m~cin81 products intended for export which. are already 
· authorized in their territory. they shall supply the summary ot the . product 
characteristics as approved in accordance with Article 25 or, m the absence 
thereof: an equivalent document · 
2. Where the manufilcturer is not in possession· of an authorization to place the product 
on the market, be shall provide the authorities responsible for. establishing the 
certificate referred to in the first plflgr8ph with a declaration explaining why . such 
authorization is not available. 
Article 96 81/851/EEC 
Art. 24a 
(as amended by 
90/676/EEC Art. 1 (16)) 
{adapted) 
Any decision set out in this Directive, taken by the competent authorities of the Member 81185 1/EEC 
States, shall state the reasons on which it is based. · Art. 41 and 40 
(adapted) 
Such a decision shall be notified to the party concerned who shall at the same time be 
informed of the remedies available to him under cwrent legislation and the time allowed 
for. seeking such remedies. · 
Marketing authorizations and revocations of such authorizations shall be published by 
each Member State in its o~cial gazette. 
Article 97 
The Member States shall not permit foodstuffs. for human consumption to'be taken from 
test animals unless maximum residue limits· have been established by the Community in 
accordance with the provisions of Regulation (EEC) No 2377/90 and an appropriate 
withdrawal period has been established to ensure that this maximum limit will not be 
exceeded in the foodstuffs. 
64 811851/EEC 
Art. 4 (2), 2nd 
subparagraph 
(as amended by 
93/40/EEC Art. 1 (2)) 
(adapted) 
.1TILEXI 
FINAL MEAsURES 
Article 98 
Directives 81/851/EEC,'. 81/852/EEC, 90/677/EEC and 92f74/EEC referred to in 
.Annex n, Part A are repealed, without ptej~ce to the obligations of the Member 
· ·Smtes in respect. of the~~ for transposition laid down_ in Annex n, Pan B. . 
The reference made to the said Repealed Directives shall be construe,d as references 
to this Directive and should be read in accordan~ with the correlation table set out 
in Annex m. 
Article 99 
This Directive enters into force on I January 2000. 
Article 100 
This Directive is addressed to the Member States. · 
Done at Bussels, 
For the European Parliament For the Council 
The President The President 
65 
~I· 
·lmQi1iR:EMENTS AND ANALYTICAL PROTOCOL, 
SAFETY TESTS, PRE-cLINICAL.AND CLINICAL. · 
FOR TESTS OF VETERINARY MEDICINAL PRODUCTS 
INTRODUCTION 81/852/EEC . 
·Annex 
The particulars and documents accompanying an application for marketing authorization (as amend~ by . 
pmsuant to Articles 12 and 13 (1) shall be presented in accordance with the requirements 92118/EEC Art 1) 
set out in this Annex and taking account of the guidance contained in the 'Notice to (adapted) 
applicants for marketing authorizations for ·veterinary medicinal prochicts in the Member 
States of the European Community', published by the Commission in The rules 
governing medicinal products in the Eur_opean Community, volume V: Veterinllry 
Medicinal Products. 
In assembling the dossier for application for marketing authorization, applicants shall 
take into account the Community guidelines relating to the quality, safety and efficacy of 
veterinary medicinal products published by the Commission in The rules govermng 
medicinal products in the European Community. · 
All information which is relevant to the evaluation of the medicinal product concerned 
shall be included in the application, whether favourable or unfavourable to the product. 
In particular, .all relevant details shall be given of any incomplete or abandoned test or 
·trial relating to the veterinary medicinal product. Moreover, after marketing 
·authorization, any information not in the original application, pertinent to the benefit/risk 
assessment, shall be submitted forthwith to the competent authority. 
Member States ensure that all experiments on animals are conducted in accordance with 
Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, 
regulations and administrative provisions of the Member States regarding the protection 
of animals used for experimental and other scientific purposes(l). 
· The provisions of Title I of this Annex shall apply to veterinary medicinal products other 
than immunological veterinary medicinal products. 
The provisions of Title 11 of this Annex shall apply to immunological veterinary 
medicinal products. 
UJ OJL3S8,18.2.1986,p.l. 
66 
TITLE I 
REQUIREMENTS FOR VETERINARY MEDICiNAL PRODUCTS OTHER THAN 
. IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS 
PARTl 
SUMMARY OF THE DOSSIER 
A. ADMINISTRATIVE DATA 
The veterinary medicinal product which is the sUbject of the application shall be 
identified by name and by name of the active substance(s}, together with the strength and 
phannaceutical form, the method and route of administration and a description of the 
final saies presentation of the product. · · 
The name and address of the applicant shall be given, together with the name and address 
of the manufacturers and the sites involved in the different stages of the manufilCture 
(including_the manufacturer of the finished product and the manufacturer(s) of the active 
substance(s)), and where relevant the name and address of the importer. 
The applicant shall identify the number and titles of volumes of documentation submitted 
in support of the application and indicate what samples, if any, are also provided. 
Annexed to the administrative data shall be a document showing that the manufacturer is 
authorized to produce the veterinary medicinal products concerned, as defined in Article 
42, together with a list of countries in which authorization has been granted, copies of all 
the summaries of product characteristics in accordance with Article . 14 as approved by 
Member States and a list of countries in which an application has been submitted. 
B. SUMMARY OF PRODUCT CHARACTERISTICS 
The applicant shall propose a summary of the product characteristics, in accordance with 
Article 14 of this Directive. · 
In addition the applicant shall provide one or more specimens or mock-ups of the sales 
presentation of the veterinary medicinal prod.uct, together with a package insert where 
one is required. 
67 81/852ffiEC 
Annex 
(as amended by. 
92/18/EEC Art. 1} 
(adapted} 
C. . EXPERT REPORTS 81/8S21EEC· 
. •, AmleX 
. In acco~ with Article 15 · (2) and (3), ·expert reports must be provided oli the (as amended by 
analytical doauilen1atioo, the · ptwmacotoxict>logical documentation, the residues 92/18/EEC Art:.l) 
.doculnetitation and th~ clinical ~on. · · "(adapted) . 
Each expert report shall consist of a critical evaluation of the various tests and/or trials 
which have been carried out in accord8nce with this Directive, and bring OUt .U the data 
relevant for. evaluation. 1be expert shall give ·his opinion as to whether sufficient 
gUarantees . have been provi~ as to the· quality, safety and efficacy of the product 
concerned. A ·fadual summary is not sufficient · 
All importairt data shall be summarized in -an appendix to the expert report, whenever 
possible in tabular or graphic form. The expert report and the summaries shall contain 
precise cross references to the inf~rmation 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 occupational experience of 
the expert. The professional relationship of the expert to the applicant shall be declared. 
68 
·PART~. stts52iEEC 
.Annex 
ANALYTi~ ~BYSIC().CBEMIC~ BIOLOGIC~ OR. . · · . · (as amended by 
MICRQBIOLOGICAL) TESTS OF VETERINARY MEDICINAL PRODUCfS 92/18/EEC Art. 1) 
OTHER THAN IMMUNOLOGICAL VETERINARY MEDiCINAL PRODUCTS (adapted) . 
All test ~ ~· comspond to the state of scientific progress ~ the time and 
.shall be wlidated procedures; results·ofthe validatiQn studieS shall be provided. . 
All the test procedure(s) sbaU be described in sufficiently precise. ~ so as to be · 
reprodUcible in control ~ canied out at the request of the competent authority; any 
special apparatus and equipment whicp maY be used shall be descnDed in adequate 
detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall 
be supplemented, if necessary, . by the method of preparation. ·In the case of test 
procedures included in tbe European Pharmacopoeia or the pharmacopoeia of a Member 
State, this description may be replaced by a detailed reference to the pharmacopoeia in 
question. 
A. QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE 
CONSTITUENTS 
The particulars and documents which must accompany applications for marketing 
authorization, pursuant to Article 12 (3) (c), shall be SlJbmitted in accordance with the 
following requirements. 
1. Qualitative particulars 
'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 animals, of the 
outer covering of the medicinal products-capsules, gelatine capsules, etc. 
These particulars shall be supplemented by any relevant data concerning the container 
and, where appropriate, its manner of closure, together with details of devices with which 
the mediciDal product will be used or administered and which will be delivered with the 
medicinal produc:t. 
69 
. 2. · The·~- termbiolOiY', to ·be ·used in describing the ·constitueilts. of i:Dedicinai .. · a·l/852/EEC · 
products,. -Shall mCan. Dotwithstanding the application of the other provisicms of Annex 
Article.l2 (3) (c): . . · • · · .-· · (as amended by 
. . 
in reSpect of substances whim appear in tbe -E~opean Phannacop()eio ·ar,. 
· failing this, in the national pbannacopc>eia of one of the Member States, the main 
·title at the head ·_of the monograph in _question. with reference to the 
pharmaco~ia concerned, 
in respect 9f . otb.ef substances, the international non-proprietary name 
· recommended by the World _Health Oipnization (WHO), which may be 
accompanied by another non-proprietary. name, or, failing these, the ·exact 
scientific designation; substances not having an intemational non-proprietary 
~ or an ·exact scientific designation shall be descnDed by a statement of how 
and from wbat they were prepared, supplemented, wb~ 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 medici;nal productsu,. 
3. Quantitative particulan 
3.1. In order to give 'quantitative particulars' of all the active substances of the medicinal 
products; it is necessary, depending on the pharmaceutical form concerned, to specify the 
mass, or the number of units of biological activity, either per dosage-~t or per unit of 
mass or volume, of each active substance. 
Units of biological activity shall be used for substances which cannot be defined 
chemically. Where an International Unit of biological activity has been defined by the 
World Health Organization, this shall be used Where no International Unit has been 
defined, the units of biological activity shall be expressed in such a way as to provide 
UJWilbiguous information on the activity of the substances. · 
Whenever possible, biological activity per units of mass or volume shall be indicated · 
This information shall be supplemented: · 
in respect of injectable preparations, by the mass or units of biological activity of 
each active substance in the unit container, taking into account the usable volume of 
th~ product, after reconstitution, where appropriate, · 
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 prep~tion, 
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. · 
CIJ OJ L 11, 14.1.1978, p. 11; Din:ctivc IS liSt IIDCDded by tbe ~-of Accession of Aus1iia, FiDIIDciiDd S'WCdcn. 
70 92/18/EECArt. 1) 
(adapted) 
3 . .2. Active'.subst8nees ~-m the'fonn of CO~Unds' or derivatives sball be described 
quimtitadvely by their total ~' and if necessmy ·or rel~vant, by the mass of the active 
~or entities of the mo~ecule. . . 
3.3. For IDCcliciDal pl\lducts containing an active substance which is the ·subject of an. 
application for ID8I'lcetiDg authorization .in ,any Member State· for the first time, the 
·qusmtitarive statement of an active substance which is a salt or hydrate shall bC 
Systematically expressed m terms of the mass of the acti~ entity or entities in the 
molecule. All subsequently iuthorized medicinal products in the Member States shall 
have their quantitative composition stated in the same way for the same active substance. 
4. ' Development pharmaceuties 
An explanation shall be provided with regard to the choice of composition, constituents 
and comainer and the intended function of the excipients in .the finished product. This 
explanation shall be supported by scientific data on development pharmaceutics. The 
ov~e, with justification thereo( shall be ~ 
B. DESCRIPTION OF THE MANUFACTURING METHOD 
The description of the manufacturing method accompanying the application for 
marketing authorization pursuant to Article 12 (3) (d), shall be drafted in such a way as to 
give_ an adequate synopsis of the nature of the operations employed. 
For this pUrpose it shall include at least: 
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 manufacture, 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 be 
made of any substances that may disappear in the course of manufacture; any 
overage ~ 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 manufactwing process, where a non-standard 
method of manufacture is used or where it is critical for the product, 
for sterile products, details of the sterilization processes and/or aseptic procedures 
used. 
71 81/852/EEC .. 
Annex 
(as.amended by 
92/18/EEC Art. 1) 
(adapted) 
C. CONTROL OF STARTING MATERIALS 
1. For the purposes of this· paragraph, 'starting -materials' sballmean all the constituents 
of the medicinal product and, if necessary, of its container, as refemd to in Section ~ 
point 1, ·above. 
In the case of 
an active substance Qot described in the Elll"opean Pharmacopoeia or in the 
pharmacopoeia of a Member State, 
or 
an active substance described in the Elll"opean ·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 manufactwing method, quality coD1rOl during manufacture 
and process validation to be supplied directly to the competent authorities by the 
manufacturer of the active substance. In this case, the manufacturer shall however 
provide the applicant with all the data which may be necessary for the latter to take 
responsibility for the medicinal product. The manufacturer shall confirm· in writing to the 
applicant that he shall ensure batch to batch. consistency and not modify the 
manufacturing process or specifications without informing 'the applicant DoCuments and 
particulars supporting the application for such a change shall be supplied to the 
competent authorities. 
The particulars and documents accompanying the application for marketing authorization 
pursuant to Article 12 (3) (i) and G) and Article 13 (1), shall include the results of the 
tests, including batch analyses particularly for active substances, relating to quality 
control of all the constituents used. These shall be submitted in accordance with the 
following provisions. 
1.1. Starting materials listed in phannacopoeias 
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 tenitory. 
Constituents fulfilling the requirements of the European Pharmacopoeia or the 
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with 
Article 12 (3) (i). In this case the description of the analytical methods may be replaced 
by a detailed reference to the pharmacopoeia in question. 
72 . 811852/EEC 
Aimex 
(as amended bY. 
92/18/EEC 
Art. 1) 
(adapted) 
Howeva;:; where a Startmg IWiterial. in the Eliropean 'Pharmacopoeia or. in the 
pharmacopoeia of a Melnber State· has been prepared by a method liable to leave 
impurities not ~ntroUed in the pharmacopoeia monograph, .these impmities and their 
maximum tolerance limits must be declared and a suitable test procedure must be described. . . 
Colouring matter ~ in all cases, ~fy the requirements of Council Directive 
78125/EEC. 
The routine tests cani~ 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 specmcation contained in a monograph of the ·European 
Pharmacopoeia or in the national pharmacopoeia of a Member State might be 
insufficient to en.sWe the quality of the substance, the competent authorities may request 
more appropriate specifications from the marketing authorization holder. 
The competent authorities shall inform the authorities responsible for the pharmacopoeia 
in question. The marketing authorization holder shall provide the authorities of that 
pharmacopoeia with· the details of the alleged insufficiency and the additional 
specifications applied. 
In cases where a starting material is described neither in the European Pharmacopoeia 
nor in the pharmacopoeia of a Member State, compliance with the monograph of a third 
country pharmacopoeia can be accepted; in such cases, the applicant shall submit a copy 
of the monograph accompanied where necessary by the validation of the test procedures · 
contained· in the monograph and by a translation where appropriate. 
1.2. 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 
suppleme~ted 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 
shall be sufficiently detailed to characterize a substance which is constant both on its 
composition and in its effects; 
(c) methods of identification may be described in the form of complete techniques as 
used for production of the substance, and in the form of tests which ought to be 
canied out as a routine matter; 
73 81/852/EEC 
Annex 
(as amended by 
92/.18/EEC Art. 1) 
(adapted) 
(cQ purity tests shall be described· iD relation to the sum total of predictable impurities, 81/852/EEC 
. especially. those whi~ ·may have a harmful effect, and,. if necessary, those whi~ Annex 
having regard to the combination of substances to which the application refers, might (as imended by-­
adversely affect the stability of the medicinal product or aistort analytical results; · · 92/18/EEC Art. 1) 
(adapted) 
(e) with regard to complex substances of plint or. animal origin, a distinction must be 
made between the case· where multiple pharmacological efrects render chemical, 
physical or biological control of the principal components necessary, and the case of 
substances containing one or inore groups of principles having similar activity, in 
respect of which an overall method of assay may be accepted; 
(f) when t:naterials of animal origin are used, measures to ensure freedom -from· 
potentially pathogenic agents shall ~ described; 
(g) any special precautions that may be necessazy during storage of the starting material 
and, if nec:essary, the maximum period of storage before retesting shall be given. 
1.3. Physico-chemical characteristics liable to affect bioavailability 
The following items of information concerning active subswices, whether or not listed in 
the pharmacopoeias, shall be provided as part of the general description of the active 
substances if the ·bio-availability of the medicinal product depends on them: 
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. Where source materials such as micro-organisms, tissues of either plant or animal 
origin, cells or fluids (including blood) of human or animal origin or biotechnological 
cell constructs are used in the manufacture of veterinary medicinal products, the origin 
and history of starting materials shall be descnbed 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 blnks are used, the cell characteristics shall be shown to have remained 
unchanged at the passage level used for the production and beyond 
U> lbe competent authorities may also n:qucst the pK/pH values if they tbiDic that this information is essential. 
74 
2.2~ Seed malmials; cell banks, ·pOols of serum ·am~ other materials of biological-origin 811852/EEC 
~ Whenever.possible, tbe source materials from which ·they are derived sb8ll be tested Annex 
for ~ous agents.. (as amended by 
92/18/EEC Art. 1) 
If the presalee:· of potentiauy pathogenic· adventitious agents is inevitable, the material (adapted) 
. sball be used Only when fUrther processing eDSlRS their elimination and/or inactivation, 
and this shin be validated · 
D. CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF 1liE 
MANUFAcnJRING PROCESS 
The particulars and documents accompanying an application for marketing authorization, 
pursuant to Article 12 (3) (i) and 0) and also Article 13 ( 1 }, shall include particulars 
relating to the product control tests that may be carried out at an intermediate stage of the 
manufacturing process, with a view to enswing the consistency of the technical 
characteristics and the production process. · 
These tests are essential for checking the conformity of the medicinal product with the 
formula when, exceptionally, an applicant proposes an analytical method for testing the 
finished product which does not include the assay of all the active substances (or of all 
the excipient components subject to the same requirements as the active substances). 
The same applies where the quality control of the finished product depends on in-process 
control tests, panicularly if the substance is_ essentially defined by its manufacturing 
m~ . 
E. TESTS ON THE FINISHED PRODUCT 
1. For the control of the finished product, a batch of a finished product comprises all the 
units of a pharmaceutical form which are made from the same initial quantity of material 
and have undergone the same series of manufacturing and/or sterilization. operations or, 
in the case of a contiJ;luous production process, all the units manufactured in a given 
period of time. 
The application for marketing authorization shall ~ those tests which are carried out 
routinely on each batch of finished product. The frequency of the tests which are not 
carried out routinely shall be stated. Release limits sball be indicated. 
The particulars and documents accompanying the application for marketing authorization 
pW'SUIIlt to Article 12 (3) (i) and (j) and also Article 13 (1), shall include particulars 
relating to conttol tests on the finished product at release. They shall be submitted in 
accordance with the following requirements. 
The provisions of the general monographs of the European .Pharmacopoeia, or failing 
that, of a Member State, sball be applicable to all products defined therein. 
If test procedures and limits other than those mentioned in the general 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 the pharmaceutical form concerned. 
1S 
1.1. G,;_;al ~cteristics ~/f!le./inisluui produc! 
Certain tests of the general. chatacteristics of a product shall always be included among 
the tests On the finistwf product. These tests shall, wherever applicable, relate to the 
control of average masses and maxirmun deviations, to mechanical, physical or 
~crobiological · tests, otganoleptic characteristics, physical characteristics such as 
density, pH, refractive index, etc. For each of these characteristics,· standards and 
tolerance limits sball 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 sball 
apply in cases where the methods preScribed by such pharmacopoeias are not applicable. 
Furthermore, solid ph.armacCutical forms having to be administered orally shall be 
~bjec:ted to in vitro studies on the hOeration and dissolution rate of the active substance 
or substances; these studies shall also be carried out where administration is by another 
means if the competent authorities of the Member State. concerned consider this 
necessary. 
1.2. Identification and as~ay of active svbstance(s) · 
Identification and assay of the ·active substance(s) shall be canied out either in a 
representative sample from the production batch or in a number of dosage-units analysed 
individually. 
Unless there is appropriate justification, the maxim'LIQl acceptable deviation in the active 
substance content of the finished product shall not exceed :t S% 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 $elf-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 ~ecessitate 
an intricate investigation difficult to carry out in respect of each production b~h, 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 ~hnique ~ be supplemented by a meth~ of quantitative 
evaluation, enablin'g 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. ~ 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. 
76 &11852/EEC . 
Almex 
(as amended by 
92/18/EEC Art. 1) 
(adapted) . 
· Wh• the. particu]ats given in section B ·show tbat a significant overage. of an active 81/852/EEC 
sabstaace js. employed in tJ:ae man~ ·of the medicinal product, the description of Annex 
the coDtrol tests on·the finish~ produCt sball include, where ~propriate, the· chemical (as ~ended by 
ancl, ·if n~, the :toxico-pharmacological investigation of the changes that this 92/18/EEC Art. 1) 
substance has undergone, and possibly the characterization and/or assay of the (ad8pted) · 
degradation products~ 
1.3. Ic/eimficalion and asstk)l ofacipient components 
In so far as is necessary, the excipient components shall . be subject at least to 
identification tests. · · · 
The test procedure proposed for identifying colouring matters must enable a verification 
to be made that such matters·appear in the· list annexed to Directive 78125/EEC~ 
An upper and lower limit test shall be obligatory in respect of preserving agents and an 
upper limit test for any other excipient component liable to affect adv~ely physiological 
functions; an upper and lower limit test shall be obligatory in reSpect of the excipient if it 
is liable to affect the bio-availability of an active substance, unless bio-availability is 
guaranteed by other appropriate tests. 
1.4. Safety tests 
Apart from the toxico-pharmacological tests submitted with the application for marketing 
authorization, particulars of safety tests, such as sterility, bacterial endotoxin, 
pyrogenicity and local tolerance in animals shall be included in the analytical particulars 
wherever such tests must be undertaken as a matter of routine in order to verify the 
quality of the product. 
F. STABILITYTEST 
The particulars and documents accompanying the application for marketing authorization 
pursuant to Article 12 (3) (t) and (i) shall be submitted in accordance with the following 
requirements. 
A description shall be given of the investigations by which the shelf life, the 
recommended storage conditions and the specifications at the end of the shelf life 
proposed by the applicant have been determined. · 
In the case of pre-mixes for medicated feedingstuffs, information shall also be given as 
necessary on the shelf life of the medicated feedingstuffs. manufactured from these pre­
mixes in accordance with the recommended instructions for use. 
Where a finished product requires reconstitution ·prior to administration, details of the 
proposed shelf life for the reconstituted product are require~ supported by relevant 
stability data. 
In the case of multi-dose vials, stability data ~ be presented to justify a shelf life for 
the vial after it has been pun~ for the first time. 
77 
. Where ·a finished product is ~le to give rise to ·degrldanon' products,. the applicant must 81/852/EEC 
dechR these and indicate characterization methods and test procedureS. · ·· 'Annex 
· · · . · (as;amendecfby. 
The conclusibus sball contain the results of analyses, justifying the proposed shelf life 92/18/EEC Art. 1) · 
\Dlder the recommended storage conditiOJlS and the specifications of the finished product (adapted) 
at the end of the shelf ~ of the finished product under these recommended storage 
conditions. 
The maximum acceptabl~ level of degradation products at the end of shelf life shall be 
indicated. 
A study of the interaction between product and container shall be submitted wherever the 
risk of such interaction is regarded as possible~ especially where injectable preparations 
·or aerosols for internal use are concerned 
PART3 
SAFETY AND RESIDUES TESTING 
The particularS and documents which shall accompany the application for marketing 
authorization pursuant to Articles 12 (3) G) and 13 (1) shall be submitted in accordance 
with the requirements below. 
Member States shall ensUre that the tests are canied out in accordance with the 
provisions relating to good laboratory practice laid. down by Council Directives 
87118/EEC0) and 88/320/EE<:<I). 
A. Safety testing 
CHAPTER I 
PERFORMANCE OF TESTS 
1 ~ Introduction 
The safety documentation shall show: · 
1. the potential toxicity of the medicinal product and any dangerous or undesirable 
effects which may occur under the proposed conditions of use in animals; these 
should be evaluated in relation to the severity of' the pathological condition 
concerned; 
2. the potential harmful effects to man of residues of the veterinary medicinal product 
or substance in foodstuffs obtained from treated animals and what difficulties these 
residues may create in the industrial processing ~f foodstuffs; 
3. the potential risks which may result from the exposure of human beings 'to the 
medicinal product, for example during its administration to the animal; 
4. the potential risks for the environment resulting from the use ·of the medicinal 
product. 
(I) OJ L 15, 17.1.1987, p. 29. 
<l) OJ L 145, 11.6.1988, p. 3S, Directive u IIIIICDded by Commissioo Directive 90/11/EEC (OJ L·11, 13.1.1990, p. 37). 
78 
All JeSUits shall~be reliable aod valid generally.: Whenever appropriate, mathaiaatical and 81/852/EEC 
statisdc:al ~ sbaJl be used in desigrdng the experimemal .. methods and· in A.Dnex 
eva1uatiDg :the·· results. AdditioD81ly, clinicians shall be giVen information about the (as amended by 
thapeutic potential oftbe product and about the hazards connected with its use. · 92/18/EEC Art .1) 
. . . . (adapted) 
In some cases .it may be neceSsaty to test the. metabolites of the parent compound where 
these represeot tbe residues of concern. 
AD excipient used in the ·pharmacCutical field for the first time shall be treated like an 
active substance. · 
2. Pba.,...~ology 
Pharmacological studies are of fun~ental importance in·clarifying the mechanisms by 
which the mediciDal product produces its therapeutic eff~ and therefore 
pharmacological studies conducted· in experimental and target species· of animal should 
be included in Part 4. · 
However, pharmacological studies may also ·assist in the understanding of toxicological 
phenomena. Moreover; where a medicinal product produces pharmacological effects in 
the absence of a toxic response, or at doses lower than those requ.ired to elicit toxicity, 
these pharmacological effects shall be taken into account during the· evaluation of the 
safety of ~e medicinal product. · 
Therefore the safety documentation shall always be preceded by details of 
pharmacological investigations undertaken in laboratory animals and all relevant 
information observed during clinical studies in the target animal. 
3. Toxicology 
3.1. Single-dose toxicity 
Single-dose toxicity studies can be used to predict: 
the possible effects of acute overdosage in the target species, · 
the possible effects of accidental administration to humans, 
the doses which may usefUlly be employed in the repeat dose studies. 
Single dose toxicity studies should reveal the acute toxic effects of the substance and the 
time course for their onset and remission. 
19 
(6) theSe studies shouid normally ~ carried out in at least two mammalian species. One 81/852/EEC 
manunalian species may ·be rep~· if appropriate, by an animal species for which the Annex 
medicinal product is intended. At least ~o different routes of administtation should (as amended by 
·normally be studied. One of these may be the same as, or similar to, that proposed for the 92/18/EEC Art. 1) 
target species. If substantial exposure of the user of the medicinal product is anticipated, (adapted) 
for example by inhalation or dermal contact, these routes should be studied. 
In order to reduce the number and suffering of the animals involved, new protocols for 
single dose toxicity testing are contiriually being developed. Studies carried out in 
accordance with these new p~dures when properly· validated will be accepted, as well 
as ·studies ·carried out in accordance . with established internationally recognized 
guidelines. 
3 .2. Repeated-dose toxicity 
Repeated-dose toxicity tests are intended to reveal any physiological and/or pathological 
changes induced by repeated administration of the active substance or combination of 
active substances under examination, and to determine how these changes are related to 
dosage. 
In the case of substances or medicinal products intended solely for use in non food· 
pl'Qd~cing animals, a repeated dose toxicity study in one species of experimental animal 
wiU normally be sufficient. This study may be rep!Ked by a studY conducted in the target 
animal. The frequency and route of administration, and the duration of the study should 
be chosen having regard to the proposed conditions of clinical use. The investigator shall 
giv~ his reasons for the extent and duration of the trials and the dosages chosen. 
In the case ·of substances or medicinal products intended for use in food producing 
animals, the study should be conducted in at least two species, one of which should be a 
non-rodent. The investigator shall give his reasons for the choice of species, having 
regard to the available knowledge ofthe metabolism_ of the prodqct in animals and man. 
. The test substance shall be administered orally. The duration of the test shall be at least 
90 days. The investigator shall clearly state and give his reasons for the method and 
frequency of administration and the length of the trials. 
The maximum dose should normally be selected so as to bring harmful effects to light. 
The lowest dose level should not produce any evidence of toxicity. 
Evaluation of the toxic effects shall be based on observation of behaviour, growth, 
haematology and physiological tests, especially those relating to the excretory organs, 
and also on autopsy reports and accompanying histological data. The choice and range of 
each group of tests depends on the species of animal used and the state of scientific 
knowledge at the time. · 
80 
li1 the case' of new combinations of mown substanceS which have been investigBted in 
&CCQrdance with the provisions of this Directive, the repeated-dose tests may, except 
where toxicity tests have demonstrated potel;ltiation or novel toxic effects, be . suitably 
modified by tbe investigator, ~o sbali submit his reasons for such modifications. 
3.3 •. Tolerance in the target species 
Details should· be provided of any signs of intolerance which have been observed dwing · 
studies conducted in the target species in accordance with the requirements of Part 4, 
Chapter I, Section B. The studies conceined, ·the dosages at which the intolerance 
occurred and the species and breeds concerned should be identified. Details ·of any 
unexpected physiological changes should also be provided. 
3.4. Reproductive toxicity including teratogenicily 
3.4.1. Study of the effects on reproduction 
The purpose of this study is to identify possible impairment of male or female 
reproductive function or harmful effects on progeny resulting from the administration of 
the medicinal products or substance under investigation. 
In the case of substances or medicinal products intended for use in food-prC>Qucing 
animals, the study ofthe effects on ~roduction shall be carried out in the form of a two­
generation study on at least one species, usually a rodent The substance or pr~duct under 
investigation shall be administered to males and females at an appropriate time prior to 
mating. Administration should continue until the. weaning of the .f2 generation. At least 
three dose levels shall be used. The maximum dose should be selected so as to bring 
harmful effects to light The lowest dose level should not produce any evidence of 
toxicity. 
Evaluation of the effects on reproduction shall -be based upon fertility, pregnancy and 
maternal behaviour; the suckling, growth and development of the Fl offspring from 
conception to maturity; the development of the F2 offspring to weaning.· 
3.4.2. Study of embryotoxic/fetotoxic effects including teratogenecity 
In the case of substances or medicinal products intended for use in food producing 
animals, studies of embryotoxic/fetotoxic effects, including teratogelii.city, shall be 
carried out These studies shall be carried out in at least two mammalian species, usually 
a rodent and the rabbit. The details of the test (number of animals, doses, time at which 
administered .and criteria for the evaluation of results) Shall depend on the state of 
scientific .knowledge at the time the application is lodged and the level of statistical 
significance which the results should attain. The rodent study may be combined with the 
study of effects on reproductive functioa 
In the case of substances or medicinal products which are not intended for use in food 
producing animalst a study of embryotoxic/fetotoxic effects, including teratogenicity, 
shall be required in at least one species, which may be the target species, if the product is 
intended for use in animals which might be used for breeding. 
81 81/852/EEC 
Ann~ .. 
(as amended by 
92/18/EEC An. I) 
(adapted) 
3.S. _Mutagenicity : 
Mutagenicity ·tests an; inteoded to ·assess the _potential of substances to , cause 
. ttansmissible changes in the genetic material of cells. -
. . 
Any new substance intended for. use in veteriDary ~cinal-products must be as~sed 
for tnutagenic properties. 
The number and types of tests and the criteria for the evaluation of tbe results shall 
depend on the state of scientific knowledge when the application is submitted. 
3 .6. Carcinogenicity 
Long term aDimal carcinogenicity studies will usually be required for substances to which 
human beings will be exposed 
which have a close chemical analogy with kno:wn carcinogens, 
which during mutagenicity testing produced results indicating a ~ssibility of 
carcinogenic effects, 
which have given rise to suspect signs during toxicity testing. 
The state of scientific knowledge at the time the application is submitted shall be taken 
into account when designing ~arcinogenicity studies and evaluating their results. 
3. 7. Exceptions 
Where a medicinal product IS intended for topical use, systemic absorption shall be 
investigated in the target species of animal. If it is proved that systemic absorption is 
negligible, the repeated dose toxicity tests, the tests for reproductive toxicity and the 
carcinogenicity tests may be omitted, unless: 
under the conditions of use laid down, oral ingestion of the medicinal product by the 
animal is to be expected, or 
the medicinal particular may enter foodstuffs obtained from the treated animal 
(intramammary preparations). . 
&2 81~852/EEC 
Ann~ 
. (as amended by 
92/18/EEC Art. .1) 
(adapted). 
4. Otlaer reqairellleats 
4.1.Jmmunotoxicity 
~ere the ~ffects observed. during repeated dose studi~ in anjmals .include specific 
changes in lylllphoid ·organ weights and/or histology and changes ·in the cellularity of 
lymphoid tissues, bone marrow or peripheral leukocytes, ·the investigator shall consider· 
the need for additioual studies of the effec:ts of the product on the immune system. 
The state of scientific knowledge at the time the application is· submitted shall be taken 
into account when designing such studies and evaluating their results. 
4.2. Microbiological properties ofresidues 
4.2.1. Potential effects on the human gut flora 
The microbiological risk presented by residucs of anti-microbial compounds for the 
human intestinal flora shall be investigated in accordance with the state of scientific 
knowledge at the time the application is submitted · 
4.2.2. Potential effects on the microorganisms used for industrial food processing 
In certain cases, it may be necessary to carry out tests to· determine whether residues 
cause difficulties affecting technological processes in industrial foodstuff processing. 
4.3. Observations in humans. 
Information shall be provided showing whether the constituents of the veterinary 
medicinal product are used as medicinal products in human therapy; if this is so, a report 
should be· made on all the effects observed (including adverse reactions) in humans and 
on their cause, to the extent that . they may be important for the assessment of the 
veterinary medicinal product, where appropriate in the light of trial results of 
bibliographical documents; where constituents of-the veterinary medicinal products are 
themselves not used or are no longer used as medicinal products in human therapy, the 
reaso~ should be stated. 
S. Ecotoxidty 
S .l. The purpose of the study of the ecotoxicity of a veterinary medicinal product is to 
assess the potential harmful effects which the use of the product may cause to the 
environment and to identify iny precautionary measures which may be necessmy to 
reduce such risks. 
5.2. An assessment of ecotoxicity shall be Compulsory for any application for marketing 
authorization for a veterinary medicinal product other than applications submitted in 
accordance with Articles 12 (3) G) and 13 (1). 
83 81/852/EEC 
'Annex 
(as amended by , 
92/18/EEC Art 1) 
(adapted) 
5.3. ·This assessment shali nOrmally be conducted in two phases. , 
In the first phase, the investigator shall assess the potential extent of exposure to ~ 
environment of the product, its active substances or releVant metabolites, taking into 
accotmt: 
the target species, and the proposed pattern of use (for example, mass-medication or 
individual animal medication), 
the method of administration; in particular the likely extent to which the product will 
enter directly into environmental systems, · 
the possible excretion of the product, its active substances or rel~vant metabolites 
into the environment by treated animals; persistence in such excretia, 
the disposal of unused or waste product 
5.4. In a second phase, having regard to the extent of exposme of the product to the 
environment, and the available information about the physical/ch~c:al, pharmacological 
and/or toxicological properties of the compound which has beeli obtained during the 
conduct of the other tests and trials required by this Directive, the investigator shall then 
consider whether further specific investigation of the effects of the product on particular 
eco-systems is necessary. 
S.S. As appropriate, further investigation may be required of: 
fate and behaviour in soil, 
fate and behaviour in water and air, 
effects on aquatic organisms, 
effects on other non-target organisms. 
These further investigations shall be carried out in accordance with the test protocols laid 
down in Annex V of Council Directive 671548/EEC'1, or where an end point is not. 
adequately covered by these protocols, in accordance with other internationally 
recognized protocols. The number and types of tests and the criteria for their evaluation 
shall depend upon the state of scientific knowledge at the time the application is 
subnriued. · Bi/8S2/EEC 
Annex 
(as ·amended by 
92/18/EEC Art. 1) 
(adapted) 
m OJ L 196, 16.8.1967, p. 1; Direc:tive u last amended by Commission DiRd:ive 98173/EC (OJ L 305, 16.U.1998, p. 1). 
84 
CHAPTER:n 
PRISENTArJON OF PARTICULARs AND DOCUMENTS 
As in any scientific work, the dossier of safety tests sball include the following: 
(a) an. iiltroduction defining the subject, accompanied by any useful ·bibliographical 
references; 
(b) the detailed identU]cation of the substance under review, including: 
international non-proprietary name ~, 
International Union of Pure and Applied Chemistry Name (IUP AC), 
Chemical Abstrac:t Service (CAS) number, 
therapeutical and pharmacological classification, 
synonyms and abb~viations, 
sttuctural formula, · 
~olecular formula, 
molecular weight, 
degree of impurity, 
qualitative and quantitative composition of impwities, 
descrip~on of physical properties, 
melting point, 
boiling point, 
vapour pressure, 
solubility in water and organic solvents exp~ in g/1, with indication of 
temperature, · 
density, 
. spectra of refraction, rotation, etc; 
{c) a detailed experimental protocol giving the reasons for any omission of certain tests 
'listed above, a description of the methods, apparatus and materials used, details of 
the species, breed or strain of animals, where they were obtained, their number and 
the conditions under which they were housed and fed, stating inter alia whether they 
were free from specific pathogens (SPF);. 
8S 811852/EEG 
Annex 
(as amended by 
92/18/EEC Art. I) 
(adapted) . 
. . ~ 
(d) all the results obtained, whether favourable or unfavourable. Th~ original data should 81/852/EEC 
be described in sufficient detail to allow the reSults to be · ciitically evaluated ·Annex 
independently of their interpretation by the author. By way of explanation, the results (as amended by 
may be accompanied by illustrations; · 92/18/EEC 
(adapted) 
(e) a statistical analysis of the results, where such is Called for by the test programme, 
and variance within the data; · 
(f) ·an objective discussion of the results obtained, leading to conclusions on the safety 
· of the substance, on its safety margin in· the test animal and the target animal and its 
possible side-effects, on its fields of application, on its active dose levels anq any 
possible incompatibilities; 
(g) a deiailed description and a thorough discussion of the results of the study of the 
safety of residues in food, and its relevance for the evaluation of potential risks 
presented by residues to humans. This discussion shall be followed by proposals to 
ensure that any danger to man is eliminated by applying internationally recognized 
assessment criteria, for example: no observed effect level in animals, proposals for a 
choice of safety factor and for acceptable daily intake (AD I); 
(h) a thorough discussion of any risks for persons preparing the medicinal product or 
administering it to animals, followed by ,proposals for appropriate measures to 
reduce such risks; 
(i) a thorough discussion of the risks which use of the veterinary medicinal product 
under the practical conditions proposed may represent for the environment followed 
by appropriate proposals to reduce such risks; 
G) all information necessary to acquaint the clinician ~ fully ~ possible with the utility 
of the proposed product. The discussion will be supplemented by suggestions as to 
side-effects and possible treannent for acute toxic reactions in animals to which the 
product is to be administ~red; 
(k) a concluding expert report which provides a detailed critical analysis of the 
information referred to above in the light of the state of scientific knowledge at the 
time the application is submitted together with a detailed summary of all the results 
of the relevant safety tests and precise bibliographical references. 
86 
a.. Residue testiaa 
CHAPTER I 
PERFORMANCE OF TESTS 
1. lati'oduetion 
For the pmposes of this Directive, 'residues' means all active substances or metabolitcs 
thereof which remam in meat or other foodstuffs produced from the animal to which the 
medicinal product in question has been administered. 
The purpose of studying residues is to determine whether, and if so under what 
conditions and to wbat extent, residues persist in foodstuffs produced from treated 
animals and to ascertain the withdrawal periods to be adhered to in order to obviate any 
hazard to human health and/or difficulties in the industrial processing of foodstuffs. 
Assessment of the hazard due to residues entails establishing whether residues are present 
in the animals treated under recommended conditions of use and investigating the effects 
of those residues. · 
In ~e case of veterinary medicinal products intended for use in food-producing animals, 
the residue documentation shall show: 
1. to what exten~ and how long, do residues of the veterinary medicinal product or its 
metabolitcs persist in the tissues of the treated animal .or ·foodstuffs obtained' 
therefrom; 
2. that in order to prevent any risk to the health of the consumer of foodstuffs of treated 
animals, or difficulties in the indus1rial processing of foodstuffs, it is possible to 
establish realistic withdrawal periods which can be observed under practical farming 
conditions; 
3. that practical analytical methods suitable for routine use are available to verify 
compliance with th~. withdrawal period. 
2. Metabolism and rtsidue kinetics 
2.1. "Phanna~oldnetics (absorption, distribution, biotransformation, excretion) 
The pUrpose of pharmacokinetic studies with respect to residue~ of veterinary medicinal 
products is to evaluale the absorption, distribution, biotransformation and excretion of 
the product in the target species. 
lbe final product, or a formulation which is bioequivalent, shall be administered to the 
target species at the maximum recommended dose. 
Having regard .to the method of administration, the extent of absorption of the medicinal 
!)I'Oduct shall be fully described. If it is demonstrated that systemic absorption of produc~ 
for topical application is negligible, further residue studies will not be required. 
87 ·8l/8S21EEC 
Annex . 
(as amended by 
92/18/EEC Art. 1) 
(adapted) 
The distribution of the bledicinal product in the target lliDDal shall be · de5cribed; the 
possibility of plasma protein binding, or passage · h1to .. milk or eggs and· of the 
· accumWati~ of lipophilic compoun~ sball be· cousidered. 
The pathways for the excretion of the product from the target animal shall be described. 
The maj~ metabo~ sball be iden~ed and characterized. 
2.2. Depletion of residues 
The purposes of these· studies, which measure the rate at which residues deplete in the 
target animal after the last administration of the medicinal product, is to permit the 
determination of withdrawal periods.. · 
At varying times after the test animal has received the final dose of the medicinal 
product, the quantities of residues present shall be determined by appropriate physical, 
chemical or biological methods; the· technical procedures and the reliability and 
sensitivity of the methods employed shall be spcc:ified. 
3. Routine analytical method for the detection or residues 
Analytical ·procedures shall be proposed which can be carried out in the course of a 
routine examination and which bave a level of sensitivity such as to enable violations of 
legally 'permitted maximum residue limits to be detected with certainty. 
The analytical method proposed shall be described in detail. It shall be validated and 
shall be sufficiently rugged for use under normal conditions of routine monitoring. for 
residues. 
The following characteristics shall be described: 
specificlty, 
•· accuracy, including sensitivity,·. 
precision, 
limit of detection, 
limit of quantitation, 
-practicability and applicability under normal laboratory conditions, 
susceptibility to interference. 
The suitability of the analytical method proposed shall be evaluated in the light of the 
state of scientific and technical knowledge at the time the application is submitted 
88 . 81/852/EEC 
Annex 
(as amended by 
'92/l~C Art. 1) 
(adapted) 
CHAPT.ERU 
PRESENT AnON OF PARnCULARS AND DOCUMENTS 
.As in any ·scientific work, the dossier of residue tests sbal1 include the following: 
(a) an iiltroduction defining the subject, accompanied by any useful bibliographical 
references; 
(b) a detailed identification of the medicinal, including: 
· composition, 
purity, 
batch identification, 
. relationship to the final product, 
specific activity and radio-purity of labelled substances, 
position of labelled atoms in the molecule;· 
(c) a detailed experimental protocol giving the reasons for any omission of certain tests 
listed above, a description of the methods, apparatus and materials used, details of 
the species, breed or strain of animals, where they were obtained, their number and 
the conditions under which they were housed and fed; 
(d) all the results obtained, whether favourable or unfavourable. The original data should 
be described in sufficient detail to allow the results to be critically evaluated 
independently of their interpretation by the author. The results may be accompanied 
by illustrations; 
(e) a statistical analysiS of the results, where such is called for by the test programme, 
and variance within the data; 
(f) an objective discussion of the results obtained, followed by proposals for maximum 
residue limits for the active substances contained in the product, specifying the 
marker residue and target tissues concerned, and proposals concerning the 
withdrawal periods necessary to ensure that no residues which might constitute a 
hazard for consumers are present ·in foodstuffs obtained from treated animals; 
(g) a concluding expert report which provides a detailed critical analysis of the 
information referred to above in the light of the state of scientific knowledge at the 
· time the application is submitted together with a detailed· summary of the results of 
the residue tests and precise bibliographical references. 
89 811852/EEC 
Annex 
(as amended by 
92/18/EEC Art. 1) 
(adapted) 
PART4 81/852/EEC 
Annex 
PRE-CLINICAL AND CLINICAL TESTING (as amended by 
92/18/.EEC Art. 1) 
The ·particulars and documents which shall accompany applications for marketing (adapted) 
authorizations pursuant to Articles 12 (3) (j) and 13 (1) shall be submitted in accordance 
with. the. provisions of this Part. 
CHAPTER I 
PRE-CLINICAL REQUIREMENTS 
Pre-clinical studies are required to· establish the pharmacological activity and· the 
tolerance of the product. 
A. Pharmacology 
A.1. PHARMACODYNAMICS 
The study of pharmacodynamics shall follow two distinct lines of approach: 
First, the mechanism of action and the pharmacological effects on which the 
recommended application in practice is based shall be adequately described. The results 
shall be expressed in quantitative terms (using, for example, dose-effect curves, time­
effect curves, etc.) and, wherever possible, in comparison with a substance the activity of 
which is well known. Where a higher efficacy is being claimed for an active substance, 
the difference shall be demonstrated and shown to be statistically significant. 
Secondly, the investigator shall give an overall pharmacological assessment of the. active 
substance, with special reference to the possibility of side-effects. In general, the main 
functions shall be investigated. 
The investigator shall identify the effect of the route of adm.inistiation, formulation, etc, 
on the pharmacological activity of the active substance. 
The investigations shall be intensified where the recommended dose approaches that 
liable to produce adverse reactions. 
The experimenia.l techniques, unless they are standard procedures, shall be described in 
such detail as to allow them to be reproduced, and the investigator shall establish their 
validity. The experimental results shall· be set out clearly and, for cenain types of tests, 
their statistical significance quoted. · 
Unless good reasons are given tO the contrary, any quantitative modification of responses 
resulting from repeated administration of the substance shall also be investigated. 
\ 
Medicinal combinations may be prompted either on pharmacological grounds or by 
clinical indications. In the first case, the pharmacodynamic and/or pharmacokinetic 
studies shall demonstrate those interactions which might make the combination itself of 
value in clinical use. In the second case, where scientific justification fcir the medicinal 
combination is sought through clinical experimentation, the investigation shall determine. 
whether the effects expected from the combination can be demonstrated in animals and, 
at least, the importance of any adverse reactions shall be checked. If a combination. 
includes a· novel active substance, the latter shall have been previously studied in depth. 
90 
. 81/852/EEC 
Annex 
Basic pharmacoldnetic information concerning a new active substance is generally useful (as amended by 
in the·clinical context. · · 92/18/EEC Art. 1) 
Pharmacokinetic objectives can be divided into two main areas: 
(i) descriptive pharmacokinetics leading to. the evaluation of basic parameters such as 
body clearance, volume(s) of distribution, mean residence time, etc; 
(ii) use or' these parameters to investigate the relationships between dosage regimen, 
· . plasma and tissue concentration and pharmacologic, therapeutic or toxic effects. 
In target species, pharmacoldnetic studies are, as a rule, necessary in order to employ 
drugs with the greateSt possible efficacy and safety. Such studies arc especially useful to 
assist the clinician in establishing dosage regimens (route and site of administration, 
dose, dosing interval, number of administrations, etc.) and to adopt dosage regimens 
according to certain population variables (e.g. age, disease). Such studies can be more 
efficient in number of animals and generally provide more ·information than classical 
dose titration studies. · 
In the case of new combinations of known substances which have been investigated in 
accordance with the provisions of this Directive, pharmacokinetic studies. of the fixed 
combination are not required if it can be justified tbat the administration of the active 
substances as a fixed combination does not change their pharmacokinetic properties. 
A.2.1. Bioavailability/bioequivalence 
Appropriate bioavailability studies ·shall be undertaken to establish bioequivalence: 
when comparing a reformulated medicinal product with the existing one, · 
when comparing a new method or route of administration with an established one, 
in all cases referred to in Article 13 (1 ). 
91 {adapted) 
B.· Toleraa~.iD the tarcet s~ of uim .. 
The pmpose of thiS stUdy, which sball be Carried out with all animal $JleCies for ~eh the 
. medicinal product is iDteDded, is to carry out in all such aDimal. species local and geo.eral 
tOlerance triaJs· designed to ~lish a tolerated ~e wide enough to allow an adequate 
safety ~ and the ·clinical symptomS of intolerance UsiDg the recommended route -or 
routes, m ·so far as this may be ~eved by increasing the therapeutic dose and/or the 
duration Of treatment The report OD the trials shall comain U many deiaiJs · 8S possible of 
the expeded pharmacological effects and the adverse reactions; the latter shall be 
assessed with due regard to the fact~ the Mjmals used may be ~f very high value. 
The medicinal product shall·be administered at least via the recommended route of 
administration. · 
C. Resistaace 
Data OD the emergence of resistant organiSms are necessary .in the case of medicinal. 
products used for the prevention or trealment of iilfectious diseases ·or parasitic 
infestations in animals. · 
CHAPTERll 
CLINICAL REQUIREMENTS 
1. Geaeral principles 
The pwposes of clinical trials are to demonstrate or substantiate the effect of the 
veterinary medicinal product after administration of the recommended dosage, to specify 
its indications and contra-indications according to species, age, breed and sex, its 
directions for use, any adverse reactions which it may have and its safety and tolerance 
under normal conditions of use. 
Unless justified, clinicai trials shall be carried out with control animals (controlled 
clinical trials). The effect obtained should be compared with a placebo or with absence of 
trealment and/or with the effect of an a~oriz.ed mediciDal product known to be of 
therapeutic value. All the results obtained, whether positive or negauve, shall be 
reponed. 
The methods used to make the diagnosis shall be specified. The results shall be set out by 
making use of quantitative or conventional clinical criteria. Adequate statistical methods 
shall be used and justified. 
92 · 81/852/EEC . AJmex . 
(as .amended by . 
92/18/EEC Art. 1) 
. (adapted) 
ID the case of a VeteriDary medicinal ploduct intended primarily for ~-as. a performance Jl/852/EBC ., 
~cert particadar. ~~n sball be given tO: · · Annex. . 
(as imlend~ by 
• the yield of animal produce, ' 92/18/EEC Art 1) 
(adapted) 
the quality of animal produce (organoleptic, nutritional, hygienic and technological 
qualities), . 
• · ·nutiitional.efficienq and growth of animal, 
the general status ofhealth of the animal. 
Experimental data shall be confinned by data obtained under ~cal field conditions. 
Where, in respect of particular therapeutic indications, the applicant can show tbat he is 
unable to provide comprehensive data on therapeutic etfect because: 
(a)' the indications for which the medicinal _product in question is intended are 
encountered so rarely that the applicant cannot reasonably be expected to provide 
comprehensive evidence; 
(b) in _the present state of scientific knowledge, comprehensive information cannot be 
provided; 
the marketing authorization may only be granted subject to the following conditions: 
(a) the medicinal product in question is to be supplied on veteriuary prescription only 
and may, in certain cases, be administered only under strict veterinary supervision; 
(b) the package insert and any other information must draw the attention of the 
veterinary practitioner to the fact that, in certain specified respects, the particulars 
. available concerning the medicinal product in question are as yet incomplete. · 
2. Performance of trials 
All veterinary clinical trials shall be conducted in accordance with a fully considered 
detailed trial protocol which shall be recorded in writing prior to commencement of the 
trial. The welfare of the trial animals sball be subject to veterinary supervision and shall 
be taken fully into consideration during the elaboration· of any trial protocol and 
throughout the conduct of the trial. 
Pre-established systematic written procedures for the organization, conduct, data 
collection, documentation and verification of clinical trials shall be required. 
93 
Before tbe·ccmuDena:mentof any .trial, the info~ consent of the oWner bfthe ;,Jma1s ·: &1/852/EEC· 
to be ·used m the triai slwlbe obu..med and documeiite~ In particular,. the anima(o\vner Annex 
shall be informed "in Writing of the ccmsequences· of participation in the ,.tri8J for the (as amended. by. 
sUbsequeDt. dispOsai of treated .animals or fot tbe taldn8 of foodstuffs: from ·treated 92/18/EECArt>1) 
ariimaJs •. A. aJPY of this notification, countersigned and dated by the animal owner, shall (idapted) · · 
be included in the lrial documentation.. · 
·Unless the trial is conducted with,a blind design, the provisions. ofArticics ss. S6 and S7 
concerning· the labelling of veterinary medicinal products shall apply by analogy to the 
labelling of formulations intended for use in veterinary clinical trials. In· all cases, the 
. words 'for veterinary clinical trial use only' siWI appear prominently ~d indehbly upon 
the labelling. 
CHAPTER ill 
PARTICULARS AND DOCUMENTS 
As in any scientific wo~ the dossier on efficacy shall include. an introduction defining . 
the subject accompanied by any usetw bibliographical documentation. 
All pre-clinical and clinical documentation must be sufficiently detailed to enable an 
objective judgement to be made. All studies and trials must be reported, whether 
favourable or unfavourable to the applicant 
i. Records of pre-cliDical observations 
Wherever possible, particulars shall be given of the results of: 
(a) tests demonstrating pharmacological actions; 
(b) tests demonstrating the pharmacological mechanisms underlying the therapeutic 
·effect; 
(c) tests demonstrating the main pharmacokinetic processes .. 
Should unexpected results occur during the course of the tests, these should be detailed. 
94 
8.1/852/EEC 
Am:iex .: -. 
(a) aslunmary; (as amended by . 
92/18/EEC Art. 1) 
(b) a detiiiCd .experim~ protocol giving a description of the methods, apparatus and (adapted) 
'materials used, details such as ·species, age, weight,. sex, number, breed or straiD of 
· animals, identification of animals, dose,. route and schedule of administration; 
·-· (c) a staJ:istical analysis· of the results where relev,ant; 
(d) an objective discussion of the results obtained, leading to conclusions on the safety 
. ~ efficacy. of the product. 
Total or partial omission of these data must be explained 
2.1. Records of clinictll observations 
All the· particulars shall be supplied by each of the investigators on individual record­
sheets in the case .of individual treatment and collective record-sheets in the case of 
collective treatment 
The particulars supplied shall take the following form: 
(a) name, address, function and qualifications of investigator in charge; 
I 
(b) place and date. of treatment; name and address of owner of the animals; 
(c) details of the trial protocol giving a description of the methods used, including 
methods of randomization and blinding, details such as the route of administration, 
schedule of administration, the dose, identification of trial animals, ~ies, breeds or 
strains, age, weight, sex, physiological status; · 
(d) method of rearing and feeding, stating the composition of the feed and the nature and 
quantity of any additives contained in the feed; 
(e) case history (as full as possible), occurrence and coW'Se of any inter-current diseases; 
{f) diagnosis and means used to make it; 
. (g) Symptoms and severity of the disease, if possible accor~g to conventional criteria; 
(h) the precise identification of the clinical trial formulation Used in the trial; 
95 
(i) dosage of the medic~ product, method, route'. and hquency of adminisiration and 81/852/EEc· , 
~oos, ·i:f any, taken~ administration (duration of ~jection, etc~);.. AnneX. 
(as amended ,by· 
(j) ~ tJftteatuient and period of subsequent obsemition; 92/18/.EEC Art. 1) 
, . . (adapted) 
(k) all.delailS concerning medicinal products (other thaD that·under study) which have 
. been ~ during the period of examination, either prior to or concmently 
with the teSt_product and, in th~ latter·case, details of the interactions observed; 
0) all results of the clinical~ (including unfavourable oi negative results) with a full 
statement of the .clinical observations and the results of the objective tests of actiVity 
{laboratory analyses, physiological te$),· required to evaluate the application; the 
techniques used must be specified, and the significance of any variations in the 
results explained (for example, variance in method, variance between individuals or 
· the effects of the medication); demonstration of the pharmacodynamic effect in 
animals shall not in itself suffice to justify conclusions concerning any therapeutic 
effect; 
. (m) all particulars of any unintended effects, whether harmful or not, and of any measures 
taken in consequence; the cause-and-effect relationship sball be investigated if 
possible; 
(n) effect of animals' performance (for example: egg-laying, milk production and 
reproductive function); 
( o) effects on the quality of foodstuffs obtained from treated animals, particularly in the 
case of medicinal products intended for use as performance enhancers; · 
(p) a conclusion on each individual case or, where collective treatment is concerned, on 
each collective case. · 
Omission of one or more items (a) to {p) shall be justified. 
The marketing authorization holder shall make all necessary arrangements to ensure that 
the original documents, which formed the basis of the data supplied, are kept for at least 
five years after the veterinary-medicinal product is no longer authorized .. 
96 
2.2:. SUiflit:iary.and conclusions of cliliica! observations 81/852/EEC 
Annex · 
In iespect of eacJi ~linical trial, the clinical observations shall ]?e suminarized in a (as amended by 
synopsiS ~~the trials and the results thereof: indicating in ~cular: · . 92/18/EEC. Ait. I) 
(adapted)' 
(a)· the . nwnber of coJ11:rOis, the number of animals treated either individually or 
· collectively, with a breakdown according to species, b~ or strain, age and sex; 
(b) the number of anjmals withdrawn prematurelY from the trials and the reasons for· 
such wi~drawal; 
{c) in the. case of control animals, whether they have: 
received no treatment; 
received a placebo; 
received another authorized medicinal product of known effect; 
~ received the active substance. under investigation in a different formulation or by a 
differeJ)t route; 
(d) the frequency of observed adverse reactions; 
(e) observations as to the effect on perfon;ance (for example, egg-laying, milk 
production, reprOductive function and food quality); 
(f) details concerning test animals which may be at increased risk owing to their age, 
their mode of ~ or feeding, or. the pmpose for which they are intended, or 
animals the physiological or pathological condition of which requires special 
consideration; 
(g) a statistical evaluation of the results, when this is called for by the test programme. 
Finally, the investigator shall·draw general conclusions from the experimental evidence, 
expressing his opinion. on the harmlessness of the medicinal product under the proposed 
conditions of use, its therapeutic effect and any useful information relating to indications 
and contra-indications, dosage and average duration of treatment and where appropriate, 
any interactions observed with other medicinal products or feed additives as well as anY, 
special precautions to be taken during treatment and the clinical symptoms of 
overdosage. 
In the case of fixed combination products, the investigator shall also draw conclusions 
concerniJlg the safety and the efficacy of the product when compared with the separate 
administration of the active substances involved. 
3. Concludin~ expert report 
The concluding expert report shall provide a . detailed critical analysis of all the pre­
clinical and. clinical documentation in the light of the state of scientific knowledge at the 
time the application is subJ;nitted together with a detailed ·summary of the results of the 
tests and trials submitted ~d precise bibliographic references. 
97 
TITLED 
REQ~ FORIMMUNOLOGI~ VElERINARY 
MEPtCINAL PRODUCTS 
WithoUt prejudice to the specific reqUirements ·iaid doWn by Community legislation tor 
the contrQI and eradication of animal desease; tbefolk>wing ~enf:S sball BJ)ply tb 
immunological veterinary medicinal products. 
PARTS 
SlJMMARY OF 'l'lm·DOSSIER 
A. ADMINISTRATIVE DATA 
The immunological veterinary medicinal product which is the subject of the application 
shall be ·identified by name and by name. of the active substances, together with the 
strength and pharmaceutical form, the method and route of administration, and a· 
description of the final sales presentation of the product. 
The name and address of the applicant shall be given, together with the name and address 
of the manufacturer and· the sites involved in the different ·scages of manufacture 
(including the manufacturer of the finished product and the manufacturer(s) of the active 
substance(s)) and where relevant the name and address .of the importer. 
The applicant sball identify the number and tides of volumes of documentation submitted 
in support of the application and indicate what samples, if any, are also provided. 
Annexed to the administrative data shall be copies of a document showing that the 
manufacturer is authorized to produce immunological veterinary medicinal products, as . I 
defined in Article 44 (with a brie( description of the production site). Moreover, the list 
of organisms bandied at the production site shall be given. 
The applicant shall submit a list of countries in which authorization has been granted, . 
copies of all the summaries of product characteristics in accordance with Article 14 as 
approved by Member States and a list of countries in which an application has been 
submitted. · · 
B. SUMMARY OF PRODUcr CBARACI'ERISTICS 
The applicant shall propose a summary of the product characteristics, in accordance with 
Article 14. 
In addition the applicant shall provide one or more specimens or mock-ups of the sales 
presentation of the immunological veterinary medicinal product,. together· with a package 
insert, where one is required. 
98 · 81/852/EEC 
.Aimex 
(as amcilded by 
92/18/EEC Art. 1) 
( adapteci) . 
. All important data shall be summarised in an appendix to the expert report, whenever 
possible in tabular or graphic form. The expert report and the summaries .shall contain 
prec~ cross references to the information containc;d in the main documentation. 
Each expert report sball be prepared by ·a suitably qualified and experienced ·person. It 
shall be signed and dated by tbe expert, ,and attached to the report shall be brief 
information about the ed~onal background, training and occupational experience of 
the expert. The professional relationship of the expert to the applicant shall be declared. 
PART6 
ANALYTICAL (PHYSICo-cHEMICAL, BIOLOGICAL OR 
MICROBIOLOGICAL) TESTS OF IMMUNOLOGICAL .VETERINARY 
MEDICINAL PRODUCfS 
All test procedures used 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 supplemente~ if necessary, by the manufacturing method. In the case of test 
procedures included in the European Pharlnllcopoeia or the pharmacopoeia of a Member 
State, this description may be replaced by a detailed reference to the pharmacopoeia in 
question. 
99 
A. QUALITATIVE· AND · QUANTITATIVE 
CONSTITUENTS PARTI~ . OF THE 81/852/EEC 
Annex 
(as amended by 
The Particulars and . documents which . must accOmpany applications for marketing 92/18/EEC Art. I) 
authorization, pursuant to. Article 12 (3) {c), shall be submitted in accordance· with the (adapted) 
following requirements. · 
1. Qualitative partieulan 
'·Qualitative particulars' of all the constituents of the· immunological veterinary medicinal · 
product shall mean the designation or description of: 
the active substance(s), 
the constituents of the adjuvants, 
the constituent(s) of the excipients, whatever their nat\U'e or the quantity used, 
including preservatives, stabilizers, emulsifiers, colouring matter, flavouring, 
aromatic substances, markers, etc., 
the constituents of the phannaceutical form administered to animals. 
These particulars shall be supplemented by any relevant data concerning ~e container 
· and, where appropriate, its manner of cloSW'e, together with details of devices with 
which the immunological veterinary medicinal product will be used or administered and 
which will be delivered with the medicinal product. 
2. The 'usual terminology', to be used in describing the constituents of immunological 
veterinary medicinal products, shall mean, notwithstanding the application of the other 
provisions of Article 12 (3) (c): 
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 of the 
monograph in question, which will be obligatory for all such substances, with 
reference to the phannacopoeia 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 cq)propriate, by any other relevant details, 
in respect of colouring matter, designation by the 'E' code assigned to them in 
Directive 78/25/EEC. 
100 
3. · Qaatitative particulars . · 
.ID older .. to give.· dle 'quantitative particUlars• of the activ~ subS.ces of· an 
immunological veterinary medicinal product, it is necessary to specify whenever possible 
the number. of organisms, the specific proteiD content, the mass, the number of 
lntemational Units ·(IU) or units· of biological activity,· either per ~sage-unit or volume, 
and with regard to the adjuvant and to the constituents of the eicipients, .the mass or the 
volume of each of them, with due allowance for the details provided in section B. · 
Where an International Unit of biological activity has been· defined, this sbaU be used. . 
The units of biological activity for which no pUblished data exist shaD ·be expressed in 
such a way as io provide unambiguous information on the activity of the ingredients, e.g. 
by :StatiJig the immunological ·effect on which the method of determining the dose is based.., . . . 
4. Development pharmaceutics 
An explanation · sbaU be provided with regard to t"Qe composition, components and 
containers, supported by scientific data on development pharmaceutics. ~ overage, 
with justification thereof: sball be stated .. The efli:cacy of any preservative system shall be 
dem9nstrated. . 
B. DESCRIPTION OF MANUFACI'URING MEmOD OF THE FINISHED 
PRODUCf 
The description of the manufacturing method accompanying the application for 
marketm.g authorization pursuant to Article 12 (3) (d), shall be drafted in such a way as to 
give an adequate description of the nature of the operations employed. 
For this purpose the description shall include at least: 
the various stages of manufacture (including ·purification procedures) so that an 
assessment can be made of the reproducibility of the manufacturing procedure and of 
the risks of adverse effects on the finished prod~cts, such as microbiological 
contamination, 
in the case of continuous manufacture, full details concerning precautions taken to 
ensure the homogeneity and consistency of each batch ~f the finished product, 
mention of substances which cannot be recovered in the course of manufacture, 
the details of the blending, with the quantitative particulars of all ~e substances used, 
a statement of the stage of manufacture at which sampling is carried out for in-
process control tests. · 
101 811852/EEC . 
Annex 
(as amended by 
92/1.81EEC Art. 1) 
(adapted) 
C. .PRODUCTION AND CONTROL OF STARTJNG.Ml\TERIALS . 811852/EEC 
.Annex 
For ·the purposes of this paragraph 'stBrting materials' means all components Used. in the (as -.nended by 
production of the immunological veterinary medicinal prodilCt. Culture media-used for 92/18/EEC Art. .I) 
the production of the active substance.are considered as one single s1artiJlg material. (adapted) . 
: . . . .. .· .. 
ln~eca5eof 
~ active.· substance not · describCd 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 pharmacopoeial monograph. and for which the 
monograph is inappropnate to adequately control its quality, 
which is manu&ctured by a person different from the applicant, the latter may mange for 
the detailed description of the manufacturing method, quality control during manufacture 
and process validation to be supplied directly to· the ~mpetent authorities by the 
manufacturer of t11e 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 slW1 ensure batch-to-batch . consistency and not modify the 
manufacturing process or specifications without informing the applicant Documents and 
particulars supporting . the application for such a change shall be supplied to the 
competent authorities. · 
The particulars and documents accompanying the application for marketing authorization 
pursuant to·Article 12 (3) (i) and 0) and Article 13 (1) shall include the results of the 
tests relating to quality control of all the components "USed and shall be submitted in 
accordanc~ with the following provisions. 
1. Starting materials listed in pharmacopoeias 
The monographs of the European Pharmacopoeia shall be applicable to all substances 
.appearing in it 
In respect of other substances, each Member State may require observance of its own 
national pharmacopoeia with regard to products manufactured in jts territory. 
Components ful.tilling the requim;nents of the European Pharmacopoeia or the 
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with 
Article 12 (3) (i). In this case the description of the analytical methods may be replaced 
by a detailed reference to the pharmacopoeia in question. · 
102 
Reference ·to pharmacopoeia~. of third ~untries may be permitted in cases ~ere the 
substan~ is described neither m the··Eurapean ·Pharmacopoeia. nor in the national 
p~ia concerned; in .that ~ the monograph shall be sUbmitted, acconipanied 
where·necessary by a tranSlation for whi~h the applicant Win be responsibl~. 
Colouring matter shall, in all· cases, satisfy the requirements· of Council Directive 
78/25/EEC. . 
The routine tests caniea out on each batch of starting materials must be as stated in the 
·application for mirketing author.izaiion. If tests o~ than those mentioned in the 
pharmacopoeia are used, proof must be .supplied that the starting materials meet. the 
quality requirements oftbat pharmacopoeia. · · 
In cases Wtiere a specification or other provisions contained in a monograph of the' 
European Pharmacopoeia or in the national pharmacopoeia of a Member State might be 
insufficient to ensure the quality of the substance, th~ competent authorities may request 
more appropriate specifications from the marketing authorization holder. 
The competent authorities shall inform the authoriti~ reSponsible for the pharmacopoeia 
in question.· The marekting auth9rization holder shall provide the authorities of that 
pharmacopoeia With the details of the alleged insutliciency 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 pharmac:opoeia can be accepted; in such ~s, the applicant shall submit a copy 
of the monograph accompanied where necessary by the validation of the test procedures 
contained in the monograph and by a translation ·where appropriate. For active 
ingredients, demonstration of the ability of the monograph adequately to control their 
quality shall be presented. 
l. Starting materials not listed in a pharmacopoeia 
2.1. Starting materials of biological origin 
The description shall be given in the form of a monograph. · 
Whenever possible, Vaccine production shall be based on a seed lot system and on 
established cell banks. For the production of immunological veterinary medicinal 
products consisting of serums, the origin, general health and immunological status of the 
producing animals shall be indicated; defined pools of source materials shall be used. 
The origin and history of starting materials shall be described .and documented. For 
genetically engineered starting materials this information shall include details such as the 
description of the starting cells or strains, the construction ·of the expression vector 
(name, origin, function of the replicon, promoter enhancer and other regulator elements), 
control ofthe,sequence of DNA or RNA effectively inserted, oligonucleotid.ic sequences 
of plasmid vector in cells, plasmid used . for cotransfection, added or deleted genes, 
biological properties of the final construct and the genes expressed, copy number and 
gen~c stability. 
103 81/852/EEC 
Annex, 
(as amended ~Y 
92/18/EEC Art. 1) 
(adapted) . 
Seed .materials, mcluding, Cell binks and raw serum for anti~serum production shall be 
tested f~ identity ~d adventitious agents. · 
Information sball be provided OD all substances of biologiCal origin used at any stage in 
the manufacturing procedure. The information shall include: . -
details.ofthe source of the materials, 
details of any processing,· purifi~on and inactivation applied, With data on the 
validation of these process and in-process controls, · 
details of any tests for contamination canicd out .. on each batch of the sUbstance. 
If the presence of adventitious agents is detected or suspected, tb:e corresponding material 
shall be discarded ·or. used in very exceptional circumstances only when further 
processing of the produCt ensilres their elimination and/or inactivation; elimination and/or 
inactivation of such adventitious agents shall be demonstrated 
When cell banks are used, the cell characteristics shall be shown to have remained 
unchanged up to the highest passage level used for the production. 
For live attenuated vaccines, proof of the stability of the attenuation characteristics of the 
seed has to be given. 
When required, samples of the biological starting material or reagents used in the testing 
procedures shall be provided to enable the competent authority to arrange for check tests 
to be carried out. 
2.2. Starting materials of non-biological or.igin 
The description shall be given in th~ form of a rqonograph under the following headings: 
the name of the starting material meeting the requirements of point 2 of Section A 
· shall be supplement~ by any trade or scientific synonyms, 
the description of the starting material, set down in a form similar to that used in a 
descriptive item m the European Pharmacopoeia, 
the function of the starting material, 
methods of identification, 
purity shall be described in relation to the sum total of predictable impurities, 
especially those which may have a harmful effect and, if necessary, those which, 
having regard to the. combination of substances to which the application ref~ may 
adversely effect the stability of the medicinal product or distort analytical. results. A 
brief description shall be provided of the tests undertaken to establish the pmity of 
each batch of the starting material, 
104 Jl/852/EEC 
Annex 
(as amended by 
92/18/EEC Art. 1) 
{adapted) 
any· special Precautious ·which may ~ necessary . during storage· of the SWting S·118S21EEC ~ and,. if necessary, its storQe life shall be given. · Annex 
(is amended by 
D. CONTRO~. TESTS DURING ~RODUCI'ION 92/18/EEC Art. 1) 
(adapted) 
1. The particulars' and documents accompanying · an application for marketing 
authorization, ·pursuant to Article 12 (3) (i) and (j) and Article 13. (1 ), shall include 
particulars ~lating to the controJ tests which are. canied out on intermediate products 
with a view ta verifying the consistency of the production process and the final 
.~ ' 
2. For inactivated or detoxified vaccines, inactivation or detoxification shall be tested 
during each production run . immediately~ after the inactivation or detoxification 
process. 
E. CONTROL TESTS ON THE FINISHED PRODUCI' 
The particulars and documents acCompanying the application for marketing authorization 
pursuant to Article 12 (3) (i) and (j) and Article 13 (1), shall include particulars relating 
to control tests on the finished product. Where appropriate monographs .exist, if 
test procedures and limits other than those mentioned in the monographs of the 
Emopean PharmaCopoeia, or failing this, in the national pharmacopoeia of a Member 
State, are used, proof must be supplied that the finished product would, if tested in 
accordance with those monographs, meet the quality requirements of that pharmacopoeia 
for the pharmaceutical form concerned. The application for marketing authorization shall 
list those tests which are. carried out on representative samples of each batch of finished 
produ~ The frequency of the teSts which are not carried out on each batch shall be 
stated. Release limits shall be indicated. 
1. General characteristics of the finished product 
Certain tests of the gene~ characteristics of a product shall be included among the tests 
on the finished product, even if they have been carried out in the course of the 
manufacturing process. 
These tests shall, wherever applicable, relate to the control of average masses and 
maximum deviations, to mechanical, physical, chemical or microbiological tests, physical 
characteristics such· as density, pH, refractive index, etc. For each of these characteristics, 
specifications, with appropriate confidence limits, shall be established by the applicant in 
each particular case. 
2. Identification and assay of active substance(s) 
For all tests, the description of the techniques for analyzing the finished product shall be 
set out in s~ciently precise detail, so that they can be reprodu~d readily. 
The assay of biological activity of the active substance(s) shall be carried out either in a 
representative sample from the production batch or in a number of dosage-units analysed 
individually. 
10S 
Wh~:nccessacy, a specific test for identification sliall also be ·canied o~ 
~ certain exCCJrti:onal cases where assay of active· substances which are very numerous or 
present in very low. ampunts would necessitate an. ~cate investigation difficult to cany._ 
. out in respect of each pociuctioh batch, the assay of one or more active substances· in. the 
finished product may ·be omitied, OQ the express condition tb8t SUCh assays are made at 
intermediate stages as late as possible in the production process. This relaxation may not 
be extended to the chara:cterization of the .substanCes concerned. This simplified 
technique shall be supplemented by a method of quantitative ~evaluation,· enabling the 
com~t. authority to verify that the immunological veterinary medicinal product iS in 
accordance with ~ts formula after it has been placed on the market 
3. ldentifieation and assay of adjuvaats . ~ 
In so far as testing Pr-ocedures are available, the quantity and natw:e of the adjuvant and 
its components shall be verified on the finished product. 
4: Identification and assay of excipient components 
In so far as is necessary, the excipient(s) shall be subject at least to identification tests. 
The test procedure proposed for identifying coloming matters must enable a verification 
to be made that such matters are permitted under Directive 78/25/EEC. 
An upper and lower limit. test shall be obligatory in respect of preserving agents; an upper 
limit test for any other excipient components liable to give rise to an adverse reaction 
shall be obligatory. 
5. Safety tests 
Apart from the results of tests submitted in accordance with Part 7 of this Annex, 
·particulars of safety tests shall be submitted. These tests shall preferably be overdosage 
studies carried out in at least ·one of the most sensitivcr target species and by at least the 
recommended route of administration posing the· greatest risk. 
6. Sterility and purity test 
Appropriate tests to demonstrate the absence of contamination by adventitious agents or 
other substances shall be carried out according to the nature-of the immunological 
veterinary medicinal product, the method and the conditions of manufacture. 
106 81/852/EEC 
Annex 
(as amended by 
92/18/EEC Art. 1) . 
(adapted) 
-7. IDactivaUOD :81/852/EEC 
Annex 
Where ·.ppncable~ a test to verify iDadivation sball ~ carried_ out on the product in the (as amended by ' 
final ~er. · 9Z/.t81£EC An. 1) 
(adapted) 
~ Residual hllllli~ 
Each batch of lyophilized ~et sball-~ tested for residual hilmi~ _. · 
9. Bateh-•bateh .eoaslsteney 
In order to eusure that efficacy of the product is reproduCible from batch to batch and to 
demonstrate conformity with specifications, potency tests based upon in vitro or in vivo 
~~;~ethods, including appropriate .reference materials whenever available, shall be carried 
out on ead1 final bulk or each batch of finished product, with apprOpriate confidence 
limits; in . exCeptional circumstances, · potency testing may be carried out at an 
intermediate stage, as late as possible in the production process. 
· F. . STABD.JTY TESTS 
The particulars and documents accompanying the application for marketing authorization 
pursuant to Article 12 (3) (f) and (i) shall be submitted in accordance with the following 
requirements. 
A description shall be given of the tests uodertaken to supJ)ort the shelf life proposed by 
the applicant. These tests shall always be real-time studies; they shall be carried out on a 
sufficient number of batches prl?duced according to the described production process and 
on products stored in the final container(s); these. tests include biological and physico­
chemical stability tests. 
The conclusions shall contain the results of analyses, justifying the proposed shelf-life 
under all proposed storage conditions. ' 
In the case of products administered in the feed, information shall also be given as 
necessary on the shelf-life of the product, at the different stages of mixing, when mixed in 
accordance with the recommended instructions. 
Where a finished product requires reconstitution prior to administration, details of the 
proposed shelf-life are reqWrec:l for the prodUct reconstituted as recommended. Data in 
support of the proposed shelf-life for the reconstituted product shall be submitted. 
' ' 
107 
PAR.T7 
SAFETY TESTING · 
,• I 
A. INTRODUCI10N 
1. The safety ~ shall show the po•tial risks from the immunol~gical veterinaly 
·medicinal prOdw:t which may occur under the proposed conditions of use in animals: 
these sbal1 be ·evaluated in relation to-the potentiaJ benefits of the product. · 
Where immunologic81 · veteriiwy· medicinal. products consist of live. organisms, 
especially those which could be shed by vaccinated animals; the potential risk to 
unvaccinated animals of the same or of any other potentially exposed species shall be 
evaluated. 
2. nie particulars and documents which shall aceompany the application for marketing 
authorization purSuant to Article 12 (3j (j) and 13 (1) shall be submitted in 
accordance with the requirements of section B. 
3. Member States shall ensure that the laboratory tests are cmied out in conformity 
with the ·principles of good laboratory practice laid down in Council Directives 
87118/EEC and 88/320/EEC. 
B. GENERAL REQ~MENTS 
1.. The safety tests shall be carped out in the target species. 
2. The dose to be used shall be that quantity of the product to be recommended for use 
and containing the maximum titre or potency for which the application is submitted. 
3. The sample used for safety testing shall be taken from a batch or batches produced 
according to the manufacturing process descnDed in the application for marketing 
authorization. 
108 81/852/EEC ·. 
Annex 
(as amended by 
92/18/EEC Art. 1) 
(adapted) . 
C •. LABORATORY~ 
1. ··Safety of the admiDJstration of. one dose 
The immunologi'* .. veterinary' medicinal product ~ be administered at the 
~ended.dose and by each recommended route ~fadu;linistration to animals of each. 
species and category. in which it is intended for use, including anjmals of the minimum 
age of administration. The animaJs sbal1 be obserVed and examined for signs of systemic 
m,d local reactions. Where appropriate, these studies shall· include detailed post-mortem 
macroscopic and microscopic examinations of tbe .injection site. Other objective criteria 
shall be~ such as-~ temperat1D'e and performance ineasurements. 
The anjmals sball be o~served and examined until reactions may no "longer be expected, 
but in all cases, the observation and examination period shall be at least 14 days after 
administration. 
2. Safety of o~e admi.Distration of an overdose 
An overdose of the immunological veterinary medicinal product shall be administered by 
each recommended route of administration to animals of the most sensitive categories of 
the target species. The animals shall be observed and examined for signs of systemic and 
local reactions. Other objective criteria shall be recorded, such as rectal temperature and 
performance measurements. 
The animals shall be observed and examined for at least 14 days after administration. 
3. Safety of the repeated administration of one dose 
Repeated administration of one dose may be required to reveal any adverse effeets 
induced by such administration. These tests shall be carried out on the most sensitive 
categories of the target species, using the recommended route of administration. 
The animals shall be observed and examined for at least 14 days after the last 
administration for signs of systemic and local reactions. Other objective criteria shall be 
recorded, such as rectal temperature and performance measurements. 
4. Examination of reproductive performance 
Examination of reproductive performance shall be considered when data suggest that the 
starting material from which the product is derived may be a potential risk factor. 
Reproductive performance of males and non-pregnant. and pregnant females shall be 
investigated with the recommended dose and by each of the recommended routes of 
administration. In addition, harmful effects on the progeny, as well as teratogenic and 
abortifacient effects, shall be investigated. 
These studies may form part of the safety. studies described in paragraph I. 
109 81/852/.EEC : . 
Annex· 
(as· imended by 
92/18/EEC Art. 1) · 
(adapted) 
5. · Eumiaatlon of lmmuaoJopcal fDDctioDJ 
Where the imDiunologic8l veterinary medicinil. produCt· might adv~IY 8tfect the 
immune respouse .of the vaccinated animal or· of. its oroRenv. suitable tests on the 
immunological f_unctiQDS sblll be cmied out 
~· S~l require10ents for live vaeeines: 
6.1. Spread of the vaccine strain 
Spread of the vaccine strain from vacc~ to unvaccinated target animals sball be 
investigated, using the recommended route of administration most likely to result in the 
spread. Moreover, it may be necessary to investigate the spread to non target species 
which could be highly susceptible to a live vaccine strain. · 
6.2. Dissemination in the vaccinated animal 
Faeces, urine, milk, eggs, oral, nasal and other secretions shall be tested for the presence 
of the organism. Moreover, studies may be required of the dissemination of the vaccine 
strain in the body, with particulir attention being paid to the j,redilection sites for 
replication of the organism. In the case of live vaccines for well established zoonotic 
diseases for food producing animals, these studies must be undertaken. 
6.3. Reversion to virulence of attenuatedvaccines 
Reversion to virulence shall be investigated with material from the passage level which is 
least attenuated between the master seed and the final product. The initial vaccination 
shall be carried out using the recommended route of administration most .likely to lead to. 
reversion to virulence. At least five serial passages through animals of the target species 
shall be undertaken. Where ~ is not technically possible due to fiilure of the organism 
io replicate adequately, as many passages as possible shall be carried out in the target 
species. If necessary, in vitro propagation of the organism may be carried out between 
passages in vivo. The passages shall be undertaken by 1;he route of administration most 
likely to lead to revers~on to virulence. 
6.4. Biological properties of the vaccine strain 
Other tests may be necessary to determine as precisely as possible the intrinsic biological 
properties of the vaccine strain (e.g. neurotropism). 
6.5. Recombination or genomic reassortmenl of strains 
The probability of recombination or genomic reassortment with field or other strains shall 
be discussed 
110 ll/IS21EEC 
Annex 
(as amended by 
92/18/EEC Art. 1) 
(adapted) 
7. Study of fesidues 811$52/EEC 
Annex 
For imDlunological veterinary medicinal products, it will normally not be ·necessary to . (as amended by 
undertake a study ofresidues. However, where adjuvants and/or preservimves are used in 92/18/EEC M 1) 
the manufacture of immuiaological veterinary medicinal prod~, consideration shall be (adapted) 
given. to ·the possibility of any ·residue remaining .in . the foodstuffs~ . If necessary, the 
effects of such residues shaD be investigated. Moreover, in the case ofli~e, vaccines for 
zoonotJc diselses, the· determinat:ion.of residues at the injection site may be required in 
~on to the-studies described m· paragraph 6.2. . . 
A proposal f~ ·a withdrawal period shall be made and its adequacy shall be_ discussed in 
relation to any·resid_ue studies which have· been undertaken. 
8. lateractioas 
Any known interactions with other products shall be .indicated. 
D. FIELD STUDIES 
Unless justified, results from laboratory studies shall be supplemented with supportive 
data from field studies. 
E. ECOTOXICITY 
The purpose of the study of the ecotoxicity of an immunological veterinary medicinal 
.product is to assess the potential harmful effects which the use of the product may cause 
to the environment and to identify any precautionary measures which may be necessary 
to reduce such risks. 
An assessment of ecotoxicity shall be compUlsory for any application for marketing 
authorization for an immunological veterinary medicinal product other than applications 
submitted in accordance with Article 12 (3}0) and 13 (I). 
111 
(8) ·This assessment shall ~o~ be~~ in two p~. . 811852/EEC 
Annex 
The first phase of the assessment shall always be carried out the inv~gator shall assess · (u amended by 
the.potential extent of exposure of the environment to the prOduct, its ~ve substances, ·.92/1.8/EEC Art. 1) 
or relevant metabolites, taking into accouD.~ (adapted) · 
the target species and the proposed pattern of use (for example, mass medication or 
individual animal medi~on), . · 
· the method of ~on, in particular th~ llkely extent to which the prOduC:t will 
enter directly into environmental system, · 
the possible excretion of the product, its active substances or relevant metabolites 
into the environment by treated animals, persistence in such excretia, · 
the disposal of unused or waste product 
Where the conclusions of the first phase indicate potential exposure of the environment 
to the. product, the applicant shall proceed to the second phase and evaluate the potential 
ecotoxicity of the product. For this purpose, he shall consider the extent and duration of 
exposure of the environment to the product, and. the information about the 
physical/chemical, pharmacological and/or toxicological properties of the compound 
obtained during the conduct of the other tests and trials required by this Directive. Where 
necessary, further investigations on the impact of the product (soil, w~r, air, aquatic 
systems, non-target organisms) shall be carried out. 
These further investigations shall be carried out in accordance with the te~ protocols laid 
down in Annex V to Council Directive 67/548/EEC or where an end point is not 
adequately covered by these protocols, in accordance with other internationally 
recognised protocols on the immunological veterinary medicinal product and/or the 
active substances and/or the excreted metabolites as appropriate. The number and types 
of tests and the criteria for their evaluation shall depend upon the state of scientific 
knowledge at the time the application is submitted. 
112 
PAllTI ·· 
EmCACY TRIALS. 
A. .INTRODUCTION. 
1. The purpose of .the trials described in this Part· ·is to demonstrate or to confirm the 
efficacy of the immunological veterinary .m~cinal product. All claims made· by the 
. appliCant with regard to the properties, effects and use of the product, shall be fully 
supported by· results of ~itic trials contained in the application for· marketing 
authorization. · · · 
2. The particulars and· documents which ~ accompany -applications for rilarketing 
authorizations pursuant ·to Article 12 .(3) (j) and 13 (1) sball be submitted· in 
accordance~ -the provisions below. · , 
3. All veterinary clinical tri8ls shall be condu~~ in accordance with a. fully considered 
detailed trial protocol which shall be recorded in w.ritlng prior to commencement of 
the trial. The welfare of the trial animals shall be subject· to veterinary supervision 
and shall be taken fully into consideration during the elaboration of any trial protocol 
and throughout the conduct of the trial. . 
Pre-established systematic written procedures for the organization, conduct, data 
c~llection, docmnentation and verification of clinical trials shall be required. 
4. Before the commencement of any trial, the informed ·consent of the owner of the 
animals to be used in the trial shall be obtained and documented. In particular, the 
animal owner shall be informed in writins of the COJl.Sequences of participation in the 
trial for the subsequent disposal of treated animals or for the taking of foodstuffs 
from treated animals. A copy of this notification, countersigned and dated by the 
animal owner, shall be included in the trial documentation. 
5. Unless the trial is conducted with a blind design, the provisions of Articles 55, 56 
and 57 shall apply by analogy to the labelling of formulations intended for use in 
veterinary clinical trials. In all cases, the words 'for veterinary clinical trial use only' 
shall appear prominently and indelibly upon the labelling. 
B. GENERAL REQUIRE~ 
1. The choice of vaccine strains shall be justified on the ba:sis of epizoological data. 
2. Efficacy trials carried out in the laboratory shall be controlled trials, including 
untreated control animals. 
113 81/852/EEC 
-Annex. 
(as amend~ by 
92/18/EEC Art. 1) 
·(adapted) 
In general, these 1rai1s shaD be supported by trials canied out hi . field. conditions, 
including untreated control animals •. 
. . 
All trials Shall be described in sufficiently precise details so as to be reproducible in 
control trials, carried out at the request of the competent authorities. The investigator 
·shall demonStrate the validity . of all the techniques involved. All results shall be 
plesented as p~isely as possible. · 
All Rsults obtained,. whether favoUrable or unfavourable, shall be reported. 
3. The efficacy . of an immunological veterin8ry . memcinal product shall be 
deDtonstrated for each category of each species recommended for vaccinatio~ by 
each recommended route of administration and using the proposed schedule of 
administration. The influence of passively acquired -and maternally derived 
antibodies on the efficacy of a vaccb:ie shall be adequately evaluated. Any claims 
·regarding the onset and duration of protection shall be supported by data froi:n trials. . 
4. The efficacy of e8ch of the components of multivalent and combined immunological 
veterinary medicinal products shall be demonstrated. If the product is recommended 
for administration in combination with or at the Sam.e time as another veterinary 
medicinal product, they shall be shown to be eompatible. 
S. Whenever a product forms part of a vaccination scheme recommended by the 
applicant, the priming or booster effect or the contribution of the p~duct to the 
efficacy of the scheme as a whole shall be demo~. 
6. The dose to be used shall ~ that quantity of the product to be recommended for use 
and containing the minimum titre or potency for which the ~plication is submitted. 
7. The samples used for efficacy trials shall be taken from a batch or batches produced 
according to the manufacturing process described in the application for marketing 
authorization. 
8. For diagnostic immunological veterinary medicinal products administered to 
animals, the applicant shall indicate how -reactions to the product are to be 
interpreted. 
1. In principle, demonstration of efficacy shall be undertaken under well controlled 
laboratory conditions by challenge after administration of the immunological 
veterinary medicinal product to the species animal under the recommended 
conditions of use. In so far as possible, the conditions under which the challenge is 
carried out shall mimic the natural conditions for infection, for example with regard 
to the_ amount of cllallenge organism and the route of ~on of the cllallenge. 
2. If possible, the immune mechanism (cell-mediated/humoral, locaJ/general classes of 
immunoglobulin) which is initiated after the administration of the immunological 
veterinary medicinal product to target -inimals by the rccon;unend~ roUte of 
administration shall be specified -and documented. · 
114 81/852/EEC · 
AnneX .. 
(as amtmded by 
92/18/EECM 1) 
(~) 
D. F1ELD TRIALs 81/852/EEC · 
· · Annex 
1.-Unlessjustified, resuits ftopl Jaboratoey trials shall· be supplemented with data from (as amended by 
. . field 1rials. · · 92/18/EEC Art. 1) 
2. ·Where laboratory trials cannot be supportive of efficacy, the peiforinance of field 
· trials ·alone may be acCeptable. 
PAR.T9' 
PARTICULARS·AND DOCUMENTS CONcERNING SAFETY TESTING AND 
EmCACY. TRIALS ·OF IMMUNOLOGIC~ VETERINARY MEDICINAL 
PRODUCfS· 
A. INTRODUCI'ION 
As in any scientific work, the dossier of safety and efficacy studies shall include an 
· introduction defining the subject and in~cating the tests ~hich have been carried out in 
compliance with Parts 7 and 8, as well as a summary, with references to the published 
literature. Omission of any tests or trials listed in Parts 7 and 8 shall be indicated and 
discussed. 
B. LABORATORY STUDIES 
The following shall be. provided for all studies: 
2. the niune of the body having carried out the studies; 
3. a detailed experimental protocol giving a description of the methods, apparatus and 
materials used, details such as species, breed or strain of animals, categories of 
animals~ where they were .obtained, their identification and number, the conditions 
under which they were housed and fed (stating inter. alia whether they were free from 
any specified pathogens and/or specified antibodies, the nature and quantity of any 
additives contained in the feed), dose, route, schedule and dates of administration, a 
description of the statistical methods used; 
4. in the case of control animals, whether they received a placebo or no treatment; 
I 
llS (adapted) . 
• •t . 
·S. ·all geoeral.and individual obserVations and results obtained (wbh averages and· 811852/EEC. 
staDdard . deviations), whether favOmable or unfavourable.· ·ne datA sball· be Annex· · · 
described in .. Jumcient detail to· allow the resUlts to be critically evaluatei:l (as amended. by 
· independently of their~ by the author •. ne raw data Sball be presented in · 92/li!EEC ~ 1) 
tabuJar:form. By way of explanltion and illus1ration, the results ~Y be acccmipai;iied (adapted) 
by reproductions of reccmtings, photomicrographs, etc.; 
. . 
6. · the nature, frequency and duration of obser:ved sido-e1fects~ 
7. the number of animals ~wn prematurely ftom the studies and reasons for sUch 
withdrawal; . 
8. a· statistical milYsis of the ~, where such is called ·for by the test· programme, 
mdwrlm~~~the~ · · 
9. OCCWTence and course of any intercuri'ent disease; 
10. all details concerning medicinal products (other than the product under study), the­
administration ofwhi~h was n~cessaey during the course of the study; 
11. an objective discussion of the results obtained, 1Qdmg. to conclusions on the .safety 
·.and efficacy of the product. 
C.· FIELD STUDIES 
Particulars concerning field studies shall be sufficiently detailed to enable an objective 
judgement to be made. ·They shall include the following: 
I. a summary; 
2. name, address, function and qualifications of the investigator in charge; 
3. place and date of administration, name and address of the owner of the animal(s); 
4. details of the trial protocol, giving a description of the methods, apparatus and 
materials. used, details such as the route of administration, the schedule of 
administration, the dose, the categories of animals, the duration of observation, the 
serological response and other investigations carried out on the animals after 
administration; · · 
... 
S. in the case of control animals, whether they received a placebo or no treatment; 
6. identification of the treated and control animals (collective or individual, as 
· appro~ }, such as species, breeds or strains, age, weight, sex, physiological status; . . 
7. •· brief clesclipion of the. ·mel;hod of rearing .and feeding, ~ the nature and 
quantity of any additives ccmtained in the feed; · 
. . 
·a. all· the. particulars on observations,. performances· and results-(~ av«ages and 
· ... stiodard deviation); individual da1a shall be. ilidicated When tests and measurements 
. OD in~ have been CIJried out; 
9. all obserVations and results of the studies, whether filvo~le or unfavourable~ With 
a tWl statement of the observati~ and the results of the objective tests of activity 
required to evaluate the product; the techniques -used must be specified and the 
significance of any variations in the results explained; 
10. effect on the animals' performances· (e.g. egg laying. milk production,· reproductive 
· performance); · · 
11. the number of animals withdrawn prematurely from the studies and reasons for ~eh 
withdrawal; 
12. the nature, frequency and duration of ob~ed adverse reactions; 
13. oecurrence and course of any intercmrent disease; 
14. all details concerning medicinal products (other than the product 1mder study) which 
have been administered either prior to or concmrently with the test prOduct or during 
the observation period; details of any interactions observed; 
IS. an objective discussion of the results obtained, leading to conclusions on the safety 
and efficacy of th~ product. 
D. GENERAL CONCLUSIONS 
General conclusions on all results of tests and trials canied out in compliance with Pans 
7 and 8 shall be given. They shall contain an objective discussion of all the results 
obtained and lead to a· conclusion on the safety and efficacy of the immunological 
veterinary medicinil product. 
E. BmLIOGRAPHICAL REFERENCES 
The bibliographical references cited in the summary mentioned under Section A shall be 
~inde~. . 
117 81/852/EEC. 
Annex . 
(as amended by · 
92/18/EEC Art. 1) 
(adapted) 
·ANNEXn 
Pan A 
Repealed DireetiVes 
(referred to by 1\rti~le 98) 
Council Directive 81/851/EEC (OJNo L 3i7, 6. 11.1981~ p.l) 
Council Directive 90/676/EEC (OJ L 373,31.12.1990, p. 15) 
. Council Directive 90/677/EEC (OJ L 373, 31.12.1990, p. 26) 
Council Directive 92f74/EEC (OJ L 297, 13.10.1992, p. 12) 
Council Directive 93/40/EEC (OJ L 214,24.8.1993, p. 31) 
Council ~irective 81/852/EEC (OJ L 317, 6.11.1981, p. 16) 
Council Directive 87/20/EEC (OJ L 15, 17.1.1987, p. 34) 
Council.Directive 92/18/EEC (OJ L 97, 10.4.1992, ·p. 1) 
Council Directive 93/40/EEC (OJ L 214,24.8.1993, p. 31) 
118 
Directive 81/851/EEC 
· Directive 81/852/EEC. 
· Directive· 87/20/EEC 
Directive 90/676/EEC 
Directive 90/677/EEC 
Directive 92/18/EEC 
.Directive 92174/EEC 
Directive 93/40/EEC ' . ~art B. 
. . . 
~~·_for tnmspositioo into oatioullaw 
'.. (referred to by Article 94) 
Directive 
119 9 October 1983 
9 October 1983 
l July 1987 
1J~1992· 
1 January 1992 
1 Aprill993 
31 December 1993 
1 January 1995 
1 January 1998 (An. I. 7) 
This Directive Dir. 6S/6SIEEC 
Art. I (1) and {2) Art. I (I) and (2) · 
Art. I ~ 3) ) 
Art. I~ 4) Art. I. point 3 
Art. I I S)and(6) 
Art. I~ 7) 
Art. I~ 8) 
Art. I~ 9) 
Art. I (10) to (13) 
Art. I (14) 
Art. I (IS) 
Art. I (16) 
Art.2 , 
Art. 3 (I), 1st 
sub h 
Art. 3 (I}, 2nd 
sub h 
Art. 
Art. 3 (2) ANNEX Ill 
CORRELATION TABLE 
Dir. 81/85 I !EEC Dir. 81/852/EEC 
Art. I (I) 
Art. 1.1 2).-2nd indent 
Art. 11 IT-
Art. I I 2). 3rd and 4th indents 
Art. S. 3rd suboara21'8Ph. point 8 
Art.42b 
Art. SOa (If 2nd SUL h 
Art.l6 (I) .. 
Art. 18 (I), footnote 
Art .. 2 I) 
Art. 2 (2), 1st indent 
Art. 2 (3) 
120 ; Dir. 90/677/EEC Dii:. 
92174/EEC 
.. 
•. 
Art. I (2} · 
Art. I 
I 
I 
I 
I 
' 
.. 
.. l 
I 
.. 
Art. I (3) · . 
This Directive · Dir. 65/65/EEC .. Dir. 81/85 I !EEC Dir. 81/852/EEC Dir. 90/677/BEC Dir. 92174/BEC 
Art. 3 (3) and (4) Art. I ( 4}_ and 1SJ Art. I (I) 
Art. 3 (5) -Art. 2 (2), 3rd indent 
Art. 3 ~ 6) Art. 1 (4) 
Art. 4 ~ I) Art. I (4) 
Art. 4 ~ 2) Art.3 
Art. 5 Art. 4_(1 ), 1st sub_parag.raph -· 
Art.6 Art. 4 (2), 1st subparagraph 
Art. 7 Art. 4 ( 1 ), 2nd subparagraph .. 
Art. 8 Art. 4 (I),_ 3rd sub_paragraph 
Art.9 Art. 4 (3)f. 1st subparagraph 
Art. 10 (I) and (2), Art. 4 (4), 1st and 2nd subparagraphs . -
lstand 2nd. "' -subparagraphs 
Art. 10 (2), Art. 2 ·(I), 2nd . 
3rd subparagraph subparagraph 
Art. 11 Art. 4 (4), 3rd subparagraph 
Art. 12 (I) Art. S, 1st subparagraph 
Art. 12 {2) Art. s, 2rid subparagraph 
Art. 12 {3) {a) to {i) Art. S, 3rd subpargraph, points I to 9 Art. 1, 1st 
.I subparagral)h I 
Art. 12 (3) (j) Art. S, 3rd subpargraph, points 10, Jst 
. I subparagt¥h 
Art, 12 {3) (k) to Art. S, 3rd subpargraph, poirits 11 to 14 I 
(n) 
Art. 13 (I) Art. S, 3rd subpargraph, points I 0, 2nd 
1 subparagraph 
~ 
121 
This Directive Dir. 6S/6SIEEC Dir. 81/8S I /EEC Dir. 81/8S2/EEC Dir. 90/677/EEC Dir. 92174/EEC 
Art. 13 (2) Art. I, 2nd sub 'h 
Art. 14 Art. Sa .. 
Art. IS (I) Art.6 
Art. IS (2) and (3) . Art. 7 ,. 
Art. 16 -Art. 6 . 
Art. 17 (1) M 7(1) . 
Art. 17 (2) ,. Art. 7 (3) 
Art. 17 (3) . Art. ~. 2rid -. 
sub . h 
Art. 18 .. Art. 8 
Art. 19 Art.9 .I 
Art. 20 Art. 2 (3) . 
Art. 21 Art. 8 
Art. 22 Art.8a 
! 
Art.23 Art.9 
Art. 24 Art. 10 
Art. 2S Art. Sb 
Art. 26 (I) and (2) Art. "12 • - I 
Art. 26 (3) Art. IS {2) ------
122 
This Directive Dir. 65/65/EEC Dir. 811851/EEC · Dir. 81/852/EEC Dir. 90/677/EBC Dir. 92174/EBC 
Art. 27 (I) Art 14 (I), I st subparagraph · 
Art. 27 (2) Art. 14 ( 1). 2nd subparagraph 
Art. 27 (3) Art. 14 (2) .. 
Art. 27 (4) and (S) Art. 14 (j) and (4) 
Art. 28 Art. IS (I) 
Art. 29 Art. 13 -
Art. 30 Art. 11 
Art. 31 (1) Art. 16(1) 
Art. 31 (2) Art. 16 (il 
Art. 31 (3) Art. 16 (3) 
Art. 32 (I) . Art. 17 (3) . 
Art. 32 {2) Art. 17 (I) 
Art.32(3) ~. 17-(2) 
Art. 32 (4 Art. 17 (4) . 
Art. 33 Art. 18 
)U1.34 Art. 19 
Art.3S Art.20 
Art. 36 Art, 21 I 
Art. 37 Art. 2fln 
Art. 38 Art. 22 {2). {3) and {4) . 
Art. 39 Art. 23 _ 
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Art. 40 Art.23a . 
Art. 41 Art. 23b 
Art.42 Art.23c 
Art. 43 Art. 22 (5) 
Art. 44 Art.24 : 
Ait.45 Art.25 
Art. 46. Art. 26 ·-
Art.47 Art. 28{1) • 0 
Art.48 Art. 28 (2) 
Art. 49 . Art. 28(3)-
Art. so Art.27 .. 
Art. 51 Art.27a 
Art. 52 Art. 29. 
Art. 53 Art. 31 .. 
Art. 54 Art.32 
Art. ss (I) M· .~0 (1 ), 1st and 2nd .. 
- su" hs ' : 
Art. ss (2) Art. 30 (1).3rd subpara~h ~ .. 
Art. ss (3) Art. 30 (2). 
Art. 56 Art.33 : .. 
Art. 57 Art.3 
Art. 58 (I) to (3) Art.43 ' 
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Art. 58 (4) Art. 47 
Art. 59 I) Art. 44 \. 
Art. 59 2) Art. 45 
Art. 59 3) Art.47 
Art.60 Art.46 ~ 
Art. 61 (I) Art.48(1) 
Art. 61 (2)' Art. 48 (2) 
Art. 61 3) Art. 48 (3) 
Art.62 Art. 49. 1st paragraph 
Art.63 Art. 50 , 
Art. 64 I) Art. 2 (2} 
Art. 64 ~2) . Art. 7(2)-
Art. 65 ~ I) Art. SOa(l~ 1st and 3rd subparagraphs 
Art. 65 ~ 2). (3) and (4) Art. SOa (2), (3) and ( 4}_ 
Art. 66 Art. SOb 
Art.67 Art. 4· (3 ), 3rd subparagraph ... 
Art.68 Art. I (5) 
Art. 69 Art.SOc 
Art. 70 Art. 4 (S) 
Art. 71 Art.4 
Art. 72 Art.42e 
Art. 73 -Art. 42a 
-L______ 
12S 
.. 
This Directive Dir. 65/65/EEC Dir. 81/851/EEC Dir. 81/852/EEC Dir. 90/677/EEC Dir. 92r/4/EBC 
Art. 74 Art.42c ' 
Art. 15 . Art. 42d .. 
Art. 76 Art.42f . ' 
Art. 77 Art. 422 I 
Art. 78 Art. 42h 
Art. 79 .. Art. 42i ~ 
Art. 80 (I) Art. 34, 1st and 2nd subparagraphs · ~ 
Art. 80 (2) Art. 3 (I) . . r 
Art. 80 {3) Art. 34, 3rd subparagraph 
Art. 81 {1) Art. 35 
Art. 81 (2) Art. 3 (2) 
Art. 82 . Art. 3 (3) .. 
.. 
Art.83 Art.36 I 
Art. 84 Art.37 .. 
Art.8S Art. 38 
Art.86 Art. 4, lst. 
sub paragraph 
Art. 87 Art. 38a 
Art.88 Art. 2b 
Art. 89 Art.2a '. 
Art.90 . Art. 42_i .. 
Art. 91· . Art.42k 
Art.92 Art.39 
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Art. 93 Art. 42 .. 
I 
Art.94. Art. 5 . . 
Art. 95 Art.24a .. 
Art. 96 Art. 40 and 41 . .. 
Art. 91 Art. 4 (2), 2nd subparagraph 
Art. 98 - - - - - -
Art. 99 - - - - -. 
'Art. lOO - - - - -
Annex I Annex , 
Annexll - - - -~ •· 
Annex Ill - - - - - ~-
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