Proposal for a European Parliament and Council Directive on the Community code relating to medicinal products for human use - (codified version)
Date: 1999-06-28
Institutions: European Commission, Legal service
Subjects: approximation of laws, codification of EU law, customs harmonisation, labelling, market approval, marketing standard, medicinal product, pharmaceutical legislation, public health

COMMISSION OF THE  EUROPEAN COMMUNITIES 

Brussels, 28.06.1999 
COM(1999)315  final 

99/0134 (COD) 

Proposal for a 

EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE 

on the Community code relating to medicinal products for human use 

(codified version) 

(presented by the Commission) 

EXPLANATORY MEMORANDUM 

I.  In the context of a people's Europe, the Commission attaches great importance to  simplifying and clarifying Community 
law so as to make it clearer and more accessible to the ordinary citizen, thus giving him new opportunities and the chance 
t~ make use of the specific rights it gives him. 

This  aim  cannot  be  achieved  so  long  as  numerous  provisions  that  have  been  amended  several  times,  often  quite 
substantially, remain scattered, so that they must be sought partly  in the original  instrument and  partly  in  later amending 
ones. Considerable research work, comparing many· different instruments, is thus needed to identify the current rules. 

For this reason a codification of rules that have frequently  been amended is also essential if Community law is to be clear 
and transparent. 

2.  On  1 April  1987  the  Commission  therefore  decided  to  instruct  its  stall· that  all  legislative  measures  should  be  codified 
after  no  more  than  ten  amendments,  stressing  that  this  was  a  minimum  requirement  and  that  departments  should 
endeavour to condify at even  shorter intervals the texts for  which  they  were  responsible,  to  ensure  that the Community 
rules were clear and readily understandable. 

3.  The  Conclusions of the  Presider:tcY  of the  Edinourgh  European  Council  (December  J 992)  confinned  this,  stressing  the 

importance of legislative codification as it offers certainty as to the law applicable to a given matter at a given time. 

It must be undertaken in full compliance with the normal Community legislative procedure. 

Given that no changes of substance may  be made to the instruments affected  by  legislative codification,  Parliament,  the 
Council  and  the  Commission  have  agreed,  by  an  interinstitutional  agreement  dated  20  December  1994,  that  an 
accelerated procedure may be used for the fast-track adoption of codification instruments. 

4.  The purpose of this  proposal I  for  legislative  codification  of Council  Dir~ctives 65/65/EEC  of 26  January  1965  on  the 
approximation  of provisions  laid  down  by  law,  regulation  or  administrative · action  relating  to  medicinal  products; 
75/318/EEC  of 20  May  1975  on  the  approximation  of the  laws  of Member  States  relating  to  analytical,  pharmaco 
toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products; 75/319/EEC 
of 20 May  1975  on  the  approximation  of provisions  laid  down  by  law,  regulation  or administrative  action  relating  to 
proprietary  medicinal  products;  89/342/EEC  of  3  May  1989  extending  the  scope  of  Directives  65/65/EEC  and 
75/319/EEC and laying down additional provisions for  immunological medicinal  products consisting of vaccines,  toxins 
or serums and allergens; 89/343/EEC of 3 May  1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and 
laying  down  additional  provisions  for  radiophannaceuticals;  89/381/EEC  of  14  June  1989  extending  the  scope  of 
Directives  65/65/EEC  and  75/319/EEC  on  the  approximation  of  provisions  laid  down  by  law,  regulation  or 
administrative  action  relating  to  medicinal  products  and  laying  down  special  provisions  for  proprietary  medicinal 
products  derived  from  human  blood  or human  plasma;  92/25/EEC  of 31  March  1992  on  the  wholesale  distribution  of 
medicinal  products  for  human  use;  92/26/EEC  of 31  March  1992  concerning  the  classification  for  the  supply  of 
medicinal  products for  human  use;  92/27/EEC of 31  March  1992  on  the  labelling of medicinal  products for  human  use 
and  on  package  leaflets;  92/28/EEC  of 31  March  1992  on  the  advertising  of medicinal  products  for  human  use;  and 
92/73/EEC of22 September 1992 widening the scope of Directives 65/65/EEC and 75/319/EEC on the approximation of 
provisions  laid  down  by  law,  regulation  or  administrative  action  relating  to  medicinal  products  and  laying  down 
additional  provisions  on. homeopathic  medicinal  products,  prepared  ~y the  Legal  Service  in  conjunction  with  the 
Directorate-General  Ill,  is  to  undertake  official  codification  of this  type.  The  new  directive  will  supersede  the  various 
directives  incorporated  in  it2,  their  content  is  fully  preserved,  and  they  are  brought  together  with  only  such  formal 
amendments as are required by the codification exercise itself. 

4a  In  order to  point out the  satisfactory  application  of the  codification  of the  Directive  mentioned  above,  in  order to  take 
into account the fact that since the  last Directive cited  in  point 4, the European Agency  for the Evaluation of Medicinal 
Products has been established by Council Regulation (EEC) 2309/9~ of22 July  1993. 

In  the same manner,  in  order to  point out that this codification  proposal  concerning  medicinal  products  for  human  use 
was created in parallel with the codification proposal for Directives relating to veterinary medicinal products. 

Entered in the legislative programme for  1998. 

2 

See Annex 11, Part A of this Proposal. 

2 

5.  This  legislative  codification  proposal  was  drawn  up  on  the  basis  of a  preliminary  consolidation,  in  all  the  official 
languages.  The.  instruments  ~ending it,  carried  out  by  the  Office  for  Official  Publications  of  the  European 
Communities, by means of the data-proeessing system referred  to  in  the conclusions of the European Council meeting at 
Edinburgh.  Although the articles have  been given  new  numbers,  the old  numbering  has  been  retained  in  the  margin  for 
ease  of reference;  the  correlation  between  the  old  and  new  numbers  is  shown  in  a table  set  out  in  Annex  Ill  of the 
consolidated Directive. 

3 

Proposal for a 
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE .•• / ... /EC 

on the Community code relating to medicinal products for human use 

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN 
UNION, 

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

Having regard to the proposal from  the Commission; 

Having regard to the opinion of the Economic and Social Committee1 

Acting in accordance with the procedure laid down in Article 251  of the Treaty2, 

the 

( 1)  Whereas  Council  Directive  65/65/EEC  of  26  January  1965  on 

testing  of  proprietary  medicinal 

the 
approximation  of provisions  laid  down  by  law,  regulation  or administrative 
action  relating  to  medicinal  products3,  .Council  Directive  7 5/318/EEC  of 
20 May  1975  on the  approximation  of the  laws  of Member  States  relating 
to  analytical,  pharmaco-toxicological  and  clinical  standards  and  protocols 
in  r~spect  of 
products4, 
Council Directive  75/319/EEC  of 20  May  1975  on  the  approximation  of 
provisions  laid  down  by  law'  regulation  or  administrative  action  relating 
to  proprietary  medicinal  productsS,  Council  Directive  89/342/EEC  of 
3 May 1989  extending  the  scope  of Directives  65/65/EEC  and  75/319/EEC 
immunological  medicinal 
and 
products  consisting  of  vaccines, 
toxins  or  serums  and  allergens6, 
Council Directive  89/343/EEC  of  3  May  1989  extending  the  scope  of 
Directives 65/65/EEC and 

laying  down  additional  provisions  for 

OJC 

2 
3 
4 
5 
6 

OJ 22, 9.2.1965, p.  369/65. Directive as last amended by Directive 93/39/EEC (OJ L 214, 24.8.1993, p. 22). 

OJ L  147, 9.6.1975, p.  I. Directive as last amended by Directive 93/39/EEC. 

OJ L,  147, 9.6.1975, p.  13. Directive as last amended by Directive 93/39/EEC. 

OJ L  142, 25.5.1989, p.  14. 

4 

on 

and 

1992 

laying 

additional 

provisions 

92125/EEC 

of  31  March 
products 

75/319/EEC 
for 
down 
radiophannaceuticals1,  Council  Directive  89/381/EEC  of  14  June  1989 
extending  the  scope  of  Directives  65/65/EEC  and  75/319/EEC  on  the 
approximation of provisions  laid down  by  law,  regulation  or administrative 
action relating to medicinal products and laying down special provisions for 
proprietary medicinal products derived from human blood or human plasma2, 
the 
Council  Directive 
usel, 
wholesale  distribution  of  medicinal 
Council Directive  92/26/EEC  of  31  March 
the 
the  supply  of  medicinal  products  for  human  usc4, 
classification for 
· Council  Directive  92/27/EEC  of  31  March  1992  on  the  labelling  of 
medicinal  products 
leafletsS, 
Council Directive  92128/EEC  of  3 f·  March  1992  on  the  advertising  of 
medicinal  products  for  human  use6,  Council  Directive  92/73/EEC  of 
22 September  1992  widening  the  scope  of  Directives  65/65/EEC  and 
75/319/EEC on the approximation of provisions laid down by law, regulation 
or  administrative  action  relating  to  medicinal  products  and  laying  down 
additional  provisions  on  homeopathic  medicinal  products 7  have  been 
frequently and substantially amended; whereas,  in the interests of clarity and 
rationality,  the  said  Directives  should  therefore  be  codified  by  assembling 
them in a single text; 

t 992  concerning 

and  on  package 

for  human  use 

human 

for 

(2)  Whereas the essential aim of any rules governing the production, distribution 

1. 

89/341/EEC 

and use of medicinal products must be to safeguard public health; 

(3)  Whereas,  however,  this  objective must be attained  by  means  which  will  not 
hinder the development of the pharmaceutical industry or trade  in  medicinal 
products within the Community; 

2. 

65/65/EEC 

I 
2 
3 
4 
s 
6 
7 

OJ L 142, 2S.S.J989, p.  16. 

OJ L  181, 21.6.1989, p. 44. 

OJ L Jl3, 30.4.1992, p.  I. 

01 L 113, 30.4.1992, p. S. 

OJ L 113, 30.4.1992, p. &. 

OJ L 113, 30.4.1992, p.  13. 

OJ L 297,  13.10.1992, p. 8. 

5 

(4)  Whereas  trade  in  medicinal  products  within  the  Community  is  hindered  by 
in  particular  between 
disparities  between  certain  r:-ational  provisions, 
(excluding  substances  or 
provisions  relating 
combinations of substances  which  are  foods,  animal  feeding-stuffs  or toilet 
preparations); and whereas such disparities directly affect the functioning  of 
the internal market; 

to  medicinal  products 

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

approximation of the relevant provisions; 

( 6)  Whereas in order to reduce the disparities which remain, rules should be laid 
down on the control of medicinal products and the duties incumbent upon the 
Member  States'  competent- authorities  should  be  specified  with  a  view  to 
ensuring compliance with legal requirements; 

(7)  Whereas  the  concepts  of harmfulness  and  therapeutic  efficacy  can  only  be 
examined  in  relation  to  each  other  and  have  only  a  relative  significance 
depending on the progress of scientific knowledge and the  use  for which  the 
medicinal product is  intended;  whereas the  particulars and documents  which 
. must accompany  an  application  for  marketing  authorization  for  a  medicinal 
product  demonstrate  that  potential  risks  are  outweighed  by  the  therapeutic 
efficacy of the product; 

(8)  Whereas  standards  and  protocols  for  the  performance  of tests  and  trials  on 
medicinal  products  are  an  effective  means  of control  of these  products  and 
hence  of protecting  public  health  and  can  facilitate  the  movement  of these 
products  by  laying  down  uniform  rules  applicable  to  tests  and  trials,  the 
compilation of dossiers and the examination of applications; 

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

3. 

65/65/EEC 
(adapted) 

4. 

2. 

7. 

3. 

2. 

65/65/EEC 

75/319/EEC 
(adapted) 

75/318/EEC 
(adapted) 

75/318/EEC 
(ad~pted) 

87/21/EEC 
(adapted) 

6 

( 1 0) Whereas,  however,  there  are  reasons  of public  policy  for  not  conducting 

4. 

87/21/EEC 

repetitive tests on humans or animals without over-riding cause; 

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

4. 

75/318/EEC 

(12)Whereas, with the exception of those medicinal products which are subject to 
the  centralized  Community  authorization  procedure  established  by  Council 
Regulation  (EEC)  No  2309/93  of 22  July  1993  laying  down  Community 
procedures  for  the  authorization  and  supervision  of medicinal  products  for 
human  and  veterinary  use  and  establishing  a  European  Agency  for  the 
Evaluation of Medicinal Products 1 a marketing authorization  for a medicinal 
product granted  by  a  competent  authority  in  one  Member State  ought to  be 
recognized  by  the  competent  authorities  of the  other  Member States  unless 
there  are  serious  grounds  for  supposing  that  the  authorization  of  the 
medicinal product concerned may present a risk to public health;  whereas,· in 
the  event  of a  disagreement  between  Member  States  about  the  quality,  the 
safety  or the  efficacy  of a  medicinal  product,  a  scientific  evaluation  of the 
matter should be undertaken according to a Community standard, leading to a 
single  decision  on  the  area  of disagreement  binding  on  the  Member  States 
concerned;  whereas  this  decision  should  be  adopted  by  a  rapid  procedure 
ensuring close cooperation between the Commission and the Member States; 

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

(14)Whereas this  Directive represents an  important step towards  achievement of 
the  objective  of the .free  movement  of medicinal  products;  whereas  further 
measures  may·  abolish  any  remaining  barriers  to  the  free  movement  of 
proprietary  medicinal  products  will  be  necessary  in  the  light  of experience 
gained,  particularly  in  the  abovementioned  Committee  for  Proprietary 
Medicinal Products; 

(15) Whereas  in  order better to  protect public  health  and  avoid  any  unnecessary 
duplication  of effort  during  the  examination  of application  for  a  marketing 
authorization  for  medicinal  products,  Member  States  should  systematically 
prepare  assessment  reports  in  respect  of each  medicinal  product  which  is 
authorized  by  them,  and  exchange  the  reports  upon  request;  whereas, 
furthermore, a Member State should be able to suspend the examination of an 
application  for  authorization  to  place  a  medicinal  product  on  the  market 
which is currently under active consideration in another Member State with a 
view to recognizing the decision reached by the latter Member State; 

4. 

93/39/EEC 
(adapted) 

4. 

5. 

75/319/EEC 
(adapted) 

75/319/EEC 
(adapted) 

5. 

93/39/EEC 
(adapted) 

OJ L214, 24.8.1993, p.  I; Regulation as amended by Commission Regulation (EC) No 649198 (OJ L 88, 24.3.1998, p.  7). 

7 

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

(17)Whereas  it  is  necessary  to  adopt  specific  provisions  for  immunological 
medicinal  products,  homeopathic  medicinal  products,  radiopharmaceuticals, 
and medicinal products based on human blood or human plasma; 

(18)Whereas  any  rules  governing  radiopharmaceuticals  must  take  into  account 
the  provisions  of Council  Directive  84/466/Euratom  of 3  September  1984 
laying  down  basic  measures  for  the  radiation  protection  of  persons 
undergoing medical examination or treatment1; whereas account should also 
be taken of Council Directive 80/836/Euratom of 15  July  1980 amending the 
Directives laying down the basic safety standards for the health protection of 
the general public and workers against the dangers of ionizing radiation2, the 
objective  of which  is  to  prevent  the  exposure  of workers  or  patients  to 
excessive or unnecessarily high levels of ionizing radiation, and  in  particular 
of Article  Se  thereof,  which  requires  prior authorization  for  the  addition  of 
radioactive substances to medicinal products as well as for the importation of 
such medicinal products; 

( 19) Whereas  the  Community  entirely  supports  the  efforts  of the  Council  of 
Europe  to  promote  voluntary  unpaid  blood  and  plasma  donation  to  attain 
self-sufficiency throughout the  Community in  the  supply of bl~od products, 
and to ensure respect for ethical principles  in trade  in  therapeutic substances 
of human origin; 

6. 

93/39/EEC 

8. 

7. 

75/319/EEC 
(adapted) 

89/343/EEC 
(adapted) 

5. 

89/381/EEC 

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

6. 

89/381/EEC 

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

10. 

92173/EEC 
(adapted) 

(22) Whereas  the  anthroposophic  medicinal  products  described  in  an  official 
pharmacopoeia and prepared  by a homeopathic  method are  to  be  treated,  as 
regards  registration  and  marketing  authorization,  in  the  same  way  as 
homeopathic medicinal products; 

4. 

92173/EEC 

I 
2 

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

OJ L 246,  17.9.1980, p.  1:  Directive as  amended by Directive 84/467/Euratom (OJ  L 265,  5.  10.  1984, p.  4); repealed with  effect from  13  May 2000 by 
Directive 96/29/Euratom (OJ L 314, 4.12.1996, p. 20). 

8 

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

8. 

92173/EEC 

(24)Whereas  the  rules  relating  to  the  manufacture,  control  and  inspection  of 
to  permit  the 
homeopathic  medicinal  products  must  be  harmonized 
circulation throughout the Community of medicinal  products which  are  safe 
~nd of good quality; 

9. 

92/73/EEC 

(25) Whereas  the  usual  rules  governing  the  authorization  to  market  medicinal 
products should be applied to  homeopathic medicinal  products placed on the 
market  with  therapeutic  indications  or  in  a  fonn  which  may  present  risks 
which  must  be  balanced  against the  desired  therapeutic  effect;  whereas,  in 
particular,  those  Member  States  which  have  a  homeopathic  tradition  should 
be able to apply particular rules  for  the  evaluation  of the results  of tests  and 
trials intended to establish the safety and efficacy of these medicinal products 
provided that they notify them to the Commission, 

92173/EEC 

(26)Whereas  in  order  to  facilitate  the  movement  of medicinal  products  and  to 
prevent the controls carried out in  one Member State  from  being repeated  in 
-another,  minimum  requirements  should  be  laid  down  for  manufacture  and 
imports  coming  from  third  countries  and  for  the  grant  of the  authorization 
relating thereto; 

6. 

75/319/EEC 
. 
(adapted) 

(27)Whereas it should be ensured that,  in the Member States, the supervision and 
control of the  manufacture  of medicinal  products  is  carried  out by  a  person 
who fulfils minimum conditions of qualification; 

· 

(28) Whereas, ·before  an  authorization  to  market  an  immunological  medicinal 
prod.uct  or derived  from  human  blood or human  plasma can  be  granted,  the 
· 
to  attain  batch-to-batch 
manufacturer  must  demonstrate  his  ability 
consistency; whereas before and authorization to market a medicinal product 
derived  from  human  blood  or  human  plasma  can  be  granted, 
the 
the  absence  of  specific  viral 
manufacturer  must  also  demonstrate 
contamination, to the extent that the state of technology permits; 

7. 

5. 

+ 
7. 

75/319/EEC 
(adapted) 

89/342/EEC 
(adapted) 

89/381/EEC 
(adapted) 

9 

(29)Whereas  the  conditions  governing  the  supply  of medicinal  products  to  the 

3. 

public should be harmonized; 

(30)Whereas  in  this  connection  persons  moving  around  within  the  Community 
have the right to  carry a  reasonable  quantity  of medicinal  products  lawfully 
obtained for their personal use;  whereas it must also be possible for a  person 
established  in  one  Member  State  to  receive  from  another  Member  State  a 
reasonable quantity of medicinal products intended for his personal use; 

{3l)Whereas,  in  addition,  by  virtue  of Regulation  (EC)  No  2309/93,  certain 
medicinal products are the subject of a  Community marketing authorization; 
whereas,  in  this  context,  the  classification  for  the  supply  of  medicinal 
products  covered  by  a  Community  marketing  authorization  needs  to  be 
established; whereas it is therefore important to set the criteria on the basis of 
which Community decisions will be taken; 

4: 

5. 

92/26/EEC 
(adapted) 

92/26/EEC 
(adapted) 

92/26/EEC 
(adapted) 

(32) Whereas  it is therefore appropriate,  as an  initial  step,  to harmonize the  basic 
principles applicable to the classification for the supply of medicinal products 
.  in  the  Community  or  in  the  Member  State  concerned,  while  taking  as  a 
starting point the principles already established on this subject by the Council 
of  Europe  as  well  as  the  work  of  harmonization  completed  within  the 
framework  of the  United  Nations,  concerning  narcotic  and  psychotropic 
substances; 

(33)Whereas the provisions dealing with  the  classification of medicinal  products 
for  the  purpose  of  supply  do  not  infringe  the  national  social  security 
arrangements  for  reimbursell)ent  or  payment  for  medicinal  products  on 
prescription; 

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

(35)Whereas  it  is  necessary  to  exercise  control  over  the  entire  chain  of 
distribution of medicinal products, from  their manufacture or import into the 
Community  through  to  supply  to  the  public,  so  as  to  guarantee  that  such 
products are  stored,  transported  and  handled  in  suitable conditions;  whereas 
the  requirements  which  must be  adopted  for  this  purpose  will  considerably 
facilitate  the  withdrawal  of defective  products  from  the  market  and  allow 
more effective efforts against counterfeit products; 

6. 

92/26/EEC 

7. 

2. 

3. 

92/26/EEC 
(adapted) 

92/25/EEC 
(adapted) 

92/25/EEC 

10 

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

(3 7) Whereas authorization must be subject to certain essential conditions and it is 
the  responsibility  of  the  Member  State  concerned  to  ensure  that  such 
conditions  are  met;  whereas  each  Member  State  must 
recognize' 
authorizations granted by other Member States; 

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

(39) Whereas  rules . should  be  laid  down  as  to  how  the  labelling  and  package 

leaflets are to be presented; 

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

4. 

92/25/EEC 
(adapted) 

5. 

92/25/EEC 

6. 

92/25/EEC 

2. 
+ 
3. 

5. 

92/27/EEC 
(adapted) 

92/27/EEC 

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

6. 

92/27/EEC 

(42)Whereas  this  Directive  is  without  prejudice  to  the  application  of measures 
adopted  pursuant  to  Council  Directive  84/450/EEC  of 10  September  1984 
relating  to  the  approximation  of the  laws,  regulations  and  administrative 
provisions ofthe Member States concerning misleading advertisingl; 

I. 

92/28/EEC 
(adapted) 

OJ L 250,  19.9.1984, p.  17. Directive as amended by Directive 97/55/EC (OJ L 290,23.  10.  1997, p.  18). 

11 

(43)Whereas  all  Member  States  have  adopted  further  specific  measures 
concerning  the  adve~ising  of  medicinal  products;  whereas  there  are 
disparities  between  these  measures;  whereas  these  disparities  are  likely  to 
have  an  impact  on  the  functioning  of the  internal  market,  since  advertising 
disseminated  in  one  Member  State  is  likely  to  have  effects  in  other 
Member States; 

(44)Whereas  Council  Directive  89/552/EEC  of  3  October  1989  on 

the 
coordination  of  certain  provisions 
law,  regulation  or 
administrative  action  in  Member States  concerning  the  pursuit  of television 
broadcasting  activities1  prohibits  the  television  advertising  of  medicinal 
the 
products  which  are  available  only  on  medical  prescription 
Member State within whose jurisdiction the television broadcaster is  located; 
whereas this principle should be  made  of general application  by extending  it 

laid  down  by 

in 

·  to oth~r media; 

( 45) Whereas  advertising  to  the  general  public,  even  of  non-prescription 
medicinal products, could affect public health, were it to be excessive and  ill 
considered; whereas advertising of medicinal  products to  the  general  public, 
where  it  is  permitted,  ought  therefore  to  satisfy  certain  essential  criteria 
which ought to be defined; 

( 46) Whereas,  furthermore,  distribution  of samples  free  of charge  to  the  general 

public for promotional ends must be prohibited; 

( 4 7) Whereas  the  advertising  of  medicinal  products  to  persons  qualified  to 
prescribe  or  supply  them  contributes  to  the  information  available  to  such 
persons;  whereas,  nevertheless,  this  advertising  should  be  subject  to  strict 
conditions  and- effective  monitoring,  referring  in  particular  to  the  work 
carried out within the framework of the Council of Europe; 

2. 

92/28/EEC 
(adapted) 

3. 

92/28/EEC 

4. 

92/28/EEC 

5. 

6. 

92/28/EEC 

92/28/EEC 

( 48) Whereas  advertising  of medicinal  products  should  be  subject  to  effective, 
adequate monitoring; whereas reference in this regard should  b~ made to  the 
monitoring mechanisms set up by Directive 84/450/EEC; 

!1. 

92/28/EEC 

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

7. 

92/28/EEC 

(50)Whereas  persons  qualified  to  prescribe  medicinal  products  must  be  able  to 
carry  out  these  functions  objectively  without  being  influenced  by  direct  or 
indirect financial inducements; 

8. 

92/28/EEC 

(5I)Whereas it should be  possible within certain restrictive conditions to provide 
samples of medicinal products free of charge to persons qualified to prescribe 
'or supply them so that they can familiarize themselves with new products and 
acquire experience in dealing with them; 

9. 

92/28/EEC 

OJ L 298, 17.10.1989, p. 23; Directive as amended by Directive 97/36/EC (OJ L 202,30. 7.  1997, p. 60). 

12 

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

10. 

92/28/EEC 

(53)Whereas  each  undertaking  which  manufactures  or  imports  medicinal 
products  should set up  a  mechanism  to  ensure  that  all  information  supplied 
about a medicinal product conforms with the approved conditions of use; 

12. 

92/28/EEC 

(54) Whereas it is desirable to regulate and improve the cooperation and exchange 
of  information  between  Member  States  relating  to  the  supervision  of 
medicinal  products  and  in  particular  the  monitoring  of adverse  reactions 
under  practical  conditions  of use  through  the  national  pharmacovigilance 
systems; 

(55)Whereas  the  Commission  should  be  empowered  to  adopt  any  necessary 
changes  to  Annex  I  in  order  to  take  into  account  scientific  and  technical 
progress; 

7. 

8. 
+ 
6. 
+ 
6. 
+ 
8. 

93/39/EEC 
(adapted) 

75/318/EEC 
(;ldapted) 
89/342/EEC 
(adapted) 
89/343/EEC 
(adapted) 
89/381/EEC 
(adapted) 

(56)Whereas  this  Directive  is  without  prejudice  to  the  obligations  of  the 
Member States concerning the deadlines for transposition set out in Annex 11, 
Part B. 

HAVE ADOPTED THIS DIRECTIVE: 

13 

TITLE I 
DEFINITIONS 

Article 1 

For  the  purposes  of  this  Directive,  the  following  tenns  shall  bear  the  following  65/65/EEC 
meanings: 

Art.  I (I) to (3) 
(adapted) 

1.  Proprietary medicinal product: 

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

· 

2.  Medicinal product: 

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

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

3.  Substance: 

Any matter irrespective of origin which may be: 

human, e.g. 

human blood and human blood products; 

animal, e.g. 

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

vegetable, e.g. 

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

chemical, e.g. 

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

14 

4. 

Immunological medicinal product: 

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

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

89/342/EEC 
Art.  I (1) 
(adapted) 

89/342/EEC 
Art.  1 (2), 2nd indent 

(i) 

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

75/319/EEC 
Annex 

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

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

anti-smallpox globulin, antilymphocytic globulin. 

(b) "allergen  product"  shall  mean  any  medicinal  product  which  is  intended  to  89/342/EEC 

identify or induce  a specific  acquired alteration  in  the  immunological  response  Art.  1 (2),  1st indent 
to an allergizing agent. 

(adapted) 

92173/EEC 
Art.  1 
(adapted) 

89/343/EEC 
Art.  1 (2) 
(adapted) 

5.  Homeopathic medicinal product: 

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

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

6.  Radiopharmaceutical: 

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

7.  Radionuclide generator: 

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

8.  Radionuc/ide kit: 

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

9.  Radionuclide precursor: 

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

15 

I 0.  Medicinal products derived from human blood or human plasma: 

Medicinal products based on  blood constitutents which are  prepared  industrially  by 
public  or prjvate  establishments,  such  medicinal  products  including,  in  particular, 
albumin, coagulating factors and immunoglobulins of human origin. 

89/381/EEC 
Art.  I  (I) 
(adapted) 

'11.  Adverse reaction: . 

75/319/EEC 
Art. 29b 
(as amended by 

A  reaction  which  is  harmful  and  unintended  and  which  occurs  at  doses  normally 
used  in  man  for  the  prophylaxis,  diagnosis  or  treatment. of  disease  or  the  93/39/EEC Art. 3 (3)) 
modification of physiological function. 

12.  Serious adverse reaction: 

An  adverse  reaction  which  is  fatal,  life-threatening,  disabling,  incapacitating,  or 
which results in or prolongs hospitalization. 

13.  Unexpected adverse reaction: 

An  adverse  reaction  which 
characteristics. 

is  not  mentioned 

in 

the  summary  of  product 

14.  Serious unexpected adverse reaction: 

An adverse reaction which is both serious and unexpected. 

15.  Wholesale distribution of medicinal products: 

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

16.  Public service obligation: 

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

· 

92/25/EEC 
Art.  1 (2) 

17.  Medicinal Prescription: 

Any medicinal prescription issued by a professional person qualified to. make such a 
prescription. 

92/26/EEC 
Art.  J. (2), 2nd sentence 
(adapted) 

16 

18.  Name of the medicinal product: 

92/27/EEC 
Art.  1 (2) 

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

19.  Common name: 

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

. 20.  Strength of the medicinal product: 

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

(adapted) 

21.  Immediate packaging: 

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

22.  Outer packaging: 

The packaging into which  is  placed the immediate packaging. 

23.  Labelling: 

Information on the immediate or outer packaging. 

24.  Package leaflet: 

A  leaflet  containing  information  for  the  user  which  accompanies  the  medicinal 
product. 

25.  Agency: 

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

26.  Risk to public health: 

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

. 

. 

75/319/EEC 
Art. 8 (1) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 

75/319/EEC 
Art.  10 (1) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 

17 

TITLE 11 
SCOPE 

Article 2 

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

This Directive shall not apply to: 

Article 3 

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

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

. 

3.  Medicinal products intended for research and development trials; 

4. 

Intermediate  products 
manufacturer; 

intended 

for·  further  processing  by  an  authorized 

5.  Any radionuclides in the form of sealed sources; 

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

Article 4 

65/65/EEC 
Art. 2 (I) 
(as amended by 
89/341/EEC Art.  I (3)) 
(adapted) 

65/65/EEC 
Art.  1 (4) and (5) and 
Art. 2 (3),  Ist'indent 
(as amended by 
89/34I/EEC Art.  1 (2) 
and (3)) 
(adapted) 

65/65/EEC 
Art. 2 (3), 2nd and 3rd 
indents 
(as amended by 
89/341/EEC Art.  I  (3)) 
(adapted) 

\ 

\ 
89/343/EEC 
Art.  I (I) 
' 
(adapted) 

89/381/EEC 
Art.  1 (2) 

1

I. Nothing in this Directive shall in any way derogate from  the Community rules for the  89/343/EEC 
radiation  protection  of persons  undergoing  medical  examination  or treatment,  or from  Art.  1 (3) 
the Community rules  laying down the basic safety standards for the health  protection of 
the general public and ~orkers against the dangers of ionizing radiation. 

(2) 

18 

2. This Directive shall be without prejudice to Council.Decision 86/346/EEC 1• 

89/381/EEC 
Art.  I (3) 

1

3.  The  provisions  of this  Directive  shall  not  affect  the  powers  of the  Member  States'  65/65/EEC 
authorities either as regards the setting of prices for medicinal products or their inclusion  Art. 3, 2nd subparagraph 
in  the scope of national health insurance schemes, on the basis of health, economic and 
social conditions. 

(as amended by 
93/39/EEC Art.  I  (I)) 

4.  This  Directive  shall  not  affect  the  application  of national  legislation  prohibiting  or  65/65/EEC 
restricting  the  sale,  supply  or  use  · of  medicinal  products  as  contraceptives  or  Art. 6 
abortifacients. The Member States shall communicate the national legislation concerned 
to the Commission. 

(as amended by 
93/39/EEC Art.  I  (5)) 

Article 5 

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

65/65/EEC 
Art. 2 (4) 
(as amended by 
89/341/EEC Art.  I  (3)) 
(adapted) 

OJ L 207, 30.7.1986, p.  I. 

19 

TITLE Ill 
PLACING ON THE MARKET 

Chapter 1 
Marketi~g authorization 

Article 6 

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

.65/65/EEC 
Art. 3 (1) 
(as amended by 
93/39/EEC Art.  1 ( 1)) 
(adapted) 

Article 7 

A  marketing  authorization  shall  not  be  required  for  a  radiopharmaceutical  prepared  at  89/343/EEC 
the  time  of use  by  a  person  or  by  an  establishment  authorized,  according  to  national  Art. 2, 2nd sentence 
legislation,  to  use  such  medicinal  products  in  an  approved  health  care  establishment 
exclusively  from  authorized  radionuclide  generators,  radionuclide  kits  or  radionuclide 
precursors in accordance with the manufacturer's instructions. 

(adapted) 

Article 8 

I.  In  order  to  obtain  an  authorization  to  place  a  medicinal  product  on  the  market  65/65/EEC 
regardless of the procedure established by Regulation (EEC) No 2309/93, an  application  Art. 4 (1) 
(adapted) 
shall be made to the competent authority of the Member State concerned. 

2.  A  marketing  authorization  may  only  be  granted  to  an  applicant ·established  in  the 
Community .. 

65/65/EEC 
Art. 4 (2) 
(as amended by 
93/39/EEC Art.  1 (2)) 
(adapted) 

20 

3.  The  application  shall  be  accompanied  by  the. following  particulars  and  documents,  65/65/EEC 
submitted in accordance with Annex 1: 

Art. 4, 3rd paragraph, 
points  I to 5 
(as amended by 
89/341/EEC Art.  1 (1)) 
(adapted) 

+ 

75/318/EEC 
Art.  i , 1st paragraph 
(adapted) 

65/65/EEC 
Art. 4, 3rd paragraph, 
point 6 
(as amended by 
93/39/EEC Art.  1 (3)) 

65/65/EEC 
Art. 4, 3rd paragraph, 
point 7 
(as amended by 
75/319/EEC Art. 35) 
(adapted) 

65/65/EEC 
Art. 4, 3rd paragraph, 
point 8.1 
·(as amended by 
87/21/EEC Art.  1 (1)) 

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

applicable, of the manufacturer: 

(b)  Name of th~ medicinal product. 

(c)  Qualitative  and  quantitative  particulars  of all  the  constituents  of the  medicinal 
product  in  usual  tenninology,  but  excluding  empirical  chemical  formulae,  with 
mention ofthe_intemational name 'recommended by the  World  Health  Organization 
where such name exists. 

(d)  Description of the manufacturing method. 

(e) · Therapeutic indications, contra-indications and adverse reactions. 

(t)  Posology,  pharmaceutical  form,  method  and  route  of administration  and  expected 

shelf life. 

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

(h)  Description of the  control  methods  employed by the  manufacturer (qualitative  and 
quantitative  analysis  of the  constituents  and  Qf the  finished  product,  special  tests~ 
e.g.  sterility  tests,  tests  for  the  presence  of pyrogenic  su.bstances,  the  presence  of 
heavy metals,  stability tests,  biological and toxicity tests,  controls carried out at an 
intermediat~ stage of the manufacturing process). 

(i)  Results of: . 

physico-chemical, biological or microbiological tests, 

toxicological and phartnacological tests, 

clinical trials. 

21 

(j)  A  summary,  in  accordance  with  Article  11,  of the  product  characteristics,  one  or 
more  specimens  or  mock-ups  of the  sales  presentation  of the  medicinal  product, 
~ogether with a package leaflet. 

(k)  A  document  showing  that  the  manufacturer  is  authorised  in  his  own  country  to 

produce medicinal.products. · 

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

· 

· 

65/65/EEC 
Art. 4, 3rd paragraph, 
point 9 
(as amended by  · 
83/570/EEC Art.  1 ( 1) 
(c) and 89/341/EEC 
Art.  I  (I)) 
(adapted) 

65/65/EEC 
Art. 4, 3rd paragraph, 
point  10 
(as amended by 
89/341 /EEC Art.  1 ( 1)) 

65/65/EEC 
Art. 4, 3rd paragraph, 
point 11 
(as amended by 
93/39/EEC Art.  1 (3)) 
(adapted) 

This information shall be updated on a regular basis. 

Article 9 

In  addition  to  the  requirements  set  out  in  Articles  8  and  10  (l ),  an  application  for  89/343/EEC 
authorization  to  market  a  radionuclide  generator  shall  also  contain  the  following  Art. 3 
information and particulars: 

(adapted) 

a  general  description  of the  system  together  with  a  detailed  description  of the 
. components  of the  system  which  may  affect  the  composition  or  quality  of the 
daughter nucleid preparation, 

· 

qualitative and quantitative particulars of the eluate or the sublimate. 

22 

65/65/EEC 
Art. 4, 3rd paragraph, 
point 8, 2nd 
subparagraph 
(as amended by 
87/21/EEC Art.  1 (I) and 
89/341/EEC Art.  1 (l)) 
(adapted). 

Article 10 

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

(a)  The  applicant  shall  not  be  required  to  provide  the  results  of toxicological  and 

pharmacological tests or the results of clinical trials if he can demonstrate: 

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

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

(iii) or that  the  proprietary  medicinal  product  is  essentially  similar  to  a  medicinal 
product which  has  been· authorized  within the  Community,  in  accordance  with 
Community provisions  in  force,  for  not  less  than  six  years  and  is  marketed  in 
the  Member  St:tte  for  which  the  application  is  made;  this  period  shall  be 
extended  to  I 0  years  in  the  case  of  high-technology  medicinal  ·products 
having  been authorised according to the procedure laid down  in Article 2 (5) of 
Council  Directive 87/22/EEC 1 ;  furthermore,  a Member State  may  also extend 
this period to  I 0 years by a single Decision covering all  the medicinal products 
marketed  on  its  territory  where  it  considers  this  necessary  in the  interest  of 
public  health.  Member  States  are  at  liberty  not  to  apply  the. six-year  period 
beyond the date of expiry of a patent protecting the original medicinal product. 

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

I  OJ LIS, 17.1.1987, p. 38; Directive repealed by ~irective 93/41/EEC (OJ L 214, 24.8.~993, p. 40). 

23 

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

· 

65/65/EEC 
Art. 4, 3rd paragraph, 
point 8, 2nd 
subparagraph 
(as amended by 
87121/EEC Art.  1 (I) and 
89/341/EEC Art.  I  (I)) 
(adapted) 

2.  Annex  I  shall  apply  by  analogy  where,  pursuant  to  point  (ii)  of paragraph  I, (a),  75/318/EEC 
bibliographic references to published data are submitted. 

Art.  1, 2nd paragraph 
(adapted) 

Article 11 

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

·1.  Name of the medicinal product. 

65/65/EEC 
Art. 4a, points  I  to 5.4, 
(as amended by 
83/570/EEC Art.  1 (2) 

2.  Qualitative  and  quantitative  composition  in  terms  of the  active  substances  and  and 89/341/EEC 

· 

constituents  of  the  excipient,  knowledge  of  which 
administration  of the  medicinal  product;  the  usual  common·  name  .or  chemical 

is  essential  for,  proper  Art.  I (I)) 
(adapted) 

. descripti.on shall be used. 

3.  Pharmaceutical form. 

4.  Pharmacological properties and, in so far,as this information is useful for therapeutic 

purposes, pharmacokinetic particulars. 

5.  Clinical particulars: 

5.1. 
5.2. 
5.3. 
5.4. 

5.5. 
5.6. 
5.7. 

5.8. 
5.9. 
~.10. 

·therapeut~c indications, 
contra-indications, 
adverse reactions (frequency and seriousness), 
special  precautions  for· use  and,  in  the  case  of immunological  medicinal 
products,  any  special  precautions  to  be  taken  by  persons  handling  such 
products and administering them  to patients, together with  any  precautions 
to be taken by the patient, 
use during pregnancy and lactation, 
interaction with other medicaments and other forms of interaction, 
posology and method of administration for adults and, where necessary,  for 
children, 
overdose (symptoms, emergency procedures, antidotes), 
special warnings, 
effects on ability to drive and to use machines. 

· 

· 

89/342/EEC 
Art.3 
(adapted) 

65/65/EEC 
Art. 4a, points 5.5 to 6.4 
(as amended by 
83/570/EEC, Art.  1 (2) 
and 89/341/EEC, 
Art.  1(1) 
(adapted) 

24 

6.  Pharmaceutical particulars: 

6.1. major incompatibi~ities, 
6.2. shelf life, when necessary after reconstitution of the medicinal product or when 

the immediate packaging is opened for the first time, 

6.3. special precautions for storage, 
6.4. nature and .contents of the immediate packaging, 

6.5  special precautions for disposal of unused medicinal products or waste materials 

derived from such medicinal products, if appropriate; 

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

holder; 

8.  For radiopharmaceuticals, fuU  details of internal radiation dosimetry; 

65/65/EEC 
Art. 4a (I) to ( 6), 
point6.4 
(as amended by 
83/570/EEC Art.  I (2) 
and 89/341/EEC 
Art.  I  (1)) 
(adapted) 

65/65/EEC 
Art. 4a (6), point 6.6 
(as amended by 
89/341/EEC Art.  1 (4)) 
(adapted) 

65/65/EEC 
Art. 4a (6), point 6.5 
(as amended by 
83/570/EEC Art.  1 (2)) 
(adapted) 

9.  For  radiopharinaceuticals,  additional  detailed  instructions  for  extemporaneous  89/343/EEC 
preparation  and  quality  control  of  such  preparation  and,  where  appropriate,  Art. 4 
maximum storage time during which any intermediate preparation such as an  eluate 
or the ready-to-use pharmaceutical will conform with its specifications. 

(adapted) 

25 

Article 12 

1.  Member States shall  take  all  appropriate  measures  to  ensure  that the  documents  and  75/319/EEC 
particulars listed ifl  Article 8 (3) (h) and (i), and Article  10  (1) are drawn  up by experts  Art.  1 
with  the  necessary technical  or professional qualifications before  they  are  submitted  to 
the  competent  authorities.  These  documents  and ·particulars  shall  be  signed  by  the 
experts. 

(adapted) 

2. The duties of the experts according to their respective qualifications shall be: 

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

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

. 

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

7 5/319/EEC 
Art. 2 
(adapted) 

· in  the· case  of the  pharmacologist  or  the  specialist  with  similar  experimental 
competence,  the  toxicity  of the  medicinal  product  and  the  pharmacological 
properties observed; 

· 

in  the  case  of the  clinician,  whether  he  has  been  able  to  ascertain  effects  on 
persons treated with the  medicinal product which  correspond to the  particulars 
given by the applicant in accordance with Articles 8 and ·I 0, whether the patient 
tolerates the medicinal product w.ell,  the posology the clinician advises and any 
contra-indications and adverse reactions; 

(c)  where  applicable, . to  state  the  grounds  for  using  the  bibliography  mentioned  in 

point (a)(ii) of Article  10 (1). 

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

26 

Chapter 2 
Specific provisions applicable to 
homeopathic medicinal products 

Article 13 

1.  Member States  shall  ensure  that  homeopathic  medicinal  products  manufactured  and  92173/EEC 
placed on  the market within  the  Community are  registered or authorized  in  accordance  Art. 6 (1) and (2) 
with Articles  14,  15  and  16.  Each Member State shall take due  account of registrations 
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 medicinal products referred to  in  Article  14.  A Member 
State  shall  inform  the  Commission  accord4tgly.  The  Member  State  concerned  shall 
allow  the  use  in  its  territory  of homeopathic"  medicinal  products  registered  by  other 
Member States in accordance with Articles 14 and  15. 

Article 14 

1.  Only  homeopathic  medicinal  products  which  satisfy  all  of the  following  conditions  92173/EEC 
m~y be subject to a special, simplified registration proced':lre: 

Art. 7 (I) and (4) 
(adapted) 

they are administered orally or externally, 

:-

no  specific therapeutic  indication appears  on  the  labelling of the  medicinal  product 
or in any information relating thereto, 

there  is  a  sufficient  degree  of dilution  to  guarantee  the  safety  of the  medicinal 
product;  in  particular,  the  medicinal  product may· not  contain  either more  than  one 
part per 10 000 of the mother tincture or more than  l/100th of the smallest dose used 
in  allopathy  with  regard  to  active  substances  whose  presence  in  an  allopathic 
medicinal product results in the obligation to submit a doctor's prescription. 

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

2.  The criteria and  rules  of procedure  provided  for  in  Articles  4  (4),  17,  18,  22  to  26, 
112,  116 and  127 shall apply by analogy to the special, simplified registration procedure 
for·  homeopathic  medicinal  products,  with  the  exception  of the  proof of therapeutic 
efficacy. 

27 

3.  The  proof of therapeutic  efficacy  shall  not  be  required  for  homeopathic  medicinal  92/73/EEC 
products registered in accordance with paragraph  I of this Article, or, where appropriate,  Art. 4, 2nd paragraph 
admitted in accordance with Article  13 (2). 

(adapted) 

Article 15 

An  application  for  special,  simplified  registration  may  cover  a  series  of  medicinal  92173/EEC 
products derived from  the same homeopathic stock or stocks~ The following  documents  Art. 8 
shall  be  included  with  the  application  in  order  to  demonstrate,  in  particular,  the 
pharmaceutical quality and the batch-to-batch homogeneity of the produc~ concerned: 

(adapted) 

scientific name or othername given in a pharmacopoeia of the homeopathic stock or 
stocks, 
together  with  a  statement  of  the  various  routes  of  administration, 
pharmaceutical forms and degree of dilution to be registered, 

dossier  describing  how  the  homeopathic  stock  or  stocks  is/are  obtained  and 
controlled,  and justifying its/their homeopathic nature,  on  the  basis  of an  adequate 
bibliography, 

manufacturing and control file for each pharmaceutical form and a description of the 
method of dilution and potentization, 

manufacturing authorization for the medicinal product concerned, 

copies of any registrations or authorizations obtained for the same medicinal product 
in other Member States, 

one  or  more  specimens  or  mock-ups  of the  sales  presentation  of the  medicinal 
products to be registered, 

data concerning the stability of the medicinal product. 

28 

Article 16 

I. Homeopathic medicinal products other than those referred ~o in Article  14 (I) shall be  92173/EEC 
authoriied in accordance witl_t Articles 8,  I 0 (I) and  11. 

Art. 9 
(adapted) 

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

In  this  case,  the  Member State  concerned  shall  notify  the  Commission  of the  specific 
rules in force. 

· 

29 

Chapter3 
Procedures relevant to the 
marketing authorization 

Article 17 

65/65/EEC 
Art. 7 
(as amended by 
93/39/EEC Art.  1 (6)) 
(adapted) 

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

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

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

Article 18 

Where  a  Member  State  is  informed  in  accordance  with  Article  8  (3)  (I)  that  another 
Member State· has authorized a medicinal pr~duct which  is  the subject of an application 
for  authorization  in  the  Member  State  concerned,  that  Member  State  shall  forthwith 
request  the  authorities  of the  Member  State  which  has  granted  the  authorization  to 
forward to it the assessment report referred to in Article 21  (4). 

65/65/EEC 
Art. 7a 
(as amended by 
93/39/EEC Art.  1 (7)) 
(adapted) 

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

30 

Article 19 

In  order to examine the application submitted  in  accordance with  Articles  8 and  I 0  (I),  75/319/EEC 
the competent authority of the Member State: 

Art. 4 (a) 
(adapted) 

I.  must verify whether the  particulars submitted  in  support of the  application  comply 
with the  said Article~ 8 and  10  ( 1)  and  examine whether the  conditions  for  issuing 
an  authorization 
the  market  (marketing 
authorization) are complied with; 

to  place  medicinal  products  on 

2 ..  may submit the medicinal product for testing by a State laboratory or by a laboratory  75/319/EEC 
designated for that purpose  in  order to ensure that the control methods employed by  Art. 4 (b) 
the  manufacturer and  described  in  the  particulars  accompanying  the  application  in 
accordance with Article 8 (3) (h) are satisfactory; 

(as amended by 
89/341/EEC Art. 3 (1)) 

3.  may,  where  appropriate,  require  the  applicant  to  supplement  the  particulars  75/319/EEC 
accompanying the application  in  respect of the  items  listed  in the Articles 8 (3) and  Art. 4 (c) 
10 (1).  Where the competent authority avails itself of this option, the time limits laid 
(adapted) 
down  in  Article  17  shall  be  suspended  until  such  time  as  the  supplementary 
information  required  has  been  provided.  Likewise,  these  time  limits  shall  be 
suspended for the time  allowed the  applicant,  where appropriate,  for  giving oral  or 
written explanation. 

31 

Member States shall take all appropriate measures to ensure that: 

Article 20 

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

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

Article 21 

75/319/EEC 
Art. 5 
(adapted) 

I.  When  the  marketing  authorization  is  issued,  the  holder  shall  be  infonned,  by  the  65/65/EEC 
competent  authorities  of the  Member  State  concerned,  of the  summary  of the  product  Art. 4b 
characteristics as approved by it. 

(as amended by 
93/39/EEC Art.  1 (4)) 
(adapted) 

2.  The.  competent  authorities  shall  take  all  necessary  measures  to  ensure  that  the 
i~formation  given  in  the  summary  is  in  confonnity  with  that  accepted  when  the 
marketing authorization is issued or subsequently. 

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

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

32 

Article 22 

In  exceptional  circumstances,  and  following  consultation  with  the  applicant,  an  65/65/EEC 
authorization may be granted subject to certain specific obligations, including: 
Art.  10 (2) 
(as amended by 
93/39/EEC Art.  I  (9)) 

the carrying out of further studies following the granting of authorization, 

the notification of adverse reactions to the medicinal product. 

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

Article 23 

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

. generally accepted scientific methods. 

65/65/EEC 
Art. 9a 
(as amended by 
93/39/EEC Art.  I (8)) 
(adapted) 

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

Article 24 

Authorization shall be valid  for  five  years and shall  be renewable  for  five-year periods,  65/65/EEC 
on  application  by  the  holder  at  least  three  months  before  the  expiry  date  and  after  Art.  I 0 (I) 
consideration  by the competent authority of a dossier containing  in  particular details of  (as amended by 
the  data on pharmacovigilance  and  other information  relevant  to  the  monitoring of the  93/39/EEC Art.  I  (9)) 
medicinal product. 

Article 25 

Authorization  shall  not  affect  the  civil  and  criminal  liability  of the  manufacturer  and,  65/65/EEC 
where applicable, of the marketing authorization holder. 

Art. 9 
(adapted) 

33 

The  marketing authorisation shall  be  refused  if,  after. verification  of the  particulars  and  65/65/EEC 
documents listed in Articles 8 and  10 ( 1 ), it proves that: 

Article 26 

Art. 5 
(as amended by 
89/341/EEC Art.  1 (I)) 
(adapted) 

(a)  the medicinal product is harmful in. the normal conditions of use, or 

(b)  that  its  therapeutic  efficacy  is  .lacking  or  is  insufficiently  substantiated  by  the 

applicant, or 

· 

(c)  that its qualitative and quantitative composition is not as declared. 

Authorisation  shall  likewise  be  refused  if the  particulars  and  docume.nts  submitted  .in 
support of the application do not comply with Articles 8 and  I 0 ( 1 ). 

(3} 

34 

Chaptcr4 
Mutual recognition of authorizations 

Article 27 

1.  In  order  to  facilitate  the  adoption  of common  decisions  by  Member  States  on  the  75/319/EEC 
authorization  of medicinal  products  on  the  basis  of the  scientific  criteria  of quality,  Art. 8 
safety  and  efficacy,  and  to  achieve  thereby  the  free  movement  of  medicinal  products 
within  the  Community,  a  Committee  for  Proprietary  Medicinal  Products,  hereinafter  93/39/EEC Art. 3 (1)) 
referred  to  as  "the  Committee",  is  hereby  set  up.  The  Committee  shall  be  part  of the 
Agency. 

(as amended by 

(adapted) 

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

3. The Committee shall draw up its own Rules of Prodecure. 

Article 28 

1.  Before  submitting  the  application  for  recognition  of a  marketing  authorization,  the  75/319/EEC 
holder  of  the  authorization  shall  infonn  the  Member  State  which  ·granted  the  Art. 9 (3) 
~uthorization on which the application is  based (hereinafter "referential Member State"), 
that an  application  is  to be made  in  accordance with this Directive and shall  notify it of  93/39/EEC Art. 3 (I)) 
any  additions  to  the  original  dossier;  that  Member  State  may  require  the  applicant  to 
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 to 
prepare  an  assessment  report  in  respect  of the  medicinal  product  concerned,  or,  if 
necessary, to update any existing assessment report. That Member State shall prepare the 
assessment report, or update it, within 90 days of the receipt of the request. 

At  the  same  time  as  the  application  is  submitted  in  accordance  with  paragraph  2,  the 
referential  Member  State  shall  forward  the  assessment  report  to  the  Member  State  or 
Member States concerned by the application. 

2.  In  order  to  obtain  the  recognition  according  to  the  procedures  laid  down  in  this  75/319/EEC 
Chapter in  one or more of the  Member States of a marketing authorization  issued  by a  Art. 9 ( 1) 
Member  State,  the  holder  of  the  authorization  shall  submit  an  application  to  the 
competent authorities  of the  Member State or Member States  conc~med, together with  93/39/EEC Art. 3 (1)) 
the  information  and  particulars referred to  in  Articles  8,  10  (1) and  11.  He  shall  testify 
that the  dossier  is  identical  to  that  accepted  by  the  referential  Member  S~te, or shall 
identify any additions or amendments  it may contain.  In  the  latter case,  he  shall  certify 
that  the  summary  of the  product  characteristics  proposed  by  him  in  accordance  with 
Article  11  is  identical  to  that· accepted  by  the  referential  Member  State  in  accordance 
with  Article  21.  Moreover,  he  shall  certify  that  all  the  dossiers  filed  as  part  of the 
procedure are identical. 

(as amended by 

(adapted) 

35 

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

75/319/EEC 
Art. 9 (2) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 

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

75/319/EEC 
Art. 9 (4) 
(as amended by 
93/39/EEC Art. 3 (I)) 
(adapted) 

Article 29 

I.  Where  a  Member  State  considers  that  there  are  grounds  for  supposing  that  the  75/3I9/EEC 
marketing authorization of the medicinal product concerned may present a risk to public  Art.  I 0 
health,  it  shall  forthwith  inform  the  applicant,  the  referential  Member  State  which 
granted the  initial  authorization,  any other Member States concerned by the  application  93/39/EEC Art. 3 (I)) 
and  the  Agency. The  Member  State  shall  s~te its  reasons  in  detail  and  shall  indicate 
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 endeavours to  reach  agreement 
on  the action to  be taken  iri  respect of the  application.  They shall  provide the  applicant 
with the opportunity to make his  point of view known  orally or in writing.  However,  if 
the  Member  States  have  not  reached  agreement  within  the  time  limit  referred  to  in 
Article  28  (4)  they  shall  forthwith  refer  the  matter  to  the  Agency  with  regard.  to  the 
Committee's reference for the application of the procedure laid down in Article 32. 

3.  Within the time limit referred to  in Article 28(4), the  Member States concerned. shall 
provide the Committee with a detailed statement of the matters on which they have been 
unable to reach agreement and the reasons for their disagreement. The applicant shall be 
provided with a copy of this information. 

4.  As  soon  as  he  is  informed  that  the  matter  has  been  referred  to  the  Committee,  the 
applicant  shall  forthwith  forward  to  the  Committee  a  copy  of the  information  and 
particulars referred.to in Article 28 (2).· 

36 

·Article 30 

- If several  applications  submitted  in  accordance  with  Articles  8,  10  (1)  and  Article  11 
have  been  made  for  marketing  'authorization  for  a  particular  medicinal  product,  and 
Member  States  have  adopted  divergent  decisions  concerning  the  authorization  of the 
medicinal product or its suspension ()r withdrawal, a Member State, or the Commission, 
or  the  marketing  authorisation  holder  may  refer  the  matter  to  the  Committee  for 
application of the procedure laid down in Article 32. 

75/319/EEC 
Art.  11 
(as amended by_ 
93/39/EEC Art. 3 (1)) 
(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, where appropriate, shall inform the holder. 

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

Article 31 

The  Member  States  or  the  Commission  or  the  applicant  or  holder  of the  marketing  75/319/EEC 
authorization may,  in specific cases where the  interests of the Community are  involved,  Art.  12 
refer  the  matter  to  the  Committee  for  the  application  of the· procedure  laid  down  in 
Article 32 before reaching a decision on~ request for a marketing authorization or on the  93/39/EEC Art. 3 (I)) 
suspension or withdrawal of an authorization, or on any other variation to the terms of a 
marketing  authorization  which  appears  necessary,  in  particular  to  take  -account  of ~he 

(as amended by 

(adapted) 

.  information collected in accordance with Title IX. 

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

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

37 

·  ·1.  When  reference  is  made  to  the  procedure  described  in  this  Article,  the  Committee  75/319/EEC 

Article 32 

shall consider the matter concerned and  issue a reasoned  opinion  within 90 days of the  Art.  13 
date on which the matter was referred to it. 

(as amended by 
93/39/EEC_Art. 3 (I)) 
(adapted) 

· 

However,  in  cases  submitted to  the  Committee  in  accordance  with  Articles  30  and  31, 
this period :"lay be extended by 90 days. 

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

2.  In  order to consider the matter, the Committee may appoint one of its members to act 
as  rapporteur.  The  Committee  may  also  appoint  individual  experts  to  advise  it  on 
specific questions.  When  appointing experts, ihe Committee shall define their tasks and 
specify the time-limit for the completion of these ~ks. 

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

In the case referred to in  Article 31, the marketing authorization holder may  be asked to 
explain .himself o~lly or in writing. 

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

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

· 

38 

4.  The  Agency  shall  forthwith  inform  the  marketing  authorization  holder  where  the  75/319/EEC 
opinion of the Committee is that: 

Art.  13 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 

the application does not satisfy the criteria for authorization, or 

the summary of the product characteristics proposed by the applicant in  accordance 
with Article  l1 should be amended, or 

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

a marketing authorization should be suspended, varied or withdrawn, 

Within  15  days  of the  receipt  of the  opinion,  the  marketing  authorization  holder  may 
notify the Agency in writing of his  intention to appeal.  In that case, he shall forward the 
detailed  grounds  for  appeal  to  the  Agency  within  60  days  of receipt  of the  opinion. 
Within  60  days  of receipt  of the  grounds  for  appeal,  the  Committee  shall  consider 
whether its opinion should be revised, and the conclusions reached on the appeal shall be 
annexed to the assessment report referred to in paragraph 5. 

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

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

(a)  a draft summary of the product characteristics, as referred to in Article  11; 

(b)  any conditions affectin~ the authorization within the meaning of paragraph 4. 

39 

Article 33 

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

In the event of a draft decision which envisages the granting of marketing authorization, 
the documents referred to in Article 34 (5) (a) and (b) shall be annexed. 

75/319/EEC 
Art.  14 (1) 
(as amended by 
93/39/EEC Art. J  (1)) 
(adapted) 

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

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

Article 34 

1.  A final  decision on the application shall be adopted in  accordance with the  procedure  7 5/319/EEC 
laid down in Article  124. 

Art.  14 (2) 
(as amended by 
93/39/EEC Art. 3 (1)) 

75/319/EEC 
Art.  14 (3) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 

2.  The rules of procedure of the Standing Committee established by Article  120 shall be 
adjusted to take account of the tasks incumbent upon it in accordance with this Chapter. 

These adjustments shall involve the following: 

except  in  cases  referred  to  in  the  third  paragraph  of Article  33,  the  opinion  of the 
Standing Committee shall be obtained in writing, 

each Member State is allowed at least 28 days to forward written observations on the 
draft decision to the Commission, 

each Member State  is  able to  require  in  writing that the  draft decision be discussed 
by th.e  Standing Committee, giving its· reasons in detail. 

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

The  provisions necessary  for  the  implementation  of this  paragraph  shall  be  adopted  by 
the Commission in accordance with the procedure laid down in Article  122. 

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

75/319/EEC 
Art.  14 (4) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 

40 

Article 35 

l.  Any  application  by  the  marketing  authorization  holder  to  vary  a  marketing  75/319/EEC 
authorimtion which has been granted in  accordance with the provisions of this Chapter  Art.  15 

· shall  be  submitted  to  all  the  Member  States  which  have  previously  authorized  the 

medicinal product concerned. 

(as amended by 
93/39/EEC Art. 3 (I)) 
(adapted) 

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

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

These arrangements shall be adopted by the Commission in the form of an  implementing 
Regulation in accordance with the procedure laid down in Article 122. 

2.  The  procedure  laid  down  in  Articles  32,  33  and  34  shall . apply  by  analogy  to 
variations made to marketing authorizations for products. 

Article 36 

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

75/319/EEC 
Art.  15a 
(as amended by 
93/39/EEC Art. 3 (I)) 
(adapted) 

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

41 

Article 37 

Articles 35 and 36 shall apply by analogy to medicinal products authorized by Member  75/319/EEC 
States  following  an  opinion  of the  Committee  given  in  accordance  with  Article  4  of  Art.  l5b 
Directive 87/22/EEC before  l Janu_ary  1995. 

(as amended by 
93/39/EEC Art. 3 (I)) 

Article 38 

l.  The  Agency shall  publish  an  annual  report· on  the  operation  of the  procedures  laid  75/319/EEC 
down  in  this Chapter and shall forward  that report to the  European  Parliament and  the  Art.l5c 
Council for information. 

(as amended by 
93/39/EEC Art. 3 (I)) 

2. By I January 2001, the Commission shall publish a detailed review of the operation of 
the procedures laid down in this Chapter and shall propose any amendments which may 
be necessary to improve these procedures. 

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

Article 39 

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

75/319/EEC 
Art.  14 (5) 
(as amended by 
93/39/EEC Art. 3 (1)) 
(adapted) 

/ 

42 

TITLE IV 
MANUFACTURE AND IMPORTATION 

Article 40 

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

75/319/EEC 
Art.  16 (1) 
(as amended by 
89/341/EEC Art. 3 (3)) 
(adapted) 

2. The authorization referred to in paragraph  1 shall be required for both total and  partial  75/319/EEC 
manufacture, and for the various processes of dividing up, packaging or presentation. 

Art.  16 (2) and (3) 
(adapted) 

However, such authorization shall  not  be  required  for  preparation,  dividing up,  changes 
in  packaging  or  presentation  where  these  processes  are  carried  out,  solely  for  retail 
supply, by phannaci~ts in  dispensing pharmacies or by persons legally authorized in  the 
Member States to carry out such processes. 

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

Article-41 

In  order to  obtain the  manufacturing authorization,  the  applicant shall  meet at  least the  75/319/EEC 
following requirements: 

Art.  17 
(adapted) 

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

(b)  have  at  his  disposal,  for  the  manufacture  or  import  of the  above,  suitable  and 
sufficient  premis~s, technical  equipment  and  control  facilities ·complying  with  the 
legal  requirements  which  the  Member  State  concerned  lays  down  as  regards  both 
manufacture and control  and the  storage  of medicinal  products,  in  accordance  with 
Article 20; 

· 

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

of Article 48. 

The appli~ant shall provide particulars in support of the above in his application. 

43 

Article 42 

1.  The  competent  authority  of  the  Member  State  shall  issue  the  manufacturing  ·  75/319/EEC 
authorization  only  after  having  made  sure  of the  accuracy  of the  particulars  supplied  Art.  18 
pursuant to Article 41, by means of an inquiry carried out by its a~ents. 

(adapted) 

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

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

Article 43 

The Member States shall take all appropriate measures to ensure that the time taken for  75/319/EEC 
the  procedure  for  granting  the  manufacturing  authorization  does  not  exceed  90  days  Art. 20 ( 1) 
from the day on which the competent authority receives the application. 

Article 44 

If .the  holder  of  the  manufacturing  authorization  requests  a  change  in  any  of  the  75/319/EEC 
particulars  referred  to  in  the  first  paragraph  of Article  41,  the  time  taken  for  the  Art. 20 (2) 
procedure  relating  to  this  request  shall  not  exceed  30  days . .In  exceptional  cases  this 
(adapted) 
period of time may be extended to 90 days. 

Article 45 

The  competent  authority  of the  Member  State  may  require  from  the  applicant  further  75/319/EEC 
information  concerning the  particulars  supplied  pursuant  to  Article  41  and  concerning  Art. 20 (3) 
(adapted) 
the qualified person referred to in Article 48; where the  competent authority  concerned 
exercises this right, application of the time-limits referred to in Article 43  and 44 shall be 
suspended until the additiomd data required have been supplied. 

44 

75/319/EEC 
Art.  19 (a) to (e) 
(adapted) 

Article 46 

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

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

(b)  to  dispose  of  the  authorized  medicinal  products  only  in . accordance  with  the 

legi~lation of the Member States concerned; 

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

(d)  to allow the agents of the competent authority of the Member State concerned access 

to his premises at any time; 

(e)  to  enable  the  qualified  person  referred  to  in  Article  48  ~o carry  out his  duties,  for 

example by placing at his disposal all the necessary facilities; 

(f)  to  comply  with  the  principles  and  guidelines  of good  manufacturing  practice  for  75/319/EEC 

medicinal products as laid down by Community law. 

Article 47 

The  principles  and  guidelines  of good manufacturing  practices  fo~ medicinal  products 
referred  to  in  Article  46  (f)  shall  be  adopted  in  the  form  of a  directive,  in  accordance 
with·the procedure laid down in Article  122. 

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

Art.  19 (f) 
(as amended by 
89/341/EEC Art. 3 (4)) 

75/319/EEC 
Art.  19a 
(as amended by 
89/341/EEC Art. 3 (5)) 
(adapt~d) 

45 

Article 48 

I.  Member  States  shall  take  all  approprjate  measures  to  ensure  that  the  holder  of the  75/319/EEC 
manufacturing  authorization  .has  permanently  and  continuously  at  his  disposal  the  Art. 21 
services of at least one· qualified person,  in  accordance with  the  conditions laid down  in 
Article 49, responsible in particular for carrying out the duties·specified in Article 51. 

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

Article 49 

1.  Member· States shall ensure  that the  qualified  person  referred  to  in  Article  48  fulfils  75/3 I 9/EEC 
the minimum conditio~s of qualification set out in paragraphs 2 and 3. 

Art. 23 
(adapted) 

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

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

Where  two  university  courses  or  two. courses  recognized  by  the  State  as  equivalent 
co-exist in a.Member State and where one of these extends over four years and the other 
over three years, the three-year course leading to a diploma, certificate or other evidence 
of formal qualifications awarded on  c~mpletion of a university course or its  recognJzed 
equivalent shall be considered to fulfil the condition of duration ref~rred to in the second 
subparagraph  in  so  far  as  the  dipl.omas,  certificates  or  other  evidence  of  formal 
qualifications  awarded  on  completion  of both  courses  are  recognized  as  equivalent  by 
the State in question. 

· 

46 

The  course  shall  include  theoretical  and  practical  study  bearing  upon  at  least  the  75/319/EEC 
following basic subjects: 

Art. 23 
(adapted) 

Applied physics 
General and inorganic chemistry 
Organic chemistry 
Analytical chemistry 
Pharmaceutical chemistry, including analysis of medicinal products 
General and applied biochemistry (medical) 
Physiology 
Microbiology 
Phannacology 
Pharmaceutical technology 
Toxicology 
Phannacognosy  (study  of  the  composition  and  effects  of  the  natural  active 
substances of plant and animal origin). 

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

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

3.  The qualified person shall have acquired practical  experienc~ ~ver at  least two  years, 
. in one or more undertakings which are authorized to manufacture medicinal products,  in 
the  activities  of qualitative  analysis  of medicinal  products,  of quantitative  analysis  of 
activ.e  substances  and  of the  testing  and  checking  necessary  to  ensure  the  quality  of · 
medicinal products. 

· 

The  duration  of practical  experit?nce  may  be  reduced  by  one  year  where  a  u~iversity 
course  lasts  for at least five  years and by a year and a half where the course  lasts  for at 
least six years. 

47 

Article 50 

I. A  person  engaging  in  the  activities  of the  person  referred  to  in  Article  48  from  the  75/319/EEC 
time of the application of Directive 75/3 I 9/EEC,  in  a Member State without complying  Art. 24 
with the provisions of Article 49 shall be eligible to continue to engage in those activities 
· 
in the State concerned. 

(adapted) 

2.  The  bolder  of  a  diploma,  certificate  or  other  evid.ence  of  formal  qualifications 
awarded on completion of a university course - or a course recognized as equivalent by 
the  Member  State  concerned  - in  a  scientific  discipline  allowing  him  to  engage  in  the 
activities of the person referred to in Article 48r in  accordance with  the  laws of that 'State 
may - if he began his course prior to 21  May  1975  - be  considered as  qualified  to  carry 
out in  that State  the  duties  of the  person  referred  to  in  Article  48  provided  that  he  has 
previously engaged in the following activities for at least two· years before 21  May  1985 
following  notification  of this  directive . in  one  or  more  undertakings  authorized  to 
manufacture:  production  supervision  and/or  qualitative  and  quantitative  analysis  of 
acti~e substances,  and the  necessary  testing and  checking  under the  direct authority  of 
the person referred to in Article 48 to ensure the quality of the medicinal products. 

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

48 

· Article 51 

I.  Member States shall take all  appropriate measures to ensure that the qualified person  75/319/EEC 
referred  to  in  Article  48,  without  prejudice  to  his  relationship  with  the  holder  of the  Art. 22 (1); 1st and 2nd 
manufacturing authorization,  is responsible,  in  the context of the procedures referred to 
in Article 52, for securing: 

subparagraphs 
(adapted) 

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

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

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

2.  In  the  case of medicinal  products  imported  from  a  third  country,  where appropriate  75/319/EEC 
arrangements  have  been made  by the  Community with  the exporting country to  ensure  Art. 22 (1}, 3rd 
that the manufacturer of the medicinal product applies standards of good manufacturing 
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  subparagraph of paragraph  1 have  been  93/39/EEC Art. 3 (2)) 
carried  out  in  the  exporting  country,  the  qualified  person  may  be  relieved  of 
responsibility for _carrying out those controls. 

subparagraph 
(as amended by 

· 

3.  In  all  cases  and  particularly  where  the  medicinal  products  are  released  for  sale,  the  75/319/EEC 
qualified  person  must  certify  in  a  register  or  equivalent  document  provided  for  that  Art. 22 (2) 
purpose,  that  each  production  batch  satisfies  the  provisions  of this  Article;  the  said 
register or equivalent document must be kept up to date as operations are carried out and 
must  remain  at  the  disposal  of the  agents  of the  competent  authority  for  the _period 
specified in  the  provisions of the  Member State concerned and in any event for at least 
five years. 

(adapted) 

· 

Article 52 

Member States shall  ensure that the duties of qualified persons referred to  in  Article 48  7.5/319/EEC 
are fulfilled,  either by means of appropriate administrative measures or by making such  Art. 25 
persons subject to a professional code of conduct. 

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

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

Article 53 

92173/EEC 
Art. 3 
(adapted) 

49 

TITLE V 
LABELLING AND PACKAGE LEAFLET 

Article 54 

The following particulars shall appear on the outer packaging of medicinal products or,  92127/EEC 
where there is no outer packaging, on the immediate packaging: 

Art. 2 (1), points (a) to 
(n) 
(adapted) 

(a)  the name of the medicinal product followed by the common name where the product 
contains  only  one  active  substance  and  if  its ·name  is  a  brand  name;  where  a 
medicinal  product  is  available  in·  several  phiU'J1laceutical  forms  and/or  several 
strengths,  the  phartnaceutical  form  and/or  the  strength  (baby,  child  or  adult  as 
appropriate) must be included in the name of the medicinal product; 

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

(c)  the  pharmaceutical  form  ~d the  contents  by  weight,  by  volume  or  by  number  of 

doses of the product; 

(d)  a list of those excipients known to have a recognized action or effect and included in 
the  guidelines. published  pursuapt  to  Article  65.  However,  if  the  product  is 
injectable, or a topical or eye preparation, all excipients must be stated; 

(e)  the method and, if necessary, the route of administration; 

(t)  a special warning that the medicinal product must be stored out of reach of children; 

(g)  a spe,ial warning, if this is necessary for the medicinal product; 

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

(i)  special storage precautions, if any; 

(j)  special  precautions  for  disposal  of unused  medicinal  products  or  waste  materials 

· from medicinal prQducts, if appropriate; 

· 

(k)  the  name  and  address  of the  holder  of the  authorization  for  placing  the  medicinal 

product on the market; 

(I)  the number of the authorization for placing the medicinal product on the market; 

(m) the manufacturer's batch number; 

(n)  in the case of self-medication, ·instructions on the use of the medicinal products. 

(4) 

so 

I. The particulars laid down in Articles 54 and 62 shall appear on immediate packagings  92/27/EEC 
other than those referred to in paragraphs 2 and 3. 

Art. 3 

Article SS 

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

the name of the medicinal product as laid down in Article 54 (a), 

·the name of the holder of the authorization for placing the product on the market, 

the expiry date, 

the batch number. 

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

the  name  of the  medicinal  product and,  if necessary,  the  strength  and  the  route  of 
administration, 

the method of administration, 

the expiry date, 

the batch nu~ber, 

the contents by weight, by volume or by unit. 

Article 56 

The  particulars  referr~d to  in  Articles  54,  55  and  62  shall  be  easily  legible,  clearly  192/27 /EEC 
comprehensible and indelible. 

Art. 4 ( 1) 

· 

Article 57 

Notwithstanding  Article  60,  Member  States  may  require  the  use  of certain  forms  of  92/27 /EEC 
labelling of the medicinal product making it possible to ascertain: 

Art. 5 (2) 
(adapted) 

the price of the medicinal product, 

the reimbursement conditions of social security organizations, 

the legal status for supply to the patient, in accordance with Titl~ VI, 

· . identification and authenticity. 

51 

Article 58 

The  inclusion  in  the  packaging  of all  medicinal  products  of a  package  leaflet  shall  be  92/27/EEC 
obligatory unless all the information required by Articles 59 and 62  is directly conveyed  Art. 6 
on the outer packaging or on the.immediate packaging 

(adapted) 

Article 59 

1.  The package leaflet shall be drawn up in accordance with the summary of the product  92127/EEC 
characteri~tics; it shall include, in the following order: 

Art. 7 ( 1) 
(adapted) 

(a)  for the identification of the medicinal product: 

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

a  full  statement of the  active  substance  and  excipients  expressed  qualitatively 
and  a  statement  of the  active  substance  expressed  quantitatively,  using  their 
common names, in the case of each presentation of the medicinal product, 

the pharmaceutical form and the contents by weight, by volume or by number of 
doses of the product, in the case of each presentation of the product, 

the  pharmaco-therapeutic  group,  or 
comprehensible for the patient, 

type  of  activity 

in 

terms  easily 

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

(b)  the therapeutic indications; 

52 

{c)  a list of information which is necessary before taking the medicinal product: 

-

-

-

contra-indications, 

appropriate precautions for use, 

forms  of  interaction  with  other  medicinal  products  and  other  forms  of 
interaction  (for  example,  alcohol,  tobacco,  foodstuffs)  which  may  affect  the 
action of. the medicinal product, 

92/27/EEC 
Art. 7 (1) 
(adapted) 

-

special warnings; 

this list must: 

-

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

- mention,  if appropriate,  potential  effects  on  the  ability  to  drive  vehicles  or to 

·operate machinery, 

detail  those  excipients,  knowledge  of which  is  important  for  the  safe  and 
effective use of the medicinal product and  included in  the guidelines published 
pursuant to Article 65; 

(d) 

the necessary and usual instructions for proper use, in particular: 

-

-

-

the dosage, 

the method and, if necessary, route of administration, 

the frequency of administration, specifying if necessary, the appropriate time at 
which the medicinal product may or must be administered, 

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

-

-

-

-

the duration of treatment, where it should be limited, 

the  action  to  be  taken  in  the  case  of an  overdose  (e.g.,  symptoms,  emergency 
procedures), 

the course of action to take when one or ~ore doses have not been taken, · 

indication, if necessary, of the risk of withdrawal effects; 

53 

(e)  a  description  of the  undesirable  effects  which  can  occur under normal  use  of th~  . 92/27/EEC 
medicinal  product  and,  if necessary,  the  action  to  be  taken  in  such  a  case;  the  Art. 7 ( 1) 
patient should be expressly invited to communicate any undesirable effect which is 
(adapted) 
not mentioned in the leaflet to his doctor or to his pharmacist; 

(f) 

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

-

a warning again~t using the product after this date, 

- where appropriate, special storage precautions, 

-

if necessary, a warning against certain visible signs of deterioration; 

(g) 

the date on which the package leaflet was last revised. 

2.  Notwithstanding  paragraph  1  (b),  the  authority  competent  may  decide  that  certain  92127/EEC 
therapeutic  indications  shall  not  be  mentioned . in  the  package  leaflet,  whe~ the  Art. 7 (2) 
dissemination of such information might have serious disadvantages for the patient. 
(adapted) 

Article 60 

Member  States  may  not  prohibit  or  impede  the  placing  on  the  market  of medicinal  92127/EEC 
products within their territory on grounds connected with labelling or the package leaflet  Art. 5 (I) and Art. 9 
where these comply with the ~equirements of this Title. 

(adapted) 

Article 61 

I.  One  or  more  specimens  or  mock-ups  of the  outer  packaging  and  the  immediate  92127/EEC 
packaging  of a  medicinal  product,  together  with  the  draft  package  leaflet,  shall  be  Art.  I 0 (I) to ( 4) 
submitted  to  the  authorities  competent  for  authorizing  marketing  when  the  marketing 
authorization is requested. 

(adapted) 

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

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

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

54 

Article 62 

The  outer  packaging  and  the  package  leaflet  may  include  symbols  or  pictograms  92127 /EEC 
designed  to  clarify certain  information  mentioned  in  Articles  54  and  59  (1)  and  other  Art. 2 (2) and 
information compatible with the summary of the  product characteristics which  is  useful  Art. 7 (3) 
for health education, to the exclusion of any element of a promotional nature. 
(adapted) 

Article 63 

1. The particulars for labelling listed in Articles 54, 59 and 62 shall appear in the official  92/27/EEC 
language or languages of the Member State where the product is placed on the market. 

Art. 4 (2) 
(adapted) 

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

2.  The package  leaflet must  be written  in  clear and  understandabl~ terms  for  the  us~rs  92/27/EEC 
and be clearly legible  in  the  official  language or languages  of the Member State where  Art. 8 
the medicinal product is placed on the market. 

(adapted) 

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

3.  The  competent  authorities  may  exempt  labels  and  package  leaflets  for  specific  92/27/EEC 
medicinal products from  the obligation that c~rtain particulars shall appear and that the  Art.  10 (5) 
leaflet  must  be  in  the  official  language  or  languages  of the  Member  State  where  the 
product is  placed on the market,· when the product is not intended to be delivered to the 
patient for self-administration. 

Article 64 

Where  the  provisions  of this  Title  are  not  complied  with,  and  a  notice  served  on  the  92/27 /EEC 
person  concerned  has  remained  without  effect,  the  competent  authorities  of  the  Art.  11  (1) 
Member States  may  suspend  the  marketing  authorization,  until  the  labelling  and  the 
(adapted) 
package leaflet of the medicinal product in question have been made to comply with the 
requirements of this Title. 

Article 65 

As necessary, the Commission shall publish guidelines concerning in particular: 

the  formulation  of certain  special  warnings  for  certain  categories  of medicinal 
products, 

92/27/EEC 
Art.  12 
(adapted) 

the particular information needs relating to self-medication, 

the legibility of particulars on the labelling and package leaflet, 

methods for the identification and authentication of medicinal products, 

the  list of excipients which must feature  on  the  labelling of medicinal products and 
the way these excipients must be indicated. 

These  guidelines  shall  be  adopted  in  the  form  of a  Directive,  in  accordance  with  the 
procedure laid down in Article 122. 

55 

Article·66 

.I. The outer packaging and the container of medicinal products containing radionuclides  89/343/EEC 
shall be labelled in accordance with the regulations for the safe transport of radioactive  Art. 5 
materials laid down by the International Atomic Energy Agency. Moreover, the labelling 
shall comply with the provisions set out in paragraphs 2 and 3. 

(adapted) 

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

3. The vial shall be labelled with the following infonnation: 

the name or code of the medicinal product,  including the name or chemical symbol 
of the radionuclide, 

the batch identification and expiry date, 

the international symbol for radioactivity, 

· the name of the manufacturer, 

the amount of radioactivity as specified in paragraph 2. 

Article 67 

The competent authority shall ensure that a detailed  instruction  leaflet is  enclosed with  89/343/EEC 
the  packaging  of radiophannaceuticals,  radionuclide  generators,  radionuclide  kits  or  Art. 6 ( 1) 
radionuclide precursors.  The text of this  leaflet shall be established  in  accordance with 
(adapted) 
·  the provisions of Article 59.  In  addition,  the  leaflet shall  include any precautions  to  be 
taken  by  the  user  and  the  patient  during  the  preparation  and  administration  of the 
medicinal  product  and  special  precautions  for  the  disposal  of the  packaging  and  its 
unused contents. 

56 

Article 68 

The homeopathic medicinal products shall be identified by a reference on their labels, in  92173/EEC 
clear and legible form, to their homeopathic nature. 

Art. 2 (2} 
(adapted)  . 

Article69 

1.  In  addition  to  the  clear mention  of the  words  "homeopathic  medicinal.product",  the  92173/EEC 
labelling and, where appropriate,  the package  insert for the·medicinal  products  referred  Art. 7 (2) and (3) 
to in Article 14 (1) shall bear the following, and no other, information: 

(adapted) 

the seientific name of the stock or stocks followed by the degree of dilution, making 
use of the symbols of the pharmacopoeia used in accordance with Article  l (5), 

name  and  address  of  the  registration  holder  and,  where  appropriate, . of  the 
manufacturer, 

method of administration and, if necessary, route, 

expiry date, in clear terms (month, year}, 

pharmaceutical form, 

contents of the sales presentation, 

special storage precautions, if any, 

a special warning if necessary for the medicinal product, 

manufacturer's batch number, 

registration number, 

"homeopathic medicinal product without approved therapeutic indications", 

a warning  advising  the  user to  consult a doctor  if the  symptoms  persist during ·the 
use of the medicinal product. 

2·.  Notwithstanding paragraph  I, Member States may  require the  use  of certain typeS' of 
labelling in order to show: 

the pri~ of the medicinal product, 

.. the conditions for refunds by social security bodies. 

57 

TITLE VI 
CLASSIFICATION OF MEDICINAL PRODUCTS 

Article 70 

I. When a marketing authorization is granted, the competent authorities shall specify the  92/26/EEC 
classification of the medicinal product into: 

Art. 2 

a medicinal product subject to medical prescription, 

a medicinal product not subject to medical prescription. 

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

2.  The competent authorities  may  fix  sub-categories  for  medici~al products  which  are 
available  on. medical  prescription  only.  In  that  case,  they  shall  refer  to  the  following 
classification: 

(a)  medicinal products on renewable or non-renewable medical prescription; 

(b)  medicinal products subject to special medical prescription; 

(c)  medicinal  products  on  restricted  medical  prescription,  reserved  for  use  in  certain 

specialized areas. 

1. Medicinal products shall be subject to medical prescription where they: 

Article 71 

are likely to present a danger either directly or indirectly, even when used correctly, 
if utilized without medical supervision, or 

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

contain  substances or preparations  thereof,  the  activity and/or adverse  reactions  of 
which require further investigation, or 

are normally prescribed by a doctor to be administered parenterally. 

92/26/EEC 
Art. 3 
(adapted) 

58 

2.  Where  Member States provide  for the  sub-category of medicinal  products subject to  92/26/EEC 
special medical prescription, they shall take account of the following factors: 

Art. 3 
(adapted) 

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

the  medicinal  product  is  likely,  if incorrectly  used,  to  present  a  substantial  risk  of 
medicinal abuse, to lead to addiction or be misused for illegal purposes, or 

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

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

the medicinal product, because of its  phannaceutical characteristics or novelty or in 
the  interests of public health,  is  reserved for treatments which can only be followed 
in a hospital environment, 

· 

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

the  medicinal  product  is  intended  f~r outpatients  but  its  use  may  produce  very 
serious  adverse  reactions  requiring  a  prescription  drawn  up  as  required  by  a 
specialist and special supervision throughout the treatment. 

4.  A competent authority may waive application of paragraphs  1, 2 and 3 having regard 
to: 

(a)  the maximum single dose, the maximum daily dose, the strength, the phannaceutical 

form, certain types of packaging; and/or 

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

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

59 

Article 72 

M~dicinal produc~ not  subject  to  prescription  shall  be  those  which  do  not  meet  the  192/26/EEC 
criteria listed in Article 71. 

Art. 4 

Article 73 

The competent authorities shall draw up a list of the medicinal products subject, on their  92/26/EEC 
territory, to medical prescription, specifying,  if necessary, the category of classification.  Art. 5 (1) 
They shall update this list annually. 

Article 74 

On the occasion of the five-yearly  renewal  of the marketing authorization  or when  new  92/26/EEC 
facts  are  brought  to  their  notice,  the  competent  authorities  shall  examine  and,  as  Art. 5 (2) 
appropriate,  amend  the  classification  of a  medicinal  product,  by  applying  the  criteria 
listed in Article 71. 

Article 75 

Each  year,  Member  States  shall  communicate  to  the  Commission  and  to  the  other  192/26/EEC  · 
Member States, the changes that have been made to the list referred to in Article 73. 

Art. 6 (2) 

60 

TITLE VII 
WHOLESALE DISTRIBUTION OF 
MEDICINAL PRODUCTS 

Article 76 

.Without prejudice to Article 6,  Member States shall take all appropriate action to ensure  92/25/EEC 
that  only  medicinal  products  in  respect  of which  a  marketing  authorization  has  been  Art. 2 
granted in accordance with Community law are distributed on their territory. 

Article 77 

I.  Member  States  shall  take  all  appropriate  measures  to  ensure  that  the  wholesale  92/25/EEC 
distribution  of medicinal  products  is  subject  to· the  possession  of an  authorization  ~o  Art. 3 
engage in activity as a wholesaler in  medicinal products, stating the place for which it is 
valid. 

(adapted) 

. 

2.  Where  persons  entitled  to  supply  medicinal  products  to  the  public  may  also,  under 
national.  law,  engage  in  wholesale  business,  such  persons  shall  be  subject  to  the 
authorization provid~d for in paragraph  1. 

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

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

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

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

7.  Should a Member State consider that,  in  respect of a  person holding an authorization 
granted  by  another  Member  State  under  the  terms  of paragraph  1,  the  conditions  of 
authorization are not, or are no longer met, it shall forthwith  inf~rm the Commission and 
the other Member State involved.  The  latter shall take the  measures necessary and shall 
inform  the  Commission  and  the  first  Member  State  of the  decisions  taken  and  the 
reasons for those decisions. 

61 

Article 78 

Member  States  shall  ensure  that  the  time  taken  for  the  procedure  for  examining  the  92/25/EEC 
application  for  the distribution  authorization  does  not  exceed  90  days  from  the  day  on  Art. 4 ( 1) 
(adapted) 
which the comj>etent authority of the Member State c:;oncerned receives the application. 

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

Article 79 

In  order  to  obtain  the  distribution  authorization,  applicants  must  fulfil  the  following  92/25/EEC 
minimum requirements: 

Art.  5 
(adapted) 

(a)  they must have suitable and adequate premises, installations and equipment, so as to 

ensure proper conservation and distribution of the medicinal pro.ducts; 

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

(c)  they must undertake to  fulfil  the  obligations  incumbent on  them  under the terms  of 

Article 80. 

Article 80 

Holders  of  the  distribution  authorization  must  fulfil 
requireptents: 

the · following  minimum  92/25/EEC 

Art. 6 
(adapted) 

(a)  they  must  make  the  premises, 

installations  and  equipment  referred  to 

in 

Article 79 (a) accessible at all times to the persons responsible for inspecting them; 

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

(c)  they  must  supply  medicinal  products  only  to  persons  who  are  themselves  in 
possession  of the  distribution  authorization  or  who  are  authorized  or  entitled  to 
.supply medicinal products to the public in the Member State concerned; 

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

62 

(e)  they  must  keep  records  either  ·in  the  form  of  purchase/sales  invoices,  or  on  92/25/EEC 
computer,  or  in  any  other  form,  giving  for  any  transaction  in  medicinal  products  Art. 6 
received or dispatched at least the following information: 

(adapted) 

date, 

name of the medicinal product, 

quantity received or supplied, 

name and address of the supplier or consignee, as appropriate; 

(f)  they  must  keep  the  records  referred  to  under  (e)  available  to  the  competen~ 

authorities, for inspection purposes, for a period of five years; 

(g)  they must comply with the principles and guidelines of good distribution practice for 

medicinal products as laid down in Article 84. 

Article 81 

With  regard to  the  supply of medicinal  products to  pharmacists  and  persons  authorized  92/25/EEC 
or entitled to  supply medicinal  prodUcts  to  the  public,  Member States  shall  not  impose  Art. 7 
upon  the  holder  of a  distribution  authorization  which  has  been  granted  by  ·another 
Member State,·  any  obligation,  in  particular  public  service  obligations,  more  stringent 
than those they impose on persons whom they have themselves authorized to engage in 
equivalent activities. 

(adapted) 

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

Article 82 

For  all  supplies  of medicinal  products  to  a  person  authorized  or  entitled  to  supply  92/25/EEC 
medicinal  products  to  the  public  in  the  Member  State  concerned,  the  authorized  Art. 8 
wholesaler must enclose a document that makes it possible to ascertain: 

the date, 

the name and pharmaceutical form of the medicinal product, 

the quantity supplied, · 

the name and address of the supplier and consignor. 

Member States shall take  all  appropriate  measures to  ensure  that persons authorized or 
entitled to  supply medicinal  products to the. public are  able to  provide  information  that 
makes it possible to trace the distribution path of every medicinal product. 

63 

Article 83 

The  provisions  of  this  Title  shall  not  prevent  the  application  of  more  stringent  92/25/EEC 
requirements laid down by Member States in respect of the wholesale distribution of: 

Art. 9 
(adapted) 

narcotic or psychotropic substances within their territory, 

medicinal products d~rived from blood, 

immunological medicinal products, 

radiopharmaceuticals. 

Article 84 

The  Commission  shall  publish guidelines  on  good  distribution  practice.  To  this  end,  it  92/25/EEC 
shall consult the Committee for Proprietary Medicinal Products and  the  Pharmaceutical  Art.  10 
Committee established by Council Decision 75/320/EECl. 

(adapted) 

Article 85 

Member  States  shall,· in  special  cases,  authorize  the  direct  distribution  of medicinal  92/28/EEC 
products to the public, by the industry for promotional purposes. 

Art. 3 (6), 2nd sentence 
(adapted) 

OJ L 147, 9.6.1975, p. 23. 

64 

TITLE VIII 
ADVERTISING 

Article 86 

I.  For the  purposes  of this  Title,  "advertising of medicinal  products" shall  include  any  92/28/EEC 
form  of  door-to-door  information,  canvassing  activity  or  inducement  designed  to  Art.  1 (3) and (4) 
promote  the  prescription,  supply,  sale  or  consumption  of medicinal  products;  it  shall 
include in particular: 

the advertising of medicinal products to the general public, 

advertising of medicinal products to persons qualified to prescribe or supply them, 

visits  by  medical  sales  representatives  to  persons  qualified  to  prescribe  medicinal 
products, 

the supply of samples, 

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

sponsorship  of promotional  meetings  attended  by persons  qualified  to  prescribe  or 
supply medicinal products, 

sponsorship  of scientific  congresses  attended  by  persons  qualified  to  prescribe  or 
supply  medicinal  products  and  in  particular  payment  of  their  travelling  and 
~ccommodation expenses in connection therewith. 

2. The following are not covered by this Title: 

the  labelling  and  the  accompanying  package  leaflets,  which  are  subject  to  the 
provisions of Title V; 

correspondence,  possibly  accompanied  by  material  of a  non-promotional  nature, 
needed to answer a specific question about a particular medicinal product; 

factual,  informative announcements and reference material relating,  for  example, to 
pack changes,  adverse-reaction warnings  as  part of general  drug  precautions,  trade 
catalogues and price lists, provided they include no product claims; 

statements relating to human health or diseases, provided there  is no reference, even 
indirect, to medicinal products. 

65 

Article 87 

I.  Member  States  shall  prohibit  any  advertising  of a  medicinal  product  in  respect  of  92/28/EEC 
which· a  marketing  authorization has  not  been  granted  in  accordance  with  Community  Art. 2 
law. 

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

3.  The advertising of a medicinal product: 

shall  encourage  the  rational  use  of  the  medicinal  product,  by  presenting  it 
objectively and without exaggerating its properties, 

shall not be misleading. 

Article 88 

I.  Member  States  shall  prohibit  the  advertising  to  the  general  public  of medicinal  92/28/EEC 
products which: 

Art. 3 (I) to (6),  1st 
sentence 
(adapted) 

are available on medical prescription only, in accordance with Title VI, 

contain psychotropic or narcotic substances, such as the United Nations Conventions 
of 1961  and 1971, 

· 

may  not  be  advertised  to  the  general  public  in  accordance  with  the  second 
subparagraph of paragraph 2. 

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

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

tuberculosis, 

sexually transmitted diseases, 

other serious infectious diseases, 

cancer and other tumoral diseases, 

chronic insomnia, 

diabetes and other metabolic ilinesses. 

(5) 

66 

3. Member States shall be able to ban, on their territory, advertising to the general public  92/28/EEC 
of medicinal products the cost of which may be reimbursed. 

Art. 3 ( 1) to ( 6) 
1st sentence 
(adapted) 

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

5.  The prohibition referred to  in  paragraph  1 shall apply without prejudice to Article  14 
of Directive 89/552/EEC. 

6. Member States shall prohibit the direct distribution of medicinal products to the public 
by the industry for promotional purposes. 

Article 89 

1.  Without  prejudice to  Article  88,  all  advertising to  the  general  public  of a  medicinal  92/28/EEC . 
product shall: 

Art. 4 
(adapted) 

(a)  be set out in such a way that it is clear that the message is an  advertisement and that 

the product is clearly identified as a medicinal product; 

(b)  include the following minim.um  information: 

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

the information necessary for correct use of the medicinal product, 

an  express,  legible  invitation  to  read carefully the  instructions  on  ~he package 
leafle~ or on the outer packaging, as the case may be. 

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

67 

Article 90 

The  advertising  of a  medicinal  product  to  the  general  public  shall  not  contain  any  92/28/EEC 
material which: 

Art. 5 
(adapted) 

(a)  gives  the 

impression  that  a  medical  consultation  or  surgical  operation 

is 
unnecessary,  in  particular  by  offering  a  diagnosis  or  by  suggesting  treatment  by 
mail; 

(b)  suggests that the effects of taking the  medicine  are  guaranteed,  are  unaccompanied 
by adverse reactions  or are better than,  or equivalent to,  those  of another treatment 
or medicinal product; 

(c)  suggests that the health of the subject can be enhanced by taking ~he medicine; 

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

(e)  is directed exclusively or principally at children; 

(f)  refers  to  a  recommendation  by  scientists,  health  professionals  or  persons  who  are 
neither  of the  foregoing  but  who,  because  of their  celebrity,  could  encourage  the 
consumption of medicinal products; 

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

product; 

(h)  suggests that the safety or efficacy of the medicinal product is  due to the fact that it 

is natural; 

· 

(i)  could, by a description or detailed representation of a case history, lead to erroneous 

self-diagnosis; 

G)  refers, in improper, alarming or misleading terms, to cli;iims of recovery; 

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

· product on the human body or parts thereof; 

(I)  mentions that the medicinal product has been granted a marketing authorization. 

68 

I.  Any  advertising  of a  medicinal  product  to  persons  qualified  to  prescribe  or  supply  92/28/EEC 
such products shall include: 

Art. 6 

Article 91 

essential infonnation compatible with the summary of product characteristics; 

the supply classification of the medicinal product. 

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

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

Article 92 

.1.  Any documentation relating to a medicinal product which  is transmitted as  part of the  92/28/EEC 
promotion of that product to persons qualified to prescribe or supply it shall include, as a  Art. 7 
minimum, the particulars listed in Article 91  (1) and shall state the date on which  it was 
drawn up or last revised. 

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

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

69 

Article 93 

1.  Medical . sales  representatives  shall  be  given  adequate  training  by  the  firm  which  92128/EEC 
employs  them  and  shall  have  sufficient  scientific  knowledge  to  be  able  to  provide  Art. 8 
information which  is  precise  and as  complete as  possible about the  medicinal  products 
which they promote. 

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

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

Article 94 

1.  Where  medicinal  products  are  being  promoted  to  persons  qualified  to  prescribe  or  92/28/EEC 
supply them, no gifts, pecuniary advantages or benefits in kind may be supplied, offered  Art. 9 
or promised to such  persons unless they are  inexpensive and  relevant to the  practice of  (adapted) 
medicine or pharmacy. 

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

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

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

· 

Article 95 

.  The provisions of Article  94  (1)  shall  not prevent hospitality  being offered,. directly  or  92/28/EEC 

indirectly, at events for purely professional and scientific purposes; such hospitality shall  Art.  10 
always be reasonable in level and remain subordinate to the main scientific objective of 
the meeting; it must not be extended to persons other than health professionals. 

70 

Article 96 

I.  Free  samples  shall  be  provided  on  an  exceptional  basis  only  to  persons  qualified  to  92/28/EEC 
prescribe them and on the following conditions: 

Art.  11 
(adapted) 

(a)  the  number of samples  for  each  medicinal  product  each  year  on  prescription  shall 

be limited; 

(b)  any  supply  of samples  shall  be  in  response  to  a written  request,  signed  and  dated, 

from the prescribing agent; 

(c)  those  supplying  samples  shall  maintain  an  adequate  system  of  control  and 

accountability; 

(d)  each sample shall be identical with the smallest presentation on the market; 

(e)  each sample shall be marked "free medical sample- not for sale" or shall show some 

other wording having the same meaning; 

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

characteristics; 

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

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

Article 97 

1.  Member States shall ensure that there are adequate and effective methods to  monitor  92/28/EEC 
the  advertising of medicinal  products.  Such  methods,  which  may  be  based  on  a  system  Art.  12 (1) and (2) 
of prior  vetting,  shall  in  any  event  include  legal  provisions  under  which  persons  or. 
organizations  regarded  under national  law  as  having a  legitimate  interest  in  prohibiting 
any  advertisement  inconsistent 'with  this  Title,  may  take  legal  action  against  such 
advertisement, or bring such advertisement before an adm!nistrative authority competent 
either to decide on complaints or to initiate appropriate legal proceedings. 

71 

2.  Under  the  legal  provisions  referred  to  in  paragraph  I,  Member  States  shall  confer  92/28/EEC 
upon the courts or administrative authorities powers enabling them,  in  cases where they  Art.  12 (1) and (2) 
deem such measures  to be necessary,  taking  into  account all  the  interests  involved,  and 
in particular the pub~ic interest: 

(adapted) 

to order the cessation of, or to institute appropriate legal proceedings for an order for 
the cessation of, misleading advertising, 

or 

·  if misleading advertising has not yet been published but publication  is  imminent,  to 
or~er the prohibition of, or to institute appropriate legal proceedings for an order for 
the prohibition of, such publication, 

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

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

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

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

· 

to  require  publication  of that  decision  in  full  or  in  part  and  in  such  form  as  they 
deem adequate~ 

to require in addition the publication of a corrective statement. 

5.  Paragraphs  1 to  4 shall not exclude the  voluntary control of advertising of medicinal  92/28/EEC 
products  by  self-regulatory  bodies  and  recourse  to  such  bodies,  if proceedings  before  Art.  12 (4) 
(adapted) 
such bodies are possible in addition to the judicial or administrative proceedings referred 
to in paragraph  1. 

72 

Article 98 

1.  The marketing authorization holder shall establish, within his undertaking, a scientific  92/28/EEC 
service  in  charge  of information  about  the  medicinal  products  which  he  places  on  the  Art.  13 
market. 

(adapted) 

2. The marketing authorization holder shall: 

keep  available  for,  or  communicate  to,  the  authorities  or  bodies  responsible  for 
monitoring  advertising  of  medicinal  products,  a  sample  of  aJI  advertisements 
emanating from  his undertaking together with  a statement  indicating the persons to 
it  is  addressed,  the  method  of  dissemination  and  the  ·date  of  first 
whom 
disse~ination, 

ensure  that  advertising  of medicinal  products  by  his  undertaking  conforms  to  the 
requirements of this Title, 

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

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

ensure  that  the  decisions  taken  by  the  authorities  or  bodies  responsible  for 
monitoring'advertising  of medicinal  products  are  immediately  and  fully  complied 
with. 

Article 99 

Member States shall take the appropriate measures to ensure that the provisions of this  92/28/EEC 
Title are applied and shall determine in particular what penalties shall be imposed should  Art.  14 
the provisions adopted in the execution of Title be infringed. 

(adapted) 

Article 100 

Advertising  of the  homeopathic  medicinal  products  referred  to  in  Article  13  (2)  and  92173/EEC 
Article  14  (I)  shall  be  subject  to  the  provisions  of this  Title  with  the  exception  of  Art. 6 (3) 
Article 87 (1). 

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

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

73 

TITLE IX 
PHARMACOVIGILANCE 

Article 101 

The  Member States shall take all  appropriate  measures  to  encourage  doctors  and  other  75/319/EEC 
health  care  professionals  to  report  suspected  adverse  reactions  to  the  competent  Art. 29e 
authorities. 

The  Member  States  may  impose  specific  requirements  on  medical  practitioners,  in 
respect  of  the  reporting  of  suspected  serious  or  unexpected  adverse  reactions,  in 
particular where such reporting is a condition of the marketing authorization. 

Article 102 

(as amended by 
93/39/EEC Art. 3 (3))  . 
(adapted) 

In  order  to  ensure  the  adoption  of appropriate  regulatory  decisions  concerning  the  75/319/EEC 
medicinal  products  authorized  within  the  Community,  having  regard  to  information  Art. 29a 
obtained al>out  adverse reactions to medicinal products under normal conditions of use, 
the Member States shall establish a pharmacovigilance system. This system shall be used  93/39/EEC Art. 3 (3)) 
to  collect  information  useful  in  the .surveillance  of medicinal  products,  with  particular 
reference  to  adverse  reactions  in  human  beings,  and  to , evaluate  such  information 
scientifically. 

(as amended by 

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

This  system  shall  also  collate  information  on  frequently  observed  misuse  and  serious 
abuse of medicinal products. 

74 

Article 103 

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

That qualified person shall be responsible for the following: 

75/31.9/EEC 
Art. 29c 
(as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 

(a)  the establishment and maintenance of a system which ensures that information about 
all suspected adverse reactions which are reported to the personnel of the company, 
and to medical representatives,  is  collected and collated at a single point within the 
Community; 

(b)  the preparation for the competent authorities of the reports referred to in Article  I 04, 
in  such  form  as  may  be  laid  down  by  those  authorities,  in  accordance  with  the 
relevant national or Community guidelines; 

(c)  ensuring  that  any  request  from  the  competent  authorities  for  the  prov1s1on  . of 
additional information necessary for the evaluation of the benefits and risks afforded 
by  a  medicinal  product  is  answered  fully  and  promptly,  including  the  provision  of 
information  about  the  volume  of sales  or  prescriptions  of the  medicinal  product 
concerned. 

Article 104 

I.  The  marketing  authorization  holder  shall  be  required  to  record  and  to  report  all 
suspected serious  adverse  reactions  which  are  brought to  his  attention  by  a  health  care 
professional to the competent authorities immediately, and in  any case within  15  days of 
their receipt at the latest. 

75/319/EEC 
Art. 29d 
(as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 

2.  The marketing authorization  holder shall  be  required  to  maintain  detailed  records  of 
all  other  suspected  adverse  reactions  which  are  reported  to  him  by  a  health  care 
professional. 

Unless  other  requirements  have  been  laid  down  as  a  condition  of  the  granting  of 
authorization, these records shall  be  submitted to the competent authorities  immediately 
upon  request  or  at  least  every  six  months  during  the  first  two  years  following 
authorization, and once a year for the following three years. Thereafter, th~ records shall 
be  submitted  at  five-yearly  intervals  together  with  the  application  for  renewal  of the 
authorization,  or  immediately  upon  request.  These  records  shall· be  accompanied  by  a 
scientific evaluation. 

75 

Article 105 

The  Member States shall  ensure that  reports  of suspected serious  adverse  reactions  are  75/319/EEC 
immediately  brought  to  the  attention  of the  Agency  and  the  marketing  authorization  Art. 29f 
hold~r, and in any case within 15 days of their notification, at the latest. 

(as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 

Article 106 

In  order to  facilitate  the  exchange  of information  about  pharmacovigilarice  within the 
Community,  the  Commission,  in  consultation  with  the  Agency,  Member  States  and 
interested parties, shall draw up guidance on the collection, verification and presentation 
of adverse reaction reports. 

75/319/EEC 
Art. 29g 
(as amended by 
93/39/EEC Art. 3 (3)) 

This  guidance  shall  take  account of international  harmonization  work  carried  out  with 
regard to terminology and classification in the field of pharmacovigilance. 

Article 107 

Where,  as  a  result  of  the  evaluation  of  adverse  reaction  reports,  a  Member  State  75/319/EEC 
considers  that a  marketing  authorization  should  be  varied,  suspended  or withdrawn,  it  Art. 29h 
shall forthwith inform the Agency and the marketing authorization holder. 

(as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 

In  case of urg~ncy,. the competent authority concerned may suspend the  marketing of a 
medicinal  product,  provided  the  Agency  is  informed ·at  the  late~t  on  the  following 
working day. 

Article 108 

Any amendments which may be necessary to update provisions of Articles  10 1 to  I 07 to  7 5/319/EEC 
take account of scientific and technical progress shall be adopted in  accordance with the  Art. 29i 
procedure laid down in Article 122. 

(as amended by 
93/39/EEC Art. 3 (3)) 
(adapted) 

76 

TITLE X 
SPECIAL PROVISIONS ON MEDICINAL PRODUCTS DERIVED FROM 
HUMAN BLOOD AND PLASMA 

Article 109 

1.  In  respect of the  use  of human  blood or human  plasma as  a starting material  for  the  89/381/EEC 
manufacture of medicinal products, Member States shall take the  necessary measures to  Art. 3 (1), (2) and (3) 
prevent  the  transmission  of infectious  diseases.  In  so  far  as  this  is  covered  by  the 
amendments referred to  in  Article  121, as  well  as the  application of the  monographs of 
the  European  Pharmacopoeia  regarding  blood  and  . plasma,  these  measures  shall 
comprise  those  recommended  by  the  Council  of  Europe  and  the  . World  Health 
Organization, particularly with reference to the selection and testing _of blood and plasma 
donors. 

(~dapted) 

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

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

Article 110 

take 

the  necessary  measures 

Member  States  shall 
self-sufficiency in human blood or human plasma. For this purpose, they shall encourage  Art. 3 (4) 
(adapted) 
the  voluntary  unpaid  donation  of  blood  and  plasma  and  shall  take  the  necessary 
measures  to  develop the  production  and  use  of products  derived  from  human  blood  or 
human  plasma  coming  from  voluntary  unpaid  donations.  They  shall  notify  the 
Commission of such measures. 

to  promote  Community  89/381/EEC 

77 

TITLE XI 
SUPERVISION AND SANCTIONS 

Article 111 

I.  The  competent authority  of the  Member  State  concerned  shall  ensure,  by  means  of  75/319/EEC 
.repeated  inspections,  that  the  legal  requirements  governing  medicinal  products  are  Art. 26,  1st paragraph 
complied with. 

(as amended by 
89/341/EEC Art. 3 (6)) 

Such  inspections  shall  be  carried out  by  officials  representing  the  competent  authority  75/319/EEC 
who shall be empowered to: 

Art. 26 (2) 
(adapted) 

(a)  inspect manufacturing or commercial establishments  and any  laboratories entrusted 
by ·the  holder  of the  manufacturing  authorization  with  the  task  of carrying  out 
checks pursuant to Article 20; 

(b)  take samples; 

(c)  examine  any  documents  relating  to  the  object  of the  inspection,  subject  to  the 
provisions  in  force  in  the  Member  States  on  21  May  1975  and  which  place 
restrictions  on  these  powers  with  regard ·to  the  descriptions  of  the  method  of 
preparation. 

2.  Member  States  shall. take  all  appropriate  steps  to  ensure  that  the  manufacturing  89/342/EEC 
processes used in the manufacture of immunological products are properly validated and  Art. 4 ( 1) 
attain batch-to-batch consistency. 

3.  After  every  inspection  as  referred  to  in  paragraph  1,  the  officials  representing  the 
competent  authority  shall  report  on  whether  the  manufacturer  complies  with  the 
principles and guidelines  of good manufacturing  practice  laid  down  in  Article  4 7.  The 
content of such reports shall be communicated to the manufacturer who has  to  undergo 
the inspection. 

75/319/EEC 
Art. 26, 3rd paragraph 
(as amended by 
89/341/EEC Art. 3 (6)) 
(adapted) 

Article 112 

Member States shall take all  appropriate  measures to ensure that the  person responsible 
the  holder  of  the 
for  marketing  a  medicinal  product  and,  where  appropriate, 
manufacturing  authoriza~ion, furnish  proof of the  controls  carried out on  the  medicinal 
product  and/or  the  ingredi~nts  and  of  the  controls  carried  out  at  an  intermediate 
stage  of the  manufacturing  process,  in  accordance  with  the  methods  laid  down  in 
Article 8 (3) (h). 

65/65/EEC 
Art. 8 
+ 
75/319/EEC 
Art. 27 
(adapted) 

78 

Article 113 

"For the purpose of implementing Article  112,  Member States may require manufacturers  89/342/EEC 
of immunological  products to  submit to  a  competent authority copies  of all  the  control  Art. 4 (2) 
reports signed by the qualified person in accordance with Article 51. 

+ 
89/381/EEC 
Art. 4 (2) 

Article 114 

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

89/342/EEC 
Art. 4 (3) 
(adapted) 

live vaccines, 

immunological medicinal products used in the primary immunization of infants or of 
other groups at risk, 

immunological medicinal products used in public health immunization programmes, 

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

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

2.  Where,  in  the  interests  of public  health,  the  laws  of a  Member  State  so  provide,  the  89/381/EEC 
competent  authorities  may  require  the  marketing  authorization  holder  for  medicinal  Art. 4 (3) 
products  derived  from  human  blood  or  human  plasma  to  submit  samples  from  each 
(adapted) 
batch  of the  bulk  and/or  the  medicinal  product  for  testing  by  a  State  laboratory  or  a 
laboratory designated for  that purpose before being released into free  circulation, unless 
the competent authorities of another Member State have previously examined the batch 
in  question  and  declared  it  to  be  in  conformity  with  the  approved  specifications. 
Member States  shall  ensure  that  any  such  examination  is  completed  within  60  days  of 
the receipt of the samples. 

79 

Article 115 

·Member States  shall  take  all  necessary  measures  to  ensure  that the  manufacturing  and  89/381/EEC 
. purifying processes used  in  the  preparation  of medicinal  products  derived  from  human  Art. 4 ( 1) 

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

Article 116 

The competent authorities of the Member States shall suspend or revoke an authorization  65/65/EEC 
to  place a  medicinal  product on the market where  that product proves  to  be  harmful  in  Art.  11,  1st paragraph 
the  normal  conditions  of use,  or where  its  therapeutic  efficacy  is  lacking,  or where  its 
qualitative  and  quantitative  composition  is  not  as  declared.  Therapeutic  efficacy  is  89/341/EEC Art.  1 (1 )) 
lacking  when  it  is  established  that  therapeutic  results  cannot  be  obtained  with  the 
medicinal product. 

(as amended by 

An authorization shall also be suspended or revoked where the particulars supporting the  65/65/EEC 
application  as  provided  for  in  Articles  8,  10  (1)  and  11  are  incorrect or have  not  been .  Art.  11, 2nd paragraph 
amended in accordance with Article 23. 

(as amended by 
· 83/570/EEC Art.  1 (6)) 

80 

Article 117 

I.  Notwithstanding  the  measures provided  for  in  Article  116,  Member States shall  take  75/319/EEC 
all  appropriate  measures  to  ensure  that  the  supply  of the  medicinal  product  shall  be  Art. 28 
prohibited and the medicinal product withdrawn from the market if: 

(adapted) 

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

(b)  it is  lacking in therapeutic efficacy, or 

(c)  its qualitative and .quantitative composition is not as declared, or 

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

2.  The  competent  authority  may  limit  the  prohibition  to  supply  the  product,  or  its 
withdrawal from  the market, to those batches which are the subject of dispute. 

Article 118 

1.  The  competent  authority  shall  suspend  or revoke  the  marketing  authorization  for  a  75/319/EEC 
category of preparations or all preparations where any one of the requirements laid down  Art. 29 
in Article 41  is no longer met. 

(adapted) 

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

The provisions ofthis Title shall apply to homeopathic medicinal products. 

Article 119 

92173/EEC 
Art. 4 (1) 
(adapted) 

81 

TITLE XII 
STANDING COMMITTEE 

Article 120 

1.  A  Standing Committee on Medicinal  Products  for  Human  Use  on  the  Adaptation  to  75/318/EEC 
Technical Progress of the Directives on the Removal ofTechni~al Barriers to trade in  the  Art. 2b 
Medicinal  Products  Sector,  hereinafter called  "the Standing Committee",  is  hereby  set 
up;  it shall consist of representatives of the  Member States with  a representative of the 
Commission as chainnan.  . 

(adapted) 

2. The Standing Co!'lmittee shall adopt its own rules of procedure. 

Article 121 

Any changes which are necessary in order to adapt Annex I to take account of scientific  7 5/3I8/EEC 
and technical  progress shall  be  adopted  in  accordance  with  the  procedure  laid  down  in  Art. 2a,  I st paragraph 
Article  122. 

(as amended by 
87/19/EEC Art.  I (I)) 
(adapted) 

(6) 

82 

Article 122 

Where the procedure laid down in this Article is to be followed, the Commission shall be  75/319/EEC 
assisted by the Standing Committee. 

Art. 37a 
(as amended by 

The representative of the Commission shall submit to the Standing Committee a draft of  93/39/EEC Art. 3 (4)) 
the measures to be taken. The Standing Committee shall deliver its opinion on the draft 
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. 

(adapted) 

The Commission shall adopt the measures envisaged  if they are  in  accordance with the 
opinion of the Standing Committee. 

If the  measures  envisaged  are  not  in  accordance  with  the  opinion  of the  Standing 
Committee, or if no opinion is delivered, the Commission shall, without delay, submit to 
the Council a  proposal relating to the  measures  to  be taken.  The  Council shall  act by a 
qualified majority. 

If on the expiry of a period of three months from  the date of referral to the Council, the 
Council has not acted, the proposed measures shall be adopted by the Commission. 

Article 123 

Where the procedure laid down in this Article is to be followed, the Commission shall be  75/319/EEC 
assisted by the Standing Committee. 

Art. 3 7b 
(as amended by 

The representative of the Commission shall submit to the Standing Committee a draft of  93/39/EEC Art. 3 (4)) 
the measures to be taken.  The Standing Committee shall deliver its opinion on the draft 
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. 

(adapted) 

The Commission shall adopt the measures envisaged if they are  in  accordance with  the 
opinion of the Standing Committee. 

If the.  measures  envisaged  are  not  in  accordance  with  the  opinion  of the  Standing 
Committee, or if no opinion is delivered, the Commission shall, without delay, submit to 
the Council a  proposal relating to the measures to  be taken.  The Council  shall  act by  a 
qualified majority. 

If on the expiry of a period of three months from  the date of referral to the Council, the 
Council has not acted, the proposed measures shall be adopted by the Commission, save 
where the Council has decided against the said measures by a simple majority.  · 

83 

TITLE XIII 
GENERAL PROVISIONS 

. Article 124 

Member  States  shall  take  all  appropriate  measures  to  ensure  that  the  competent  75/319/EEC 
authorities  concerned communicate to  each  other such  information  as  is  appropriate  to  Art. 30,  1st paragraph 
guarantee  that  the  requirements  for  the  manufacturing  authorizations  or  marketing 
authorizations are fulfilled. 

(adapted) 

Upon reasoned request, Member States shall forthwith communicate the reports referred  75/319/EEC 
to  in  Article  Ill  (3)  to  the  competent  authorities  of another  Member  State.  If,  after  Art. 30, 2nd paragraph 
considering the reports,  the  Member  State  receiving the  reports  considers that it cannot 
accept  the  conclusions  reached  by  the  competent  authorities  of the  Member  State  in  89/341/EEC Art. 3 (8)) 
which the report was established,  it shall  inform the competent authorities concerned of 
its reasons and may request further information. The Member States concerned shall use 
their best endeavours to reach agreement.  If necessary,  in the case of serious differences 
of opinion, the Commission shall be informed by one of the Member States concerned. 

(as amended by 

Article 125 

1.  Each  Member  State  shall  take  all  the  appropriate  measures  to  ensure  that  decisions  75/319/EEC 
authorizing  marketing,  refusing  or  revoking  a  marketing  authorization,  cancelling  a  Art. 33 (1) 
decision  refusing  or  revoking  a  marketing  authorization,  prohibiting  supply,  or 
(adapted) 
withdrawing  a  product  from  the  market,  together  with  the  reasons  on  which  such 
decisions are based, are brought to the attention of the Agency forthwith. 

2.  The  marketing  authorization  holder  shall  be  obliged  to  notify  the  Member  States  75/319/EEC 
concerned forthwith of any action taken by him to suspend the marketing of a medicinal  Art. 33  (2) to (4) 
product or to  withdraw  a medicinal  product from  the market,  together with  the  reasons 
(as amended by 
for  such  action  if the  latter  concerns  the  efficacy  of the  medicinal  product  or  the  89/341/EEC Art. 3 (9)) 
protection  of public health.  Member States  shall ensure  that this  information  is  brought 
to the attention of the Agency. 

(adapted) 

3.  Member States  shall ensure that appropriate  information about action taken pursuant 
to paragraphs  1 and 2 which may affect the protection of public health in third countries 
is forthwith brought to the attention of the World Health Organization, with a copy to the 
Agency. 

4.  The  Commission  shall  publish  annually  a  list  of the  medicinal  products  which  are 
prohibited in the Community. 

84 

Article 126 

Member  States  shall  communicate  to  each  other  all  the  information  necessary  to  92173/EEC 
guarantee the quality  and  safety of homeopathic  medicinal  products  manufactured  and  Art. 5 
marketed  within  the  Community,  and  in  particular  the  information  referred  to  in 
Articles 124 and 125. 

Article 127 

Every decision referred to in this Directive which is taken by the competent authority of  65/65/EEEC 
a Member State shall state in detail the reasons on which it is based. 

Art.  12 
(adapted) 

Such  decision  shall  be  notified to  the  party concerned,  together with  information  as  to  + 
the  redress  available  to  him  under the  laws  in  force  and  of the  time-limit  allowed  for  75/319/EEC 
access to such redress. 

Art. 31 
(adapted) 
+ 
92/25/EEC 
Art. 4 (2) 
(adapted) 
+ 
92/27/EEC 
Art.  11  (2) 
(adapted) 
+ 
92/28/EEC 
Art.  12 (3) 
(adapted) 

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

85 

An  authorization  to  market  a  medicinal  product  shall  not  be  refused,  suspended  or 165/65/EEC 
revoked except on the grounds set out in this Directive. 

Art. 21 

Article 128 

No  decision  concerning  suspension  of manufacture  or  of importation  of medicinal  75/319/EEC 
products  coming  from  third  countries,  prohibition  of supply  or  withdrawal  from  the  Art. 32 
market of a medicinal product may be taken except on the ground set out in Articles  117 
and  118. 

(adapted) 

· 

Article 129 

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

(a)  they  shall  have  regard  to  the  prevailing  administrative  arrangements  of the  World 

Health Organi7.ation; 

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

2.  When  the  manufacturer  is  not  in  possession  of a  marketing  authorization  he  shall 
provide  the  authorities  responsible  for  establishing  the  certificate  referred  to . in 
paragraph  I, with a declaration explaining why no marketing authorization is available. 

75/319/EEC 
Art. 28a 
(as amended by 
89/341/EEC Art. 3 (7)) 
(adapted) 

86 

TITLE XIV 
FINAL PROVISIONS 

Article.130 

89/343/EEC, 
Directives  65/65/EEC,  . 75/318/EEC, 
89/381/EEC, 92/25/EEC, 92126/EEC, 92/27/EEC, 92/28/EEC and 92/73/EEC, amended 
by the Directives referred to in  Annex 11,  Part A,  are repealed, without prejudice to the 
obligations ~f the Member States concerning the time-limits  for  implementation set out 
in Annex 11,  Part B. · 

75/319/EEC, 

89/342/EEC, 

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

Article 131 

This Directive shall enter into force on 1 January 2000. 

Article 132 

This Directive is addressed to the Member States. 

Done at Brussels, 

For the European Parliament 

The President 

For the Council 

The President 

87 

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

INTRODUCTION 

The particulars and documents accompanying an application for marketing authorization 
pursuant to Articles 8 and  10 (1) shall be presented in four parts,  in accordance with the  91/507/EEC Art.  1) 
requirements set out in  this Annex and taking account of the guidance published by the 
Commission  in  The  rules  governing  medicinal products  in  the  European  Community, 
Volume 2: Notice to applicants for marketing authorizations/or medicinal products for 
human use in the Member States of the European Community. 

(adapted) 

75/318/EEC 
Annex 
(as amended 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 
medicinal  products  published  by  the  Commission  in  The  rules  governing  medicinal 
products in the European Community,  Volume 3 and its supplements: Guidelines on the 
quality, safety and efficacy of medicinal products for human use. 

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

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

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

OJ L 358, 18.12.1986, p.  I. 

88 

PART I 

SUMMARY OF THE DOSSIER 

A. Administrative data 

75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art.  1) 
(adapted} 

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

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

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

Annexed to the administrative data shall be copies of the manufacturing authorization as 
defmed  in  Article 40,  together with  a list of countries  in  which  authorization  has  been 
granted, copies of all the summaries of product characteristics in accordance with Article 
11  as  approved  by  Member  States  and  a  list  of countries  in  which  an  application  has 
been submitted. 

B. Summary of product characteristics 

The applicant shall propose a summary of the product characteristics, in accordance with 
Article 11. 

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

89 

C. Expert reports 

In  accordance  with  Article  12  (2),  expert  reports  must  be  provided  on  the  chemical, 
phannaceutical and biological documentation, the phannacotoxicological documentation  91/507/EEC Art.  1) 
and the clinical documentation respectively. 

(adapted) 

75/318/EEC 
Annex 
(as amended by 

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

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

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

90 

75/318/EEC 
Annex 
(as amended by 
911507/EEC Art.  1) 
(adapted) 

PART2 

CHEMICAL,  PHARMACEUTICAL  AND  BIOLOGICAL  TESTING  OF 
MEDICINAL PRODUCTS 

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

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

A. Qualitative and quantitative particulars of the constituents 

The  particulars  and  documents  which  must  accompany·  applications  for  marketing 
auth~rization, pursuant to  point  3  of Article  8  (3)  (c)  shall  be  submitted  in  accordance 
with the following requirements. 

I. Qualitative partiCulars 

1.1. "Qualitative particulars" of all  the  constituents of the medicinal product shall  mean 
the designation or description of: 

the active substance(s), 

the  constituent(s)  of the  excipients,  whatever  their  nature  or  the  quantity  used, 
including  colouring  matter,  preservatives,  adjuvants,  stabilizers, 
thickeners, 
emulsifiers, flavouring and aromatic substances, etc., 

the constituents,  intended to be ingested or otherwise administered ,to the patient, of 
the  outer  covering· of the  medicinal  products  - capsules,  gelatine  capsules,  rectal 
capsules, etc. 

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

91 

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

75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art.  1) 
(adapted) 

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

2.  The  ''usual  tenninology",  to  be  used  in  describing  the  constituents  of medicinal 
products, shall mean, notwithstanding the application of the other provisions in  Article 8 
(3) (c): 

in  respect  of substances  which  appear  in  the  European  Pharmacopoeia  or,  failing 
this, in the national pharmacopoeia of one of the Member States, the main title at the 
head of the monograph in question, with reference to the pharmacopoeia concerned, 

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

in  respect  of colouring  matter,  designation  by  the  "E"  code  assigned  to  them  in 
Council ·Directive  78/25/EEC  of 12  December  1977  on  the  approximation  of the 
rules  of the  Member States  concerning the  colouring matters  authorized  for  use  in 
medicinal products 1 • 

. 3. Quantitative particulars 

3.1.  In  order to  give "quantitative particulars"  of the  active substances of t~e medicinal 
products,  it  is  necessary,  depending  on  the  pharmaceutical  fonn  concerned,  to  specify 
the mass, or the number of units of biological activity, either per dosage-unit or per unit 
of mass or volume, of each active substance. 

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

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

OJ L 11, 14.1.1978, p.  18. Directive as last amended by the Act of Accession of Spain and Portugal. 

92 

This information shall be supplemented: 

75/318/EEC 
Annex 

in  respect  of injectable  preparations,  by  the  mass  or units  of biological  activity  of  (as amended by 
each active substance in the unit container, taking into account the usable volume of  91/507/EEC Art.  1) 
the product, after reconstitution, where appropriate, 

(adapted) 

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

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

· 

3.2.  Active  substances  present  in  the  form  of  compounds  or  derivatives  shall  be 
designated quantitatively by their total mass, and if necessary or relevant, by the mass of 
the active entity or entities of the molecule. 

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

3.4.  For  immunological  medicinal  products,  the  quantitative  particulars  shall  be 
expressed  by  units  of  biological  activity,  except  for  well  defined  immunoligical 
medicinal  products  for  which  the  concentration  may  be  expressed  by  mass/unit  of 
volume. 

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

4. Development pharmaceutics 

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

For 

4.2. 
chemical/radiochemical purity and its relationship to biodistribution. 

radiopharmaceuticals, 

include 

should 

this 

a 

consideration  of 

93 

B. Description of manufacturing method 

75/318/EEC 
Annex 
(as amended by 

1.  The  description  of the  manufacturing  method  accompanying. the  application  for  911507 /EEC Art 1) 
marketing authorization pursuant to point 4 of Article 8 (3) (d), shall be drafted in such a 
way ·as to give an adequate synopsis of the nature of the operations employed. 

(adapted) 

For this purpose it shall include at least: 

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

in  the  case  of continuous  ma~ufacture, full  details  concerning  precautions  taken  to 
ensure the homogeneity of the finished product, 

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

:-

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

experimental  studies  validating  the  manufacturing  process,  where  a  non-standard 
method of manufacture is used or where it is critical for the product, 

for  sterile  medicinal  products,  details  of the  sterilization  processes  ~d/or aseptic 
procedures used. 

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

For radionuclides, the nuclear reactions involved shall be discussed. 

C. Controls of starting materials 

1.  For the  purposes of this section, "starting materials" shall mean all the constituents of 
the  medicinal  product  and,  if necessary,  of its  container,  as  referred  to  in  Section  A, 
point  I~ above. 

94 

In the case of: 

an  active  substance  not  described  in  the  European  Pharmacopoeia  or  in  the 
pharmacopoeia of a Member State, or 

75/318/EEC 
·Annex 
(as amended by 
91/507/EEC Art.  1) 
(adapted) 

an  active  substance  described 
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, 

the  European  Pharmacopoeia  or  in 

in 

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

The  particulars  and  documents  accompanying 
for  marketing 
authorization pursuant to Article 8 (3) (h) and (i) and  10  (1), shall include the results of 
the  tests,  including  batch  analyses  particularly  for  active  substances,  relating  to  quality 
control  of all  the  constituents  used.  These  shall  be  submitted  in  accordance  with  the 
following provisions. 

the  application 

1.1. Starting materials listed in pharmacopoeias 

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

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

Constituents  fulfilling- the  requirements  of  the  European  Pharmacopoeia  or  the 
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with 
Article 8 (3) (h).  In  this case the  description  of the  analytical  methods  may be  replaced 
by a detailed reference to the pharmacopoeia in question. 

95 

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

75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art.  I) 
(adapted) 

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

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

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

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

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

1.2. Starting materials not in a pharmacopoeia 

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

(a)  The name of the substance, meeting the requirements of Section A,  point 2,  shall be 

supplemented by any trade or scientific synonyms; 

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

(c)  methods  of identification  may  be  described  in  the  form  of complete  techniques  as 
used  for  production  of the  substance,  and  in  the  form  of tests  which  ought  to  be 
carried out as a routine matter; 

96 

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

75/318/EEC 
Annex 
(as amended by 
911507/EEC Art.  I) 
(adapted) 

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

(f)  when  materials of animal/human origin  are  used,  measures  to  ensure  freedom  from 

potentially pathogenic agents shall be described; 

(g)  for  radionuclides,  the  nature  of the  radionuclide,  the  identity  of the  isotope,  likely 

impurities, the carrier, the use and the specific activity shall be given; 

(h)  any special precautions that may be necessary during storage of the starting material 
and, if necessary, the maximum period of storage before retesting shall be given. 

1.3. Physico-chemical characteristics liable to effect bio-availabi/ity 

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

crystalline form  and solubility coefficients, 

particle size, where appropriate after pulverization, 

state of solvation, 

oiVwater coefficient of partition 1 • 

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

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

The competent authorities may also request the pK and pH values if they think this infonnation is essential. 

97 

For the purposes  of this paragraph,  starting materials shall mean  any substance  used  in  75/318/EEC 
the manufacture of the medicinal product; this includes the constituents of the medicinal  Annex 
product, and, if necessary, of its container, as referred to  in  paragraph A,  point  I above, 
as  well  as  source  materials  such  as  microorganisms,  tissues  of either  plant  or  animal  91/507/EEC Art.  I) 
origin, cells or fluids (including blood) of human or animal origin, and biotechnological 
cell  constructs.  The  origin  and  history  of starting  materials  shall  be  described  and 
documented. 

(as amended by 

(adapted) 

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

2.1.  When  cell  banks are used,  the  cell characteristics shall  be  shown  to  have  remained 
unchanged at the passage level used for the production and beyond. 

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

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

2.3.  Whenever possible, vaccine  production shall  be  based on a seed  lot system  and on 
established cell banks; for serums, defined pools of starting materials shall be used. 

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

2.4.  For immunological  medicinal  products,  the  specifications  and  control  methods  for 
the  source  materials  shall  be  described  in  as  much  detail  as  possible.  The  description 
shall include particulars concerning collection, pretreatment and storage. 

2.5.  For  medicinal  products  derived  from  human  blood  or  plasma,  the  origin  and  the 
criteria and  procedures  for  collection,  transportation  and  storage  of the  source  material 
shall be described and documented . 

.Defined pools of source material shall be used. 

3. For radiopharmaceuticals, starting materials include irradiation target materials. 

(7) 

98 

D. Control tests carried out at intermediate stages of the manufacturing process 

I.  The  particulars  and  documents  accompanying  an  application  for  marketing 
authorization,  pursuant to  Article  8  (3)  (h)  and  (i)  and  Article  IO,  paragraph  I  of this  911507/EEC Art.  1) 
Directive,  shall  include  particulars  relating  to  the  product  control  tests  that  may  be 
carried  out  at  an  intermediate  stage  of the  manufacturing  process,  with  a  view  to 
ensuring the consistency of the technical characteristics and the production process. 

(adapted) 

7 5/318/EEC 
Annex 
(as amended by 

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

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

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

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

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

E. Control tests on the finished  product 

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

99 

The  application  for  marketing  authorization  shall list those  tests  which  are  carried  out  75/318/EEC 
routinely  on  each  batch  of finished  product.  The  frequency  of the  tests  which  are  not  Annex 
carried out routinely shall be stated. Release Jjmits shall be  indicated. 

(as amended by 
91/507/EEC Art.  I) 
(adapted) 

The  particulars  and  documents  accompanying 
for  marketing 
authorization  pursuant to  Article  8 (3)  (b)  and  (i)  and  Article  10  (I) of this  Directive, 
shall include particulars relating to control tests on the  finished product at release.  They 
shall be submitted in accordance with the following requirements. 

the  application 

The provisions of the monographs for pharmaceutical forms,  immunosera,  vaccines and 
radiopharmaceutical  preparations  of the  European  Pharmacopoeia  or  failing  that,  of a 
Member  State,  shall  be  applicable  to  all  products  defined  therein.  For  all  controls  of 
biological medicinal  products such  as  immunological medicinal proqucts and  medicinal 
products derived from  human  blood or plasma which  are  not specified  in  the European 
Pharmacopoeia or failing this,  in the pharmacopoeia of a Member State, the procedures 
and 
the  WHO 
(Requirements for Biological Substances) shall serve as guidelines. 

the  criteria  of  acceptability  published  as  recommendations 

in 

If test  procedures  and  limits  other  than  those  mentioned  in  the  monographs  of the 
European  Pharmacopoeia,  or failing  this,  in  the  national  pharmacopoeia  of a  Member 
State,  are  used,  proof shall  be  supplied . that  the  finished  product  would,  if tested  in 
accordance  with 
requirements  of  that 
pharmacopoeia for ~e pharmaceutical form  concerned. 

those  monographs,  meet 

the  quality 

1.1. General characteristics of the finished product 

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

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

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

100 

1.2. JdenJijication and assay of active substan~e(s) 

Identification  and  assay  of the  active  substance(s)  shall  be  carried  out  either  in  an 
average representative sample from  the production batch or in  a number of dosage-units  91/507/EEC Art.  I) 
analysed individually. 

(adapted) 

75/318/EEC 
Annex 
(as amended by 

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

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

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

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

Where  the  particulars  given  in  section  B show  that  a  significant  overage  of an  active 
substance  is  employed  in  the  manufacture  of the  medicinal  product,  the  description  of 
the  control tests  01:1  the  finished  product shall include,  where  appropriate,  the  chemical 
and,  if necessary,  the  toxico-pharmacological  ~nvestigation  of the  changes  that  this 
substance  has  undergone,  and  possibly  the  characterization  and/or  assay  of  the 
degradation products. 

1.3. Identification and assay of excipient constituents 

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

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

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

101 

1.4. Safety tests 

Apart from the phannacotoxicological tests submitted with the application for marketing 
authorization,  particulars  of  safety  tests,  such  as  sterility,  bacterial  endotoxin,  91/507/EEC Art.  I} 
pyrogenicity and local tolerance in animals shall be  included in the analytical particulars 
wherever such  tests  must  be  undertaken  as  a  mauer  of routine  in  order  to  verify  the 
quality of the product 

(adapted) 

75/318/EEC 
Annex 
(as amended by 

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

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

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

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

F. Stability tests 

I.  The  particulars  and  documents  accompanying  the  application  for  marketing 
authorization pursuant to Article 8 (3}  (g) and (h) shall be submitted in accordance with 
the following requirements. 

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

· Where  a  finished  product  is  liable  to  give  rise  to  degradation  products,  the  applicant 

mus~ declare these and indicate characterization methods and test procedures. 

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

102 

The maximum  acceptable  level of degradation products at the end of shelf-life  shall  be  75/318/EEC 
'indicated. 

Annex 
(as amended by 

A  study of the  interaction  between  product  and  container shall  be  submitted  wherever  91/507 /EEC Art.  I) 
the  risk  of  such  interaction  is  regarded  as  possible,  especially  where  injectable 
prep~ations or aerosols for internal use are concerned. 

(adapted) 

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

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

103 

PART3 

TOXICOLOGICAL AND PHARMACOLOGICAL TESTS 

I. Introduction 

75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art.  1) 
(adapted) 

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

Member States  shall  ensure  that the  safety  tests  are  carried  out  in  conformity  with  the 
provisions  relating  to  good  laboratory  practice  laid  down  by  Council  Directives 
87/18/EECI  and 88/320/EEC2. 

The toxicological and pharmacological tests must show: 

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

(b)  the  pharmacological  properties  of the  product,  in  both  qualitative  and  quantitative 
relationship to th'e ptoposed use in human beings. All results must be reliable and of 
general applicability. Whenever appropriate, mathematical and statistical procedures 
shall be used in designing the experimental methods and in evaluating the results. 

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

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

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

In  all  cases,  tests  of local  tolerance  after  repeated  application  shall.  be  carried  out with 
particular  care  and  include  histological  examinations;  the  possibility  of sensitization 
shall be investigated and any carcinogenic potential investigated  in the cases referred to 
in Section 11  E of this Part. 

I 
2 

OJ LIS, 17.1.1987, p. 29. 

OJ L 145,  11.6.1988, p. 35; .Directive as amended by Direc:tive 90/18/EEC (OJ L 11,  13.l.l990, p.  37). 

104 

3.  For  biological  medicinal  products  such  as  immunological  medicinal  products  and  75/318/EEC 
medicinal  products derived  from  human  blood  or plasma,  the  requirements  of this  Part  Annex 
may have to be adapted for  individual products; therefore the testing programme carried 
. out shall be justified by the applicant. 

(as amended by 
9 11507/EEC Art.  I) 
(adapted) 

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

all  tests  requiring  repeated  administration  of the  product shall  be  designed  to  take 
account of the possible induction of, and interference by, antibodies; 

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

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

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

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

11. Performance of tests 

A.  Toxicity 

I. Single dose toxicity 

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

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

I05 

This  study  will  cover the  signs  observed,  including  local  reactions.  The  period  during  7 5/318/EEC  · 
which the test animals are observed shall be  fixed  by the  investigator as  being adequate  Annex 
tc;l  reveal tissue or organ d8:ffiage or recovery, usually for a period of 14 days but not less 
than  7  days,  but  without  exposing  the  animals  to  prolonged  suffering.  Animals  dying  91/507/EEC Art.  1) 
during  the  observation  period  should  be  subject  to  autopsy  as  also  should  all  animals 
surviving to the end of the observation period. Histopathological examinations should be 
considered  on  any  organ  showing  macroscopic  changes  at  autopsy.  The  maximum 
amount of information should be obtained from the animals used in the study. 

(as amended by 

(adapted) 

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

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

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

2. Repeated dose toxicity (sub-acute or chronic toxicity), 

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

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

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

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

Reasons should.also be given forthe dosages chosen. 

106 

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

75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art.  I) 
(adapted) 

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

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

The evaluation of the toxic effects  shall  be  ba8ed on observation of behaviour,  growth, 
haematological  and  biochemical  tests,  especially  those  relating  to  the  excretory 
mechanism, and also on autopsy reports and accompanying histological data.  The choice 
and range of each group of tests will depend on the speci~s of animal used and the· state 
of scientific knowledge at the time. 

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

B.  Examination of reproductive function 

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

C. Embryo/foetal and perinatal toxicity 

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

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

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

107 

Embryo/foetal toxicity studies shall normally  be conducted on  two  mammalian  species,  75/318/EEC 
one  of which  should  be  other  than  a  rodent.  Peri- and  postnatal  studies  shall  be  Annex 
conducted  in  at  least  one  species.  Where  metabolism  of a  medicinal  product  in  a 
particular species  is  known  to  be  similar  to  that  in  man,  it  is  desirable  to  include  this  91/507 /EEC Art.  1) 
species.  Also,  it  is  desirable that one of the  species  is  the  same  as  in  the  repeated  dose 
~oxicity studies. 

(as amended by 

(adapted) 

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

D.  Mutagenic potential 

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

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

E.  Carcinogenic potential 

Tests to reveal carcinogenic effects shall normally be required: 

(a)  in  respect of substances having a close chemical analogy with  known  carcinogenic 

or cocarcinogenic compounds; 

(b)  in  respect  of substances  which  have  given  rise  to  suspicious  changes  during  the 

long-term toxicological tests; 

(c)  in respect of substances which have given rise to suspicious results in the mutagenic 

. potential tests or in other short-term carcinogenicity tests. 

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

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

108 

75/318/EEC 
Annex 
(as amended by 
911507/EEC Art.  I) · 
(adapted) 

F. Pharmacodynamics 

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

This study shall follow two distinct lines of approach. 

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

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

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

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

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

In  the first  case, the pharmacodynamic study shall demonstrate those  interactions which 
might make the combination of value in therapeutic use. 

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

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

109 

G. Pharmacokinetics 

PharmacokineticS  means  the  study  of  the  fate  of  the  active  substance  within  the 
organism,  and  covers  the  study  of the  absorption,  distribution,  biotransformation  and  91/507 /EEC Art.  1) 
excretion of the substance. 

(adapted) 

75/318/EEC 
Annex 
(as amended by 

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

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

Pharmacokinetic investigation ofpharmacologically active substances is necessary. 

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

H. Local tolerance 

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

110 

75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art.  I) 
(adapted) 

PART 4 

CLINICAL DOCUMENTATION 

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

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

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

A.  General requirements 

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

. trials should be communicated, both favourable and unfavourable. 

the  conclusions  drawn.  from 

investigator  must  acquaint  himself  with 

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

Ill 

B. Conduct of trials 

l. Good clinical practice 

1.1.  All  phases  of clinic~)  investigation,  including  bioavailability and  bioequivalence 
studies,  shall  be  designed,  implemented  and reported  in  accordance  with  good  clinical 
practice. 

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

75/318/EEC 
Annex 
(as·amcndcd by 
91/507/EEC Art.  1) 
(adapted) 

trial  protocol  (including  statistical  design), 

The 
technical  application  and 
documentation  shall  be  submitted  by  the  sponsof and/or  investigator  for  an  opinion  to 
the  relevant  ethics  committee.  The  trials  shall  not  begin  before  the  opinion  of this 
committee has been received in writing~ 

the 

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

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

2. Archiving 

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

(a)  The investigator shall arrange for the retention of the patient identification codes for 

at least 15 years after the completion or discontinuation of the trial. 

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

permitted by the hospital, institution or private practice. 

(c)  The  sponsor  or  other  owner  of  the  data  shall  retain  all  other  documentation 
pertaining  to  the  trial  as  long  as  the  product  is  authorized.  These  procedures  shall 
include: 

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

standard operating procedures, 

all written opinions on the protocol and procedures, 

112 

the investigator's brochure, 

case report forms on each trial subject, 

final report, 

audit certificate(s), if available. 

75/318/EEC 
Annex 
(as amended by 
91/507/EEC Art.  I) 
(adapted) 

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

after the medicinal product is no longer authorized. 

Any change of ownership of the data shall be documented. 

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

C. Presentation of results 

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

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

audit certificate(s), if available, 

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

final  report  signed  by  the  investigator  and  for  multicentre  trials,  by  all  the 
investigators or the coordinating (principal) investigator. 

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

3. The clinical observations shall be summarized for each trial indicating: 

(a)  the number and sex of patients treated; 

(b)  the  selection· and  age-distribution  of the  groups  of patients  being  investigated  and 

the comparative tests; 

113 

(c)  the  number of patients  withdrawn  prematurely  from  the  trials  and  the  reasons  for  75/318/EEC 

such withdrawal; 

Annex 
(as amended by 

(d).  where  controlled  trials  were  carried  out  under  the  above  conditions,  whether  the  91~507/EECArt. I) 

control group: 

received no treatment, 

received a placebo, 

(adapted) 

received another medicinal product of known effect, 

received treatment other than therapy using medicinal products; 

(e)  th~ frequency of observed adverse reactions; 

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

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

parameters; 

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

and the variable factors involved. 

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

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

(a)  ~Y signs  of  habituation,  addiction  or  difficulty  in  weaning  patients  from  the 

medicinal product; 

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

concomitantly; 

· 

(c)  the criteria determining exclusion of certain patients from the trials; 

(d)  ~y deaths whi~h occurred during the trial or within the follow-up period. 

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

(8) 

114 

7.  Total or partial omission of data must be explained.  Should unexpected results occur  75/318/EEC 
during the course of the trials, further preclinical toxicological and pharmacological tests  Annex 
must be undertaken and reviewed. 

(as amended by 
91/507/EEC Art.  1) 
(adapted) 

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

D. Clinical pharmacology 

I. Pharmacodynamics · 

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

ihe dose-response relationship and its time course, 

justification for the dosage and conditions of administration, 

the mode of action, if possible. 

The pharmacodynamic action not related to efficacy shall be described. 

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

2. Pharmacokinetics 

The following phannacokinetic characteristics shall be described: 

absorption (rate and extent), 

distribution, 

metabolism, 

.  excretion. 

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

.... 

115 

3./nteractions 

If the  medicinal  product  is  ·normally  to  be  administered  concomitantly  with  other 
medicinal  products, particulars shall be given  of joint administration  tests  performed to  911507 /EEC Art.  I)· 
demonstrate possible modification of the pharmacological action. 

(adapted) 

75/3I8/EEC 
Annex 
(as amended by 

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

E. Bioavailability/bioequivalence 

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

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

F. C~inical efficacy and safety 

I.  In  g~neral, clinical trials  shall· be  done  as  "controlled clinical trials"  and  if possible, 
randomized; any other design shall be justified. The treat.ment of the control groups will 
vary  from  ca8e  to  case  and  also  will  depend  on  ethical  considerations;  thus  it  may,  in 
some  instances,  be more pertinent to  compare the  efficacy  of a  new  medicinal  product 
with  that  of an  established  medic~nal product  of proven  therapeutic  value  rather  than 
with the effect of a placebo. 

· 

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

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

116 

3.  Clinical  statements  concerning  the  efficacy  or safety  of a  medicinal  product  under  75/318/EEC 
normal conditions of use which are not scientifically substantiated cannot be accepted as  Annex 
valid evidence. 

(as· amended by 
91 /507/EEC Art.  1) 
(adapted) 

· 

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

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

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

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

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

7.  All  adverse  events  including  abnormal  laboratory  values  shall  be  presented 
indiviilually -and discussed, ~specially: 

in terms of overall adverse experience and 

as a function of the nature, seriousness and causality of effects. 

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

the disease to be treated, 

other therapeutic approaches, 

particular characteristics in sub-groups of patients, 

preclinical data on toxicology and pharmacology. 

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

117 

G. Documentation for applications in ex~eptional circumstances 

75/318/EEC 
Annex 

'When,  in  respect of particular therapeutic  indications, the applicant can show  that he  is  {as amended by 
unable  to  provide  comprehensive  data  on  the  efficacy  and  safety  under  normal  91/507/EEC Art.  I) 
conditions of use, because: 

{adapted) 

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

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

it  would  be  contrary  to  generally  accepted  principles  of medical  ethics  to  collect 
such information, 

marketing authorization may be granted on the following conditions: 

(a)  the  applicant  completes  on  identified  programme  of studies  within  a  time  period 
. specified by the competent authority, the results of which  shall  form  the basis of a 

reassessment of the benefit/risk profile, 

· 

(b)  the medicinal product in question may be supplied on medical prescription only and 
may in certain cases be administered only under strict medical supervision, possibly 
in a hospital and for a radiophannaceutical, by an authorized person, 

(c)  the  package  leaflet  and  any  medical  information  shall  draw  the  attention  of the 
medical  practitioner  to  the  fact  that  the  particulars  available  concerning  the 
medicinal product in question are as yet inadequate in certain specified respects. 

H. Post-marketing experience 

I. If the medicinal product is already authorized in other countries, information shall be 
given  in  respect  of adverse  drug  reactions  of the  medicinal  product  concerned  and 
medicinal products containing the same active substance{s), in relation to the usage rates 
if possible.  Information  from. worldw.ide  studies relevant to the safety of the  medicinal 
product shall be included. 

118 

For this purpose, an adverse drug reaction is a reaction which is  noxious and unintended  75/318/EEC 
and which occurs at doses normally used in.man for prophylaxis, diagnosis or therapy of  Annex 
disease or for the modification of physiological function. 

(as amended by 
91/507/EEC Art.  1) 
(adapted) 

2.  In  the  case  of vaccines  already  authorized  in  other  countries,  information  on  the 
monitoring of vacc~nated subjects to evaluate the prevalence of the disease in question as 
compared to non vaccinated subjects shall be submitted, .when availa~le. 

3.  For  immunological  medicinal  products,  response  in  periods  of  increased  antigen. 
exposure shall be identified. 

119 

ANNEXII 

Part A 

Repealed Directives, with their successive amendments 
(referred to by Article  130) 

Council Directive 65/65/EEC (OJ 22, 9. 2.  1965, p. 369) 

Council Directive 66/454/EEC (OJ  144, 5.  8.  1966, p. 2658/66) 
Council Directive 75/319/EEC (OJ  L 147, 9.6.1975, p.  13) 
Council Directive 83/570/EEC (OJ L 332,28. 11.  1983, p.  1) 
Council Directive 87121/EEC (OJ L 15,  17.  I.  1987, p. 36) 
Council Directive 89/341/EEC (OJ L 142,25. 5.  1989, p.  11) 
Council Directive 92127/EEC (OJ L 113, 30.4.1992, p. 8) 
Council Directive 93/39/EEC (OJ L 214,24. 8.  1993, p. 22) 

Council Directive 75/318/EEC (OJ L 147, 9. 6.  1975, p.  1) 

Council Directive 83/570/EEC 
Council Directive 87/19/EEC (OJ L 15,  17.  1.  1987, p. 31) 
Council Directive 89/341/EEC 
Commission Directive 91/507/EEC (OJ L 270, 26. 9.  1991, p: 32) 
Council Directive 93/39/EEC 

Council Directive 75/319/EEC 

Council Directive 78/420/EEC (OJ L 123,  11. 5.  1978, p. 26) 
Council Directive 83/570/EEC 
Council Directive 89/341/EEC 
Council Directive 92127/EEC 
Council Directive 93/39/EEC 

Council Directive 89/342/EEC (OJ L 142,25. 5.  1989, p.  14) 
Council Directive 89/343/EEC (OJ L 142,25. 5.  1989, p.  16) 
Council Directive 89/381/EEC (OJ L 181,28. 6.  1989, p. 44) 
Council Directive 92/25/EEC (OJ L 113,30. 4.  1992, p.  1) 
Council Directive 92/26/EEC (OJ L 113, 30. 4.  1992, p. 5 
Council Directive 92127/EEC . 
Council Directive 92/28/EEC (OJ L 113, 30. 4.  1992, p.  13) 
Council Directive 92173/EEC (OJ L 297,  13.  10.  1992, p.  8) 

. 120 

PartB 

Deadlines for transposition into national law 
(referred to by ~rticle  130) 

Directive 

Deadline for transposition 

Directive 65/65/EEC 

Directive 66/454/EEC 

Directive 75/318/EEC 

Directive 75/319/EEC 

Directive 78/420/EEC 

Directive 83/570/EEC 

Directive 87/19/EEC 

Directive 87/21/EEC 

Directive 89/341/EEC 

Directive 89/342/EEC 

Directive 89/343/EEC 

Directive 89/381/EEC 

Directive 91/507/EEC 

Directive 92/25/EEC 

Directive 92/26/EEC 

Directive 92127/EEC 

Directive 92/28/EEC 

Directive 92173/EEC 

Directive 93/39/EEC 

31  December 1966 
---
21  November 1976 

21  November 1976 
--
31  October 1985 

l July  1~87 

1 July  1987. 
1 January  19921 

1. January 1992 

1 January 1992 

1 January 1992 

1 January  1992 

1 January  19922 
1 January  19953 

1 January  1993 

1 January  1993 

I January 1993 

1 January 1993 

31  December 1995 

I January  19954 
I January 19985 

Deadline for transposition applicab~e to Greece, Spain and Portupl. 
Except Section A. point 3.3 in Part U of the Aanex. 
Deadline for transposition applicable to Section A. point 3.3 in Part U of the Annex. 

Except with reprd to Article I (6). 

Deadline for transposition applic:able to Article I (7). 

2 

3 
4 
s 

65/65/EEC 
Art.  1 (I) to 
(3) 

Art. 2 (1) 
Art.  1 (4) 
and (S) 
Art 2 (3),  1st 
indent 
Art.2 (3), 
2nd and 3rd 
indents 

ThisDir. 
Art. 1 (1) to 
(3) 
Art.  1 (4) 

Art.  1 (S) 
Art.  1 (6) to 
(9) 
Art.  1 (10) 
Art.  1 (11) to 
(14) 
Art.  1 (IS) 
and (16) 
Art.  1 (17) 

Art.  1 (18) to 
(24) 
Art.  1 (25) 
Art.  1 (26) 
Art.2 
Art. 3 (1) 
and (2) 

Art. 3 (3) 
and (4) 

Art. 3 (5) 
Art. 3 (6) 

ANNEX Ill 
CORRELATION TABLE 

75/318/EEC 

75/319/EEC 

89/342/EEC 

89/343/EEC 

89/381/EEC 

92/25/EEC 

92/26/EEC 

92127/EEC 

92128/EEC 

92/73/EEC 

Annex 

Art. 1 (1) 
and(2) 

Art.  1 (2) 

Art.  1 (1) 

Art. 29b 

.Art. 8 (1) 
Art.  10 (1) 

Art.  1 

. 

Art.  1 (2) 

Art.  1 (2), 
2nd 
sentence 

Art.  1 (2) 

Art.  1 (1) 

Art.  1 (2) 

122 

This Dir. 

65/65/EEC 

75/318/EEC 

75/319/EEC 

89/342/EEC 

Art. 4 (1) 
Art. 4 (2) 
Art. 4 (3) 

Art. 4 (4) 
Art.  5 
Art.6 
Art.  7 

Art.3,2nd 
sub paragraph 
Art.6 
Art. 2 (4) 
Art.  3 (l) 

Art.  8 (1) and (2) 
Art.  8 (3) (a) to (e) 

Art.  8 (3) (f) to (i) 

Art. 8 (3) G) to (I) 

Art. 4.(1) and (2) 
Art. 4, 3rd paragraph,  Art.  1 (l) 
points 1 to 5 
Art. 4, 3rd paragraph, 
points 6 to 8.1 
Art. 4, 3rd paragraph, 
points 9 to  11 

Art. 4, 3rd paragraph, 
point 8.2 

Art. 4a, points 1 to 
5.3 
Art.  4a, point 5.4 
Art. 4a, points 5.5 
to6.4 
Art. 4a, point 6.6 
Art.  4a, point 6.5 

Art.9 
Art.  10 (l) 

Art.  10.(2) 

Art.  11 , points 1 to 
5.3 
Art.  11, point 5.4 
Art.  11, points 5.5 
to6.4 
Art.  11, point 6.5 
Art.  11, point 7 
Art.  11, points 8 
to 9 
Art.  12 (l) 
Art.  12 (2) and (3) 
Art.13 

Art.  1, 
2nd paragraph 

' 
Art.3 

Art.  1 
Art.2 

- - -

89/343/EEC 
Art.  1 (3) 

Art. 2, 
2nd sentence 

. 

Art.3 

Art.  4 

123 

89/381/EEC 

92/25/EEC 

92/26/EEC 

92/27/EEC 

92/28/EEC 

92173/EEC 

Art.  1 (3) 

I 

I 

Art. 6 (I) 
and (2) 

.  This Dir. 
Art.  14 (1) 
and (2) 
Art.  14 (3) 

Art.  15 
Art.  16 
Art.  17 
Art.  18 
Art.  19 
Art. 20 
Art. 21 
Art.22 
Art.23 
Art.24 
Art.25 
Art.26 
Art. 27  . 
Art. 28 (1) 
Art. 28 (2) 
Art. 28 (3) 
Art. 28 (4) 
Art. 29 
Art.  30 
Art.  31 
Art.32 
Art.  33 

~ 

65/65/EEC 

75/318/EEC 

75/319/EEC 

89/342/EEC 

89/343/EEC 

89/381/EEC 

92125/EEC 

92126/EEC 

. 92/27/EEC 

92/28/EEC 

Art. 7 
Art.  7a 

Art. 4b 
Art.  10 (2) 
Art. 9a 
Art.  10 (I) 
Art.9 
Art. s 

Art.4 
Art.S 

Art. 8 
Art. 9 (3) 
Art. 9 (1) 
Art. 9 (2) 
Art. 9 (4) 
Art.  10 
Art.ll 
Art.  12 
Art.  13 
Art.  14 (I) 

124 

92173/EEC 
Art. 7 (1) and 
(4) 
Art. 4, 
2nd paragraph 
Art.8 
Art.9 

: 

'" 

ThisDir. 

.6S/6SIEEC 

75/318/EEC 

Art.34 

Art. 35 
Art.36 
Art.37 
Art.38 
Art. 39 
Art. 40 
Art. 41 
Art. 42 
Art.43 
Art. 44 
Art. 4S 
Art. 46 
Art.47 
Art.48 
Art. 49  . 
Art. so 
Art. 51  (1) 
and (2) 
Art. S1  (3) 
Art. 52 
Art.S3 
Art.S4 
Art. SS 

75/319/EEC 
Art.  14 (2) to 
(4) 
Art.  IS  · 
Art.  1Sa 
Art.  1Sb 
Art.  1Sc 
Art.  14 (S) 
Art.  16 
Art.  17 
Art.  18 
Art. 20 (1) 
Art. 20 (2) 
Art. 20 (3) 
Art.  19 
Art.  19a 
Art.21 
Art.23 
Art.24 
Art. 22 (1) 

Art. 22 (2) 
Art.2S 

89/342/EEC 

89/343/EEC 

89/381/EEC 

92/25/EEC 

92/26/EEC 

92/27/EEC 

.92/28/EEC 

92/73/EEC 

Art. 2 (1) 
Art.3 

Art~3 

125 

This Dir. 

65/65/EEC 

-75/318/EEC 

75/319/EEC 

89/342/EEC 

89/343/EEC 

89/381/EEC 

92125/EEC 

92126/EEC  · 

92127/EEC 

92128/EEC 

.92/73/EEC 

Art. 56 
Art. 51 
Art. 58 
Art. 59 

Art. 60 

Art. 61 

Art. 62 

Art. 63"(1) 
.Art. 63 (2) 
Art. 63 (3)  . 
Art. 64 
Art. 65 
Art. 66  . 
Art. 67 
Art.68 
Art. 69 

Art. 70 
Art. 71 
Art. 72 
Art.  73 
Art. 74 

Art. 4 (1) 
Art. 5 (2) 
Art.6 
Art. 7 (1) and 
(2) 
Art. 5 (1) and 
Art.9 
Art.  10 (1) to 
(4) 
Art. 2 (2) and 
·Art. 7 (3) 
Art. 4 (2) 
Art.8 
Art.  10 (5) 
Art.  11  (1) 
Art.  12 

Art:2 (2) 
Art. 7 (2) 
and (3) 

i 

Art.2 
Art.3 
Art.4 
Art. S (I) 
Art. 5 (2) 

Art. 5 
Art. 6 (1) 

126 

This Dir. 

65/65/EEC 

75/318/EEC 

75/319/EEC 

89/342/EEC 

89/343/EEC 

89/381/EEC 

92/25/EEC 

92/26/EEC 

92/27/EEC 

92/28/EEC 

92173/EEC 

Art. 75 
Art.  76 
Art. 77 
Art. 78 
Art.  79 
Art.80 
Art.81 
Art.82 
Art.83 
Art.84 
Art.85 

Art.  86 

Art.87 
Art.88 

Art.89 
Art.90 
Art.91 
Art.92 
Art.93 
Art.94 
Art. 95 
,Art. 9~ 

Art. 6 (2) 

Art.2 
Art.3 
Art. 4 (1) 
Art. 5 
Art.6 
Art. 7 
Art.8 
Art.9 
Art.  10 

Art. 3 (6), 
2nd sentence 
Art.  1 (3) 
and (4) 
Art. 2 
Art. 3 (1) to 
(6),  1st 
sentence 
Art.4 
Art.5 
Art.6 
Art.  7 
Art.8 
Art.9 
Art.  10 
Art.ll 

I 

I 

127 

92128/EEC 
Art.  12 (1) 
and (2) 
Art.  12 (4) 
Art.  13 
Art.  14 

92/73/EEC 

Art. 6 (3) 

I 

' 

This Dir. 
Art. 97 (1) 
to (4) 
Art. 97 (5) 
Art.98 
Art99 
Art.  100 
Art.  101 
Art.  102 
Art.  103 
Art.  104 
Art.  105 
Art.  106 
Art.  107 
Art.  108 
Art.  109 
Art.llO 
Art.  111  (I) 

Art.  111  (2) 
Art.  111  (3) 

Art.  112 
Art.113 
Art.  114 (1) 
Art.  114 (2) 
Art.  115 
Art.  116 
Art.  117 

65/65/EEC 

75/318/EEC 

75/319/EEC 

.89/342/EEC 

89/343/EEC 

89/381/EEC 

92/25/EEC 

92/26/EEC 

92127/EEC 

/ 

Art.29e 
Art.29a 
Art.29c 
Art. 29d 
Art.29f 
Art.29g 
Art.29h 
Art. 29i 

Art. 26,  1st 
and 2nd 
paragraph 

Art. 26, 3rd 
paragraph 
Art.27 

Art.28 

Art. 4 (I) 

Art. 4 (2) 
Art. 4 (3) 

Art.  8 

Art.  11 

Art.3 
Art. 3 (4) 

Art. 4 (2) 

Art. 4 (3) 
Art. 4 (1) 

128 

This Dir. 

65/65/EEC 

75/318/EEC 

Art.ll8 
Art.ll9 
Art.  120 
Art.  121 
Art.  122 
Art.  123 
Art.  124 
Art.  125 
Art.  126 
Art.  127 
Art.  128, 
I st paragraph 
Art.  128, 
2nd paragraph 
Art.  129 
Art.  130 
Art.  131 
Art.  132 

. 

Art.2b 
Art. 2a (1) 

Art.  12 
Art. 21 

-
-
-

-
-
-

75/319/EEC 
Art.29 

Art.  37a 
Art.37b 
Art.30 
Art. 33 

Art. 31 

Art. 32 

Art.28a 
-
-
-

89/342/EEC 

89/343/EEC 

89/381/EEC 

92/25/EEC 

92/26/EEC 

92/27/EEC 

92/28/EEC 

92/73/EEC 

Art. 4 (1) 

Art.5 

.  Art. 4 (2) 

Art.  11  (2) 

Art.  12 (3) 

-
-
-

-
-
-

-
-
-

-
-
-

-
-
- .  

-
-
-

-
-
-

-
-
-

I 

I 

This Dir. 
Annex I 
Annexll 
-Annex Ill 

65/65/EEC 

-
-

75/318/EEC 
Annex 
-
-

75/319/EEC 

8.9/342/EEC 

89/343/EEC 

89/381/EEC 

92125/EEC 

92126/EEC 

92/27/EEC 

92128/EEC 

92n3/EEC 

-
-

-
-

-
-

-
-

-
-

-
-

-
-

-
-

-
-

129  . 

ISSN  0254-1475 

COM(1999) 315  final 

DOCUMENTS 

EN 

05  15  02  01 

Catalogue number : CB-C0-99-320-EN-C 

Office for Official Publications of the European Communities 

L-2985  Luxembourg