Proposal for a European Parliament and Council Directive on the Community code relating to veterinary medicinal products - (codified version)
Date: 1999-09-08
Institutions: European Commission
Subjects: approximation of laws, codification of EU law, marketing, public health, veterinary drug

COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels, 08.09.1999 
COM( 1999) 213  final 

99/0180 (COD) 

Proposal for a 

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 

Brussels, 08.09.1999 
COM( 1999) 213  final 

99/0180 (COD) 

Proposal for a 

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, 
interinstitutional  agreement 
dated 20 December  1994,  that  an  accelerated  procedure  may  be  used  ·for  the  fast-track  adoption  of 
codification instruments. 

the  Commission  have  agreed,  by  an 

the  Council  and 

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  products0 l,  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 
·  of vetefin:uY medicinal products must be the ~guarding of public health; 

1. 

811851/.£EC 

(3)  Whereas,  however, this objective must be achieved bY  means which will not 
hinder the development of indusby and trade in medicinal products within the 
Co~unity; 

2. 

81/851/EEC 

( 4)  Whereas,  in so  far as the Member States already have certain provisions laid 
down  by  law,  regulation  or  administrative  action  governing  veterinary 
medicinal products, such provisions differ in essential principles; whereas this 
results in the hindering of trade in medicinal-products within the Community, 
thereby directly affecting the fimctioning of the intemal market;· 

3. 

811851/EEC 
(adapted) 

4. 

81/851/EEC 

3. 

90/676/EEC 

3. 

' 
93/40/EEC 
(adapted) 

(5)  Whereas such hindrances must, accordingly, be removed; whereas this entails 

approximation of the ~Ievant provisions; 

( 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 
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 
Regulation  (EEC)  No  2309/93  of 22  July  1993  laying  down  Community 
procedures  for  the  authorization  and  supervision  of medicinal  products  for 
human  and  veterinary  use  and  establishing  a  Emopean  Agency  for  the 
),  a marketing authorization in one Member 
Evaluation of Medicinal Products«1
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 
(EEC) No 2309/93. 

10. 

81/851/EEC 
(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 
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; 

11. 

811851/EEC 
. 
(adapted) 

(lO)Whereas  medicated  feedingstuffs  do  not  come  within  the  scope  of this 
·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; 

6. 

.81/851/EEC 

.(ll)Whereas  the  concepts  of  harmfulness  and  therapeutic  efficacy  can  be 
examined only in relation to one another and have only a relative significance, 
· 
depending on the progress of scientific knowledge and the  use for which the 
medicinal product is intended;  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; 

(12)Whereas  marketing  authorization  should  be  refused  where  a  medicinal 
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; 

I 

(13)Wbereas  such  marketing  authorization  should  cilso  be  refused  where  the 
withdrawal  period  indicated  is  not  long  enough  to  eHminate  health  hazards 
arising from residues; 

(14)Whereas,  before  an  authorization  to  market  an .immunological  veterinary 
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 
use  of  an 
the 
immunological responses of the treated animal will interfere with a national or 
Community  programme  for  the  diagnosis,  eradication  or  control  of animal 
disease; 

immunological  veterinary  medicinal·  product  when 

7. 

811852/EEC 
(adapted} 

7. 

8. 

811851/EEC 
(adapted) 

81/851/EEC 
{adapted) 

5. 

90/677/EEC 

,.  6. 

90/677/EEC 

( 16) Whereas  it  is  desirable  in  the  first  instance to  provide  users  of homeopathic 
medicinal products with a very clear indication of their homeopathic character 
and with sufficient guarantees of their quality and saf~ty; 

7. 

92174/EEC 

(17)Whereas  the  rules  relating  to  the  manufiscture,  control  and  inspection  of 
homeopathic veterinaey medicinal. products must be harmonized to permit the 
circulation throughout the  Community  of medicinal  products  which  are  safe 
. and of good quality; 

8. 

92174/EEC 

s 

(li)Wbereas, having.regard to· the particill8r characteristics.ofthese·hm;neopadiic 
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 
·.  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 
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; 

9. 

92!14/EEC 
(adapted) 

11. 

92n4/EEC 
(adapted) 

4. 

93/40/EEC 
(adapted) 

(21 )Whereas, in order to facilitate the movement of veterinary medicinal products 
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, 

12 

811851/EEC 
(adapted) 

(22)Whereas the quality of veterinary medicinal products manufactured within the 
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; 

7. 

90/676/EEC 
(adapted) 

(23)Whereas  measures  should  also  be  taken  to  ensure  that  distributors  of 
veterinary medicinal products are authorized by MCJQber States and maintain 
adequate records; 

10. 

90/676/EEC 

6 

(24)Whereas standards  and.protocols for. the  perfouliance  of tests  on veterinary 
·  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 
the  basis of UDifom  tests and by reference to uniform  criteria,  and therefore 
helping to obviate diff~ces in evaluatioD; 

3. 

+ 

4. 

811852/EEC 
(adapted) 

(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 
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. 
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 
exchange of 
the 
information  between  Member  States 
surveillance o( veterinary medicinal· products and in particular the monitoring 
of adverse  reactions  under  practical  conditious  of use  through  the  natio!W 
phannacovigilance systems; 

relating 

to 

(28)Whereas in order to improve the protection of public health, .it is necessary to 
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 

the 
necessary changes  laid  down  in  Annex  I  in  order  to  adapt  to  scientific  and 
technical progress; . 

should  be  empowered 

to  adopt 

· 

6. 

90/676/EEC 

s. 

93/40/EEC 

6. 

93/40/EEC 

7. 

93/40/EEC 

7. 

90/677/EEC 
(adapted) 

(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: 

(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) 
(adapted) 

81/851/EEC 
Art.  1 (1) 
(adapted) 

81/851/EEC 
Art.  1 (2), 2nd indent 

65/65/EEC 
Art.  1 (3) 
81/851/EEC 
Art.  1 (1) 
(adapted) 

1. 

.Propriet'al'y medicinal product: 

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

. 

. 

2.  Veterinluy medicinlll product: 

Ally  substance  or  combination  of substances _presented  for  treating  or  preventing 
. 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 

•  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. 

. 5.  Pr.,mi% for medicatedftedingstuffs 

65165/EEC, 
Art. 1 (3) 
81/85 1/EEC . 
Art.  1 (1) 
(adapted) 

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 

90/677/EEC 
Art.  I (2) 

92n4/EEC 
Art.  I 

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 
in  the 
Member States. 

the  pharmacopoeias  CUil'ently  used  officially 

thereof:  by 

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

9.  Withdrawal period 

Period between the last administration of the veterinary medicinal product to animals 
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 
of the maximum limits laid down in applying Regulation (EEC) No 2377/90. 

(adapted) 

. 81/851/EEC 
Art. 5, 3rd paragraph, (8) 
(as amended by 

9 

·1 0.  Adverse l'eaction 

·  81/SS 1/EEC · 
Art.42b 
(as amended by 

A reaction which is harmfUl and uninteJided and which occurs at doses normally used 
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. 

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) 

10 

The provisions of this Directive shall·apply to veterinacy medicinal products 

. 

. 

. 

I 

,Artiele2 · 

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 
prescriptions of a  pbannacopoeia  and  is  intended  to  be  supplied  directly  to  the.  Art. 1 (1) 
(adapted) 
end-user (commonly known as the official formula); 

in  accordance  with 

the  81/851/EC 

· 

5.  Veterinary medicinal products based on radio-active isotopes; 

811851/EEC 
Art. 2 (2), 3rd inden~ 

1

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 
accordance with that Directive. 

.Art. 1 ( 4) 
(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 
(as amended by 
Commission of the detailed conditions of use. 
90/676/EEC Art. 1 (4)) 
(adapted) 

· 

· 

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) 

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 
·veterinary  . medicinal  product  prepared 
Member  State  concern~  of  a 
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 

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. 

811851/EEC  . 
Art. 4 (4), 1st and 2nd 
subparagraphs 
(as amended by 
90/676/EEC Art.  I_  (4)) 
(adapted) 

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. 

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 
(adapted) 

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. 

811851/EEC 
Art. 4 (4), 3rd 
subparagraph 
(as amended by 
90/676EEC Art I ( 4)) 
(adapted) 

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. 

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) 

14 

· 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 
(adapted) 

(c)  qualitative  and  quantitative  particulars  of all  the  constituents  of the  veterinary 
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. 

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) 

16 

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 
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; 

that 

the 

81/851/EEC 
Art. S, 3rd paragraph, 
point 10, 2nd. 
subparagraph  . 
(as amended by 
90/676/EEC Art.  1 (S)) 
(adapted) 

(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. 

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; 

81/851/EEC 
Art. Sa 
· {as amended by~ 
90/676/EEC Art. 1 (6)) 
(adapted) 

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 

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, 

81/851/EEC 
Art Sa 
(as amended by 
90/676/EEC Art 1 (6)) 
(adapted) 

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 

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: 

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

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

(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; 

811851/EEC 
An. 7 (1), (2) and (3),  1st 
subparagraph 
(adapted) 

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. 

81/851/EEC 
Art. 7 (3), 2nd 
subparagraph 
(as amended by 
90/676/EEC An.  I (8)) 

20 

··  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 
State shall take due account of registrations and ·authorizations previously granted by 
another Member State. 

(adapted) 

·  · 

· 

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 
quality and the batch-to-batch homogeneity of the products concerned: 

(adapted) 

· 

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~. 

· 

-

This Chapter shall not apply to immunological veterinary medicinal products. 

Ardele20 

92174/EEC 
Art. 2 (3) 
(adapted) 

23 

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) . 

81/851/EEC 
Art. 8 
(as amended by 
93140/EEC Art. 1 (6)) 
(adapted) 

.. 

. 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). 

81/851/EEC 
Art.8a 
(as amended by 
93/40/EEC Art.  1 (7)) 
(adapted) 

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 

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;  ·  · 

811851/EEC 
Art. 9 (2) 
(as amended by 
90/676/EEC Art.' 1 (9)) 
(adapted) 

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; 

81/851/EEC 
Art. 9 {3) 
(adapted) 

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. 

81/851/EEC 
Art. 9 (4) 
(as amended by 
90/676/EEC An.  I (10)) 
(adapted) 

811851/EEC 
Art. 10 

Member States shall take all appropriate measures to ensure that:. 

Article%4 

(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. 

811851/EEC 
Art. Sb 
(as amended by 
93/40/EEC Art. 1 (5)) 
(adapted) 

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 

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 
from  the  clinical  and 
relating 
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. 

to  use  and  any  other  Warnings  . resultiDg 

(adapted) 

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. 

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) 

27 

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. 

81/851/EEC 
Art.  16 (1) 
(as amended by 
93/40/EEC Art.  i (l 0)) 
(adapted) 

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.(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 
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 
require the applicant to provide it with all the particulars and documents necessary to 
enable it to check that the dossiers filed are identical. 

(as amended by 

(adapted) 

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) 
(as amended by  . · 

· . a Member  State,  the holder. of_ the authorization  sbal1  submit an  application  to the 

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 
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. 

(adapted)  · 

· 

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 

811851/EEC 
Art. 17 (4) 
(as amended by 
93/40/EEC Art. 1 (1 0)) 
(adapted) 

Article33 

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 
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 
shall indicate what action may be necessary to correct any defect in the application. 

(as amended by 

(adapted) 

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 
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 
matter to the Committee for application ofthe p~ wd down in Article 36. 

(as amended by 

(adapted) 

. 

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· 
marketing  authorization  which  appears  necessary,  in  particular  to  take  account  of the 
information collected in accordance with Title vn. 

(adapted) 

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. 

81/851/EEC 
Art. 21 
(as amended by 
93/40/EEC Art.  1 (10)) 
(adapted) 

In case of urgency,  on a proposal from  its Chairman, the Committee may agree to a. 
shorter deadline. 

· 

· 

2. 

3. 

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. 

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 

811851/EEC 
Art. 21  . 
(as amended·by 
93/40/EBC Art. 1 ( 1 0)) 
{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 

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. 

81/851/EEC 
Art. 22 (2), (3) and (4) 
(as amended by 
93/40/EEC Art 1 (1 0)) 
·(adapted) 

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. 

in  the  opinion  of  the  Commission, 

Where, 
the  written  observations  of  a 
Member State raise important new questions of a scientific or technical nature which 
have  not been  addressed  in  the  opinion of the  Agency,  the  Chairman  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 

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. 

81/851/EEC 
Art. 2~ 
(as amended by 
93/40/EEC Art. 1 ( 1 0)) 
(adapted) 

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

These arrangements shall include a notification. system or administration 'procedures 
concerning minor variations and define precisely the concept of "a minor variation". 

These  arrangements  shall  be  adopted  by  the  Commission  in  the  form  of  an 
implementing regulation in ~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 

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 
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 
Articles 36, 37 and 38. 

(as amended by 

(adapted) 

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. 

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

·Artiele43 

81/851/EEC 
Art. 22 {5) 
{as amended by 
93/40/EEC Art. 1 (10)) 
(adapted) 

36 

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. 

811851/EEC 
Art. 24 (3), 2nd 
subparagraph 
(as amended by 
90/676/EEC Art. 1 (15)) 

Article45 

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) 
(adapted) 
the day on which the competent authority receives the application. 

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: 

. (a) -have  at  his  disposal  the  services  of Staff complying  with  the  legal  requireDients 
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; 

81/85 1/BEC· 
Art. 27 (a) to (e) 
(adapted) 

(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. 

811851/EEC 
Art. 27a 
(as amended by 
90/676/EEC An. 1 {18)) 
(adapted) 

39 

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 
(adapted) 

-

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 

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. 

3. 

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 
standards of good manufacturing practice  at least .equivalent to those  laid down  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. 

subparagraph 
(as amended by 

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. 

-

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

·Article 57 

92n4/EEC 
Art.3· 
(adapted) 

43 

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. 

81/851/EEC 
Art. 43 (1), points  1 and 
2 (as amended by 
90/676/EEC Arl1 (23)) 
.(adapted) 

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; 

81/851/EEC 
Art. 43  (1 ), points 3 to 6 
(adapted) 

(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 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". 

2. 

lbe.pharmaceutical·form and  the  contents  by weight,  volume  or num~ of dose-
. units need only be shown on the outer package. 

81/8$1/BEC 
Art. 43 {1), points 10 
andll 

81/851/EEC 
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 
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. 

(as amended by 

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) 
(adapted) 
clearly separate from such particulars. 

46 

Article 62 

Where tbe ps:ovisiollS of this Title are not observed and a formal notice addressed to the 
person conceriaed bas been  ineffectual, tbe  competent authorities  of the  Member States  Art. 49, 1st paraaraph 
may suspend or withdraw lll81'ketinl authorization 

. 81/IS li£EC 

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: 

· 

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) 

(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 

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: · 

81/851/EEC 
Art. SOb 
(as amended by 
90/676/EEC Art. 1 (27)) 
(adapted) 

(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 

811851/EEC 
Art. 4 (3), 3rd 
subparagraph 
(as amen~ by 
90/676/EEC Art.  I (4)) 
(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 

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 
inflammatoty, honnoJ.ial ~r psychotropic properties~ 

that  have  anabolic,  anti-infectious,  anti-parasitic;  anti 

81/851/EEC 
Art. 1 (5) 
(as amended by 
90/676/EEC An.  I (1 )) 
(adapted): 

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: 

811851/EEC 
Art. 50c 
(as amended by 
90/676/EEC Art.  1 (27)) 
(adapted) 

(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 

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 
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: 

(as.amended by 

· 

· 

· 

(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 
·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 . 

(adapted) 

·· 

. 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.. 

. 

Si/851/EEC 
.Art.42e 
(as amended by 
93/40/EEC Art. l {12)) 
(idapted) 

Artie~73 

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 
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. 

'(as amended by 

· 

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. 

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) 

Article 77 

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 
of adverse reaction reports. 

(as amended by 
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. 

·si!Bsi!EEc  . 
Arl42h 
(as amended by ·.  · 
93/40/EEC Art.  1 (12)) 
(adapted)  . 

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 

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 
Art 34, 2nd 
authoritywho·sballbe empowered to: 
subparagrapb 
(adapted) 

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

(b)  take samples; 

(c)  examine any documents relating to the object of the inspection, subject to current 
provisions  in the  Member States from  9 October  1981  which  place  restrictions 
on 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) 
(adapted) 
are completely validated and batch-to-batch consistency ·is ensured. 

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. 

811851/EEC 
Art. 34, 3rd 
subparagrapb 
(as amended by 
90/676/EEC Art.  1 (19)) 

Article 81 

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 
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. 

(adapted) 

,, 

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 
~orization wh~ 1i is clea;r tbat: · 

· 

· 

· 

' 

'81/85 1/EEC 
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 
other  requirement  or  obligation  relating  to  the  grant  of the  manufacturing 
authorization referred to in Article 44 (I) has not been complied with. 

(adapted) 

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. 

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

Article 86 

92n4/EEC 
Art. 4 (1) 
(adapted) 

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. 

· 

81/851/EEC 
Art. 38a 
(as amended by 
90/676/EEC Art. 1 (20)) 

.  (adapted) 

60 

.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. 

811852/EEC 
Art. 2b  . 
(as amended by  . 
87/20/EEC Art. 1 (1)) 
(as amended by 
93/40/EEC Art. 2) 

2.  The Standing Committee shall.adopt its own rules of procedure. 

.  (adapted) 

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. 

81/852/EEC 
Art. 2a 
(as amended 87/20/EEC 
Art.  1 (1)) 
(adapted) 

61 

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) 

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 

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 
. authorization to place J)roducts on·the mlrket.· 

· 

(as amended by 
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 
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 
based. 

(as amended by 

(adapted) 

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. 

81/851/EEC 
Art. 24a 
(as amended by 
90/676/EEC Art. 1 (16)) 
{adapted) 

~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 

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. 

811851/EEC 
Art. 4 (2), 2nd 
subparagraph 
(as amended by 
93/40/EEC Art.  1 (2)) 
(adapted) 

64 

.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. 

This Directive enters into force on  I January 2000. 

Article 99 

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 

The particulars and documents accompanying an application for marketing authorization 
. 
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 
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. 

(adapted) 

81/852/EEC  . 
·Annex 
(as amend~ by 

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 
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. 

to 

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 

81/852ffiEC 
Annex 
(as amended by. 
92/18/EEC Art.  1} 
(adapted} 

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 

C.  . EXPERT REPORTS 
. 

. In  acco~ with  Article  15 · (2)  and  (3), ·expert  reports  must  be  provided  oli  the 
analytical  doauilen1atioo, 
.doculnetitation and th~ clinical ~on.  · 

the · ptwmacotoxict>logical  documentation, 

· 

the  residues  92/18/EEC Art:.l) 

"(adapted)  . 

81/8S21EEC· 

•,  AmleX 

(as amended by 

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 

ANALYTi~ ~BYSIC().CBEMIC~ BIOLOGIC~ OR. 
MICRQBIOLOGICAL)  TESTS  OF  VETERINARY  MEDICINAL  PRODUCfS  92/18/EEC Art. 1) 
OTHER THAN IMMUNOLOGICAL VETERINARY MEDiCINAL PRODUCTS 

(adapted) . 

.  · 

. · 

· 

stts52iEEC 
.Annex 
(as amended by 

·PART~. 

. 

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, 

92/18/EECArt. 1) 
(adapted) 

· 
. 

international  non-proprietary  name 
in  respect  9f  . otb.ef  substances, 
the 
· 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 

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. 

81/852/EEC .. 
Annex 
(as.amended by 
92/18/EEC Art. 1) 
(adapted) 

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 

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. 

. 811852/EEC 
Aimex 
(as amended bY. 
92/18/EEC 
Art. 1) 
(adapted) 

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 

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. 

. 

. 

81/852/EEC 
Annex 
(as amended by 
92/.18/EEC Art. 1) 
(adapted) 

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  a  monograph  of  the  ·European 
In  cases  where  a  specmcation  contained 
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 

(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 
adversely affect the stability of the medicinal product or aistort analytical results;  · 

(as imended by- 
·  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) 
(adapted) 

If the presalee:· of potentiauy pathogenic· adventitious  agents  is  inevitable,  the  material 
. 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 

&11852/EEC . 
Almex 
(as amended by 
92/18/EEC Art. 1) 
(adapted) 

. 

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 

· 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 
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 
degradation products~ 

(as ~ended by 

(ad8pted) 

· 

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. 
· 
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 
at  the  end  of the  shelf ~ of the  finished  product under  these  recommended  storage 
conditions. 

'Annex 
(as;amendecfby. 

(adapted) 

· ·· 

· 

· 

· 

. 

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. 

2. 

3. 

4. 

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

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

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

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 
thapeutic potential oftbe product and about the hazards connected with its use.  · 

(as amended by 
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 

the  mediciDal  product  produces 

Pharmacological studies are of fun~ental importance in·clarifying the mechanisms by 
which 
therefore 
pharmacological studies conducted· in  experimental and  target species· of animal  should 
be included in Part 4. 

therapeutic  eff~  and 

its 

· 

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. 

· 

the  safety  documentation  shall  always  be  preceded  by  details  of 
Therefore 
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 

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 
·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, 
for example by inhalation or dermal contact, these routes should be studied. 

(as amended by 

(adapted) 

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 

(6) 

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. 

81/852/EEC 
.. 
Ann~ 
(as amended by 
92/18/EEC An. I) 
(adapted) 

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 

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. 

81~852/EEC 
Ann~ 
. (as amended by 
92/18/EEC Art. .1) 
(adapted). 

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 
'Annex 
(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 

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: 

Bi/8S2/EEC 
Annex 
(as ·amended by 
92/18/EEC Art.  1) 
(adapted) 

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 
,  or  where  an  end  point  is  not. 
down  in  Annex  V  of Council  Directive  671548/EEC'1
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. 

· 

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; 

811852/EEG 
Annex 
(as amended by 
92/18/EEC Art.  I) 
(adapted) 

. 

(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 

. 

. 

~ 

(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 
independently of their interpretation by the author. By way of explanation, the results 
may be accompanied by illustrations; 

· 

·Annex 
(as amended by 
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 

·8l/8S21EEC 
Annex 
. 
(as amended by 
92/18/EEC Art. 1) 
(adapted) 

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. 

2. 

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; 

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 

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. 

. 81/852/EEC 
Annex 
(as amended by 
'92/l~C Art. 1) 
(adapted) 

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 

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: 

811852/EEC 
Annex 
(as amended by 
92/18/EEC Art. 1) 
(adapted) 

· 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 

PART4 

PRE-CLINICAL AND CLINICAL TESTING 

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

81/852/EEC 
Annex 
(as amended by 
92/18/.EEC Art.  1) 
(adapted) 

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 

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

· 

. 81/852/EEC 
Annex 
(as amended by 
·  92/18/EEC Art. 1) 

{adapted) 

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 

· 81/852/EEC  . 
. 
AJmex 
(as .amended by . 
92/18/EEC Art. 1) 
. (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 

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 
92/18/EEC Art 1) 
(adapted) 

• 

the yield of animal produce,  ' 

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 
(as amended. by. 
shall  be  informed "in  Writing  of the  ccmsequences· of participation  in the ,.tri8J  for  the 
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 
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. 

(idapted)  · · 

· 

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  .:  -. 
(as amended by  . 
92/18/EEC Art. 1) 
(adapted) 

(a)  aslunmary; 

(b)  a detiiiCd .experim~ protocol giving a description of the methods,  apparatus and 
'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· 
92/18/.EEC Art. 1) 
(adapted) 

(j)  ~ tJftteatuient and period of subsequent obsemition; 

, 

. 

. 

(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 

In  iespect  of eacJi  ~linical trial,  the  clinical  observations  shall  ]?e  suminarized  in  a 
synopsiS ~~the trials and the results thereof: indicating in ~cular: 
. 

· 

(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; 

81/852/EEC 
Annex  · 
(as amended by 
92/18/EEC. Ait.  I) 
(adapted)' 

{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 

· 81/852/EEC 
.Aimex 
(as amcilded by 
92/18/EEC Art. 1) 
( adapteci)  . 

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 
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. 

. 

I 

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 

. 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 
MEDICINAL PRODUCfS 

.VETERINARY 

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 

PARTI~ . OF  THE  81/852/EEC 

CONSTITUENTS 

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 
following requirements. 

(adapted) 

· 

Annex 
(as amended by 

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. . 

811852/EEC  . 
Annex 
(as amended by 
92/1.81EEC Art. 1) 
(adapted) 

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 

C.  .PRODUCTION AND CONTROL OF STARTJNG.Ml\TERIALS  . 

For ·the purposes of this paragraph 'stBrting materials' means all components Used. in the 
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)  . 

. 

. 

.. 

.· 

.. 

: 

. 

811852/EEC 
.Annex 
(as -.nended by 

ln~eca5eof 

~ active.· substance  not · describCd  in  the  European  Pharmacopoeia  or  in  the 
pharmacopoeia of a Member State, 

or 

.-

in  the  European  Pharmacopoeia  or  in  the 
an  active  substance  described 
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~. 

81/852/EEC 
Annex, 
(as amended ~Y 
92/18/EEC Art. 1) 
(adapted)  . 

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 

Jl/852/EEC 
Annex 
(as amended by 
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 

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 
92/18/EEC Art. 1) 
(adapted) 

D.  CONTRO~. TESTS DURING ~RODUCI'ION 

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 

81/852/EEC 
Annex 
(as amended by 
92/18/EEC Art. 1) . 
(adapted) 

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 

-7. 

IDactivaUOD 

Where ·.ppncable~ a test to verify iDadivation sball ~ carried_ out on the product in the 
final ~er. 

· 

:81/852/EEC 
Annex 
(as amended by ' 
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 

81/852/EEC ·. 
Annex 
(as amended by 
92/18/EEC Art. 1) 
(adapted)  . 

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· imended 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 

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 

ll/IS21EEC 
Annex 
(as amended by 
92/18/EEC Art. 1) 
(adapted) 

~·  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 

7.  Study of fesidues 

For imDlunological  veterinary medicinal  products,  it will normally  not  be ·necessary to 
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 
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. 

(adapted) 

. 

. 

811$52/EEC 
Annex 
. (as amended by 

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 

·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 
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. 

the  product,  and.  the 

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 

(8) 

PAllTI  ·· 

EmCACY TRIALS. 

A.  .INTRODUCTION. 

81/852/EEC 
-Annex. 
(as amend~ by 
92/18/EEC Art.  1) 
·(adapted) 

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 

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. · 

81/852/EEC  · 
AnneX  .. 
(as amtmded by 
92/18/EECM 1) 
(~) 

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 amended by 
·  92/18/EEC Art. 1) 

(adapted) 

. 

D.  F1ELD TRIALs 

·  · 

1.- Unlessjustified, resuits  ftopl Jaboratoey trials shall· be supplemented with data from 
. .  field 1rials. 

· 

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 

• 

•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 
· 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 
by reproductions of reccmtings, photomicrographs, etc.; 

·  · 
(as amended. by 

(adapted) 

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 

. 

81/852/EEC. 
Annex 
(as amended by  · 
92/18/EEC Art. 1) 
(adapted) 

. 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 

·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 

~art B. 

. 

.  . 

~~·_for tnmspositioo into oatioullaw 
'..  (referred to by Article 94) 

Directive 

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 

' 

. 

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) 

119 

This Directive 

Dir. 6S/6SIEEC 

Dir. 81/85 I !EEC 

Dir. 81/852/EEC 

Dir. 90/677/EEC  Dii:. 

ANNEX Ill 
CORRELATION TABLE 

Art.  I (I) and (2) 
) 

· 

Art.  I. point 3 

Art.  I (I) 
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'Art.  lOO 
Annex I 
Annexll 
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