CELEX: 51999PC0213
Language: en
Date: 1999-09-08
Title: Proposal for a European Parliament and Council Directive on the Community code relating to veterinary medicinal products - (codified version)

COMMISSION OF THE EUROPEAN COMMUNITIES
                                         Brussels, 08.09.1999
                                         COM( 1999) 213 final
                                         99/0180 (COD)
                        Proposal for a
   EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE
on the Community code relating to veterinary medicinal products
                    . (codified version)
               (presented by the Commission)
 ---pagebreak---        COMMISSION OF THE EUROPEAN COMMUNITIES
                                        Brussels, 08.09.1999
                                        COM( 1999) 213 final
                                        99/0180 (COD)
                        Proposal for a
   EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE
on the Community code relating to veterinary medicinal products
                    . (codified version)
               (presented by the Commission)
 ---pagebreak---  ---pagebreak---                                              . EXPLANATORYMEMORANDUM
  1. In the co~tcXt of a people's Europe, the Commission attaches great importance to simplifying and clarifying
     Community law so·as to make it clearer and more accessible to the ordinary citUcn, thus. giving him new
      opportunities and the chance to make use of the specific rights it gives him.         ·
     This aim cannot be achieved so long as numerous provisiQDS that have been amended several tilnes, often quite·
     substantially, remain scattered, so that they must be sought partly in the original instrument and partly in later
      amending ones. Considerable research work, comparing many different instruments, is thus needed to identify
     the current rules.                                                        ·
     For this reason a codification of rules that have frequently been amended is also essential if Community law is
     to .be clear and transparent
 2. On 1 April 1987 the Commission therefore decided to instruct its staff that all legislative measures should be
     ~ after no more than ten amendments, stressing that this was a minimum requirement and that
     departments should endeavour to condify at even sboncr intervals the texts for which they were responsible, to
      ensure that the Community rules were clear and readily understandable.
 3. The Conclusions of the Presidency of the Edinburgh European Council (December 1992) confinned this,
     stressing the importance of legislative codification as it offers certainty as to the law applicable to a given
     matter at a given time.
      It must be undertaken in full compliance with the nonnal Community legislative procedure.
     Given that no changes of substance may be made to the instruments affected by legislatjve codification.
     Parliament, the Council and the Commission have agreed, by an interinstitutional agreement
     dated 20 December 1994, that an accelerated procedure may be used ·for the fast-track adoption of
     codification instruments.
 4. The purpose of this proposalU> for legislative codification of Council Directives 81/8S 1/EEC of
     28 September 1981 on the approximation of the laws of the Member States relating to veterinazy medicinal
     products; 81/8S2/EEC of 28 September 1981 on the approximation of the laws of the Member States relating
     to analytical, pharmaco-toxicological and clinical standards and protocols in respect ofthe testing of veterinary
     medicinal products; 90/677/EEC of 13 December 1990 extending the scope of Directive Sf/851/EEC on the
     approximation of the laws of the Member States relating to veterinary medicinal products and laying down
     additional provisions for immunological veterinary medicinal products; 92/74/EEC of 22 September 1992 .
     widening the scope of Directive 8118S 1/EEC on the approximation of provisions laid down by law, regulation
     or administrative action relating to veterinary medicinal products and laying down additional provisions on
     homeopathic veterinary medicinal products, is to undertake official codification of this type. The new directive
     will supersede the various directives incorporated in it(2), their content is fully preserve~ and they are brought
     together with onlv such fonnal amendments as are required b;.· the codification exercise itself.
 4a In order to point out the satisfactory application of the codification of the Directive mentioned above, in order
     to take into account the fact that since the last Directive cited in point 4, the European Agency for the
     Evaluation of Medicinal Products has been established by Council Regulation (EEC) 2309/93 of22 July 1993.
     In the .same manner, in order to point out that this codification proposal concerning medicinal products
     for human use was created in parallel with the codification proposal for Directives relating to veterinary
     medicinal products.
 S. This legislative codification proposal was drawn up on the basis of a prelimina.rv consolidation. in all the
     official languages. The instruments amending it, carried out by the Office for Official Publications of the
     European Communities, by means of the data-processing SVstcm referred to in the conclusions of the European
     Council meeting at Edinburgh. Although the articles have been given new numbers, the old numbering has
     been retained in the margin for case of reference; the correlation between the old and new numbers is shown in
     a table set out in Annex lll of the consolidated Directive.                                                 ·
(1)    Enta'Cd in the legislative programme for 1998.
en     Sec Annex n, Part A of this Proposal.
                                                            2
 ---pagebreak---                                                        Proposal for a
                       EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE
                                                               of •••
                                           oa tbe Coblbluility code relatiDg to.
                                               veterillary medicblal products
, THE EUROPEAN PARLIAMENT AND THE CQUNC~ OF THE EUROPEAN
  UNION,
  Having regard to the Treaty establishing the European Community, and in
   particular Article 95 ·thereof:                ·
  Having regard to the proposal from the- Commission,·
   Having regard to the opinion of the Economic and Social Committee«n.
  Acting in accordance with the procedure laid down in Article 25 1 of the Treaty<l>,
   (1) Whereas Council Directive 81/851/EEC of 28 September 1981 on the
       approximation of the laws of the Member States relating to veterinary
       medicinal products0 l, Council Directive 81/852/EEC of 28 September 1981
       on the approximation of the laws of the Member States relating· to analytical,
       pharmaco-toxicological and clinical standards and protocols in respect of the
       testing of veterinary medicinal products<•>, Council Directive 90/677/EEC of
        13 December 1990 extending the scope of Directive 81/85 1/EEC on the
       approximation of the laws · of the Member States relating to veterinarY
       medicm.l products and laying down additional provisions for immunological
       veterinary medicinal prod~S). and Council Directive 92174/EEC of
       22 September 1992 widening the .scope of Directive 81/851/EEC on the
       approximation of provisions laid down by law, regulation or administrative
       action relating to veterinary medicinal products and laying down additional
       provisions on homeopathic veterinary medicinal products(l) have been
       frequently and substantially amended; whereas, in the interests of clarity and
       rationality, the said Directives should therefore be codified by assembling
       them in a single text;
  U>   OJ C
  (2)
  P>   OJ L 317, 6.11.1981, p. 1. Din:ctive as last amended by Dilutive 93/40/EEC (OJ L 214, 24 ..8.1993, p. 31).
  <•>  OJ L 317, 6.11.1981, p. 16. Directive as last amended by Directive 93/40/EEC.
   5
  <>   OJ L 373, 31.12. 990, p. 26.
  <6>  OJ L 297, 13.10.1992, p. 12.
                                                                3
 ---pagebreak--- (2) Whereas the primmy purpose of any rules for the production and distribution                          1.       811851/.£EC
   · of vetefin:uY medicinal products must be the ~guarding of public health;
(3) Whereas, however, this objective must be achieved bY means which will not                           2.        81/851/EEC
     hinder the development of indusby and trade in medicinal products within the
     Co~unity;
(4) Whereas, in so far as the Member States already have certain provisions laid                        3.        811851/EEC
     down by law, regulation or administrative action governing veterinary                                       (adapted)
     medicinal products, such provisions differ in essential principles; whereas this
     results in the hindering of trade in medicinal-products within the Community,
     thereby directly affecting the fimctioning of the intemal market;·
(5) Whereas such hindrances must, accordingly, be removed; whereas this entails
     approximation of the ~Ievant provisions;                                                          4.        81/851/EEC
(6) Whereas it is necessary from the ~int of view of pu_blic health and the free
     movement of veterinary medicinal products for the competent authorities to                        3.        90/676/EEC
     have at their disposal all useful information on authorized veterinary
     medicinal products in the form of approved summaries of the characteristics
     of products;
(7) Whereas, with the exception of those medicinal products which are subject to
     the centralized Community authorization procedure established by Council                          3.          '
                                                                                                                 93/40/EEC
     Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community                                           (adapted)
     procedures for the authorization and supervision of medicinal products for
     human and veterinary use and establishing a Emopean Agency for the
     Evaluation of Medicinal Products«1), a marketing authorization in one Member
     State ought to be recognized by the competent authority of the other Member
     States unless there are serious grounds for supposing that the authorization of
     the veterinary medicinal product concerned may present a risk to human or
     animal health, or to the environment; whereas, in the event of a disagreement
     between Member States about the quality, the safety or the efficacy of a
     medicinal product, a scientific evaluation of the matter should be undertaken
     according to a Community standard, lead to a single decision on the area of
     disagreement, binding on the Member States concerned; whereas this
     Decision should be adopted by a rapid procedure ensuring close cooperation
     between the Commission and the Member States;
(8) Whereas, for this purpose, a Committee for Veterinary Medicinal Products
     should be set up in accordance with the EW'Opean Agency for the
     Evaluation of Medicinal Products laid down in the aforementioned Regulation                      10.       81/851/EEC
     (EEC) No 2309/93.                                                                                          (adapted)
U>   OJ L 214, 24.8.1993. p. 1; Regulation as IIDCDded by Commission Regulation (EC) No 649198 (OJ L 81, 24.3.1998, p. 7).
                                                             4
 ---pagebreak--- -(9): Wheioas this Directive is only one stage in the achievement. of ihe ahn of             11.   811851/EEC
       freedom. of movement of vete,riDar)r medicinal     products;  wh~, however,                 (adapted) .
       for tbiS purj)ose, new .measures will prove necessary, in the light of experience
     · gained • especially within the CoiDD)ittee for ·veterinary Medicinal Products •
    · for the· removal of the remaining barriers ~ freedom of movement;
 (lO)Whereas medicated feedingstuffs do not come within the scope of this                    6.  .81/851/EEC
      ·Directive; whereas, however, it is necessary~ for ~th public health· and
     . economic reasons, to prohibit the use of unauthorized medicinal. products in
       the manufacture of medicated feedingstuffs;
.(ll)Whereas the concepts of harmfulness and therapeutic efficacy can be                     7.   811852/EEC
 · examined only in relation to one another and have only a relative significance,                (adapted}
       depending on the progress of scientific knowledge and the use for which the
       medicinal product is intended; whereas the partic:ulars and documents which
       must accompany an application for marketing authorization must demOilStrate
       that potential hazards are outweighed by the benefits due to efficacy;
                                               I
 (12)Whereas marketing authorization should be refused where a medicinal                    7.    811851/EEC
       product lacks therapeutic effect or where there is insufficient proof of such             (adapted)
       effect; whereas the concept of therapeutic effect must be understood as being
       the effect promised by the manufacturers;
 (13)Wbereas such marketing authorization should cilso be refused where the                 8.   81/851/EEC
       withdrawal period indicated is not long enough to eHminate health hazards                 {adapted)
       arising from residues;
 (14)Whereas, before an authorization to market an .immunological veterinary                5.   90/677/EEC
       medicinal product can be granted, the manufacturer must demonstrate his
       ability to attain batch-to-batch consistency;
 (IS)Wbereas the competent authorities should also be empowered to prohibit the          ,. 6.   90/677/EEC
       use of an immunological veterinary medicinal· product when the
       immunological responses of the treated animal will interfere with a national or
       Community programme for the diagnosis, eradication or control of animal
       disease;
 ( 16)Whereas it is desirable in the first instance to provide users of homeopathic         7.   92174/EEC
       medicinal products with a very clear indication of their homeopathic character
       and with sufficient guarantees of their quality and saf~ty;
 (17)Whereas the rules relating to the manufiscture, control and inspection of              8.   92174/EEC
       homeopathic veterinaey medicinal. products must be harmonized to permit the
       circulation throughout the Community of medicinal products which are safe
     . and of good quality;
                                                        s
 ---pagebreak--- (li)Wbereas, having.regard to· the particill8r characteristics.ofthese·hm;neopadiic         9.  92!14/EEC
       veterinary medicinal products, such as the very low level of active principles           (adapted)
       they comain·and the difficulty of applying to them the conventional statistical
       methods · relating to clinical trials, it is desirable to provide a special,
       simplified registratiOn procedure for those traditional homeopathic medicinal
       products which are placed on ·the market without ·therapeutic .indications in a
       phalmaceutical form and dosage which do not present a risk for the animal;
( 19)Whereas the usual· rules governing the authorization to market_ veteriDary            11.  92n4/EEC
   ·. medicinal ·prOducts must be applied to homeopathi<;. veteriDary medicinal                 (adapted)
       productS · marketed with therapeutic indications or in. a form which may
    . present risks which must be balanced against the desired therapeutic effect;
       whereas· Member States should ·be able to apply particular rules for· the
       evaluation of the results of tests and trials intended to establish the safety and
       efficacy of these medicinal products for pet animals and exotic species,
     · provided that they notify them to the Commission;
(20)Whereas in order to better protect human and animal health and avoid any               4.  93/40/EEC
       unnecessary duplication of effort during the examination of application for a           (adapted)
       marketiDg authorization, Member :States should systematically prepare
       assessment reports in respect of each veterinary medicinal product which is
       authorized by them, and exchange the reports upOn request; whereas,
       furthermore, a Member State should be able to suspend the examination of an
      .application for authorization to place a veterinary medicinal product on the
       market which is currently under active consideration in another Member State
       with a view to recognizing the decision reached by the latter Member State;
(21 )Whereas, in order to facilitate the movement of veterinary medicinal products        12   811851/EEC
       and to prevent the checks canied out in one Member· State from being                    (adapted)
       repeated in another, harmonised requirements for manufacture and imports
       from third countries,. and the grant of corresponding authorization, should be
       applied to veterinary medicinal products,
(22)Whereas the quality of veterinary medicinal products manufactured within the          7.   90/676/EEC
       Community should be guaranteed by requiring compliance with the principles              (adapted)
       of good manufacturing practice for medicinal products irrespective of the
       final destination of the medicinal products;
(23)Whereas measures should also be taken to ensure that distributors of                  10.  90/676/EEC
       veterinary medicinal products are authorized by MCJQber States and maintain
       adequate records;
                                                         6
 ---pagebreak---  (24)Whereas standards and.protocols for. the perfouliance of tests on veterinary             3.      811852/EEC
   · medicioal.produds ·arc an e1fective meaos of control of these products and,                      (adapted)
      hence, of protecting public health and can facilitate the moveme.ot of these            +
      productS by laying down WUform rules applicable to tests and the compilation
      of dossiers,·allowing the competent authorities to·anive .at their decisions on         4.
      the basis of UDifom tests and by reference to uniform criteria, and therefore
      helping to obviate diff~ces in evaluatioD;
 (2S)Whereas it is advisable to stipulate more precisely the cases in which the
      results pfpharmacological and toxicological tests or clinical trials do not have       6.      90/676/EEC
     to. be provided with .a view to obtaining authorization for a. veterinary
      mediciDal product which is essentially similar to an innovative product, while
      ensuring that innovative forms are not placed at a disadvantage; whereas,
      however, there are reasons of public policy for not repeating tests carried out
     on aliimals without overiding cause;
 (26)Whereas following the establishment of the        mtemal market, specific controls.     s.      93/40/EEC
     to guarantee the quality of veterinary medicinal products imported from third
     countrieS can be waived only if appropriate arrangements have been made by
     the Community to ensure that the necessary controls are tarried out in th,e
     exporting COtmtry;
 (27)Whereas it is desirable to codify and improve ·the· cooperation and                     6.      93/40/EEC
     exchange of information between Member States relating to the
     surveillance o( veterinary medicinal· products and in particular the monitoring
     of adverse reactions under practical conditious of use through the natio!W
     phannacovigilance systems;
 (28)Whereas in order to improve the protection of public health, .it is necessary to       7.      93/40/EEC
     specify that foodstuffs for human consumption may not be taken from animals
     which have been used in clinical trials of veterinary medicinal products unless
     a· maximum residue limit has b~ laid down for residues of the veterinary
     medicinal product concerned in accordance with the provisions of Cotmcil· .
     IU:gulation (EEC) No 2377/90. of 26 June 1990 laying down a Community
     prOcedme for the establishment of maximum residue limits of veterinary
     medicinal products in foodstuffs of animal originU);;
(29) Whereas        the Commission should be empowered to adopt the                         7.      90/677/EEC
     necessary changes laid down in Annex I in order to adapt to scientific and                     (adapted)
     technical progress; .                                             ·
(30) Whereas, this Directive is without prejudice to the obligations of the
     Member States concerning the deadlines for transposition set out in Annex Il,
     PartB; ·
HAVE ADOPTED THIS DIRECTIVE:
(I)  OJ L 224, 18.1.1990, p.· 1; RCgu1alioa u·llst acadcd by Cm~mission Rcpllticm (EC) No 1958198 (OJ L 2S4,
     16.9.1998, p. 7).
                                                        7
 ---pagebreak---                                               . tTI'i.J:'I
                                             DEFINITIONS
                                                 Article 1
For the pm-poses of this Directive, the following terms sbaU bear the following meanings:   65/65/EEC
                                                                                            Art. 1 (1) and (2)
1. .Propriet'al'y medicinal product:                                                        (adapted)
     Any ready-prepared medicinal product placed on the market under a special name
   ·and ma special pack.                                   .                      .
2.   Veterinluy medicinlll product:                                                         81/851/EEC
                                                                                           Art. 1 (1)
     Ally substance or combination of substances _presented for treating or preventing (adapted)
   .disease in animals.
     Ally substance or combination of substances which may be administered to animals
     with a view to making a medical diagnosis or to restoring, correcting or modifying
     physiological functions in animals is likewise considered a veterinary medicinal
     product.
3.   Ready-made veterinary medicina~ product                                               81/851/EEC
                                                                                           Art. 1 (2), 2nd indent
    shall mean any veterinary medicinal product prepared· in advance which does not
     comply with the definition of proprietary medicinal products and which is marketed
     in a pharmaceutical form which may be used without further processing. ·
4. Substance:                                                                              65/65/EEC
                                                                                           Art. 1 (3)
    Any matter iiTespective of origin which may be:                                        81/851/EEC
                                                                                           Art. 1 (1)
    .. human, e.g. human blood and human blood products;                                   (adapted)
   -    animal, .e.g. micro-organisms, whole animals, parts of organs, animal secretions,·
        toxins, extracts, blood products;
                                                    8
 ---pagebreak---       • vegetable~ e.g. micro-orpnisms, plants, ·parts of plams, vegetable secretions,          65165/EEC,
         ~;                   .                                                .                Art. 1 (3)
                                                                                                81/85 1/EEC .
      • chemical, e.g. elements, naturally occurring chemical materials and chemiall.           Art. 1 (1)
         products .obtained by chemical change or synthesis.                                    (adapted)
. 5. Pr.,mi% for medicatedftedingstuffs                                                         81185 1/EEC
                                                                                                Art. 1 (2), 3rd and
     Any veterinary medicinal product pRpared in advance with a view to the subsequent 4th indents
     manufacture   of medicated feedingstuffs,
  6. Medicatedfeedinptuffs.
     Any mixture of a veterinary medicinal product or products and feed or feeds which is
     ready prepared ·for marketing and intended to be fed to animals without further
     processing. because of its curative or preventive properti~s or other properties as a
     medicinal product covered by point 2.
  7. Immunological veteri1U11')' medicinal product                                             90/677/EEC
                                                                                               Art. I (2)
     A veterinary medicinal product administered to animals in order to produce active or
     passive immunity or to diagnose the ~ of immunity.
 8.  J!omeopathic veterinary medicinal product                                                 92n4/EEC
                                                                                               Art. I
     Any veterinary medicinal product prepared from products, substances or
     compositions called homeopathic stocks in accordance with a homeopathic
     manufacturing procedure described by the EW'Opean Pharmacopoeia or, in the
     absence thereof: by the pharmacopoeias CUil'ently used officially in the
     Member States.
     A homeopathic veterinary · medicinal product may also contain a number of
     principles.
 9. Withdrawal period                                                                        . 81/851/EEC
                                                                                               Art. 5, 3rd paragraph, (8)
     Period between the last administration of the veterinary medicinal product to animals (as amended by
     under normal conditions of use and the production of foodstuffs from such animals, 90/676/EEC Art. 1 (5))
     in order to ensure that such foodstuffs do not contain residues in quantities in excess (adapted)
     of the maximum limits laid down in applying Regulation (EEC) No 2377/90.
                                                     9
 ---pagebreak--- ·1 0. Adverse l'eaction                                                                      · 81/SS 1/EEC ·
                                                                                                 Art.42b
      A reaction which is harmfUl and uninteJided and which occurs at doses normally used (as amended by
      in animals for the prophylaxis, diagnosis or .1J'eatment of disease or the modification 93/40/EEC Art 1 (12))
      of physiological function.
 11. Serious adverse reaction
      An adverse reaction which is fatal, life-threatening lesion-producing, disabling,
      incapacitating, or which results in permanent or prolonged symptoms in the animals
      treated.
 12. Unexpected adverse reaction
      An adverse reaction which is not mentioned in the summary of the product
      characteristics.
 13. Serious unexpected aiherse reaction
      An adverse reaction which is both serious and unexpected.
 14. .Wholesale dealing in veterinary medicinal products                                        811851/EEC
                                                                                                Art. SOa (1 ), 2nd
      Any activity which includes the purchase, sale, import, export, or any other              subparagraph
      commerCial transaction in veterinary medicinal products, whether or not for profit,       (as amended by
      exceptfor.                                                        ·                      90/676/EEC Art. 1 (27))
                                                                                               (adapted)
      - the supply by a manufacturer of veterinary medicinal products manufactured by
         himself,
      - retail supplies of veterinary medicinal products by persons entitled to caiTY out
         such supplies in accordance with Article 66.
 15. Agency                                                                                    811851/EEC
                                                                                               Art. 16 (1),
      EW'opean Agency for the evaluation of medicinal products set up by Regulation            (as amended by
      (EEC) No 2309/93.                                                                        93/40/EEC Art. 1 (10))
                                                                                               (adapted)
 16. Risk to human or animal health or the environment                                         811851/EEC
                                                                                               Art. 18 ( 1), footnote
      Any risk referring to the quality, safety and efficacy of the veterinary medicinal       (as (lmended by
      product.                                                                                 93/~0/EEC Art. 1 ( 10))
                                                                                              (adapted)
                                                     10
 ---pagebreak---                                                         ,Artiele2 ·
 The
   .
      provisions. of this Directive shall·apply   .
                                                     to veterinacy medicinal products
                                                                                    I
                                                                                                              811851/EEC
                                                                                                             Art..2.(1)
                                                                                                             (adapted)
                                                         Artiele3
This Directive sball not apply to: .                                                                         81/851/EEC
                                                                                                             Art 2 (2), 1st indent ·
 1. Medicated feedingstuffs set out in Council Directive 90/167/EECO,;                                       (adapted)
     However, ·medicated feedingstuffs may. be prepared only from pre-mixes which have 81/851/EEC
     been authorized Under this Directive;                                                                   Art. 2 (3)
                                                                                                             (adapted)
2.   inactivated immunological veterinary medicinal products which are manufactured 90/677/EEC
     from pathogens obtained from an animal or aDimals from a hc;>lding and used for the Art 1 (3)
     treatment oftbat animal or the animals of that holding in the same locality;                           (adapted)
3. Any medicinal product prepared in a pharmacy in accordince with a prescription for 65/65/EEC
     an individual animal (commonly known as the magistral formula);                                        Art. 1, points 4 and S
                                                                                                            (as amended by
                                                                                                            89/341/EEC Art. 1 (2))
                                                                                                            (adapted)
4. Any medicinal product· prepared in a pharmacy in accordance with the 81/851/EC
     prescriptions of a pbannacopoeia and is intended to be supplied directly to the. Art. 1 (1)
     end-user (commonly known as the official formula);                                              ·      (adapted)
5. Veterinary medicinal products based on radio-active isotopes;                                            811851/EEC
                                                                                                          1 Art. 2 (2), 3rd inden~
6. Any additives covered by Council Directive 70/524/EEC'l•, where they are 81/851/EEC
     incoiP.Orated in animal feedingstuffs and supplementary animal feedingstuffs in .Art. 1 (4)
     accordance with that Directive.                                                                        (adapted)
(I)  OJ L 92. 7. 4.1990, p. 42.
C:Z) OJ L 270, 14.12.1970, p. 1~ DileciM as 1.st IIDCDdcd by CommissiaD DiJective 98119/EC (OJ L 96,28.3.1998, p. 39).
                                                             11
 ---pagebreak---                                                 Artide4
1. Member States ~Y. provicSe that t;his Directive shall not apply to non-ictivated 90/677/EEC
     immunological veteJjnarymedicinal products manufactured from. pathogens obtained· Art. 1· (4)
     from an animal or animals from a holdhlg and used for ·tbe treatment of that animal (adapted)
     of that holdiDg in the same IQCality.
2. Member States may permit exemptions on their tenitory in respect of. veterinaJy 81/85 1/EEC .
    medicinal products intended solely for aquarilDD ·fish, cage birds, hommg pigeons, An. 3
    terrarilDD animals and small rodents, from tbe provisions in Articles 5, 7 and ·8,
    provided that such producEs do not' contain substances the use of which requires
    veterinary control and that all possible measures have been taken to prevent
    unauthorized use of the product$ for ~ther animals.
                                               TITLE    m
                                            MARKETIN'G
                                              Chapter 1
                                    · Marketing ·authorization
                                                Article 5
No veterinary medicinal product may be placed on the market of a Member State unless a     811851/EEC
marketing authorization has been issued by the competent authorities of that Member        An. 4 (1), 1st
State in accordailce with this Directive or a marketing authorization has been granted in  subparagraph
accordance with Regulation (EEC) No 2309/93.                                       ·       (as amended by
                                                                                           93/40/EEC Art. 1 (1 l'
                                                                                          (adapted)
                                                Article 6
               .          .                                .
In order that a veterinary medicinal product may be the subject of a marketing            81/851/EEC
authorization for the pU;fpOse of administering it to food-producing animals, the active  Art. 4 (2), 1st
substances which it contains must be shown in Annexes I, ll or mof Regulation (EEC)       subparagraph
No2377/90.                                                                                (as 'amended by
                                                                                          90/676/EEC Art. 1 (4))
                                                                                          (adapted)
                                               Article 7
Where the health situation so requires, a Member State may authorize the marketing or 81/851/EEC·
administration to animals of veterinary medicinal products which have been authorized Art. 4 (1 ), 2nd
by another Member State in accordance with this Directive.                                subparagraph
                                                                                          (as amended by
                                                                                          90/676/EEC Art. 1 (4))
                                                                                          (adapted)
                                                   12
 ---pagebreak---                                                   Article 8
In. the· event .of serious disease epidemic, Member States may provisionally allow the use · 811851/EEC ·
of immunological veterinary mediciDal products without the authorization for placing on Art. 4 (1), 3rd
the market, in ·the . absence of ·a suitable mediciDal product and after informing the subparagraph
Commission of the detailed conditions of use.               ·                                   (as amended by
                                                                                                90/676/EEC Art. 1 (4))
                                                                                                (adapted)
                                                  Article 9
No veterinary medicinal product may be administered to animals unless the marketing             81/SS I!EEC .
authorization has been issued, except for the tests of veterinary medicinal products            Art. 4 (3), 1st
referred to in Article 12 (3) (j) which bave been accepted by the competent national            subparagraph
authorities, following notification or authorization, in accordance with the national rules     (as amended by
in force.                                                                                      90/676/EEC Art. 1 (4))
                                                                                               _(adapted)
                                                  Article 10
 1. Where there is no authorized medicinal product for a condition, Member States may          81/851/EEC
      exceptionally, in particular in order to avoid causing unacceptable suffering to the     An. 4 (4), 1st and 2nd
      animals concerned, pemut the administration by a veterinarian or under his/her direct    subparagraphs
      personal responsibility to an animal·or to a small number of animals on a particular     (as amended by
      holding:                                                                                 90/676/EEC Art. 1 (4))
                                                                                               (adapted)
(a) of a veterinaty medicinal product authorized in the Member State cOncerned under
      this Directive or under Regulation (EEC) No 2309/93 for use in another animal
      species, or f~r another condition in the same species; or
(b) if there is no product as referred to in point (a), of a medicinal product authorized for
      use in the Member State concerned in human beings in accordance with Directive
      [65/65/EEC] or under Regulation (EEC) No 2309!93; or
(c) if there is no product as referred to in point (b) and within the limits of the law of the
      Member State concern~ of a ·veterinary . medicinal product prepared
      extemporaneously by a person authorized to do so under national legislation in
      accordance with the terms of a veterinary prescription.
      For the purposes of this paragraph, the phrase 'an animal or a small number of
      animals on a particular holding' also covers pets, and shall be interpreted more
      flexibly for minor or exotic animal species which do not produce food.
                                                      13
 ---pagebreak---  2. The Provisions of paragraph 1 shall apply provided tbat the inediciDal product, where     811851/EEC .
      _administ.ered to food-producing animals, contains only substances to be found in a     Art. 4 (4), 1st and 2nd
      veterinary medicinal product· authorized for such animals in the Member State           subparagraphs
      concerned and that in the case of food·produ~ing animals the veterinarian               (as amended by
      responsible ·specifies an appropriate withdrawal period- to eDS1U'e that food produced  90/676/EEC Art. I_ (4))
      from the treated animals does not contain residues harmfUl to consumers.                (adapted)
      Unless the medicinal. product used indicates -a withdrawal period for the species
      concerned, the specified withdrawal period sball not be less than: ·
      7.days                 eggs,
      7days                  milk,
      28 days                meat fr'Qm'poultry and mammals including fat and oftal,
      500 degree· days       meat from fish.
      With· regard to homeopathic veterinary medicinal products -in which the level· of 92174/EEC
     ·active principles is equal to or less than one part per million, the withdrawal period Art. 2 (1), 2nd
      referred to in the first and second subparagraphs is reduced to zero.                   subparagraph
                                                                                             (adapted)
                                                   Artiele 11
  The veterinarian shall keep adequate records of the date of examination of the animals,    811851/EEC
· details of the owner, the number of animals treated, the diagnosis, the medicinal products Art. 4 (4), 3rd
  prescrib~ the dosages administered, the duration of treatment and the withdrawal           subparagraph
  periods recommended, and make these records available for inspection by the competent      (as amended by
  authorities for a period of at least three years. This requirement may be extended by the  90/676EEC Art I (4))
  Member States to food-producing animals.                                                   (adapted)
                                                   Artiele 12
  1.  For the pmposes of obtaining an authorization for placing on the market irrespective 81/851/EEC
      ofthe procedure established by Regulation (EEC) No 2309/93, an application shall Art. 5, 1st subparagraph,
      be lodged by the competent authority of the Member State concerned.                    (as amended by
                                                                                             90/676/EEC Art. I (5))
                                                                                             (adapted)
  2. A marketing authorization may only be granted to an applicant established in -the 81/851/EEC
      Community.                                                                             Art. 5, 2nd subparagraph
                                                                                             (as amended by ·
                                                                                             93/4~/EEC Art. 1 (3))
                                                                                             (adapted)
                                                       14
 ---pagebreak--- · 3. 1be following partiCulars ·and documents shall be appeDded               tO the;application· in '81/851/E2C .
         ~e with Almu 1:.                                            -                                Art. s, 3rd subparagraph,
                                                                                                      points 1 to 9
  (a) name or business name and permanent a&tress or registered place of business of the (as amended by
        ~.responsible for placiDg. the product on the market and, if different,. of the 99/676/EEC Art. 1 (5))
        IDID1Ificturer or manufacturers ·involved and of the sites ofmanufilculre;                    (adapted)
· (b)   name of the veterinary medicinal prodUct (brand name, non-proprietary ~e;· with +
        or without a trademark, or· name of the II1IIWfacturer or scientific name or formula,
        with or without a tradeirwk, or the name of the manufacturer); · ·               ·           81/852/EEC
                                                                                                     Art. 1t 1st paragraph
  (c) qualitative and quantitative particulars of all the constituents of the veterinary             (adapted)
        medicinal product, using the ·usua1 terminology, but not empirical chemical formulae
     .· lnd giving the intemational non-proprietary name recommended by the World
        Health OrpnilJltiozi. where such a name exists;
  (d) description of the method of~; .
 ·(e) therapeutic indications, contra-indications and adverse reactions;
. (f) clOsaae for the various species of animal for which the veterinary medicinal product
      . is intended, its pharmaceutical form, method and route of administration and
        proP,sed shelf life; ·
  (g) if applicable, explanations of the precautiomuy and safety measures to be taken when
        the product is stored, when it is administered to animals and when waste therefrom is
        disposed of, together with an indication of any potential risks the medicinai product
        might pose to tbe environment and the health of humans, animals or plants;.
 (h) indication of the withdrawal period. Where necessary, the applicant shall propose
        ind justify a tolerance level for residues which may be accepted in foodstuffs without
        risk for the conslimer, together with routine analysis methods which could be used by
        the cOmpetent authorities to trace residues;
 (i) description of the control testing methods employed by the manufacturer (qualitative
        and quantitative analysis of the co~tuents and the finished product, specific tests
        e.g. sterility tests, test for the presence of pyrogens, for the presence of heavy metals,
        stability tests, biological and toxicity tests, tests on intermediate products);
                                                            IS
 ---pagebreak---  (j) results of.                                                                               81/SSl/EEC
                                                                                              .Art. s, ~rd paragraph,
     -    physico-chemical, biological or microbioiogical tests,                              point 10, 1st .
     •    toxicological and pharmacological tests,                                           .subparagraph
          cliJrlcal trials.                                                                   (as amended by .
                                                                                              90/61~<?Art. 1 (5))
 (k) a summary in accordance with Article 14 of the product characteristics, one or more      81/851/EEC
     specimens or mock-ups of the sales presentation of the veterinary medicinal product Art.· 5, 3rd paragraph,
     together with the package insert;                                                        points 11 and 12
                                                                                              (as amended by
 0) a document showing that the manufacturer is authorized in his own country to 90/676/EEC Art. 1 (S))
     ~uce veterinary medicinal products;                                                      (adapted)
.(m) copies of any marketing authorization obtained in another Member State or in a third.    81/851/EEC
     country for the relevant veterinary medicinal product, together with a list of:those    Art. 5, 3rd paragraph,
     Member States in which an application for authorization submitted in accordance          point 13
     with this Directive is under examination. Copies of the summary of the product          (as amended.by
     characteristics proposed by the applicant in accordance with Article 14 -or approved    93/40/EEC Art. 1 (4))
     by the competent authority of the Member. State in accordance with Article 25 and       (adapted)
     copies of the package insert proposed, details of any decision to refuse authorization,
     whether in the Community or a third country and the reasons for that deeision.
     This information shall be updated on a regular basis;
 (n) in the case ·of medicinal products containing new active substances which are not       81/851/EEC
     mentioned in Annex I, D or m to Regulation (EEC) No 2377/90, a copy of the              Art. 5, 3rd paragraph,
     documents submitted to the Commission in accordance with Annex V to that                point 14
     Regulation.                                                                             (as amended by
                                                                                             90/676/EEC Art. l (5))
                                                                                             (adapted)
                                                    16
 ---pagebreak---                                                        Artldell
1. By way. of derogation from point 0) of Article 12 (3), and without prejudice to ·the 81/851/EEC
    law relating to the protection of industrial and commercial property:                              Art. S, 3rd paragraph,
                                                                                                       point 10, 2nd.
(a) the applicant sball not· be required to provide the results of toxicological and subparagraph .
    pharmaco!ogical tests and clinical trials if he can demonstrate:                                   (as amended by
                                                                                                       90/676/EEC Art. 1 (S))
    (i) either that the v~terinaly medicinal product is essentially similar to a medicinal (adapted)
          product authorized in the Member State concerned by the application and that
          ~e mark~ting authorization · holder · has agreed that the toxicological,
          pharmacological and clinical ~ferences contained in :the file on the original
          veterinary ·medicinal product may be used for the purpose of examining the
         'application·in question;
    (ii) or that the constituent or constituents of the veterinary medicinal product have a
          well-established medicinal use, with recognized efficacy'· and also an acceptable
          level of safety, with detailed references to the scientific literature;
    (iii) or that the veterinary medicinal product is essentially similar to a medicinal
          product which has been authorized .within the Community, in accordance with
          Community provisions in force; for not less than six years and is marketed in the
          Member State for which the application is made; this period shall be extended to
          10 years  in the case of high-technology having been authorized in pursuance of
          the procedwe established by Article 2 (5) of Council Directive 87122/EE01• •
          Furthermore, a Member State may also .extend this period to 10 years by a single
          Decision covering all the medicinal products marketed in its territory where it
          considers this necessary in the interest of public health. Member States are at
          liberty not to apply the six-year period beyond the date of expiry of patent          a
        · protecting the origibal medicinal product.
(b) in the. case of new veterinary medicinal products containing known constituents not
    hitherto used in combination for therapeutic purposes, the results of toxicological
    and pharmacological tests and of clinical trials relating to that combination must be
    provided, but it shall not be necessary to provide the relevant documentation for each
    individual constituent.
2. Annex I shall apply in like manner where, pursuant to point (aXii) of paragraph. I,                81/852/EEC
    references to published data are submitted.                                                       Art. 1, 2nd paragraph
                                                                                                      (adapted)
U>   OJ LIS, 17.1.1987, p. 38, DiRctivc repealed by Direclive 93/41/EEC (OJ L 214, 24.8.1993, p. 40).
                                                            17
 ---pagebreak---                                                     Article 14 .·
 The summary of the product characteristics shall contain the following information:  81/851/EEC
                                                                                      Art. Sa
 1. Name of the veterinary medicinal products;                                       ·{as amended by~
                                                                                      90/676/EEC Art. 1 (6))
 2. Qualitative and ciwmtitative composition in terms of the active substances and (adapted)
      constituents of the excipient, knowledge of which is essential ·for . proper
      ~on of the medicinal product; the inter.nltional non-proprietary names
      recommended bY the World Health Organi~tion shall be used, where such names
      exist, or failing this, the usual non-proprietary name o~ chez;nical ~ption;
 3. Pharmaceutical form;
 4. Pharmacological properties and, in so far as this information .is useful for the
      therapeutic purposes, pharmacokirietic particulars;
·5. · clinical particulars;
      5.1 target species,
      5.2 indications for use, specifying the target species,
      5.3 contra-indications,
      S.4 undesirable e~ects (frequency and seriousness),
      5.5 special precautions for use,
      5.6 use during pregnancy and lactation,
      5.7 interaction with other medicaments and other forms of interaction,
      S.8 posology Jnd method of administration,
      S.9 overdose (symptoms, emergency procedures, antidotes) (if necessary),
      S.I 0 special warnings for each target species,
      5.11 withdrawal periods,
      S.I2 special precautions to be taken by the per59n administering the medicinal
            product to animals;
                                                       18
 ---pagebreak--- 6. · Pharmaceutical particulars:                                                               81/851/EEC
                                                                                               Art Sa
      6.1 major in~mpatibllities,                                                              (as amended by
                                                                                               90/676/EEC Art 1 (6))
      6.2 shelf life; when neceSSII'Y- after reconstitution of the medicinal product or when   (adapted)
         · the container is opened for the first time,       ·
      6.3 special precautions for storage,
      6.4 na11u'e and contents of container,
      6.5 special precautions for the disposal of unused medicinal product or waste
        · materials' if any·t ·.         •
                                                                         '
7. Name or corporate name and address or registered place of business of the .
     .authoriZation holder.                ·
                                                    Article 15
 1. Member States shall make all necessary arrangements to eDSW'e ~ the documents 81/85 1/EEC
      an~ particulars listed in Article 12 (3) {h), (i), 0) and Article 13 (1) are drafted by Art. 6
      experts with the requisite technical or professional qualifications before being
      submitted to the competent authorities.
      These documents and particulars shall be signed by the experts in question.
2. According to their particular qualifications, the role ofthe experts shall be:             811851/EEC
                                                                                              An. 7 (1), (2) and (3), 1st
(a) to carry out such work as falls within their particular discipline (analysis,             subparagraph
      pharmacology and similar experimental sciences,. clinical trials)- and to describe      (adapted)
      objectively the results obtained in both quantitative and qualitative terms;
(b) to describe their findings in accordance with Annex I and in particular to state:
      (i) in the case of analysts, whether the medicinal product conforms with the stated
           composition, providing any reasons for the control testing methods which the
           manufacturer is·to use;
                                                       19
 ---pagebreak---      (ii) in the  ease of pharmacologists and appropriately qualified specialists:            81/85 1/EEC ·
                                                                                              Art. ,.(1), (2) and (3), 1st
            • the toxicity of the medicinal product and the pharmacological pro~ subparagraph
                observed,                                                                  · (adapted)
            -   whether, after administration of the veterinary medicinal product under
                normal conditions of use and observance Qf ~e recommended withdrawal
              . period, foodstuffs obtained from the treated animals contain residues wliich
                might constitute a health hazard to the consumer;             ·
   . (iii) in the case of clinicians, whether they have .found in animals treated with the
           medicinal product effects corresponding to the information furnished by the
           manufacturer pursuant to Articles 12 and .13 (1 ), whether the medicinal product
           is well tolerated,. what dosage they recommend and what are the contra-
           indications and adverse reactions, if any;
(c) to give reasons for the use of the references to published data referred to in
     point (a) (ii) of Article 13(1).
3. The experts' detailed reports shall form part of the documentation which the 81/851/EEC
     applicant shall lodge with the competent authorities. A brief curriculum vitae of the Art. 7 (3), 2nd
     expert shall be appended to each report.                                                subparagraph
                                                                                             (as amended by
                                                                                             90/676/EEC An. I (8))
                                                       20
 ---pagebreak---                                               ·· Chapter2
                                · Particular provisions applicable to ·
                           homeopathic veterin81)' medi~al pro~ucts
                                                  Artiele 16
1. Member States · shall eDSW'e that homeopathic veterinary ·medicinal products 92f14/EEC
    manufactured· and marketed Within the ·Community are registered or authorized ~ Art. 6
    ·accordance with the provisions of Articles 17 (1) and (2), 18 ~d ·J9. Each Member (adapted)
    State shall take due account of registrations and ·authorizations previously granted by
    another Member State.            ·             ··
2. A• Member State may refrain from establishing a special, simplified registration
     procedure for the homeopathic veterinary mediciDal products referred to in
    Article 17 ( 1) and (2). A Member State applying this provision shall inform the
    Commission accordingly. The Member State concerned shall, by 31 December 1995
    at the latest, allow. use in its tenitory of homeopathic veterinary medicinal products
    registered .by other Member States in accordance with Article 17 (I) and (2) and
    Article 18.
                                                  Artielel7
"1. Only homeopathic veterinary medicinal products which satisfy all of the following       92174/EEC
    conditions may be subject to a special, simplified registration procedure:              Art. 7 ( 1)
                                                                                            (adapted)
          they are. intended for administration to pet animals or exotic species which are.
        . non food-producing,
          they are administered by a route described in the European Pharmacopoeia or,
          in absence thereot by the pharmacopoeias cwrently used officially in the
          Member States,
          no specific therapeutic indication appears on the labelling of the ·veterinary
          medicinal product or in any information relating thereto,
          there is a sufficient degree of dilution to guarantee the safety of the medicinal
          product; in p~icular, the medicinal product may not contain either more than
          one part per 10 000 of the mother tincture or more than 1/1 OOth of the smallest
          dose used in allopathy with regard to active principles whose presence in an
          allopathic medicinal product results in the obligation to submit a veterinary
          prescription.
    At the time of registration, Member States shall determine the classification for the
    dispensing of the medicinal product.
2. The criteria and rules of procedure provided for in Chapter 3 shall apply by analogy 92174/EEC
    to the special, simplified registration procedure for homeopthaic veterinary medicinal Art. 7 (3)
    products laid down in paragraph 1, with the exception of the proof of therapeutic (adapted)
    effect.
                                                     21
 ---pagebreak--- 3. . The proof of therapeutic effect ·sb8u not. be require.d for homeopathic. veteriDary    J92fl.4/EEC ·      .
     medicinal products registered in accordance with paragraph 1. of this Article or,. Art. 4, 2nd subparagraph
     where appropriate, admitted in accordance~ ~cle 16 (2).                                . (adapted)
                                                  Article 18
~ special,  simplified application for registration may cover a series of medicinal products 92174/EEC ·
derived from the same homeopathic stock or stocks. The following document sbal1 be Art. 8
included with the application in order to demonsttate, in particular, the pharmaceutical (adapted)
quality and the batch-to-batch homogeneity of the products concerned:                 ·
     scientific name or. other name given in a pharmacopoeia of the homeopathic stock or
     stocks, tOgether with a statement of the various routes. of administration,
     pharmaceutical forms and degree of dilution to be registered,
     dossier describing ·how the homeopathic stock or stocks is/are obtained and
     controlled, and justifying its/their homeopathic nature, on the basis of an adequate
     bibliography; in the case of homeopathic veterinary m~cinal products containing
     biological substances, a description of the measures taken to ensure the abSence of
     pathogens;
     manufacturing and control file for each pharmaceutical form and a description of the
     method of dilution and ~tentiation,
     manufacturing authorization for the medicinal products concerned,
-· copies of any registrations or authorizations obtained for the same medicinal
     products in other Member States,
     one or more specimens or mock-ups of the sales presentation of the medicinial
    products to be registered,                        ·
     data concerning the stability of the medicinal product
                                                     22
 ---pagebreak---                                                Artiele 19
1. 'Homeopathic veteriDary products other than those referred to in Article 17 (1) shin 92174/EEC
    be authorized in KCOrdance with the provisions of Articles 12 and 13 and Chapter 3. Art. 9
                                                                                           (adapted)
2~ A Member State may introduce or retain in itS territoty specific rules for the
    phartnatological and toxicological tests and clinical trials of homeopathic veterinary
    medicinal products intended .for pet animals and exotic species which are non foocJ..
    producing other tban those referred to in Article 17 (1), in accordance with the
    principles and characteristics of homeopathy as practised· in that Member State.
    In this case, the Member State concerned sball notify the Commission of the specific
    ~esinf~.                   -                                        ·
                                               Ardele20
This Chapter shall not apply to immunological veterinary medicinal products.               92174/EEC
                                                                                           Art. 2 (3)
                                                                                           (adapted)
                                                  23
 ---pagebreak---                                                 Chapter~
                             · Procedure for marketing authorization·. .
                                                     .
                                                 Artide21
1. Member States shall take all appropriate measures to ·ensure that the procedure for 81/851/EEC
      granting an authorizatiOn to place a veterinary medicinal product on the market· is Art. 8
      completed within 210 days of the submis~ion of a valid. application.            ·     (as amended by ..
                                                                                           93140/EEC Art. 1 (6))
2. Where a Member State notes that an application for authorization submitted is (adapted)
      already under active examination in another Member State in respect of that
     ·veterinary medicin81 prod~ the Member State concerned may decide to .suspend
    .the detailed examination of the application in order to await the assessment report
      prepared by the other Member State in accordance with Article 25 (4).
     .The Member State concerned shall inform the other Member State and the applicant
    ·.of .its decision to suspend detailed examination of the application in question. As
      soon as it has completed the examination of the application and reached a decision,
    · the other Member State shall forward a copy of its assessment report to the Member
      State concerned.            ·
                                                 Artide22
Where a Member State is informed in accordance with Article 12 (3) (m), that another       81/851/EEC
Member State has authorized a veterinary medicinal product which is the subject of an      Art.8a
application for authorization in the Member State con~ed, that Member State shall          (as amended by
forthwith request the authorities of the Member State which has granted the authorization  93/40/EEC Art. 1 (7))
to forward to it the assessment report referred to in Article 25 (4).                      (adapted)
Within 90 days of receipt of the assessment report, the Member State concerned shall
either recognize the decision of the first Member State and the summary of the product
characteristics as approved by it or, if it considers that there are groun~ for supposing
that the authorization of the veterinary medicinal product concerned may present a risk to
human or animal health or the environment, it shall apply the procedures set out in
Articles 19 and 33 to 38.
                                                      24
 ---pagebreak---                                                  Article 23
In order to examine the application submitted pursuant to Articles 12 and 13 (l), the         81/85.1/EEC
competent authority of the Member States:                                                 ·  Art. 9 (I)
                                                                                             (adapted)
1. sball check that the documentation submitted msupport of the appliCation' complies
    with Articles 12 and 13 (l) and, on the basis :of the reports drawn up by the experts
    puisuant to Article 15. (2) and (3), ascertain whether the conditions for the issue of
    the marketing authorizatiC?n have been fulfilled; ·
2. may· submit the medicinal product, its raw materials and if necessary intermediate        811851/EEC
    products or other constituent materials .for testing by a State laboratory or by a·      Art. 9 (2)
    laboratory designated for that pmpose, in order to ensure that the testing methodS       (as amended by
    employed by the manufacturer and described in the application documents, in              90/676/EEC Art.' 1 (9))
    accordance with Article 12 (3) (i), are satisfactory; · ·                                (adapted)
3. may, where appropriate, require the applicant to provide further information as 81/851/EEC
    regards the items listed in Articles 12 ~ 13 (1). Where the competent' authorities Art. 9 {3)
    take this course of action, the time-limits specified in -Article 21 shall be suspended (adapted)
    until the further data required have been provided. Similarly, these time-limits shall
    be suspended for any period which the applicant may be given to provide oral or
    written explanatioas;
4.  may require the applicant to submit substances in the quantities necessary to 81/851/EEC
    verify the analytical detection method proposed by the applicant in accordance with Art. 9 (4)
    Article 12 (3) (h) and to put it into effect as part of routine checks to reveal the (as amended by
    presence of residues of the veterinary ·medicinal products concerned.                   90/676/EEC An. I (10))
                                                                                            (adapted)
 ---pagebreak---                                                  Article%4
Member States shall take all appropriate measures to ensure that:.                            811851/EEC
                                                                                              Art. 10
(a) the _competent authorities ascertain that the manufacturers and importers of veterinary
    medicinal products from third countries are able tO manufacture them in compliance.
    with the details. supplied pursuant to Article ·12 (3) (d), and/or· to carry out control
    tests· in accordance with the methods described in the application docwnents under
    Article 12 (3) (i);
(b) the competent authorities may authorize manufacturers and importers of veterinary
    medicinal-products from third countries, where cin:umstances so justify, to ·have
    certain stages of manufacture and/or certain of the control tests,.referred to in (a)
    carried out by third parties; in such cases, checks by the competent authorities shall
    also be carried out in the establishments concerned.
                                                 Article-25
1.  Wh~ the marketing authorization is issued, the holder shall be informed by the 811851/EEC
    competent authorities of the Member State concerned, of the summary of the product Art. Sb
    characteristics as approved by it                                                        (as amended by
                                                                                             93/40/EEC Art. 1 (5))
2. The competent authorities shall take all necessary measures to ensure tbat the            (adapted)
    information given· in the summary is in conformity with that accepted when the
    marketing authorization is issued or subsequently.
3. The competent authorities shall forward to the Agency a copy of the authorization
    together with the summary of the product characteristics..
4. The competent authorities Shall draw up an assessment report and comments on the
    dossier as regards the results of the analytical and pharmacotoxicological tests and
    the clinical trials of the veterinary medicinal product concerned. The assessment
    report shall be updated whenever new information becomes available which is of
    importance for the evaluation of the quality, safety or efficacy of the veterinary
    medicinal product concerned.
                                                    26
 ---pagebreak---                                                 Articlel6
1. The ·marketing authorization may require the holder to indicate on the container 81/85 1/EEC
   and/or the outer wrapping ~ the package insert, where the Jauer iS required, other Art. 12
   particulars essential for safety or health protection, including any special prCcautions (adapted)
   relating to use and any other Warnings .resultiDg from the clinical and
   pharmacological trials prescnDed in Articles 12 (3) (j) and 13 (1) or from experience
   gained during the use of the veterinary medicinal product once it has been marketed.
2. The authorization may also require the inclusion of a tracer substance in the
   veterinary medicinal product..
3. In exceptional circumstances,. an4 following consultation with the applicant, an 81/851/EEC
   authorization may be granted subject to certain specific obligations, and subject to Art. 15 (2)
   annual review, including:                                                                {as amended by
                                                                                             93/40/EEC Art. 1 (9))
   - the carrying out of tbrther ~es following the granting of authorization,
   -     the notification of adverse ·rea~ons to the veterinary medicinal product.
   These exceptional decisions may only be adopted for objective and verifiable
   reasons.
                                                Article 27
1. After a marketing authorization has been issued, the holder must, in respect of the      811851/EEC
   manufacturing methods and control methods provided for in Article 12 (3) (d) and         Art. 14 (1), 1st
   (i), take account of scientific and technical progress and intrOduce any changes that    subparagraph
   may be required to enable tbat veterinary medicinal product to be manufactured and       (as amended by
   checked by means of generally accepted scientific methods.                               93/40/EEC Art. 1 (8))
                                                                                            (adapted)
   These changes shall be subject to the approval of the competent. authority of the
   Member State concerned.
2. Upon request from the competent authority, the marketing authorization holder shall 81/851/EEC
   also review the analytical detection methods provided for in Article 12 (3) (h) and Art. 14 (1), 2nd
   propose any changes w~ch may be necessary ·to take account of scientific and subparagraph and (2)
   technical progress.                                                                      (as amended by
                                                                                            90/676/EEC Art. I (11))
3. The marketing authorization holder shall ford.twith inform the competent authority of (adapted)
   any new. information which might entail the amendment of the particulars and
   documents referred to in Articles 12 and 13 (I) or of the approved summary of the
   product characteristics. ID particular, he shall forthwith inform the competent
   authority of any prohibition or restriction imposed by the competent authority of any
   country in which the veterinary medicinal product is marketed and of any. serious
   unexpected adverse effect occurring in the animals concerned or hlUilaD beings.
                                                    27
 ---pagebreak--- 4. The~ authorization ~der ~.be~ tO maintain records                                    of all ,81/851/EEC.
     adverse reictions observed in animals or human beings. The records ·so estabisbed          Art. 14 (3) and (4}
     sbal1 be kept at least five 'years and shall be made available_ to the competent           (u amended by
     authorities upon request.                             ·                                    90/676/EEC Art. 1 (11)}
                                                                                                (adapted)
S. The marketing .authorization holder sball immediately infonn the conlpetent
     authoriti~, with a view to ~orization, of any alteration he proposes to make to the
     particulars and documents refemd to.~ Articles 12 and 13 (1).                          ·
                                                  Article 28 ·
Authorization shall be valid for five years and shall be renewable for five-year periods, 81185 1/EEC
on application by the holder at. least three months before the expiry date and after An. 15 (1)
consideration .of a dossier updating ~e infonDation previously submitted.                       (as amended by
                                                                                                93/40/EEC Art. 1 (9))
                                                 Article 29
The granting of authorization shall not diminish the general legal liability of the 81185 1/EEC
manufacturer and, where appropriate, of the authorization holder.                              Art. .13
                                                                                               (adapted)
                                                 Article 30
The marketing authorization shall be withheld if examination .of the documents and. 81185 1/EEC
particulars listed in Articles 12 and 13 (1) establishes that:                                 Art. 11
                                                                                               (adapted)
(a) the veterinary medical product is harmfUl under the conditions of use stated .at the
     time of application for authorization; or
(b) has no therapeutic effect or the applicant has not provided sufficient proof of such
     effect as regards the species of animal which is to be tr~d; or
(c) its qualitative or quantitative composition is not as stated; or
(d) the withdrawal period recommended by the applicant is not long enough to ensure
     that foodstuffs obtained from the treated animal do not contain residues which might
     constitute a health hazard to the consumer, or is insufficiently substantiated; or
(e) the veterinary medicinal product is offered for sale for a use prohibited under other
     community provisions; or                                  ·    ·
(f) a veterinary medicinal product presents a risk for the protection of public health,
     consumer or animal·health.
Authorization shall also be withheld .if the application documents submitted to· the
competent authorities do not comply with Articles 12, 13 (1) and 15.
 ---pagebreak---                                                 Chapter4
                             ·Mutual reeopition of authorizations
                                                 Artlcl~31'
1. In order to facilitate the adoption of common decisions by Member States on the            81/851/EEC
   authorization.ofveterinary·medicinal products on the basis of the scientific criteria of   Art. 16 (1)
   quality, safety and efficacy, and to achieve thereby the free .movement of veterinary      (as amended by
   medicinal products .within the Community, a Committee for Veteriiwy Medicinal              93/40/EEC Art. i (l 0))
   Products, hereinafter referred to as "the Committee", is hereby set up. The                (adapted)
   Committee shall be part oftb.e Agency.
2~ In addition to the other responsibilities conferred upon it by Community law, the          81/851/EEC
   Committee shall examine -.ny question relating to the granting, variation, suspension      Art. 16.(2)
   or withdrawal of marketing authorization which is submitted to it in accordance with       (as amended by
   the provisions of this Directive. It shall also examine any question relating to tests of  93/40/EEC Art. 1 (10))
   veterinary medicinal products.                                             ·              +
                                                                                              81/852/EEC
                                                                                             Art. 2
                                                                                             (adapted)
3. The Committee shall adopt its own rules of procedure.                                     81/851/EEC
                                                                                             Art. 16 (3)
                                                                                             (as amended by
                                                                                             93/40/EEC Art. I (lO)J
                                                 Artide32
1. Before submitting an application for mutual recognition of marketing authorizations,      81/851/EEC
   the holder of the authorization shall inform the Member State which granted               Art. 17 (3)
   the authorization on which the application is based (hereinafter: the referential         (as amended by
   Member State) that an application is to be made in accordance with this Directive         93/40/EEC Art. I (10))
   and shall notify it of any additions to the original dossier; that Member State may       (adapted)
   require the applicant to provide it with all the particulars and documents necessary to
   enable it to check that the dossiers filed are identical.
                                                                    "
   In addition, the holder of the authorization shall request the referential Member State
   which granted the initial authorization to prepare an assessment report in respect of
   the veterinary medicinal product concerned, or, if necessary, to update it. That
   Member State shall prepare it within 90 days of receipt of the request
   At the same time as the application is submitted in accordance with paragraph 2 the
   referential Member Sate which granted the initial authorization shall forward the
   assessment report to the Member State or Member States concerned by the
   application.
                                                    29
 ---pagebreak--- 2. In order to obtain the recognition according to the procedure laid· down in this              81/85 1/EEC
       Chapter in one or·more of the Member StateS of a marketing authorization issued by.       Art. 17 (0 and (2)
   · . a Member State, the holder. of_ the authorization sbal1 submit an application to the      (as amended by . ·
       competent authority .of the Member State. or Member States concerned, together with       93/40/EEC Art. 1 (1 0))
       the information- and pani~ refemd to in Articles 12, 13 (1) and 14. He sball              (adapted) ·
       testify tbat the dossier is identical to that accepted by the referential Member State,.
       or .sball identify any ~ons or amendments it may ·contain. In the latter case,
       he shall certify that the summary of the product characteristics proposed by him in
       accordance with Article · 14 is identical to that accepted by the referential
       Member State. Moreover, he shall certify that all the dossiers tiled as part o.f this
       procedure are identical.                                            ·
3; The holder of the marketing authorization shall transmit the application to the
      .Agency, inform it ofthe Member States concerned and of the dates of submission of
       the application and send it a copy of the authorization granted by the referential
       Member State. He shall ~ send the Agency copies of any such authorization which
       may have been granted by the other Member States in respect of the veterinary
       medicinal product concerned, and shall ·~dicate whether any application for
       authorization is currently under consideration in any Member State.
4. Save in the exceptional case provided for in Article 33 (1), each Member State shall         811851/EEC
       recognize the marketing authorization granted by ·the referential Member State within    Art. 17 (4)
       90 days of receipt of the application and the assessment report. It shall inform the     (as amended by
       referential Member State, the other Member States concerned by the application, the      93/40/EEC Art. 1 (1 0))
       Agency, and the authorization bolder for placing the product on the market               (adapted)
                                                    Article33
1.     Where a Member State considers that there are grounds for supposing that the             811851/EEC
    . marketing authorization of the veterinary medicinal product concerned may present a       Art. 18
      risk to human or animal health or the environment, it sb8n forthwith inform the           (as amended by
      applicant, the referential Member State, any other Member States concerned py the         93/40/EEC Art. 1 (1 0))
      application and the Agency. The Member State shall state its reason in detail and         (adapted)
      shall indicate what action may be necessary to correct any defect in the application.
2.    All the Member States concerned shall use their best endeavoms to reach agreement
      on ·the action to be taken in respect of the application. They shall ptovide the
      applicant with the opportunity .to make his point of view known orally or in writing.
      However, if the Member States have not reached agreement within the time-limit
      referred tQ in Article 32 (4) they shall forthwith refer the matter to the Agency,
      according to the reference to the Committee, for the application of the procedure laid
      down in Article 36.                         ,
3·. Wif:hin the time-limit referred to in Article 32 (4), the Member States concerned shall
      provide the Committee with a detailed statement of the matters on which they have
      been unable to reach agreement and the reasons for their disagreement The applicant
      shall be provided with a copy of this information.
4.    As soon as he is informed that the matter has been referred to the Committee, the
      applicant shall forthwith forward to the Committee a copy of the information and
     particulars referred to in Article 32 (2).
                                                        30
 ---pagebreak---                                                 Article34
If several applications submitted in accordance with Articles 12, ·13 (1 ).and 14 have been  81/85 1/EEC
made for marketing authonz.tion for a particular veterinary medicinal .product and           Art. 19
Member States have adopted divergent ~isious concerning the authorization of that            (as amended by
veterinary medicinal prod~ or suspension or withc;trawar· of that authorimtion, a            93/40/EEC Art 1 (10))
Member· State, or the Commissi~ or the marketing authorization holder may refer the          (adapted)
matter to the Committee for application ofthe p~ wd down in Article 36. .
The Member State concerned, the marketing authorization holder or the Commission
shall clearly identify the question which is referred to the Committee for .consideration
and, if appropriate, shall inform the aforemention~d holder thereof.
The Member States and the marketing authorization holder shall forward to the
Committee all available information relating to the matter in question.
                                                Article35
The Member States or the Commission or the applicant or holder of the marketing             81/851/EEC
authorization may, in specific cases where the interests of the Community are involved,     Art 20
refer the matter to the Committee for the application of the procedure laid down in.        (as amended by
Article 36 before reaching &·decision on a request for a marketing authorization or on the  93/40/EEC Art. 1 (10))
suspension or withdrawal of an authorization, or on any other variations to the terms of a· (adapted)
marketing authorization which appears necessary, in particular to take account of the
information collected in accordance with Title vn.
The Member State concerned or the Commission shall clearly identify the question which
is referred to the Committee for consideration and shall inform the marketing
authorization holder.
The Member States .and the holder shall forward to the Committee all available
information relating to the matter in question.
                                                   31
 ---pagebreak---                                                  Artiele36
1. When ~ference is pwie to the procedure described in this Article, the Committee 81/851/EEC
   sbal1 consider the matter concerned. and issue a reasoned· opinion within. 90 days of Art. 21
   the date on which the matter was referred to it                                        (as amended by
                                                                                          93/40/EEC Art. 1 (10))
   However, in cases submitted to the Committee in accofdance with Articles 34 and (adapted)
   35, this period may be extended l>Y 90 .days.
   In case of urgency, on a proposal from its Chairman, the Committee may agree to a.
   shorter deadline.                                    ·                             ·
2. In order to consider the matter, ·the Committee may appoint one of its members to. ad
   as rapporteur. The Committee may also appoint individual experts to advise it on
   specific questions. When appointing experts, the Committee shall define their tasks
   and specify the time-limit for the completion of these tasks.
3. In the cases ·referred to in Articles 33 and 34, before issuing its opinion, the
   Committee shall provide the· marketing authorization holder with an opportunity to
   present written or oral explanations.
   In the case referred to in Article 35, the marketing authorization holder may be asked
   to explain himself orally or. in writing.
   If it considers it appropriate, the Committe.e may invite any other person to provide
   infonnation relating to the matter before it.
   The Committee may suspend the time-limit referred to in paragraph 1 in order to
   allow the marketing authorization holder to prepare explanations.
                                                   32
 ---pagebreak--- 4. ,·The ApDty sball forlhwith inform the         marketiDg   authorization holder where the  811851/EEC
    · opinion oflhe Committee is that:                                                        Art. 21 .
                                                                                              (as amended·by
           the ippUcation does not ~fy the criteria for authorization, or.                    93/40/EBC Art. 1 (10))
                                                                                              {adapted).
           the summary of the product characteristics· proposed by the applicant in
           iccordance with Article 14 should be amended, or
           the authorization should be granted subject to conditions, with regard to
           conditions considered essential for the safe and effective use of the ·veterinary
           medicinal product including pharmBcovigilance, or                       ·
           a marketing authorimtion should be suspended, ~ed or withdrawn.
      Within 15 days of the receipt of the opinion, the holder may notify the Agency in
      writing of his intention to appeal. In that case, he sball forward the detailed grounds
      for appeal to the Agency within 60 days of receipt of the opinion. Within 60 days of
   . receipt of the grounds for appeal, the Committee shall consider whether its opinion
      should be revised, and the conclusions reached on the appeal shall be annexed to the
   · assessment report referred to in paragraph 5.
S. Within 30 days of its adoption, the Agency shall forward the final opinion of the
      Committee to the Member States, the Commission and the marketing authorization
      holder together with a report describing th~ assessment of the veterinary medicinal
      product and the reasons for its conclusions.
      In the event of an opinion in favo\D" of granting or maintaining an authorization to
     place the veterinary medicinal product concerned on the market, the following
      documents shall be annexed to the opinion:
      (a) a draft summary of the product characteristics, as referred to in Article 14; where
          necessary this will reflect differences in the veterinary conditions pertaining in
          the Member States.·
      (b) any conditions affecting the authorization within the meaning of paragraph 4. ·
                                                      33
 ---pagebreak---                                                     Artlcle3'7
 Within 30 days of receipt of the opinion, the Commission shall prepare a ~ of the · 811851/EEC
 decision to be~ in respect ofth~ application, taldng into ·account Community law.               Art. 22 (1)
                                                                                                 (as amended by
·In the event of a draft decision which enVisages the granting of marketing authorization,. 93/~0/EEC Art 1 (1 0))
 the documents referred to in Article 36 (5), 2nd mbparagraph, (a) and (b) shall be
 annexed.
 Where, exceptionally, the draft decision is not in accordance with the opinion of the
 Agency, the Conimission sball· also apnex a detailed explanation of the reasons for the
 differences.                                            ·
 The draft decision sbal1 be foovard~ to. the Member States and the applicant.
                                                    Artiele38
 1. A final decision on the application sball bf: adopted in accordance with the procedure 81/851/EEC
      laid down in Article 91.                                                                  Art. 22 (2), (3) and (4)
                                                                                                (as amended by
 2. The rules of procedure of the Standing Committee set up by Article 88 shall be 93/40/EEC Art 1(1 0))
      adjusted to take account of the tasks incumbent upon it in accordance with thiS ·(adapted)
      Chapter.
      These adjustments shall involve the following:
           except in cases referred to in the third paragraph of Article 37, the opinion of the
           Standing Committee shall be obtained in. writing,       ·
           each Member State is allowed at least 28 days to forward written observations on
          the draft decision of the Commission,
          each Member State is able to require in writing that the draft decision be
          discussed by the Standing Committee, giving its reasons in detail.
      Where, in the opinion of the Commission, the written observations of a
     Member State raise important new questions of a scientific or technical nature which
     have not been addressed in the opinion of the Agency, the Chairman sball suspend
     the procedure and refer the application back to the Agency for further consideration.
     The provisions necessary for the implementation of this paragraph shall be adopted
     by the Commission in accordance with the procedure laid down in Article 90.
3. A decision as referred to in paragraph 1 shall be addressed to the Member States
     concerned by the matter and communicated to the marketing authorization holder.
     The Member States shall either grant or withdraw marketing authorization, or vary
     the terms of a marketing authorization as necessary to comply With the decision
     within 30 days of its notification. They shall inform the Commission and the Agency
     thereof.                                                                               .
                                                       34
 ---pagebreak---                                                  Artide39
. 1.' Any application.· by' the. marketing authorization holdei to         varY a    malteting   81/851/EEC
       autborization Which bas been granted in accordance with         the provisions of this    Art. 2~
       Chapter shall be submitted to all thf.' Member States which have previously               (as amended by
       authorized the veterinary medicinal product concerned.                                    93/40/EEC Art. 1 ( 10))
                                                                                                 (adapted)
       The · Commission shall, in consultation with. the Agency, adopt appropriate .
       arrangements for the examination of ·variations to the terms of a marketing
       authorization.
       These arrangements shall include a notification. system or administration 'procedures
       concerning minor variations and define precisely the concept of "a minor variation".
       These arrangements shall be adopted by the Commission in the form of an
       implementing regulation in ~ce with the-procedure laid down in Article 89. ·
  2. The procedure laid down in Articles 36, 37 and 38 shall apply by analogy                to
     · variations made to marketing authorizations for products.
                                                 Article 40
  1. Where a Member State .considers that the variation of the terms of a marketing             81/851/EEC
       authorization which has been granted in accordance with the provisions of this           Art. 23a
       Chapter or its suspension or withdrawal is necessary for the protection of human or      (as amended by
       aitimai health or the environment, the Member State concerned shall forthwith            93/40/EEC Art. 1 (10))
       refer the matter to the Agency for the application of the procedures laid down in        (adapted)
       Articles 36, 37 and 38.
  2. Without prejudice to the provisions of Article 35, in exceptional cases, where mgent
       action is essential to protect human or animal health or the environment, until a
       definitive decision is adopted, a Member State may suspend the marketing and the
       use of the veterinary medicinal product concerned on its territory. It shall inform the
       Commission and the other Member States no later than the following working day of
       the reasons for its action.                                                        ·
                                                     3S
 ---pagebreak---                                                Artide41
Articles 39 and 40 shall apply by analogy tO veteriiwy medicinal productS authorized by 81/851/BEC
Member States following an opinion of the Committee given in accordance with Article 4 Art. 23b
of Directive 87f22/EEC before 1 January·t995.              ··                            (as amended by
                                                                                         93/40/EEC Art. 1 (1 0))
                                               Artide4l
1. The Agency shall publish. an annual repOrt on the operation of the procedures laid· 81/85 1/EEC
    doWn in this Chapter and sba1l forward it to the European P.-liament and the Art. 23c
    Council for information.                                         ·                  (as amended by
                                                                                        93/40/EEC Art. 1 (1 0))
2. By 1 January 2001, the Commission shall.publish a detailed review of the operation
    of the procedures laid down in this Chapter and shall propose any amendments
    which may be necessary to improve these procedures.
    The Council shall decide, under the conditions provided for in the Treaty, on the
    Commission proposal within one year of its submission.
                                              ·Artiele43
The provisions of Articles 31 to 38 shall not apply to homeopathic veterinary medicinal 81/851/EEC
products referred to in Article 19 (2).                                                 Art. 22 {5)
                                                                                        {as amended by
                                                                                        93/40/EEC Art. 1 (10))
                                                                                        (adapted)
                                                  36
 ---pagebreak---                                                   TITLE IV
                                 MANUFACTURE AND IMPORTS
                                                   Article 44
 1. · Member Swes shall take all appropriate measures. to ensure that the manufacture of       ·811851/EEC
       veteJinary medicinal products in their tenitory is subject. to the holding of an        Art. 24 (1)
       authorization. This manufacturing authorization shall likewise be required for          (as amended by
       veterinary medicinal products intended for export.                                      90/676/EEC Art..l (14))
                                                                                               (adapted)
                                   .     .                                           '
2. The authorizatiOn refened to in paragraph 1 sball·be requirCd both for total and 81/851/EEC
       partial manufacture _and for the various ·processes of dividing up, packaging or· Art. 24 (2) and (3), 1st
     · presentation.                                                                           subparagraph
                                                                                               (adapted)
       However, sueh authorization shall not be rCqu.ired for preparation, dividing up,
       changes in packaging or presentation where these processes are ~ed out solely for
       the dispensing of retail supply by pharmacists ·in dispensing pharmacies or by
       persons legally authorized in the Member States to c:any out such processes.
3. The authorization referred to in paragraph l shall also be required for imports from
       third countries into a Member State; this Title and Article 83 shall apply to such
 ' impons in the same way as to manufacture.
       Member States shall take all appropriate measures to ensure that veterinary            811851/EEC
       medicinal products brought. into their territory from a third country and destined for Art. 24 (3), 2nd
       another Member State are accompanied by a copy of the authorization refemd to in       subparagraph
       paragraph 1.                                                                           (as amended by
                                                                                              90/676/EEC Art. 1 (15))
                                                   Article45
In order to obtain the manufacturing authorization, the applicant shall meet at least the 81/85 1/EEC
following requirements:                                                                       Art. 25
                                                                                              (adapted)
(a) he shall specify the veterinary medicinal products and pharmaceutical forms which
       are to be manufactured or imported and also the place where they are to be
       manufactured and/or controlled;
(b) he shall have at his disposal, for the manufacture or impon of the above, suitable and
       sufficient premises, technical equipment and control. facilities .complying with the
       legal requirements which the Member State concerned lays down· as regards both
       manufacture and control and the storage of products, in accordance with Article 24;
(c) he shall have at his disposal the services of at least one qualified person within the
       meaning of Article 52.
The applicant shall provide particulars in his application to establish his compliance with
the above requirements.
                                                       37
 ---pagebreak---                                                  Article46
1. The compdent authority 9f the Member ·State sbalf not issue the manufaCuuing 81/85 llEEC
     authorization until. it ~ established the accuracy of the particulars supplied pursuant ·Art. 26
     to Article 45 by means of an inquiry carried out by its representatives. .               (adapted)
2. In order to ensure that the requirements referred tO in Article 45 ·are complied with,
     authorization may be made ·conditional on the ful1ilment ~f certain obligations
     imposed either when authorizatio~ is granted or at a later date.
3. The authorization shall apply only to the premises specified in the application and to
     the veterinary medicinal products and pharmaceutical forms Specified in that
     application.     ·        ·
                                                 Article 47
The Member States shall take all appropriate measures to ensure that the time taken for 81185 1/EEC
the procedure for granting the manufacturing authorization does not exceed 90 days from An. 28 (1)
the day on which the competent authority receives the application.                            (adapted)
                                                 ArticleU
If th~ holder of the manufacturing authorization requests a change in any of the 81/85 1/EEC
particulars referred to in Article 45 (1) (a) and (b), the time taken for the procedure An. 28 (2)
relating to this request shall not exceed 30 days. In exceptional cases, this period of time (adapted)
may be extended to 90 days.
                                                 Article 49
The competent authority of the Member States may require from the applicant further 81/851/EEC
information concerning both the particulars supplied pursuant· to Article 45 and the Art. 28 (3)
qualified person referred to in Article 52; where the competent authority concerned (adapted)
exercises this right, application of the time-limits referred to in Articles 47 and 48 shall
be suspended until the additional data required have been supplied.
                                                     38
 ---pagebreak---                                                       Artlde50 .
· The ~~of a m""nfacturing aUthorization shall at least be obliged to:                             81/85 1/BEC·
                                                                                                   Art. 27 (a) to (e)
. (a) -have at his disposal the services of Staff complying with the legal requireDients (adapted)
        existing in the Member State concerned as iegards ~th manufacture and controls;
· (b) dispOse of tbe. authorized veterinary medicinal products only in accordance with the
        legislation of the Member States conceme!i;
  (c) give prior notice to the competent authority of any changes which he may wish to
       make to any of the particulars supplied pursuant to Article 45; the competent'
       ·authority shall, in any event, be immediately informed if the qualified person referred
        to mArticle 52 is replaced unexpectedly;
  (d) .allow the representatives of the competent authority of the Member State concerned
        access to his premises at any time;                  ·
  (e) enable ·the qualified person referred to in Article 52 to carry out             hiS duties,
        particularly by placing at.bis disposal all the necessary facilities.
  (t) comply with the principles and the guidelines of good manufacturing practice for 811851/EEC
        medicinal products laid down by Community law;                                            Art. 27 (t) ~d (g)
                                                                                                  (as amended by
  (g) keep detailed records of all veterinary medicinal products supplied by him, including 90/676/EEC An. 1 (17))
       samples, in accordance ·with the laws of the countries of destination. The following
        information at least sbaU be recorded in respect of each transaction, whether or not it
        i$ made for payment:
        -   date,
        -   name of the veterinary medicinal product,
            quantity supplied,
       •    name and address of the recipient,
            batch number.
  These records shall be available for inspection by the competent authorities for a period
  of.at least three years.
                                                      Article 51
  The principles and guidelines. of good manufacturing practice for veterinary meqicinal 811851/EEC
  products referred to in Article SO (f) shall be adopted in   the form of a Directive addr~sed Art. 27a
  to the Member States in accordance with the procechu'e laid down in Article 90.                 (as amended by
                                                                                                  90/676/EEC An. 1 {18))
  Detailed guidelines shall be published by the Commission and revised as appropriate to (adapted)
  take account of scientific and teclmical progress.
                                                          39
 ---pagebreak---                                                  Artlde52
1. Member States sbal1 take all appropriate measures to ensure tbat. the holder of the 81/851/EEC
    manufacturing authorization has permanently and continuo~ly at his disposal the Art. 29
    services of·at least one qualiDed person who 1Wfils the conditions laid down in (adapted)
    Article 53 and is responsible, in particular, for carrying out· the duties specified in
   Article SS.                                            ·
2. If he personally fulfils the conditions laid down in· Article 53, the holder of the
    authorization may himself assume the responsibility referred to in paragraph 1.
                                                 Article 53
1. Member States shall ensme tbat the qualified person referred to in Article 52 fulfils 81/851/EEC
   the minimum conditions of qualification set oUt in paragraphs 2 and 3.                    Art. 31 ·
                                                                                             (adapted)
2. The qualified person shall be . in possession of a diploma, certificate or other
    evidence· of formal qualifications awarded on completion of a university course of
    study, or a course recognized as equivalent by the· Member 'State concerned,
    extending over a period of at least four years of theoretical and practical study in one
    of the following scientific disciplines: pharmacy, medicine, veterinary science,
    chemistry, pharmaceutical chemistry and technology, biology.
   However, the minimum duration of the university course may be three and a half
   years where the coW'Se is followed by a period of theoretical and practical training of
   at least one year and includes a training period of at least six months in a pharmacy
   open to the public, corroborated by an examination at university level,
   Where two university or recognized equivalent courses co-exist in a. Member State
   and where one of these extends over four ,years and the other over three years, the
   diploma, certificate or, other evidence of formal qualifications awarded on
   completion of the three-year university course or its recognized equivalent shall be
   -considered to fulfil the condition ·of duration referred to in the first subparagraph.in
   so far as the diplomas, certificates or other evidence of formal qualifications awarded
   on completion of both courses are recognized as equivalent by the State in question.
                                                    40
 ---pagebreak---    The   course  shall include theoretic81 and practical tuition bearing upon at least the 8118SliEEC
   foubwing basic subjects:               · .·                                              Art. 31
                                                                                            (adapted)
        experim.emal physics,
        general andjnorpaic chemistry,
        organic chemistry,
   - "analytical chemistry,
        pbannaceutical chemistry, including analysis of medicinal products,
        general and applied biochemistry (medical) ,
        physiology,
        microbiology,
        pharmacology,
        phar.maceutical technology,
        toxicology,
        pharmacognosy (study of the composition and effects of the active principles of
        natural substances of plant and animal origin).
   Tuition in these subjects should be so balanced as to enable the person concerned to
   fulfil the obligations specified in Article SS.
   In so far as certain diplomas, certificates or other evidence of formal qualifications
   mentioned in this paragraph do not fulfil the criteria laid down above, the competent
   authority of the Member State shall ensure that the person concerned provides
   evidence that he has, in the subjects involved, the knowledge required for the
   man~ and control of veterinary medicinal Products.
3. The qualified person shall have acquired practical experience over~ least two years,
   in one or more undertakings which are authorized manufacturers, in the activities of.
   qualitative analysis of medicinal products, of quantitative analysis of active
   substances and of the testing and checking necessary to ensure the quality of
   veterinary medicinal products.
   The duration of practical experience may be reduced by one year where a university
   course lasts for at least five years and by a year and a half where the course lasts for
   at least six years.
                                                   41
 ---pagebreak---                                                      Artide54
1. A person engaging mthe activities of the person referred to in Article 52 from the 81185 1/EEC
       time of the application of Directive 81/85 1/EEC, but not complyiDg with the.· An. 32
       provisions of Article 53 shall·})e eligJ.ole to continue to engage in those activities in (~ted)
       the State concerned.                                                          ·
2. The · bolder of a diploma, certificate or other evidence of formal qualifications
     ·awarded on completion of a university course • or a course recognized as equi~ent
       by the Member State concerned • in a scientific discipline allowing him to engage. in
  ,. · the. activities of the person referred tO in Article 52. in accordance with the laws of
       that State may - if be began his course prior to 9 October _1981 • be conSidered as
       qualified to cany out in that State. the duties of the person referred to in Article· 52,
       provided that be has previouSly engaged in the following activities for· at least two
       years before before 9 October 1991 . in ·one or more 1mdertakings authorized ·to
       manufactlue: production supervision .and/or qualitative and quantitative analysis of
       active substances, and the neceSS81)' testing and checking under the direct authority
       of a person as refemd to in Article 52 to ensure the quality of veterinary medicinal'
       products.
       If the person concerned has acquired the practical experience referred to in the first
       subparagraph before 9 October 1971, a further one year's practical experience in
       accordance with the Conditions referred to . in the first subparagraph shall · be
       completed by him immediately before be engages in such activities.
                                                        42
 ---pagebreak---                                                      ArtltleSS
 l. · Member States shall take all appropriate measures to ensure that the qualified ~n            81/85 1/EEC
     ·referred to in Article 52 is, without prejudice to his relati~ with the holder          of   Art. 30 (1), 1st and 2nd
      the manufacturing authorizatiOD, . ~ible, in the context of the. procedures                  subparagraphs .
      referred to in Article 56, for ·ensuring that:          ·                                   (adapted) .
      (a) in the case of veterinary medicinal products manufactured within the Member
           State concerned, each batch of veterinary medicinal ·products has been
           manufactured and checked in·compliance with the laws in force in that Member
           State and in accordance with the requirements of the marketing .authorization;
      (b) in the case of veterinary medicinal prOducts coming from third countries, each
           production batch imported has undergone in the importing Member State a full
           qualitative 8D8lys~, a quantitative analysis. of at least all. the active substances
           and all the other tests or checks necessary to ensure the quality of veterinary
           medicinal products in accordance \\ith the ~ments of the marketing
           authorization.
      Batches of veterinary medicinal products which have undergone such controls in a
      Member State shall be exempt from the above controls if they are marketed in
      another Member State, accompanied by the control reports signed by the qualified
      person.
2. In the case of veterinary medicinal products imported from a third country, where 81/851/EEC
      appropriate arrangements have been made by the Community with the exporting Art. 30 (I), 3rd
      country to ensure that the manufacturer of the veterinary medicinal product applies subparagraph
      standards of good manufacturing practice at least .equivalent to those laid down by (as amended by
      the Community and to ensure that the controls referred to under point (b) of the first 93/40/EEC Art. 1 (11))
      subparagraph of paragraph 1 have been carried out in the exporting country, the
      qualified person may be relieved of responsibilil:}' for carrying out those controls.
3. In all cases, and particularly where the veterinary medicinal products are released for 81/851/EEC
      sale, the qualified person shall certify, in a register or equivalent document provided Art. 30 (2)
      for the purpose, that each production batch satisfies the provisions of this Article; the
      said register or equivalent document shall be kept up to date as operations are. carried
      out and shall remain at the disposal of the representatives of the competent authority
      for the period specified in the provisions of the Member State concerned an~ in any
      event, for at least five years.
                                                    Article 56
Member States shall ensure that the obligations of qualified persons referred to in Article 81/85 1/EEC
52 are fulfilled, either by means of appropriate administrative measures or by making Art. 33
such persons subject to a professional code of conduct.
Member States may provide for the temporary suspension of such a person upon the
commencement of administrative or disciplinary proceedings against him for failure to
fulfil his obligations.                                 -
                                                  ·Article 57
The provisions of this Title shall apply to homeopathic veterinary medicinal products.           92n4/EEC
                                                                                                 Art.3·
                                                                                                 (adapted)
                                                       43
 ---pagebreak---                                  .                  TITLEV
                                 LABELLING AND PACKAGE INSERT
                                                    Artiele58
l. The following information, which shall conform with the particulars and documents           81/85 1/EEC
    provided pursuant    to Articles 12 and 13 (1) and be .approved by the competent           Art. 43 (1)
  · authorities, shall ·appear in legible characters on containers and outer packages of
    medicinal products: ·
    (a) Name of the veterinary medicinal product, which may be a brand name or a non- 81/851/EEC
         proprietary name accompanied by a trade mark or the name of the manufacturer, or a Art. 43 (1), points 1 and
         scientific name or foimula, with or without ,a trade mark, or the name of the 2 (as amended by
         manu1Dcturer.                                                                         90/676/EEC Arl1 (23))
                                                                                              .(adapted)
         Where the special name of a medicinal product· containing only one active substance
         is a brand name, this name must be .accompanied in legible characters by the
         international non·propriety name recommended by the World Health Organization,
         where such name exists or, where no such name exists, by the usual non-proprietary
         name.
    (b) A statement of the active substances expressed qualitatively and quantitatively per
         dosage unit or according to the form of administration for a particular volume or
         weight, using the international non-proprietary names recommended by the World
         Health Organization, where such names exist or, where no such names exist, the
         usual non-proprietary names.
    (c) Manufacturer's batch number;                                                          81/851/EEC
                                                                                              Art. 43 (1 ), points 3 to 6
    (d) Marketing authorization number;                                                       (adapted)
    (e) Name or corporate name and permanent address or registered place of business of
         the marketing authorization holder and of the manufacturer, if different;
    (f) The species of animal for which the veterinary medicinal pro9uct is intended; the
         method and route of administration;
    (g) The withdrawal period, even if nil, in the case of veterinary medicinal products      81/851/EEC
         administered to food-producing animals;                                              Art. 43 (1), points 7
                                                                                              and8
    (b) Expiry date, in plain language;                                                       (as amended by
                                                                                              90/676/EEC Art. 1 (23))
                                                                                              (adapted)
    (i) Special storage precautions, if any;                                                  81/851/EEC
                                                                                              Art. 43 (1), point 9
                                                                                              811851/EEC
     (j) Special precautions for disposal of unused medicinal products or waste material from Art. 43 (1 ), point 9a
         medicinal products, if any;                                                          (as amended by
                                                                                              90/676/EEC Art. 1 (23))
                                                                                              (adapted)
                                                       ·44
 ---pagebreak---       (k) Particulars ~to be indicated pursuant to Article 26_ {1), if ~y;                    81/8$1/BEC
                                                                                              Art. 43 {1), points 10
     (I) The wOrds "For animal ~ent only".                                                    andll
2. lbe.pharmaceutical·form and the contents by weight, volume or num~ of dose- 81/851/EEC
    .units need only be shown on the outer package.                                           Art. 42 (2) and (3)
                                                                                              (adapted)
3. The provisions of Pan 1, A of Almex I, in so far as they concern the qualitative and
     quantitative composition of veteriruuy medicinal prpducts in respeCt of active
   . substances, shall apply to the particulars provided for in paragraph 1 (b)..
4. · The pam_'culars mentioned in paragraph 1 (f) to (1) shall appear on the outer package 181/851/EEC
     and on the container of:the medicinal products in the language or languages of the Art. 47
     country in which they. are placed on the market                                         (adapted)
                                                  Article 59
 1. As regards ampoules, the paniculars listed in the first paragraph of Article SS (1)      81/851/EEC
      shall be given on the outer package.· On the containers, .however, only the following  Art. 44
     particulars shall be necessary:                                                ·        (adapted) ·
     ..   name of veterinary medicinal product,
     •    quantity of the.active substances,
     -    routeof~o~
     ..   manufacturer's batch number,
     -    date of expiry,
     •    the words 'For aniinal treatment only'.
2. As regards small single-dose containers, other than ampoules, on which it is 811851/EEC
     impossible to give the particulars mentioned in paragraph 1, the requirements of Art. 45
     Article 58 (1),·(~) and (3}, shall apply only to the outer package.
3. The particulars mentioned in the third and sixth indents of paragraph I shall appear 81/85 1/EEC
     on the outer package and on the container of the medicinal products in the language Art. 47
    or languages of the country in which they are placed on the market
                                                  Article 60
Where there is no outer package, all the particulars which Should feature on such a 81/85 1/EEC
package pursuant to the Articles 58 and 59 shall be shown on the container.                 Art. 46
                                                                                            (adapted)
 ---pagebreak---                                                    Artide61.
. 1. ·The inclusion of a package insert in. the packaging of veterinary medicinal prOducts 81/85 1/EEC
      shall be obligatory unless all the information required by this Article can be Art 48 (1)
      conveyed .on the CODtainer and the eXtemal packaging M~ States shall take all (as amended by
      appropriate measures to ensure that the insert relates solely to the veterinary 90/676/EEC An. 1 (24))
      mediciDal product with which it is included. The .insen shall be in the· official
      langUage or languages of the fdember State in. which the medicinal product is
      marketed.
  2. The package insert shall contain at least the following information, which· shall 81185 1/EEC
      conform to the particulars and documents provided pursuant to Art;icles .12 and Art. 48 (2) (a) to (d)
     · 13 (1) and be approved by the competent authorities:                       ·     ·      (adapted)
      {a) name or corporate name and permanent address or registered place of business
            of the marketing authorization holder and ofthe·manufacturer, if different;
       (b) name of the veterinary. medicinal product and a statement of its active substances
            expressed qualitatively and quantitatively;
            The international non-proprietary names recommended by the World Trade
            Organization shall be used wherever they exist;           ·
       (c) the therapeutic indications;
       (d) contra-indications and adverse reactions in so far as these particulars are
            necessary for the use of the veterinary medicinal product;
       (e) the species of animal for which the veterinary medicinal product is intended, the
            dosage for each species, the method and route of administration and advice on
            correct administration, if necessary;
       (f) the withdrawal period, even if this is nil, in the case of veterinary medicinal    81/851/EEC
          · products administered to food-producing animals;                                  Art. 48 (2) (e)
                                                                                              (as amended by
                                                                                              90/676/EEC An. 1 (25)
                                                                                              (a))
       (g) special storage precautions, if any;                                               81/851/EEC
                                                                                              Art. 48 (2) (t) and (g)
       (h) particulars required to be indicated pW'Suant to Article 26 (1), if any.
       (i) special precB:Utions for the disposal of unused medicinal products or waste        81/851/EEC
            materials from medicinal products, if any;                                        Art- 48 {2) (h)
                                                                                              (as amended by
                                                                                              90/676/EEC An. 1 (25)
                                                                                              (b)).
  3. The particulars referred to in paragraph 2 shall appear in the language or languages 81185 1/EEC
       of the counny in which the produa is marketed. The other infonnation shall be Art. 48 (3)
       clearly separate from such particulars.                                                (adapted)
                                                        46
 ---pagebreak---                                                    Article 62
  Where tbe ps:ovisiollS of this Title are not observed and a formal notice addressed to the .81/IS li£EC
  person conceriaed bas been ineffectual, tbe competent authorities of the Member States Art. 49, 1st paraaraph
  may suspend or withdraw lll81'ketinl authorization
                                                   Artide63
  The requirements of Member states· concerning conditions of supply to the public, the       81/851/EEC
  marldQg of prices on medicinal products for veterinary use and industrial property rights  Art. SO
. shall not be affe~ by the provisions of this Title.
                                                   Artlcle.64
  1. Without prejudice .to paralraph 2, the homeopathic veterinary products shall be 92174/EEC
      identified by the inclusion on their labels, in clearly legible form, of the words Art. 2 (2)
       'homeopathic m.ediciDal· product for veterinary use'.                                 (adapted)
  2. In addition to the clear mention of the words 'homeopathic veterinary medicinal 92174/EEC
      product without approved therapeutic indications', the labelling and, where Art 7 (2)
      appropriate, package insert for the homeopathic veterinary medicinal products (adapted)
      referred to in Article 17 (1) ·shall bear the following information and no other
      information:
      •    the scientific name of the stock or stocks followed by the degree of dilution,
           using the symbols of the pharmacopoeia used in accordance with point 8 of
           Article 1,
      -    name and address of the marketing authorization holder and, where appropriate,
           of the manufacturer,
           method of administration and, if necessary, route,
           expiry date, in clear terms (month, year),
           pharmaceutical ~orm,
           contents of the sales presentation,
           special storage precautions, if any,
      -   target species,
          a. special warning if necessary for the medicinal product,
     ·-   manufacturer's batch number,
      -   registration number.
                                                      47
 ---pagebreak---                                                TITLE VI
                         POSSESSION~ WHOLESALE DISTRIBUTION
            AND DISPENSIN'G OF VETERINARY MEDICIN'AL PRODUCTS
                                                Article 65
1. Member States shall take all appropriate measures to ensure that wholesale                 81/851/EEC
     distribution of ·veterinary medicinal products is subject to the holding of an           Art. 50a (1), 1st
     authorization. and to ensme that the time taken for the procedure for granting this      subparagraph·
     authorization does not exceed 90 days from the date on which the competent               (as amended by
     authority receives the application.             ·                                        90/676/EEC Art. 1 (27))
                                                                                              (adapted)
     Member States may also exclude supplies of small q~tities of veterinary medicinal        81/851/EEC
     products from one retailer to another.                                                   Art. 50a (1), 3rd
                                                                                              subparagraph and {2), {3)
2. · In order to obtain the authorization for· distribution, the applicant shall have at his and{4) ·
     disposal technically competent staff and suitable and sufficient premises comp}ying (as amended by
     with the requirements laid down in the Member State concerned as regards the 90/676/BEC Art. 1 (27))
     storage and handling of veterinary medicinal products.                                  ·(adapted)
3. The holder of the authorization for distribution shall be required to keep detailed
     records. The following minimum· information shall be recorded in respect of each
     incoming or outgoing transaction:                                                 ·
     (a) date;
     (b) precise identity of the veterinary medicinal prod~ct;
     (c) manufacturer's batch number,;
     (d) quantity received or supplied;
     (e) name and address ofthe supplier or recipient.
     At least once a year a detailed audit shall be carried out to compare incoming and
     outgoing medicinal supplies with supplies currently held in stock, any discrepancies
     being recorded.
     These records shall be available for inspection by the competem authorities for· a
     period of at least three years.
4.   Member States shall take all appropriate measures to ensure that wholesalers supply
     veterinary medicinal products only to persons permitted to carry out retail activities
     in accordance with Article 66, or to other persons who are lawfully permitted to
     receive veterinary medicinal products from wholesalers.
                                                     48
 ---pagebreak---                                                Article 66
1. Member States shall take all appropriate measures to ensure that the retail supply of 81/851/EEC
   veterinary medicinal products is conducted only by persons who are permitted to Art. SOb
   c1rry out such operations by the legislation of the Member State concerned.           (as amended by
                                                                                         90/676/EEC Art. 1 (27))
2. Any· person permitted under paragraph 1 to sell veterinary medicinal products shall (adapted)
   be required to keep detailed records. The following information shall be recorded in
   ~.of each incoming or outgoing transaction: ·
   (a) date; ·
   (b) precise identity of the veterinary medicinal product;
   (c) manufacturer's batch number;
   (d) quantity received or supplied;
   (e) name and address of the supplier or recipient;
   (f) where relevant, name and address of the prescribing veterinarian and a copy of
        the prescription.
   At least once a year a detailed audit shall be carried out, and incoming and outgoing
   veterinary medicinal products shall be reconciled with products currently held in
   stock, any discrepancies Qc:ing recorded.
   These records shall be available for inspection by the competent authorities for a
   period of three years.
3. Member States may limit the number of detailed documenting requirements referred
   to in paragraph 2. However, these requirements shall always be applied in case of
   veterinary medicinal products which are intended for administration to food-
   producing animals and which are available only on veterinary prescription or in
   respect of which a withdrawal period must be observed.
4. Not later that I January 1992, Member States shall communicate to the Commission
   a list of the veterinary medicinal products which are available without prescription.
   After having taken note of the communication from the Member States, the
   Commission shall examine whether suitable measures should be proposed for
   drawing up a Community list of such medlcinal products.
                                                   49
 ---pagebreak---                                                      Artide67
Without prejudice· to stricter Community or national rules relating to dispensing 811851/EEC
veterinary medicinal products and to protect human and animal health,. a prescription Art. 4 (3), 3rd
shall be required' for dispensing to the public the following veterinary medicinal products; subparagraph
                                                                                             (as amen~ by
(a) those'products     subject to official restrictions on supply or use, s~ch as:           90/676/EEC  Art. I (4))
        .                               .
                                                                                             (adapted)
          the restrictions resulting from the implementation of the relevant United Nations
          conventions on narcotic and psychotropic sub~ces,                            ·
          the restrictions on the use of veterinary medicmai products resulting from
          Community law;
(b) those products in respect of which special precautions must be taken by the
     veterinarian in order to avoid any unnecessary risk to:
          the target species,
          the person administering the products to the animal,
          the consumer of foodstuffs obtained from the treated animal,
          the environment;
(c) those products intended for treatments or pathological processes which require a
     precise prior diagnosis or the use of which may cause effects which impede or
     interfere with subsequent diagnostic or therape~c measures;
(d) magistral fonnulae intended for animals.
In addition, a prescription shall be required for new veterinary medicinal products
containing an active substance which has been authorized for use in a veterinary
medicinal product for less than five years unless, having regard to the· information and
particulars provided by the applicant, or experience acquired. in the practical use of the
veterinary medicinal product, the competent authorities are satisfied that none of the
criteria referred to in (a) to (d) of the first paragraph apply.
                                                         so
 ---pagebreak---                                                      Article 68
  :1. -··Member.· States shaii ·take ail measures necessazy · to ensure· that only pei-sons   81/851/EEC
         empowered UJider their national legislation ·in for~· possess or have under their    Art. 1 (5)
         control v~.medicina1 products or substances which may be .used as veterinary.        (as amended by
         medicinal products that have anabolic, anti-infectious, anti-parasitic; anti-        90/676/EEC An. I (1 ))
         inflammatoty, honnoJ.ial ~r psychotropic properties~                                 (adapted):
   2. .Member States. shall main~ a register. of manufacturers and dealers permitted· to
         be· in possession .Of· active .substances ·which may be used in the manufacture of
     - veterinary ·medicinal products having the ·properties referred ·to in ·paragraph 1.
         Such persons must jnaintain detailed records of all deaHn~ in subStances which may
         be used in the manufacture. of veterinary medicinal products and keep these records
    ' available for inspection by the competent authorities for a period of at least
         three years.
   3. Any amendments to be made to the list of substances referred to in paragraph 1 shall
         be adopted in accordance with the procedure refetred to in Article 90.
                                                     Article 69
   Member States shall ensure that the owners or keepers of food-producing animals can       811851/EEC
   provide proof of purchase, possession and administration of veterinary medicinal          Art. 50c
   products containing the substances set out in Article 68; Member States may extend the    (as amended by
   scope of this obligation to other veterinary medicinal products.                          90/676/EEC Art. 1 (27))
                                                                                             (adapted)
   In particular, Member States may require the maintenance of a record giving at least the
   following information:
   (a) date;
· (b) name of the veterinary medicinal product;
  (c) quantity;
  (d) name and address of the supplier of the medicinal product;
  (e) identification of the animals treated.
                                                         Sl
 ---pagebreak---                                                 Artide70 ·
Nothwithstand.ing Articles 9 and 67, Member States shall ensure that veterinarians            81/851/EEC
providing services in another Member State can take with them and adm.inister to animals      Art. 4 (S)
 ~ quantities of ready-made veterinary medicinal products not exceeding daily                 (as.amended by
requirements. other than im.nlunological veterinary medicinal products which are not          90/676/EEC Art. I (4))
 authorized for use in the M~ber State in which the ser;vlces are provided (hereinafter:      (~pted)
host Member State), providing that the ·foll9wing conditions ~ satisfied:         · ·      ·
(a) the authorization to place the product on the market provided for in .Articles S, 7 and
      8 has been issued by    the competent authorities of th~ Member State in which      the
     veterinarian is established;                                             ·
(b) the veterinary medicinal products are transported by the veterinarian in the Original
     manufacturer's packaging;                     ·
(c) the veterinary medicinal products intended for administration to food-producing
     animals have the same qualitative and quantitative composition in terms of active
     substances as the medicinal products authorized in accordance with Articles s, 7 and
      8 in the host Member State;
(d) the veterinarian providing services in another Member Stite acquaiiJ.ts himself with
     the good veterinary practices applied in that Member State and ensures that the
   . Withdrawal period specified on the labelling of the veterinary medicinal product
     concerned is complied with, unless he could reasonably be expected to know that a
     longer withdrawal period should be specified to comply with these good veterinary
     practices;
(e) the veterinarian shall not furnish any veterinary medicinal product to the owner or
     keeper of the animals treated in the host Member State unless this is permissible on
     the basis of the rules of the host Member State; in this case he shall, however, supply
     only in relation to animals under his care and only the minimmn quantities of ·
     veterinary medicinal product necessary to complete the treatment of animals
     concerned on that occasion;
(f) the veterinarian shall be required to keep detailed records of the animals treated, the
     diagnosis, the veterinary medicinal products administered, the dosage arlminist~
     the dmation of treatment and the withdrawal period applied. These records shall be
     available for inspection by the competent authorities of the host Member State for a
     period of at least three years;
(g) the overall range and quantity of veterinary medicinal products canied by the
     veterinarian shall not exceed that generally .required for the daily needs of good
     veterinary practice.
                                                    52
 ---pagebreak---                                                   Artiele71
1. · In th~ absence· of ·speCific CommunitY legislation concerning · the use of 90/677/EEC
    iliunuoologicai veteimary mediciDal products for the eradication or cOntrOl of animal Art. 4·
     disease, a Members-. ·may, in ~rdance with its national legislation, prohlbit the (adapted)
    ·man~, import, ·posstsion, sale, supply and/or use of immunological veterinary
     medicinal   Proctucts on the whole or part of its territorY if it is established tbat: ··
     (a) the administration of the product .to axUmalS Will ·interfere ·With ihe .
        . implementation of a uationai programme for the ciiaSnosis, control or eradiction
          of: aniJDal· ·disease, . or will cause difficulties in certifying the ·absence · of.
          Contamination in. live animals or in foodstuffs or other products obtaip.ed from
          treated anjfnals;
     (b) the disease to ·which the product is intended to confer immunity is largely absent
          from the territoty in question.
2. The competerit authorities of the Member States shall inform the Commission of all
     instances in which the provisions of paragraph 1 are applied.
                                                       S3
 ---pagebreak---                                                   TITLE VU
                                       PHARMACOVIGILANCE.
                                                   Article 72
 Member States ·shall take aii apprQpriate measures ·to ·encourage the reporting to the Si/851/EEC
 c~ authorities of Suspected . adverse reactions to the veterinmy mediciDal .Art.42e
products.. .                                                                                  (as amended by
                                                                                              93/40/EEC Art. l {12))
                                                                                              (idapted)
                                                   Artie~73
 in order to ensure the adoption of appropriate regulatory decisions concerning the 81/85 1/EEC
 veterinary medicinal products authorized· withiD the Commui'lity, having regard to Art. 42a ·
 information obtained ab9ut suspected adverse.· r:eacuons to medicinal products        under '(as amended by
normal conditions of use, the Mem~ States ·shall establish a pharmacovigilance system. 93/40/EEC J_\rt. 1 (12))
 This system shall be used to collect information useful in the surveillance of veterinmy.
medicinal products, with particular reference to adverse reactions in animals, and to
 evaluate such information scientifically.                           ·
Such information shall be collated with data on consumption of veterinary medicinal
products.
This system shall also collate information on frequently observed misuse and serious
abuse of veterinmy medicinal products.
                                                  Article 74
The marketing authorization· holder shall have permanently and continuously at his 81/851/EEC
disposal an appropriately qualified person responsible for pharmacovigilance.                Art. 42c
                                                                                             (as amended by
That qualified person shall be responsible for the follo~g:                                  93/40/EEC Art. I (12))
                                                                                             (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,
     including its representatives, is collected and collated at a single point;
(b) the preparation for the competent authorities of the reports referred to in Article 75,
     in such form as    may  be laid down by those authorities, .in accordance with the
     relevant national or Community guidelines;
(c) ensuring that lilY request from the competent authorities for the provision of
     additional information necessary for the evaluation of the benefits and risks afforded
     by a veterinary medicinal product is answered fully and promptly, including the
     provision of information about the volume of sales or prescriptions of the veterinary
     medicinal product concerned
 ---pagebreak---                                                       Articl~ 75
· 1. The marketing aUthorization holder sball be required to record and to report all 8~/851/EEC.
       · suspected. serious . ad~ ·.reactions which are· brought ~ his. attention _to ·the Art.42d
         competent authoritieS immediately, .and in any case~ 15 days. of~eir·i'eceipt at {is amended by
     .   the~              .                       .                                               93/40/EEC Art. 1 (12))
                                                                                                   (adapted) .
  2. . The marketing aluthorization holder. shall be Rquired to maintain detailed records of
     : all other suspected adverse reactions which are reported to him.            ·
         Unless _other requirements·· have been laid down as a condition of the granting of
         authorizatioli. ~ese records .. shall be subuiitted to the competeat authorities
         immec:Uare~ upon request or at· least every six months during the fiist' two years
         following authorization, and once a year for ·the following three years. Thereafter, the
         records· sball be· submitted at five-yearly intervals together with the application for
         renewal of the authorization, or ~ediateJY upon request. These records shall be
         accompanied by a scientific evaluation.                                              ·
                                                     Article 76
  Member States shall ensure that reports of suspected serious adverse reactions are 811851/EEC
  immediately brought to the attention of the Agency and the marketing authorization Art.42f
  holder, and in any case within 15 days of their notification, at the latest.                    (as amended by
                                                                                                  93/40/EEC Art. 1 (12))
                                                                                                  (adapted)
                                                     Article 77
 In order to facilitate the exchange of information about pharmacovigilancc; within the 81/851/EEC
 Community, the Commission, in consultation with the Agency, Member States and An. 42g
  interested parties, shall draw up guidance on the collection, verification and presentation (as amended by
  of adverse reaction reports.                                                                    93/40/EEC Art. 1 (12))
 This guidance shall take account of international harmonization work carried out with
 regard to terminology and classification in the field of pharmacovigilance when use of
 such worlc can be made in the field of the vet&mnaly medicinal product concerned.
                                                         ss
 ---pagebreak---                                                   Article 78
·.1 ~ WbCre as~a reSUlt. ·of the evaluation Qf adverse reaction Je.Potts a c:Ompetem authority ·si!Bsi!EEc .
      ma ··Member State. cousiders .that a ID8Iketii1g. authorization should be Wrled, Arl42h
      suspended ,br withdra~ · it shall -forthwith infOrm the .Agency and the       ~          (as amended by ·. ·
      authOrization holder.                                                                    93/40/EEC Art. 1 (12))
                                                                                               (adapted) .
 2.   In case of urgency,. the toulpetcnt authority ·of a M* State concerned may
      suspend the ID8Iketii1g of. a. veterinary medicinal product,. provided the Agency is
      informed no later than on the first following working day.              ·
                                                  Article 79
 Any amendments which may be necessary to update the provisions of Articles 72 to 78 to 81/85 I!EEC
 take account of scientific and technical progress shall be· adopted in accordance witb.the An. 42i ··
 procedure laid down in Article 90.                                                            (as amended by
                                                                                               93/40/EEC Art. 1 (12))
                                                                                               (adapted)
                                                      S6
 ---pagebreak---                                               TITLEVlll
                               SUPERVISION AND SANCTIONS
                                               Article 80
L The _co.tDpetent authority ~f the Member State concerned shall ensure by means of 81/851/EEC
   repeated inspection that the legal requirements relating to veterinary medicinal M 34, 1st subparagraph
   products are complied:with. ·                                                          · (as amended by
                                                                                             90/676/EEC Art. 1 {19))
   SuCh inspections sball'be cmied out by authorized representatives of the competent 81185 1/EEC
   authoritywho·sballbe empowered to:                                                        Art 34, 2nd
                                                                                             subparagrapb
   (a) inspect manufacturing or trading estabbsbments and any laboratories entrusted (adapted)
        by the holder of the manufacturing authorization,. with the task of carrying out
        control tests pursuant to Article 24;
   (b) take samples;
   (c) examine any documents relating to the object of the inspection, subject to current
        provisions in the Member States from 9 October 1981 which place restrictions
        on these powers with regard to the description of the manufacturing method.
2. Member States shall take all appropriate measures to ensure that the manufacturing 90/677/EEC
   processess used in the manufacture of immunologi~ veterinary medicinal products Art 3 (1)
   are completely validated and batch-to-batch consistency ·is ensured.                     (adapted)
3. The officials representing the competent authority shall report after each of the        811851/EEC
   inspections mentioned in the first paragraph on whether the manufacturer complies        Art. 34, 3rd
   with !he principles and guidelines of good manufacturing practice referred to in         subparagrapb
   Article 5 I. The inspected manufacturer shall be informed of the content of such         (as amended by
   reports.                                                                                 90/676/EEC Art. 1 (19))
                                               Article 81
1. Member States shall take all appropriate measures to ensure that the marketing 81185 I !EEC
   authorization holder and, where appropriate, the holder of the manufacturing Art. 35
   authorization fwnish proof of the control tests carried out on the veterinary medicaf (adapted)
   product and/or on the constituents and intermediate products of the manufacturing
   process, in accordance with the methods laid down for the purposes cf marketing
   authorization.
                                                  ,,
 ---pagebreak--- 2. ·For the puqJOses of_implementing paragraph 1, .Membrer States            ·may reqUire the. 90/671tEEC
      marketing authorization holder for mmiunologiCal veterlnary medicinal· products to Art. 3(2)
    . sobmit to. the competeilt authorities copies of ·all the control reports signed by the .(adapted)
    ."qualified person maccOrdance with Article 55.
      The·~etiug ~rizatioil holder for immlDlological veterinary medicinal proaucts
    _shall ensure that an ad~ ·number _of representative samples. of eaA;h batch of
      veterimuy medical products is held in stock. at least up to the expiry date, and
     provide samples promptly to the competent authorities on request
                                                   Article 82
1; Where it considers it necessary, . a Metn:ber State may require the marketing 90/677/EEC
      authorization holder for immunological products to submit samples from the batches Art. 3 (3)
      of tbe bulk and/or medical product for examination by a State laboratory or .an (adapted)
      approved laboratory before entry into circulation.
      In the case of a batch manufactured in another Member State, examined by ·the
      competent authority of another Member State and declared to be in conformity with
      national specifications, such a control may be canied out only after the control
      reports of the batch in question have been examined, after the Commission has been
      informed, and where the difference in veterinary conditions between the two Member
      States concerned justifies it.
2. Except where the Commission has been informed that a long period is necessary to
      complete the analyses, Member States sball ensure that any such examination is
     completed within 60 days of receipt of the samples. The marketing authorization
     holder shall be notified of the results of the examination within the same time-limit.
3. Before 1 January 1992, the Member States shall notify the Commission of the
      immunological veterinary medicinal products subject to compulsory· official control
     before being placed on the market.
                                                      ss
 ---pagebreak---                                                 .. ·.~~83··.
 -The  Competem auth~rities of the Member States shall suspend or ~draw marketing              '81/85 1/EEC
  ~orization wh~ 1i is clea;r tbat: ·               ·       ·        '          ·              Art. 36
                                                                                               (adapted).
· (a) 1he ~·medicinal product proves to .be harmful .pnder the -conditions of use
      stated at the time of appli~on for authorization or ~bsequently;
  (b) the veteriDaJy medicinal product does not have any therapeutic effect on the specieS
      of animal for which the .treatment ~ intended;
  (e) its qualitative and quantitative eomposition is not as stated;
  (d) the recommended withdrawal period is inadequate to ensure that foodstuffS obtained
      from the treated animal do not contain residues which might constitute a health
      hazard to the consumer;                       ·                                       ·
  (e) the veterinary medicinal product is offered for sale for a use which is prohibited by
      other community provisions.
      However, pending Community rules, the competent authorities may refuse to grant
      authorization for a veterinary medicinal product where such action is necessary for
      tbe protection of public, consumer or animal health;
 (f) the information given in the application documents pursuant to Article 12, 13 (1) and
      27 is incomct;                                               '
 (g) the control tests referred to in Article 81 (I) have ~ot been carried out;
 (h) the obligation referred to in Article 26 (2) has not been twfilled.
 Authorization may also be suspended, or withdrawn where it is established that:
 (a) the particulars supporting the aPPlication, as provided for in Articles 12 and 13 (1),
      have not been amended in accordance with Article 27 (I),
.(b) any new information as referred to in paragraph 3 of Article 27 has not been             (adapted)
      communicated to the competent authorities.
                                                       S9
 ---pagebreak---                                                   Artide~
 1. Witholl_t prejudice .to. Article 83,.Member States ·shall take. all necessary measures to   811851/EEC.
     ensure tbat supply of a veterinary medicinal product is prohibited: and ·that die          Art.·37 {1)
     tnediciDal ~ ~ed is withdrawn form the market, where:
     (a) it is clear that the veteiiQary medicinal product is harmful under the conditions of
          1ase stated ait the time of the application for authorization or subsequently,
       . pursumit to Article 27 (5);               ·           ·         ·         ·
     {b) the. veterinary medicinal     product has DO therapeutic effect. OD the species of
          animal for which the treatment was intended;
     (c). the qualitative and quantitative composition of the veterinaJy medicinal product
          is not as stated;               ·
     (d) the rKOmmended withdrawal ·period is· inadequate to ensure that 'foodstuffs
          obtained from the treated animal do not contain residues which might constitute
          a health hazard to the consumer;
     (e) the control tests referred to in Article 81 (1) have not been canied out, or any (adapted)
          other requirement or obligation relating to the grant of the manufacturing
          authorization referred to in Article 44 (I) has not been complied with.
2. . The competent authority may. confine the prohibition on supply and withdrawal from
     the market solely to the contested production batches.
                                                  Article 85
I.   The competent authority of a Member State shall suspend or withdraw the 81/851/EEC
     manufacturing authorization for a category of preparations or for all preparations if Art. 38
     any of the requirements laid down in Article 45 are no longer met.                        (adapted)
2.   The competent authority of a Member State may, -in addition to the measures
    provided for in Article 84, either suspend manufacture or im~ of veterinary
    medicinal products from third countries or suspend or withdraw the manufacturing
    authorization for a category of preparations or for all preparations in the event of
    non-compliance with the provisions regarding manufacture or imports from third
    countries.
                                                  Article 86
The provisions of this Title shall apply to homeopathic veterinary medicinal products.        92n4/EEC
                                                                                              Art. 4 (1)
                                                                                              (adapted)
                                                 Artide 87
Member States shall. take appropriate measures to encourage veterinarians and other 81/851/EEC
professionals concerned to report to the competent authorities any adverse reaction of Art. 38a
veterinary medicinal products.                     ·                                          (as amended by
                                                                                              90/676/EEC Art. 1 (20))
                                                                                            . (adapted)
                                                      60
 ---pagebreak---                                                .TITLE IX
                                    STANDING .coMMITrEE
                                                Ai1ide88
 1. A Standing Committee on Veterinary Medicinal Pl-oducts for the Adaptation to               811852/EEC
     Technical Progress of the Directives on the Removal of Technical Baniers to Trade        Art. 2b .
     in ·the Veterinary Medicinal Products. Sector, hereinafter called "the Standing          (as amended by .
     Committee", is hereby set up; it sba1l consist of representatives of the Member States    87/20/EEC Art. 1 (1))
     with a ~tative of the Commission a.S· Chairman.                                          (as amended by
                                                                                              93/40/EEC Art. 2)
 2. The Standing Committee shall.adopt its own rules of procedure.                          . (adapted)
                                                Article 89
 Any changes which are necessary in order to adapt Annex I to take account of scientific 81/852/EEC
·and technical progress sball be adopted in accordance with the procedure laid down in Art. 2a
 Article 90.                                                                                  (as amended 87/20/EEC
                                                                                              Art. 1 (1))
                                                                                              (adapted)
                                                    61
 ---pagebreak---                                                  Article9.0
  Where the procedure laid down in thiS Article. is ~.be followed the Commission shall be sv~silEEc
. assisted by _the Standing ~mmi~. .                  ·                                    ·    Art. 42j
                                                                                                (as· amelided by
  the rePresentative -of the·.Commissio~ shall submit to the Standing Committee a draft of. 93/40/EEC Art. 1 {13))
  the IPeasures to be taken. The StandiJig Committee sbal~ deliver its opinion on the draft (adapted)
  within a time-limit which the 'Chairman may lay down _according ~-the· urgency of the
  matter. The opinion shall be delivered by the majority laid do~ in Article 205 (2) of the
  Treaty in the case of decisions which the Council is required to adopt on .a proposal froiJl
  the Conu:nission. The votes of the representatives .of the Member States .within the
  Standing Committee: shall be ·weighted in the manner set out in that Anicle. The
  Chairman shall not vote.
  The Commission shall adopt the measures envisaged if they are in accordance with the
  opinion of the Standing Committee.
  If the measures envisaged are not in accordance with the . opinion of the Standing
  Committee, or if no opinion is delivered, the Commission shall, without delay, submit to
  the Council a proposal ~lating to the measures to be taken. The Council shall. act by a
  qualified majority.
  If on the expiry of a period of three months from the date of referral to the Council, the
  Council has not acted, the proposed measures shall be adopted by the Commission.
                                                 Article 91
  Where the procedure laid down in this Article is to be followed the Commission shall be 81/851/EEC
  assisted by the Standing Committee.                                                          Art.42k
                                                                                               (as amended by
  The representative of the Commission shall submit to the Standing Committee a draft of 93/40/EEC Art. 1 (13))
  the measures to be taken. The Standing Committee shall deliver its opinion on the draft (adapted)
  within a time-limit which the Chairman may lay down according to the urgency of the
  matter. The opinion shall be delivered by the majority laid down in Article 205 (2) of the
  Treaty in the case of decisions which the Council is required to adopt on a proposal from
  the Commission. The votes of the representatives of the Member States within the
  Standing Committee shall be weighted in the manner set out in that Article. The
  Chairman shall not vote.
  The Commission shall adopt the measures envisaged if they are in accordance with the
  opinion of the Standing Committee.                          ·
  If the measures envisaged are not in accordance with the opinion of the Standing
  Committee, or if no opinion is delivered, the Commission shall, without delay, submit to
  the Council a proposal relating to the measures to be taken. The Council shall act by a
  qualified majority.
  If on the expiry of a period of three months from the date of referral to the Council, the
  Council has not acted, the proposed measures shall be adopted by the Commission, save
  where the Council has decided against the said measures by a simple majority.
                                                     62
 ---pagebreak---                                                   TITLEX. ·
                                     . G~ PROy.ISIONS
                                                   Article9l
 Member States ·shall take all measures necessary. to ensure that the competent authorities 81/85 I!EEC
 COii~ communicate . the appropriate· information to each other, in particular regarding . Art. 39
 complian~· with the rCquin:uients adopted for manufacturing authorization, . or for (as amended by
.authorization to place J)roducts on·the mlrket.·                       ·                    90/676/EEC Art: 1 (21))
          ·'                                                                                 (adapted)
 Upon reasoned request, Member States ·shall forthwith communicate the reports referred
 to iD the third ~h of Article 80 (3) to the competent authorities of another Member
 State. If; after. CODSideriDg .the ~ the Member State receiving the repons considers
 that it caDDot acc:ept the conclusions reached by the competent authority of the Member
 State. in which the report was established, it sball inform the competent authorities
 concemed of i1s reasons ·and may request further information. The Member States -
 concerned shall attempt to reach agreement If necessary, in the event of serious
 differences of opinion, one of the M~bcr States concerned shall inform the
 Commission.
                                                   Artiele 93
  I. Each Member State shall take all appropriate measW'eS to ensure that the Agency is 81/85 1/EEC
      informed immediately of. decisions granting marketing authorization .and of all Art. 42
      decisions refusing or withdrawing marketing authorization, cancelling a decision (as amended by
      refusing or withdrawing marketing authorization, prohibiting supply or withdrawing 90/676/EEC Art. 1 (22))
      a product from the market, together with the reasons on which such decisions are (adapted)
      based.
 2. The marketing authorization holder shall be obliged to notify the Member States
      forthwith of any action taken by him to suspend the marketing of a veterinary
      medicinal prOduct or to withdraw a product from the market, together with the
      reasons for such action if it concerns the effectiveness of the veterinary medicinal
      product or the protection of public health. Member States shall ensure that this
      information is brought to the attention of the Agency.
 3. Member States shall ensure that appropriate information about actions tiken pursuant
      to paragraphs 1 and 2 which may affect the protection of health in third countries is
      forthwith brought to the attention of the relevant international organizations, with a
      copy to the Agency.                      ·
                                                  Artiele 94
 Member States shall communicate to eaeh other. all the information necessary to 92!74/EEC
 guarantee the quality and safety· of homeopathic veterinary medicinal products Art. 5
 manufactured and marketed within the Community, and in particular the information
 referred to in Articles 92 and 93.
                                                      63.
 ---pagebreak---                                                    ~de95
 1. · At the mp.aest of rhe DlallU&cturer or exporteJ: of veterinarY blediciDBI produ~ or     81/851/EEC
      the ~orities of an Importing third country, Member. States shall certify ·that such     Art. 24a
      marDJfacturer is in possession of the manUfacturing authOrization. When issuing such.   (as amended by
      certificates, ~einber States shall comp~ with the _following conditio~~$:               90/676/EEC Art. 1 (16))
                                                                                              {adapted)
      (a) ·they shall have regard to the prevailing administrative arrangements of the
           World Health Organization;                             ·
      (b) for veterinary m~cin81         products intended for export which. are already
        · authorized in their territory. they shall supply the summary ot the . product
                                                                              m
           characteristics as approved in accordance with Article 25 or, the absence
           thereof: an equivalent document           ·
2. Where the manufilcturer is not in possession· of an authorization to place the product
      on the market, be shall provide the authorities responsible for. establishing the
      certificate referred to in the first plflgr8ph with a declaration explaining why .such
      authorization is not available.
                                                   Article 96
Any decision set out in this Directive, taken by the competent authorities of the Member 81185 1/EEC
States, shall state the reasons on which it is based. ·                                      Art. 41 and 40
                                                                                             (adapted)
Such a decision shall be notified to the party concerned who shall at the same time be
informed of the remedies available to him under cwrent legislation and the time allowed
for. seeking such remedies.                               ·
Marketing authorizations and revocations of such authorizations shall be published by
each Member State in its o~cial gazette.
                                                   Article 97
The Member States shall not permit foodstuffs. for human consumption to'be taken from        811851/EEC
test animals unless maximum residue limits· have been established by the Community in        Art. 4 (2), 2nd
accordance with the provisions of Regulation (EEC) No 2377/90 and an appropriate             subparagraph
withdrawal period has been established to ensure that this maximum limit will not be         (as amended by
exceeded in the foodstuffs.                                                                  93/40/EEC Art. 1 (2))
                                                                                             (adapted)
                                                       64
 ---pagebreak---                                              .1TILEXI
                                        FINAL MEAsURES
                                               Article 98
     Directives 81/851/EEC,'. 81/852/EEC, 90/677/EEC and 92f74/EEC referred to in
    .Annex n, Part A are repealed, without ptej~ce to the obligations of the Member
  · ·Smtes in respect. of the~~ for transposition laid down_ in Annex n, Pan B. .
     The reference made to the said Repealed Directives shall be construe,d as references
     to this Directive and should be read in accordan~ with the correlation table set out
     in Annex  m.
                                               Article 99
This Directive enters into force on I January 2000.
                                               Article 100
This Directive is addressed to the Member States. ·
Done at Bussels,
For the European Parliament                                       For the Council
The President                                                     The President
                                                   65
 ---pagebreak---                                                     ~I·
                       ·lmQi1iR:EMENTS AND ANALYTICAL PROTOCOL,
                         SAFETY TESTS, PRE-cLINICAL.AND CLINICAL. ·
                   FOR TESTS OF VETERINARY MEDICINAL PRODUCTS
  INTRODUCTION                                                                                   81/852/EEC .
                                                                                                ·Annex
  The particulars and documents accompanying an application for marketing authorization (as amend~ by .
  pmsuant to Articles 12 and 13 (1) shall be presented in accordance with the requirements 92118/EEC Art 1)
  set out in this Annex and taking account of the guidance contained in the 'Notice to (adapted)
  applicants for marketing authorizations for ·veterinary medicinal prochicts in the Member
  States of the European Community', published by the Commission in The rules
  governing medicinal products in the Eur_opean Community, volume V: Veterinllry
  Medicinal Products.
  In assembling the dossier for application for marketing authorization, applicants shall
  take into account the Community guidelines relating to the quality, safety and efficacy of
  veterinary medicinal products published by the Commission in The rules govermng
  medicinal products in the European Community.                                               ·
  All information which is relevant to the evaluation of the medicinal product concerned
  shall be included in the application, whether favourable or unfavourable to the product.
  In particular, .all relevant details shall be given of any incomplete or abandoned test or
·trial relating to the veterinary medicinal product. Moreover, after marketing
 ·authorization, any information not in the original application, pertinent to the benefit/risk
  assessment, shall be submitted forthwith to the competent authority.
  Member States ensure that all experiments on animals are conducted in accordance with
  Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws,
  regulations and administrative provisions of the Member States regarding the protection
  of animals used for experimental and other scientific purposes(l).
· The provisions of Title I of this Annex shall apply to veterinary medicinal products other
  than immunological veterinary medicinal products.
  The provisions of Title 11 of this Annex shall apply to immunological veterinary
  medicinal products.
 UJ   OJL3S8,18.2.1986,p.l.
                                                       66
 ---pagebreak---                                           TITLE I                                            81/852ffiEC
  REQUIREMENTS FOR VETERINARY MEDICiNAL PRODUCTS OTHER THAN                                  Annex
          . IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS                                      (as amended by.
                                                                                             92/18/EEC Art. 1}
                                                                                             (adapted}
PARTl
SUMMARY OF THE DOSSIER
A. ADMINISTRATIVE DATA
The veterinary medicinal product which is the sUbject of the application shall be
identified by name and by name of the active substance(s}, together with the strength and
phannaceutical form, the method and route of administration and a description of the
final saies presentation of the product.      ·                       ·
The name and address of the applicant shall be given, together with the name and address
of the manufacturers and the sites involved in the different stages of the manufilCture
(including_the manufacturer of the finished product and the manufacturer(s) of the active
substance(s)), and where relevant the name and address of the importer.
The applicant shall identify the number and titles of volumes of documentation submitted
in support of the application and indicate what samples, if any, are also provided.
Annexed to the administrative data shall be a document showing that the manufacturer is
authorized to produce the veterinary medicinal products concerned, as defined in Article
42, together with a list of countries in which authorization has been granted, copies of all
the summaries of product characteristics in accordance with Article .14 as approved by
Member States and a list of countries in which an application has been submitted.
B. SUMMARY OF PRODUCT CHARACTERISTICS
The applicant shall propose a summary of the product characteristics, in accordance with
Article 14 of this Directive.     ·
In addition the applicant shall provide one or more specimens or mock-ups of the sales
presentation of the veterinary medicinal prod.uct, together with a package insert where
one is required.
                                                    67
 ---pagebreak---  C. .EXPERT REPORTS                                                                               81/8S21EEC·
              .                                                                               •, AmleX
.In acco~ with Article 15 ·(2) and          (3), ·expert  reports must be provided oli the (as amended by
 analytical doauilen1atioo, the · ptwmacotoxict>logical documentation, the residues 92/18/EEC Art:.l)
.doculnetitation and th~ clinical ~on.                     ·          ·                          "(adapted) .
 Each expert report shall consist of a critical evaluation of the various tests and/or trials
 which have been carried out in accord8nce with this Directive, and bring OUt .U the data
 relevant for. evaluation. 1be expert shall give ·his opinion as to whether sufficient
 gUarantees . have been provi~ as to the· quality, safety and efficacy of the product
 concerned. A ·fadual summary is not sufficient ·
 All importairt data shall be summarized in -an appendix to the expert report, whenever
 possible in tabular or graphic form. The expert report and the summaries shall contain
 precise cross references to the inf~rmation contained in the main documentation.
 Each expert report shall be prepared by a suitably qualified and experienced person. It
 shall be signed and ·dated by the expert, and attached to the report shall be brief
 information about the educational background, training and occupational experience of
 the expert. The professional relationship of the expert to the applicant shall be declared.
                                                     68
 ---pagebreak--- ·PART~.                                                                                       stts52iEEC
                                                                                             .Annex
 ANALYTi~ ~BYSIC().CBEMIC~ BIOLOGIC~                               OR.        .·      · . ·   (as amended by
 MICRQBIOLOGICAL) TESTS OF VETERINARY MEDICINAL PRODUCfS                                      92/18/EEC Art. 1)
 OTHER THAN IMMUNOLOGICAL VETERINARY MEDiCINAL PRODUCTS                                       (adapted) .
 All test ~ ~· comspond to the state of scientific progress ~ the time and
.shall be wlidated procedures; results·ofthe validatiQn studieS shall be provided.
          .
 All the test procedure(s) sbaU be described in sufficiently precise. ~ so as to be ·
 reprodUcible in control ~ canied out at the request of the competent authority; any
 special apparatus and equipment whicp maY be used shall be descnDed in adequate
 detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall
 be supplemented, if necessary, . by the method of preparation. ·In the case of test
 procedures included in tbe European Pharmacopoeia or the pharmacopoeia of a Member
 State, this description may be replaced by a detailed reference to the pharmacopoeia in
 question.
 A. QUALITATIVE AND                  QUANTITATIVE           PARTICULARS          OF    THE
      CONSTITUENTS
 The particulars and documents which must accompany applications for marketing
 authorization, pursuant to Article 12 (3) (c), shall be SlJbmitted in accordance with the
 following requirements.
 1. Qualitative particulars
 'Qualitative particulars' of all the constituents of the medicinal product shall mean the
 designation or description of:
-     the active substance(s),
      the constituent(s) of the excipients, whatever their· nature or the quantity used,
      including colouring matter, preservatives, adjuvants, stabilizers, thickeners,
      emulsifiers, flavouring and aromatic substances, etc,
      the constituents, intended to be ingested or otherwise administered to animals, of the
      outer covering of the medicinal products-capsules, gelatine capsules, etc.
These particulars shall be supplemented by any relevant data concerning the container
and, where appropriate, its manner of closure, together with details of devices with which
the mediciDal product will be used or administered and which will be delivered with the
medicinal produc:t.
                                                     69
 ---pagebreak--- . 2. · The·~- termbiolOiY', to ·be ·used in describing the ·constitueilts. of i:Dedicinai.. · a·l/852/EEC ·
       products,. -Shall mCan. Dotwithstanding the application of the other provisicms of Annex
       Article.l2 (3) (c):           . . ·                •            ·                   · .-         ·       · (as amended by
                  .                              .                                                                  92/18/EECArt. 1)
             in reSpect of substances whim appear in tbe -E~opean Phannacop()eio ·ar,. (adapted)
          · failing this, in the national pbannacopc>eia of one of the Member States, the main
            ·title at the head ·_of the monograph in _question. with reference to the
             pharmaco~ia concerned,
             in respect 9f .otb.ef substances, the international non-proprietary name
           · recommended by the World _Health Oipnization (WHO), which may be
             accompanied by another non-proprietary. name, or, failing these, the ·exact
             scientific designation; substances not having an intemational non-proprietary
             ~ or an ·exact scientific designation shall be descnDed by a statement of how
             and from wbat they were prepared, supplemented, wb~ appropriate, by any
             other relevant details,
             in respect of colouring matter, designation by the 'E' code assigned to them in
             Council Directive 78/25/EEC of 12 December 1977 on the approximation of the
             rules of the Member States concerning the colouring matters authorized for use
             in medici;nal productsu,.
  3. Quantitative particulan
  3.1. In order to give 'quantitative particulars' of all the active substances of the medicinal
  products; it is necessary, depending on the pharmaceutical form concerned, to specify the
  mass, or the number of units of biological activity, either per dosage-~t or per unit of
  mass or volume, of each active substance.
  Units of biological activity shall be used for substances which cannot be defined
  chemically. Where an International Unit of biological activity has been defined by the
  World Health Organization, this shall be used Where no International Unit has been
  defined, the units of biological activity shall be expressed in such a way as to provide
  UJWilbiguous information on the activity of the substances.                                             ·
  Whenever possible, biological activity per units of mass or volume shall be indicated ·
  This information shall be supplemented:                                          ·
       in respect of injectable preparations, by the mass or units of biological activity of
       each active substance in the unit container, taking into account the usable volume of
       th~ product, after reconstitution, where appropriate,              ·
       in respect of medicinal products to be administered by drops, by the mass or units of
       biological activity of each active substance contained in the number of drops
       corresponding to 1 ml or 1 g of the prep~tion,
       in respect of syrups, emulsions, granular preparations and other pharmaceutical
       forms to be administered in measured quantities, by the mass or units of biological
       activity of each active substance per measured quantity. ·
  CIJ  OJ L 11, 14.1.1978, p. 11; Din:ctivc IS liSt IIDCDded by tbe ~-of Accession of Aus1iia, FiDIIDciiDd S'WCdcn.
                                                                  70
 ---pagebreak--- 3..2. Active'.subst8nees ~-m the'fonn of CO~Unds' or derivatives sball be described 81/852/EEC ..
quimtitadvely by their total ~' and if necessmy ·or rel~vant, by the mass of the active Annex
~or entities of the mo~ecule. .                               .                              (as.amended by
                                                                                             92/18/EEC Art. 1)
3.3. For IDCcliciDal pl\lducts containing an active substance which is the ·subject of an. (adapted)
application for ID8I'lcetiDg authorization .in ,any Member State· for the first time, the
·qusmtitarive statement of an active substance which is a salt or hydrate shall bC
Systematically expressed mterms of the mass of the acti~ entity or entities in the
molecule. All subsequently iuthorized medicinal products in the Member States shall
have their quantitative composition stated in the same way for the same active substance.
4. ' Development pharmaceuties
An explanation shall be provided with regard to the choice ofcomposition, constituents
and comainer and the intended function of the excipients in .the finished product. This
explanation shall be supported by scientific data on development pharmaceutics. The
ov~e, with justification thereo( shall be ~
B. DESCRIPTION OF THE MANUFACTURING METHOD
The description of the manufacturing method accompanying the application for
marketing authorization pursuant to Article 12 (3) (d), shall be drafted in such a way as to
give_ an adequate synopsis of the nature of the operations employed.
For this pUrpose it shall include at least:
     mention of the various stages of manufacture, so that an assessment can be made of
     whether the processes employed in producing the pharmaceutical form might have
     produced an adverse change in the constituents,
•   ·in the case of continuous manufacture, full details concerning precautions taken to
     ensure the homogeneity of the finished product,
     the actual manufactUring formula, with the quantitative particulars of all the
     substances used, the quantities of excipients, however, being given in approximate
     terms in so far as the pharmaceutical form makes this necessary; mention shall be
     made of any substances that may disappear in the course of manufacture; any
     overage ~ be indicated and justified,
     a statement of the stages of manufacture at which sampling is carried out for in-
     process control tests, where other data in the documents supporting the application
     show such tests to be necessary for the quality control of the finished product,
     experimental studies validating the manufactwing process, where a non-standard
     method of manufacture is used or where it is critical for the product,
     for sterile products, details of the sterilization processes and/or aseptic procedures
     used.
                                                      71
 ---pagebreak--- C. CONTROL OF STARTING MATERIALS                                                              . 811852/EEC
                                                                                                Aimex
 1. For the purposes of this· paragraph, 'starting -materials' sballmean all the constituents (as amended bY.
of the medicinal product and, if necessary, of its container, as refemd to in Section ~ 92/18/EEC
point 1, ·above.                                                                               Art. 1)
                                                                                               (adapted)
In the case of
      an active substance Qot described in the Elll"opean Pharmacopoeia or in the
      pharmacopoeia of a Member State,
      or
      an active substance described in the Elll"opean ·Pharmacopoeia or in the
      pharmacopoeia of a Member State when prepared by a method liable to leave
    . impurities not mentioned in the pharmacopoeia! monograph· and for which the
      monograph is inappropriate to adequately control its quality,
which is manufactured by a person different from the applicant, the latter may arrange for
the detailed description· of the manufactwing method, quality coD1rOl during manufacture
and process validation to be supplied directly to the competent authorities by the
manufacturer of the active substance. In this case, the manufacturer shall however
provide the applicant with all the data which may be necessary for the latter to take
responsibility for the medicinal product. The manufacturer shall confirm· in writing to the
applicant that he shall ensure batch to batch. consistency and not modify the
manufacturing process or specifications without informing 'the applicant DoCuments and
particulars supporting the application for such a change shall be supplied to the
competent authorities.
The particulars and documents accompanying the application for marketing authorization
pursuant to Article 12 (3) (i) and G) and Article 13 (1), shall include the results of the
tests, including batch analyses particularly for active substances, relating to quality
control of all the constituents used. These shall be submitted in accordance with the
following provisions.
1.1. Starting materials listed in phannacopoeias
The monographs of the European Pharmacopoeia shall be applicable to all substances
appearing in it.
In respect of other substances, each Member State may require observance of its own
national pharmacopoeia with regard to products manufactured in its tenitory.
Constituents fulfilling the requirements of the European Pharmacopoeia or the
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with
Article 12 (3) (i). In this case the description of the analytical methods may be replaced
by a detailed reference to the pharmacopoeia in question.
                                                      72
 ---pagebreak--- Howeva;:; where a Startmg IWiterial. in the Eliropean 'Pharmacopoeia or. in the 81/852/EEC
pharmacopoeia of a Melnber State· has been prepared by a method liable to leave Annex
impurities not ~ntroUed in the pharmacopoeia monograph, .these impmities and their (as amended by
maximum tolerance limits must be declared and a suitable test procedure must be 92/.18/EEC Art. 1)
described.                  .                .                                                (adapted)
Colouring matter      ~      in all cases, ~fy the requirements of Council Directive
78125/EEC.
The routine tests cani~ out on each batch of starting materials must be as stated in the
application for marketing. authorization. If tests other than those mentioned in the
pharmacopoeia are used, proof must be supplied that the starting materials ·meet the
quality requirements of that pharmacopoeia.
In cases where a specmcation contained in a monograph of the ·European
Pharmacopoeia or in the national pharmacopoeia of a Member State might be
insufficient to en.sWe the quality of the substance, the competent authorities may request
more appropriate specifications from the marketing authorization holder.
The competent authorities shall inform the authorities responsible for the pharmacopoeia
in question. The marketing authorization holder shall provide the authorities of that
pharmacopoeia with· the details of the alleged insufficiency and the additional
specifications applied.
In cases where a starting material is described neither in the European Pharmacopoeia
nor in the pharmacopoeia of a Member State, compliance with the monograph of a third
country pharmacopoeia can be accepted; in such cases, the applicant shall submit a copy
of the monograph accompanied where necessary by the validation of the test procedures ·
contained· in the monograph and by a translation where appropriate.
1.2. Starting materials not in a pharmacopoeia
Constituents which are not given in any pharmacopoeia shall be described in the form of
a monograph under the following headings:
(a) the name of the substance, meeting the requirements of Section A point 2, shall be
     suppleme~ted by any trade or scientific synonyms;                                      ·
(b) the definition of the substance, set down ·in a form similar to that used in the
     European Pharmacopoeia,. shall be accompanied by any necessary explanatory
     evidence, especially concerning the molecular structure where appropriate; it must be
     accompanied by an appropriate description of the method of synthesis. Where
     substances can only be described by their manufacturing method, the description
     shall be sufficiently detailed to characterize a substance which is constant both on its
     composition and in its effects;
(c) methods of identification may be described in the form of complete techniques as
     used for production of the substance, and in the form of tests which ought to be
     canied out as a routine matter;
                                                      73
 ---pagebreak--- (cQ  purity tests shall be described· iD relation to the sum total of predictable impurities,                       81/852/EEC
   . especially. those whi~ ·may have a harmful effect, and,. if necessary, those whi~                              Annex
     having regard to the combination of substances to which the application refers, might                          (as imended by--
     adversely affect the stability of the medicinal product or aistort analytical results; · ·                     92/18/EEC Art. 1)
                                                                                                                    (adapted)
(e) with regard to complex substances of plint or. animal origin, a distinction must be
     made between the case· where multiple pharmacological efrects render chemical,
     physical or biological control of the principal components necessary, and the case of
     substances containing one or inore groups of principles having similar activity, in
     respect of which an overall method of assay may be accepted;
(f) when t:naterials of animal origin are used, measures to ensure freedom -from·
     potentially pathogenic agents shall ~ described;
(g) any special precautions that may be necessazy during storage of the starting material
     and, if nec:essary, the maximum period of storage before retesting shall be given.
1.3. Physico-chemical characteristics liable to affect bioavailability
The following items of information concerning active subswices, whether or not listed in
the pharmacopoeias, shall be provided as part of the general description of the active
substances if the ·bio-availability of the medicinal product depends on them:
     crystalline form and solubility coefficients,
     particle size, where appropriate after pulverization,
     state of solvation,
     oiVwater coefficient of partition'1).
The first three indents are not applicable to substances used solely in solution.
2. Where source materials such as micro-organisms, tissues of either plant or animal
origin, cells or fluids (including blood) of human or animal origin or biotechnological
cell constructs are used in the manufacture of veterinary medicinal products, the origin
and history of starting materials shall be descnbed and documented.
The description of the starting material shall include the manufacturing strategy,
purification/inactivation procedures with ·their validation and all in-process control
procedures designed to ensure. the quality, safety and batch to batch consistency of the
finished product
          "
2.1. When cell blnks are used, the cell characteristics shall be shown to have remained
unchanged at the passage level used for the production and beyond
U>   lbe competent authorities may also n:qucst the pK/pH values if they tbiDic that this information is essential.
                                                             74
 ---pagebreak---  2.2~ Seed malmials; cell banks, ·pOols of serum ·am~ other materials of biological-origin 811852/EEC
 ~ Whenever.possible, tbe source materials from which ·they are derived sb8ll be tested Annex
 for ~ous agents..                                                                             (as amended by
                                                                                               92/18/EEC Art. 1)
 If the presalee:· of potentiauy pathogenic· adventitious agents is inevitable, the material (adapted)
.sball be used Only when fUrther processing eDSlRS their elimination and/or inactivation,
 and this shin be validated                                     ·
 D. CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF 1liE
      MANUFAcnJRING PROCESS
 The particulars and documents accompanying an application for marketing authorization,
 pursuant to Article 12 (3) (i) and 0) and also Article 13 ( 1}, shall include particulars
 relating to the product control tests that may be carried out at an intermediate stage of the
 manufacturing process, with a view to enswing the consistency of the technical
 characteristics and the production process.            ·
 These tests are essential for checking the conformity of the medicinal product with the
 formula when, exceptionally, an applicant proposes an analytical method for testing the
 finished product which does not include the assay of all the active substances (or of all
 the excipient components subject to the same requirements as the active substances).
 The same applies where the quality control of the finished product depends on in-process
 control tests, panicularly if the substance is_ essentially defined by its manufacturing
 m~                                                                                   .
 E. TESTS ON THE FINISHED PRODUCT
 1. For the control of the finished product, a batch of a finished product comprises all the
 units of a pharmaceutical form which are made from the same initial quantity of material
 and have undergone the same series of manufacturing and/or sterilization. operations or,
 in the case of a contiJ;luous production process, all the units manufactured in a given
 period of time.
 The application for marketing authorization shall ~ those tests which are carried out
 routinely on each batch of finished product. The frequency of the tests which are not
 carried out routinely shall be stated. Release limits sball be indicated.
 The particulars and documents accompanying the application for marketing authorization
 pW'SUIIlt to Article 12 (3) (i) and (j) and also Article 13 (1), shall include particulars
 relating to conttol tests on the finished product at release. They shall be submitted in
 accordance with the following requirements.
 The provisions of the general monographs of the European .Pharmacopoeia, or failing
that, of a Member State, sball be applicable to all products defined therein.
If test procedures and limits other than those mentioned in the general monographs of the
European Pharmacopoeia, or failing this, in the national pharmacopoeia of a Member
 State, are used, proof shall be supplied that the finished product would, if tested in
accordance with those monographs, meet the quality requirements of that pharmacopoeia
for the pharmaceutical form concerned.
                                                      1S
 ---pagebreak--- 1.1. G,;_;al ~cteristics ~/f!le./inisluuiproduc!                                             &11852/EEC .
                                                                                             Almex
Certain tests of the general. chatacteristics of a product shall always be included among (as amended by
the tests On the finistwf product. These tests shall, wherever applicable, relate to the 92/18/EEC Art. 1)
control of average     masses    and maxirmun deviations, to mechanical, physical or (adapted)          .
~crobiological · tests, otganoleptic characteristics, physical characteristics such as
density, pH, refractive index, etc. For each of these characteristics,· standards and
tolerance limits sball be specified by the applicant in each particular case.      ·
The· conditions of the tests, where appropriate, the equipment/apparatus employed and
the standards shall be described. in precise details whenever they are not given in the
European Pharmacopoeia or the pharmacopoeia of the Member States; the same sball
apply in cases where the methods preScribed by such pharmacopoeias are not applicable.
Furthermore, solid ph.armacCutical forms having to be administered orally shall be
~bjec:ted to in vitro studies on the hOeration and dissolution rate of the active substance
or substances; these studies shall also be carried out where administration is by another
means if the competent authorities of the Member State. concerned consider this
necessary.
 1.2. Identification and as~ay ofactive svbstance(s) ·
Identification and assay of the ·active substance(s) shall be canied out either in a
representative sample from the production batch or in a number of dosage-units analysed
individually.
Unless there is appropriate justification, the maxim'LIQl acceptable deviation in the active
substance content of the finished product shall not exceed :t S% at the time of
manufacture.
 On the basis of the stability tests, the manufacturer must propose and justify maximum
acceptable tolerance limits in the active substance content of the finished product up to
the end of the proposed $elf-life.
In certain exceptional cases of particularly complex mixtures, where assay of active
substances which are very numerous or present in very low amounts would ~ecessitate
an intricate investigation difficult to carry out in respect of each production b~h, the
assay of one or more active substances in the finished product may be omitted, on the
express condition that such assays are made at intermediate stages in the production
process. This relaxation may not be extended to the characterization of the substances
concerned. This simplified ~hnique ~ be supplemented by a meth~ of quantitative
evaluation, enablin'g the competent authority to have the conformity of the medicinal
product with its specification verified after it has been placed on the market
An in vivo or in vitro biological assay shall. ~ obligatory when physico-chemical
methods cannot ·provide adequate information on the quality of the product. Such an
assay shall, whenever possible, include reference materials and statistical analysis
allowing calculation of confidence limits. Where these tests cannot be carried out on the
finished product, they may be performed at an intermediate stage, as late as possible in
the manufacturing process.
                                                      76
 ---pagebreak--- ·Wh• the. particu]ats given in section B ·show tbat a significant overage. of an active          81/852/EEC
 sabstaace js. employed in tJ:ae man~ ·of the medicinal product, the description of              Annex
 the coDtrol tests on·the finish~ produCt sball include, where ~propriate, the· chemical         (as ~ended by
 ancl, ·if n~, the :toxico-pharmacological investigation of the changes that this                92/18/EEC Art. 1)
 substance has undergone, and possibly the characterization and/or assay of the                  (ad8pted)    ·
 degradation products~
 1.3. Ic/eimficalion and asstk)l ofacipient components
 In so far as is necessary, the excipient components shall .be subject at least to
 identification tests.                                   ·                       ·             ·
 The test procedure proposed for identifying colouring matters must enable a verification
 to be made that such matters·appear in the· list annexed to Directive 78125/EEC~
 An upper and lower limit test shall be obligatory in respect of preserving agents and an
 upper limit test for any other excipient component liable to affect adv~ely physiological
 functions; an upper and lower limit test shall be obligatory in reSpect of the excipient if it
 is liable to affect the bio-availability of an active substance, unless bio-availability is
 guaranteed by other appropriate tests.
 1.4. Safety tests
 Apart from the toxico-pharmacological tests submitted with the application for marketing
 authorization, particulars of safety tests, such as sterility, bacterial endotoxin,
 pyrogenicity and local tolerance in animals shall be included in the analytical particulars
 wherever such tests must be undertaken as a matter of routine in order to verify the
 quality of the product.
 F. STABILITYTEST
 The particulars and documents accompanying the application for marketing authorization
 pursuant to Article 12 (3) (t) and (i) shall be submitted in accordance with the following
 requirements.
 A description shall be given of the investigations by which the shelf life, the
 recommended storage conditions and the specifications at the end of the shelf life
 proposed by the applicant have been determined.                                      ·
 In the case of pre-mixes for medicated feedingstuffs, information shall also be given as
 necessary on the shelf life of the medicated feedingstuffs. manufactured from these pre-
 mixes in accordance with the recommended instructions for use.
 Where a finished product requires reconstitution ·prior to administration, details of the
 proposed shelf life for the reconstituted product are require~ supported by relevant
 stability data.
 In the case of multi-dose vials, stability data ~ be presented to justify a shelf life for
 the vial after it has been pun~ for the first time.
                                                      77
 ---pagebreak--- .Where ·a finished product is ~le to give rise to ·degrldanon' products,.               the applicant must       81/852/EEC
 dechR these and indicate characterization methods and test procedureS.                         · ··            'Annex
 ·                                                ·            ·        .          ·                             (as;amendecfby.
 The conclusibus sball contain the results of analyses, justifying the proposed shelf life                       92/18/EEC Art. 1) ·
 \Dlder the recommended storage conditiOJlS and the specifications of the finished product                       (adapted)
 at the end of the shelf ~ of the finished product                 under   these recommended storage
 conditions.
 The maximum acceptabl~ level of degradation products at the end of shelf life shall be
  indicated.
 A study of the interaction between product and container shall be submitted wherever the
 risk of such interaction is regarded as possible~ especially where injectable preparations
·or aerosols for internal use are concerned
 PART3
 SAFETY AND RESIDUES TESTING
 The particularS and documents which shall accompany the application for marketing
 authorization pursuant to Articles 12 (3) G) and 13 (1) shall be submitted in accordance
 with the requirements below.
 Member States shall ensUre that the tests are canied out in accordance with the
 provisions relating to good laboratory practice laid. down by Council Directives
 87118/EEC0 ) and 88/320/EE<:<I).
 A. Safety testing
  CHAPTER I
 PERFORMANCE OF TESTS
  1~ Introduction
 The safety documentation shall show: ·
  1. the potential toxicity of the medicinal product and any dangerous or undesirable
      effects which may occur under the proposed conditions of use in animals; these
      should be evaluated in relation to the severity of' the pathological condition
      concerned;
 2. the potential harmful effects to man of residues of the veterinary medicinal product
      or substance in foodstuffs obtained from treated animals and what difficulties these
      residues may create in the industrial processing ~f foodstuffs;
 3. the potential risks which may result from the exposure of human beings 'to the
      medicinal product, for example during its administration to the animal;
 4. the potential risks for the environment resulting from the use ·of the medicinal
      product.
 (I)  OJ L 15, 17.1.1987, p. 29.
 <l)  OJ L 145, 11.6.1988, p. 3S, Directive u IIIIICDded by Commissioo Directive 90/11/EEC (OJ L·11, 13.1.1990, p. 37).
                                                               78
 ---pagebreak--- All JeSUits shall~be reliable aod valid generally.: Whenever appropriate, mathaiaatical and 81/852/EEC
 statisdc:al ~ sbaJl be used in desigrdng the experimemal. methods and· in                  A.Dnex
 eva1uatiDg :the·· results. AdditioD81ly, clinicians shall be giVen information about the   (as amended by
thapeutic potential oftbe product and about the hazards connected with its use. ·           92/18/EEC Art .1)
     .         .    .           .                                                           (adapted)
 In some cases .it may be neceSsaty to test the. metabolites of the parent compound where
these represeot tbe residues of concern.
AD excipient used in the ·pharmacCutical field for the first time shall be treated like an
 active substance. ·
 2.    Pba.,...~ology
 Pharmacological studies are of fun~ental importance in·clarifying the mechanisms by
which the mediciDal product produces its therapeutic eff~ and therefore
 pharmacological studies conducted· in experimental and target species· of animal should
 be included in Part 4.                                                  ·
 However, pharmacological studies may also ·assist in the understanding of toxicological
 phenomena. Moreover; where a medicinal product produces pharmacological effects in
the absence of a toxic response, or at doses lower than those requ.ired to elicit toxicity,
these pharmacological effects shall be taken into account during the· evaluation of the
safety of ~e medicinal product.                    ·
Therefore the safety documentation shall always be preceded by details of
pharmacological investigations undertaken in laboratory animals and all relevant
information observed during clinical studies in the target animal.
3. Toxicology
3.1. Single-dose toxicity
Single-dose toxicity studies can be used to predict:
       the possible effects of acute overdosage in the target species, ·
       the possible effects of accidental administration to humans,
       the doses which may usefUlly be employed in the repeat dose studies.
Single dose toxicity studies should reveal the acute toxic effects of the substance and the
time course for their onset and remission.
                                                       19
 ---pagebreak---       theSe studies shouid normally ~ carried out in at least two mammalian species. One           81/852/EEC
      manunalian species may ·be rep~· if appropriate, by an animal species for which the          Annex
      medicinal product is intended. At least ~o different routes of administtation should         (as amended by
      ·normally be studied. One of these may be the same as, or similar to, that proposed for the  92/18/EEC Art. 1)
      target species. If substantial exposure of the user of the medicinal product is anticipated, (adapted)
      for example by inhalation or dermal contact, these routes should be studied.
      In order to reduce the number and suffering of the animals involved, new protocols for
      single dose toxicity testing are contiriually being developed. Studies carried out in
      accordance with these new p~dures when properly· validated will be accepted, as well
      as ·studies ·carried out in accordance . with established internationally recognized
      guidelines.
      3.2. Repeated-dose toxicity
      Repeated-dose toxicity tests are intended to reveal any physiological and/or pathological
      changes induced by repeated administration of the active substance or combination of
      active substances under examination, and to determine how these changes are related to
      dosage.
      In the case of substances or medicinal products intended solely for use in non food·
      pl'Qd~cing           a
                  animals, repeated dose toxicity study in one species of experimental animal
      wiU normally be sufficient. This study may be rep!Ked by a studY conducted in the target
      animal. The frequency and route of administration, and the duration of the study should
      be chosen having regard to the proposed conditions of clinical use. The investigator shall
      giv~ his reasons for the extent and duration of the trials and the dosages chosen.
      In the case ·of substances or medicinal products intended for use in food producing
      animals, the study should be conducted in at least two species, one of which should be a
      non-rodent. The investigator shall give his reasons for the choice of species, having
      regard to the available knowledge ofthe metabolism_ of the prodqct in animals and man.
    . The test substance shall be administered orally. The duration of the test shall be at least
      90 days. The investigator shall clearly state and give his reasons for the method and
      frequency of administration and the length of the trials.
      The maximum dose should normally be selected so as to bring harmful effects to light.
      The lowest dose level should not produce any evidence of toxicity.
      Evaluation of the toxic effects shall be based on observation of behaviour, growth,
      haematology and physiological tests, especially those relating to the excretory organs,
      and also on autopsy reports and accompanying histological data. The choice and range of
      each group of tests depends on the species of animal used and the state of scientific
      knowledge at the time.                                                      ·
                                                          80
(6)
 ---pagebreak---  li1 the case' of new                 of
                       combinations mown substanceS which have been investigBted in           81/852/EEC
 &CCQrdance with the provisions of this Directive, the repeated-dose tests may, except        Ann~         ..
where toxicity tests have demonstrated potel;ltiation or novel toxic effects, be .suitably    (as amended by
modified by tbe investigator, ~o sbali submit his reasons for such modifications.             92/18/EEC An. I)
                                                                                              (adapted)
 3.3 •. Tolerance in the target species
Details should· be provided of any signs of intolerance which have been observed dwing ·
 studies conducted in the target species in accordance with the requirements of Part 4,
 Chapter I, Section B. The studies conceined, ·the dosages at which the intolerance
occurred and the species and breeds concerned should be identified. Details ·of any
 unexpected physiological changes should also be provided.
 3.4. Reproductive toxicity including teratogenicily
 3.4.1. Study of the effects on reproduction
 The purpose of this study is to identify possible impairment of male or female
 reproductive function or harmful effects on progeny resulting from the administration of
the medicinal products or substance under investigation.
In the case of substances or medicinal products intended for use in food-prC>Qucing
animals, the study ofthe effects on ~roduction shall be carried out in the form of a two-
generation study on at least one species, usually a rodent The substance or pr~duct under
investigation shall be administered to males and females at an appropriate time prior to
mating. Administration should continue until the. weaning of the .f2 generation. At least
three dose levels shall be used. The maximum dose should be selected so as to bring
harmful effects to light The lowest dose level should not produce any evidence of
toxicity.
Evaluation of the effects on reproduction shall -be based upon fertility, pregnancy and
maternal behaviour; the suckling, growth and development of the Fl offspring from
conception to maturity; the development of the F2 offspring to weaning.·
3.4.2. Study of embryotoxic/fetotoxic effects including teratogenecity
In the case of substances or medicinal products intended for use in food producing
animals, studies of embryotoxic/fetotoxic effects, including teratogelii.city, shall be
carried out These studies shall be carried out in at least two mammalian species, usually
a rodent and the rabbit. The details of the test (number of animals, doses, time at which
administered .and criteria for the evaluation of results) Shall depend on the state of
scientific .knowledge at the time the application is lodged and the level of statistical
significance which the results should attain. The rodent study may be combined with the
study of effects on reproductive functioa
In the case of substances or medicinal products which are not intended for use in food
producing animalst a study of embryotoxic/fetotoxic effects, including teratogenicity,
shall be required in at least one species, which may be the target species, if the product is
intended for use in animals which might be used for breeding.
                                                    81
 ---pagebreak---   3.S. _Mutagenicity :                                                                        81~852/EEC
                                                                                              Ann~
  Mutagenicity ·tests an; inteoded to ·assess the _potential of substances to , cause . (as amended by
. ttansmissible changes in the genetic material of cells.                               -     92/18/EEC Art. .1)
     .           .                                                                            (adapted).
  Any new substance intended for. use in veteriDary ~cinal-products must be as~sed
  for tnutagenic properties.
  The number and types of tests and the criteria for the evaluation of tbe results shall
  depend on the state of scientific knowledge when the application is submitted.
  3.6. Carcinogenicity
  Long term aDimal carcinogenicity studies will usually be required for substances to which
  human beings will be exposed
       which have a close chemical analogy with kno:wn carcinogens,
       which during mutagenicity testing produced results indicating a         ~ssibility  of
       carcinogenic effects,
       which have given rise to suspect signs during toxicity testing.
  The state of scientific knowledge at the time the application is submitted shall be taken
  into account when designing ~arcinogenicity studies and evaluating their results.
  3.7. Exceptions
  Where a medicinal product IS intended for topical use, systemic absorption shall be
  investigated in the target species of animal. If it is proved that systemic absorption is
  negligible, the repeated dose toxicity tests, the tests for reproductive toxicity and the
  carcinogenicity tests may be omitted, unless:
       under the conditions of use laid down, oral ingestion of the medicinal product by the
       animal is to be expected, or
       the medicinal particular may enter foodstuffs obtained from the treated animal
       (intramammary preparations).                    .
                                                      &2
 ---pagebreak---  4. Otlaer reqairellleats                                                                    81/852/EEC
                                                                                            'Annex
 4.1.Jmmunotoxicity                                                                          (as amended by ,
                                                                                             92/18/EEC Art 1)
 ~ere the ~ffects observed. during repeated dose studi~ in anjmals .include specific (adapted)
 changes in lylllphoid ·organ weights and/or histology and changes ·in the cellularity of
 lymphoid tissues, bone marrow or peripheral leukocytes, ·the investigator shall consider·
the need for additioual studies of the effec:ts of the product on the immune system.
 The state of scientific knowledge at the time the application is· submitted shall be taken
 into account when designing such studies and evaluating their results.
4.2. Microbiological properties ofresidues
4.2.1. Potential effects on the human gut flora
 The microbiological risk presented by residucs of anti-microbial compounds for the
human intestinal flora shall be investigated in accordance with the state of scientific
knowledge at the time the application is submitted                                 ·
4.2.2. Potential effects on the microorganisms used for industrial food processing
In certain cases, it may be necessary to carry out tests to· determine whether residues
cause difficulties affecting technological processes in industrial foodstuff processing.
4.3. Observations in humans.
Information shall be provided showing whether the constituents of the veterinary
medicinal product are used as medicinal products in human therapy; if this is so, a report
should be· made on all the effects observed (including adverse reactions) in humans and
on their cause, to the extent that .they may be important for the assessment of the
veterinary medicinal product, where appropriate in the light of trial results of
bibliographical documents; where constituents of-the veterinary medicinal products are
themselves not used or are no longer used as medicinal products in human therapy, the
reaso~ should be stated.
S.   Ecotoxidty
S.l. The purpose of the study of the ecotoxicity of a veterinary medicinal product is to
assess the potential harmful effects which the use of the product may cause to the
environment and to identify iny precautionary measures which may be necessmy to
reduce such risks.
5.2. An assessment of ecotoxicity shall be Compulsory for any application for marketing
authorization for aveterinary medicinal product other than applications submitted in
accordance with Articles 12 (3) G) and 13 (1).
                                                      83
 ---pagebreak--- 5.3. ·This assessment shali nOrmally be conducted in two phases. ,                                          Bi/8S2/EEC
                                                                                                            Annex
In the first phase, the investigator shall assess the potential extent of exposure to ~ (as ·amended by
environment of the product, its active substances or releVant metabolites, taking into 92/18/EEC Art. 1)
accotmt:                                                                                                   (adapted)
     the target species, and the proposed pattern of use (for example, mass-medication or
     individual animal medication),
     the method of administration; in particular the likely extent to which the product will
     enter directly into environmental systems,                         ·
     the possible excretion of the product, its active substances or rel~vant metabolites
     into the environment by treated animals; persistence in such excretia,
     the disposal of unused or waste product
5.4. In a second phase, having regard to the extent of exposme of the product to the
environment, and the available information about the physical/ch~c:al, pharmacological
and/or toxicological properties of the compound which has beeli obtained during the
conduct of the other tests and trials required by this Directive, the investigator shall then
consider whether further specific investigation of the effects of the product on particular
eco-systems is necessary.
S.S. As appropriate, further investigation may be required of:
     fate and behaviour in soil,
     fate and behaviour in water and air,
     effects on aquatic organisms,
     effects on other non-target organisms.
These further investigations shall be carried out in accordance with the test protocols laid
down in Annex V of Council Directive 671548/EEC'1, or where an end point is not.
adequately covered by these protocols, in accordance with other internationally
recognized protocols. The number and types of tests and the criteria for their evaluation
shall depend upon the state of scientific knowledge at the time the application is
subnriued.                                                                      ·
m   OJ L 196, 16.8.1967, p. 1; Direc:tive u last amended by Commission DiRd:ive 98173/EC (OJ L 305, 16.U.1998, p. 1).
                                                             84
 ---pagebreak---  CHAPTER:n                                                                                   811852/EEG
                                                                                             Annex
 PRISENTArJON OF PARTICULARs AND DOCUMENTS                                                   (as amended by
                                                                                             92/18/EEC Art. I)
 As in any scientific work, the dossier of safety tests sball include the following:         (adapted)  .
 (a) an. iiltroduction defining the subject, accompanied by any useful ·bibliographical
      references;
 (b) the detailed identU]cation of the substance under review, including:
      international non-proprietary name ~,
      International Union of Pure and Applied Chemistry Name (IUPAC),
      Chemical Abstrac:t Service (CAS) number,
      therapeutical and pharmacological classification,
      synonyms and abb~viations,
      sttuctural formula, ·
      ~olecular formula,
      molecular weight,
      degree of impurity,
      qualitative and quantitative composition of impwities,
      descrip~on   of physical properties,
     melting point,
     boiling point,
     vapour pressure,
     solubility in water and organic solvents        exp~         in g/1, with indication of
     temperature,                     ·
     density,
    .spectra of refraction, rotation, etc;
{c) a detailed experimental protocol giving the reasons for any omission of certain tests
    'listed above, a description of the methods, apparatus and materials used, details of
     the species, breed or strain of animals, where they were obtained, their number and
     the conditions under which they were housed and fed, stating inter alia whether they
     were free from specific pathogens (SPF);.
                                                     8S
 ---pagebreak---              .                                                                     .  ~
(d) all the results obtained, whether favourable or unfavourable. Th~ original data should 81/852/EEC
     be described in sufficient detail to allow the reSults to be ·ciitically evaluated ·Annex
     independently of their interpretation by the author. By way of explanation, the results (as amended by
     may be accompanied by illustrations;                         ·                           92/18/EEC
                                                                                              (adapted)
(e) a statistical analysis of the results, where such is Called for by the test programme,
     and variance within the data;                  ·
(f) ·an objective discussion of the results obtained, leading to conclusions on the safety
   · of the substance, on its safety margin in· the test animal and the target animal and its
     possible side-effects, on its fields of application, on its active dose levels anq any
     possible incompatibilities;
(g) a deiailed description and a thorough discussion of the results of the study of the
     safety of residues in food, and its relevance for the evaluation of potential risks
     presented by residues to humans. This discussion shall be followed by proposals to
     ensure that any danger to man is eliminated by applying internationally recognized
     assessment criteria, for example: no observed effect level in animals, proposals for a
     choice of safety factor and for acceptable daily intake (ADI);
(h) a thorough discussion of any risks for persons preparing the medicinal product or
     administering it to animals, followed by ,proposals for appropriate measures to
     reduce such risks;
(i) a thorough discussion of the risks which use of the veterinary medicinal product
     under the practical conditions proposed may represent for the environment followed
     by appropriate proposals to reduce such risks;
G)   all information necessary to acquaint the clinician ~ fully ~ possible with the utility
     of the proposed product. The discussion will be supplemented by suggestions as to
     side-effects and possible treannent for acute toxic reactions in animals to which the
     product is to be administ~red;
(k) a concluding expert report which provides a detailed critical analysis of the
     information referred to above in the light of the state of scientific knowledge at the
     time the application is submitted together with a detailed summary of all the results
     of the relevant safety tests and precise bibliographical references.
                                                      86
 ---pagebreak--- a.. Residue testiaa                                                                           ·8l/8S21EEC
                                                                                              Annex        .
CHAPTER I                                                                                     (as amended by
                                                                                              92/18/EEC Art. 1)
PERFORMANCE OF TESTS                                                                          (adapted)
 1. lati'oduetion
For the pmposes of this Directive, 'residues' means all active substances or metabolitcs
thereof which remam in meat or other foodstuffs produced from the animal to which the
medicinal product in question has been administered.
The purpose of studying residues is to determine whether, and if so under what
conditions and to wbat extent, residues persist in foodstuffs produced from treated
animals and to ascertain the withdrawal periods to be adhered to in order to obviate any
hazard to human health and/or difficulties in the industrial processing of foodstuffs.
Assessment of the hazard due to residues entails establishing whether residues are present
in the animals treated under recommended conditions of use and investigating the effects
of those residues.                   ·
In ~e case of veterinary medicinal products intended for use in food-producing animals,
the residue documentation shall show:
1. to what exten~ and how long, do residues of the veterinary medicinal product or its
     metabolitcs persist in the tissues of the treated animal .or ·foodstuffs obtained'
     therefrom;
2.   that in order to prevent any risk to the health of the consumer of foodstuffs of treated
     animals, or difficulties in the indus1rial processing of foodstuffs, it is possible to
     establish realistic withdrawal periods which can be observed under practical farming
     conditions;
3. that practical analytical methods suitable for routine use are available to verify
     compliance with th~. withdrawal period.
2.   Metabolism and rtsidue kinetics
2.1. "Phanna~oldnetics (absorption, distribution, biotransformation, excretion)
The pUrpose of pharmacokinetic studies with respect to residue~ of veterinary medicinal
products is to evaluale the absorption, distribution, biotransformation and excretion of
the product in the target species.
lbe final product, or a formulation which is bioequivalent, shall be administered to the
target species at the maximum recommended dose.
Having regard .to the method of administration, the extent of absorption of the medicinal
!)I'Oduct shall be fully described. If it is demonstrated that systemic absorption of produc~
for topical application is negligible, further residue studies will not be required.
                                                       87
 ---pagebreak---  The distribution of the bledicinal product in the target lliDDal shall be ·de5cribed; the . 81/852/EEC
 possibility of plasma protein binding, or passage ·h1to .. milk or eggs and· of the         Annex
·accumWati~ of lipophilic compoun~ sball be· cousidered.                                     (as amended by
                                                                                            '92/l~C Art.    1)
 The pathways for the excretion of the product from the target animal shall be described.   (adapted)
 The maj~ metabo~ sball be iden~ed and characterized.
 2.2. Depletion ofresidues
 The purposes of these· studies, which measure the rate at which residues deplete in the
 target  animal after the last administration of the medicinal product, is to permit the
 determination of withdrawal periods..           ·
 At varying times after the test animal has received the final dose of the medicinal
 product, the quantities of residues present shall be determined by appropriate physical,
 chemical or biological methods; the· technical procedures and the reliability and
 sensitivity of the methods employed shall be spcc:ified.
 3. Routine analytical method for the detection or residues
 Analytical ·procedures shall be proposed which can be carried out in the course of a
 routine examination and which bave a level of sensitivity such as to enable violations of
 legally 'permitted maximum residue limits to be detected with certainty.
 The analytical method proposed shall be described in detail. It shall be validated and
 shall be sufficiently rugged for use under normal conditions of routine monitoring. for
 residues.
 The following characteristics shall be described:
      specificlty,
 •·   accuracy, including sensitivity,·.
      precision,
      limit of detection,
      limit of quantitation,
 -    practicability and applicability under normal laboratory conditions,
      susceptibility to interference.
 The suitability of the analytical method proposed shall be evaluated in the light of the
 state of scientific and technical knowledge at the time the application is submitted
                                                      88
 ---pagebreak---  CHAPT.ERU                                                                                   811852/EEC
                                                                                             Annex
 PRESENTAnON OF PARnCULARS AND DOCUMENTS                                                     (as amended by
                                                                                             92/18/EEC Art. 1)
.As in any ·scientific work, the dossier of residue tests sbal1 include the following:       (adapted)
 (a) an iiltroduction defining the subject, accompanied by any useful bibliographical
      references;
 (b) a detailed identification of the medicinal, including:
    · composition,
      purity,
      batch identification,
     .relationship to the final product,
      specific activity and radio-purity of labelled substances,
      position of labelled atoms in the molecule;·
 (c) a detailed experimental protocol giving the reasons for any omission of certain tests
      listed above, a description of the methods, apparatus and materials used, details of
      the species, breed or strain of animals, where they were obtained, their number and
      the conditions under which they were housed and fed;
 (d) all the results obtained, whether favourable or unfavourable. The original data should
      be described in sufficient detail to allow the results to be critically evaluated
      independently of their interpretation by the author. The results may be accompanied
      by illustrations;
 (e) a statistical analysiS of the results, where such is called for by the test programme,
      and variance within the data;
 (f) an objective discussion of the results obtained, followed by proposals for maximum
      residue limits for the active substances contained in the product, specifying the
      marker residue and target tissues concerned, and proposals concerning the
      withdrawal periods necessary to ensure that no residues which might constitute a
      hazard for consumers are present ·in foodstuffs obtained from treated animals;
(g) a concluding expert report which provides a detailed critical analysis of the
      information referred to above in the light of the state of scientific knowledge at the
    · time the application is submitted together with a detailed· summary of the results of
      the residue tests and precise bibliographical references.
                                                       89
 ---pagebreak--- PART4                                                                                         81/852/EEC
                                                                                              Annex
PRE-CLINICAL AND CLINICAL TESTING                                                             (as amended by
                                                                                              92/18/.EEC Art. 1)
The ·particulars and documents which shall accompany applications for marketing               (adapted)
authorizations pursuant to Articles 12 (3) (j) and 13 (1) shall be submitted in accordance
with. the. provisions of this Part.
CHAPTER I
PRE-CLINICAL REQUIREMENTS
Pre-clinical studies are required to· establish the pharmacological activity and· the
tolerance of the product.
A. Pharmacology
A.1. PHARMACODYNAMICS
The study of pharmacodynamics shall follow two distinct lines of approach:
First, the mechanism of action and the pharmacological effects on which the
recommended application in practice is based shall be adequately described. The results
shall be expressed in quantitative terms (using, for example, dose-effect curves, time-
effect curves, etc.) and, wherever possible, in comparison with a substance the activity of
which is well known. Where a higher efficacy is being claimed for an active substance,
the difference shall be demonstrated and shown to be statistically significant.
Secondly, the investigator shall give an overall pharmacological assessment of the. active
substance, with special reference to the possibility of side-effects. In general, the main
functions shall be investigated.
The investigator shall identify the effect of the route of adm.inistiation, formulation, etc,
on the pharmacological activity of the active substance.
The investigations shall be intensified where the recommended dose approaches that
liable to produce adverse reactions.
The experimenia.l techniques, unless they are standard procedures, shall be described in
such detail as to allow them to be reproduced, and the investigator shall establish their
validity. The experimental results shall· be set out clearly and, for cenain types of tests,
their statistical significance quoted.                     ·
Unless good reasons are given tO the contrary, any quantitative modification of responses
resulting from repeated administration of the substance shall also be investigated.
                                                                             \
Medicinal combinations may be prompted either on pharmacological grounds or by
clinical indications. In the first case, the pharmacodynamic and/or pharmacokinetic
studies shall demonstrate those interactions which might make the combination itself of
value in clinical use. In the second case, where scientific justification fcir the medicinal
combination is sought through clinical experimentation, the investigation shall determine.
whether the effects expected from the combination can be demonstrated in animals and,
at least, the importance of any adverse reactions shall be checked. If a combination.
includes a· novel active substance, the latter shall have been previously studied in depth.
                                                      90
 ---pagebreak---                                                                                              .81/852/EEC
                                                                                              Annex
Basic pharmacoldnetic information concerning a new active substance is generally useful (as amended by
in the·clinical context.                                                        ·          · 92/18/EEC Art. 1)
                                                                                              {adapted)
Pharmacokinetic objectives can be divided into two main areas:
(i) descriptive pharmacokinetics leading to. the evaluation of basic parameters such as
     body clearance, volume(s) of distribution, mean residence time, etc;
(ii) use or' these parameters to investigate the relationships between dosage regimen,
 · . plasma and tissue concentration and pharmacologic, therapeutic or toxic effects.
In target species, pharmacoldnetic studies are, as a rule, necessary in order to employ
drugs with the greateSt possible efficacy and safety. Such studies arc especially useful to
assist the clinician in establishing dosage regimens (route and site of administration,
dose, dosing interval, number of administrations, etc.) and to adopt dosage regimens
according to certain population variables (e.g. age, disease). Such studies can be more
efficient in number of animals and generally provide more ·information than classical
dose titration studies.                      ·
In the case of new combinations of known substances which have been investigated in
accordance with the provisions of this Directive, pharmacokinetic studies. of the fixed
combination are not required if it can be justified tbat the administration of the active
substances as a fixed combination does not change their pharmacokinetic properties.
A.2.1. Bioavailability/bioequivalence
Appropriate bioavailability studies ·shall be undertaken to establish bioequivalence:
     when comparing a reformulated medicinal product with the existing one, ·
     when comparing a     new method or route of administration with an established one,
     in all cases referred to in Article 13 (1 ).
                                                     91
 ---pagebreak---   B.· Toleraa~.iD the tarcet s~ of uim..                                                       ·81/852/EEC .
                                                                                                AJmex .
  The pmpose of thiS stUdy, which sball be Carried out with all animal $JleCies for ~eh the (as .amended by .
.medicinal product is iDteDded, is to carry out in all such aDimal. species local and geo.eral 92/18/EEC Art. 1)
 tOlerance triaJs· designed to ~lish a tolerated ~e wide enough to allow an adequate .(adapted)
  safety ~ and the ·clinical symptomS of intolerance UsiDg the recommended route -or
          m
 routes, ·so far as this may be ~eved by increasing the therapeutic dose and/or the
 duration Of treatment The report OD the trials shall comain U many deiaiJs ·8S possible of
 the expeded pharmacological effects and the adverse reactions; the latter shall be
  assessed with due regard to the fact~ the Mjmals used may be ~f very high value.
 The medicinal product shall·be administered at least via the recommended route of
 administration.                                                                     ·
 C. Resistaace
 Data OD the emergence of resistant organiSms are necessary .in the case of medicinal.
 products used for the prevention or trealment of iilfectious diseases ·or parasitic
 infestations in animals.                                    ·
 CHAPTERll
 CLINICAL REQUIREMENTS
 1. Geaeral principles
 The pwposes of clinical trials are to demonstrate or substantiate the effect of the
 veterinary medicinal product after administration of the recommended dosage, to specify
 its indications and contra-indications according to species, age, breed and sex, its
 directions for use, any adverse reactions which it may have and its safety and tolerance
 under normal conditions of use.
 Unless justified, clinicai trials shall be carried out with control animals (controlled
 clinical trials). The effect obtained should be compared with a placebo or with absence of
trealment and/or with the effect of an a~oriz.ed mediciDal product known to be of
 therapeutic value. All the results obtained, whether positive or negauve, shall be
 reponed.
 The methods used to make the diagnosis shall be specified. The results shall be set out by
 making use of quantitative or conventional clinical criteria. Adequate statistical methods
 shall be used and justified.
                                                    92
 ---pagebreak--- ID the case of a VeteriDary medicinal ploduct intended primarily for ~-as. a performance Jl/852/EBC .,
~cert particadar. ~~n sball be given tO: ·                         ·                           Annex. .
                                                                                               (as imlend~ by
• the yield of animal produce, '                                                               92/18/EEC Art 1)
                                                                                               (adapted)
      the quality of animal produce (organoleptic, nutritional, hygienic and technological
      qualities), .
• · ·nutiitional.efficienq and growth of animal,
      the general status ofhealth of the animal.
Experimental data shall be confinned by data obtained under ~cal field conditions.
Where, in respect of particular therapeutic indications, the applicant can show tbat he is
unable to provide comprehensive data on therapeutic etfect because:
(a)' the indications for which the medicinal _product in question is intended are
      encountered so rarely that the applicant cannot reasonably be expected to provide
      comprehensive evidence;
(b) in _the present state of scientific knowledge, comprehensive information cannot be
      provided;
the marketing authorization may only be granted subject to the following conditions:
(a) the medicinal product in question is to be supplied on veteriuary prescription only
      and may, in certain cases, be administered only under strict veterinary supervision;
(b) the package insert and any other information must draw the attention of the
      veterinary practitioner to the fact that, in certain specified respects, the particulars
    . available concerning the medicinal product in question are as yet incomplete. ·
2. Performance of trials
All veterinary clinical trials shall be conducted in accordance with a fully considered
detailed trial protocol which shall be recorded in writing prior to commencement of the
trial. The welfare of the trial animals sball be subject to veterinary supervision and shall
be taken fully into consideration during the elaboration· of any trial protocol and
throughout the conduct of the trial.
Pre-established systematic written procedures for the organization, conduct, data
collection, documentation and verification of clinical trials shall be required.
                                                      93
 ---pagebreak---   Before tbe·ccmuDena:mentof any .trial, the info~ consent of the oWner bfthe ;,Jma1s ·:       &1/852/EEC·
  to be ·used  mthe triai slwlbe obu..med and documeiite~ In particular,. the anima(o\vner     Annex
  shall be informed "in Writing of the ccmsequences· of participation in the ,.tri8J for the   (as amended. by.
  sUbsequeDt. dispOsai of treated .animals or fot tbe taldn8 of foodstuffs: from ·treated      92/18/EECArt>1)
  ariimaJs•.A. aJPY of this notification, countersigned and dated by the animal owner, shall   (idapted) · ·
  be included in  the lrial documentation..                                   ·
 ·Unless the trial is conducted with,a blind design, the provisions. ofArticics ss. S6 and S7
  concerning· the labelling of veterinary medicinal products shall apply by analogy to the
  labelling of formulations intended for use in veterinary clinical trials. In· all cases, the
. words 'for veterinary clinical trial use only' siWI appear prominently ~d indehbly     upon
  the labelling.
  CHAPTER ill
  PARTICULARS AND DOCUMENTS
  As in any scientific wo~ the dossier on efficacy shall include. an introduction defining .
  the subject accompanied by any usetw bibliographical documentation.
  All pre-clinical and clinical documentation must be sufficiently detailed to enable an
  objective judgement to be made. All studies and trials must be reported, whether
  favourable or unfavourable to the applicant
  i. Records of pre-cliDical observations
  Wherever possible, particulars shall be given of the results of:
  (a) tests demonstrating pharmacological actions;
  (b) tests demonstrating the pharmacological mechanisms underlying the therapeutic
      ·effect;
  (c) tests demonstrating the main pharmacokinetic processes..
  Should unexpected results occur during the course of the tests, these should be detailed.
                                                      94
 ---pagebreak---                                                                                                8.1/852/EEC
                                                                                               Am:iex .: -.
 (a) aslunmary;                                                                                (as amended by .
                                                                                               92/18/EEC Art. 1)
 (b) a detiiiCd .experim~ protocol giving a description of the methods, apparatus and (adapted)
      'materials used, details such as ·species, age, weight,. sex, number, breed or straiD of
     · animals,  identification of animals, dose,. route and schedule of administration;
                        ·-·
 (c) a staJ:istical analysis· of the results where relev,ant;
 (d) an objective discussion of the results obtained, leading to conclusions on the safety
    . ~ efficacy. of the product.
 Total or partial omission of these data must be explained
 2.1. Records ofclinictll observations
 All the· particulars shall be supplied by each of the investigators on individual record-
 sheets in the case .of individual treatment and collective record-sheets in the case of
 collective treatment
 The particulars supplied shall take the following form:
 (a) name, address, function and qualifications of investigator in charge;
                                                                 I
 (b) place and date. of treatment; name and address of owner of the animals;
 (c) details of the trial protocol giving a description of the methods used, including
       methods of randomization and blinding, details such as the route of administration,
       schedule of administration, the dose, identification of trial animals, ~ies, breeds or
       strains, age, weight, sex, physiological status;                                ·
 (d) method of rearing and feeding, stating the composition of the feed and the nature and
       quantity of any additives contained in the feed;
 (e) case history (as full as possible), occurrence and coW'Se of any inter-current diseases;
 {f) diagnosis and means used to make it;
.(g) Symptoms and severity of the disease, if possible accor~g to conventional criteria;
 (h) the precise identification of the clinical trial formulation Used in the trial;
                                                         95
 ---pagebreak---                                                                            of
 (i) dosage of the medic~ product, method, route'. and hquency adminisiration and                81/852/EEc· ,
      ~oos, ·i:f any, taken~ administration (duration of ~jection, etc~);..                      AnneX.
                                                                                                 (as amended ,by·
 (j) ~tJftteatuient and period of subsequent obsemition;                                         92/18/.EEC Art. 1)
       ,    .                 .                                                                  (adapted)
 (k) all.delailS concerning medicinal products (other thaD that·under study) which have
    . been ~ during the period of examination, either prior to or concmently
      with the teSt_product and, in th~ latter·case, details of the interactions observed;
 0) all results of the clinical~ (including unfavourable oi negative results) with a full
      statement of the .clinical observations and the results of the objective tests of actiVity
      {laboratory analyses, physiological te$),· required to evaluate the application; the
      techniques used must be specified, and the significance of any variations in the
      results explained (for example, variance in method, variance between individuals or
    · the effects of the medication); demonstration of the pharmacodynamic effect in
      animals shall not in itself suffice to justify conclusions concerning any therapeutic
      effect;
.(m) all particulars of any unintended effects, whether harmful or not, and of any measures
      taken in consequence; the cause-and-effect relationship sball be investigated if
      possible;
 (n) effect of animals' performance (for example: egg-laying, milk production and
      reproductive function);
 (o) effects on the quality of foodstuffs obtained from treated animals, particularly in the
      case of medicinal products intended for use as performance enhancers; ·
 (p) a conclusion on each individual case or, where collective treatment is concerned, on
      each collective case.                                  ·
 Omission of one or more items (a) to {p) shall be justified.
 The marketing authorization holder shall make all necessary arrangements to ensure that
 the original documents, which formed the basis of the data supplied, are kept for at least
 five years after the veterinary-medicinal product is no longer authorized..
                                                       96
 ---pagebreak--- 2.2:. SUiflit:iary.and conclusions ofcliliica! observations                                    81/852/EEC
                                                                                               Annex ·
In iespect of eacJi ~linical trial, the clinical observations shall ]?e suminarized in a (as amended by
synopsiS ~~the trials and the results thereof: indicating in ~cular:                 ·       . 92/18/EEC. Ait. I)
                                                                                               (adapted)'
(a)· the .nwnber of coJ11:rOis, the number of animals treated either individually or
    · collectively, with a breakdown according to species, b~ or strain, age and sex;
(b) the number of anjmals withdrawn prematurelY from the trials and the reasons for·
      such wi~drawal;
{c) in the. case of control animals, whether they have:
      received no treatment;
      received a placebo;
      received another authorized medicinal product of known effect;
~     received the active substance. under investigation in a different formulation or by a
      differeJ)t route;
(d) the frequency of observed adverse reactions;
(e) observations as to the effect on perfon;ance (for example, egg-laying, milk
      production, reprOductive function and food quality);
(f) details concerning test animals which may be at increased risk owing to their age,
      their mode of ~ or feeding, or. the pmpose for which they are intended, or
      animals the physiological or pathological condition of which requires special
      consideration;
(g) a statistical evaluation of the results, when this is called for by the test programme.
Finally, the investigator shall·draw general conclusions from the experimental evidence,
expressing his opinion. on the harmlessness of the medicinal product under the proposed
conditions of use, its therapeutic effect and any useful information relating to indications
and contra-indications, dosage and average duration of treatment and where appropriate,
any interactions observed with other medicinal products or feed additives as well as anY,
special precautions to be taken during treatment and the clinical symptoms of
overdosage.
In the case of fixed combination products, the investigator shall also draw conclusions
concerniJlg the safety and the efficacy of the product when compared with the separate
administration of the active substances involved.
3.    Concludin~     expert report
The concluding expert report shall provide a .detailed critical analysis of all the pre-
clinical and. clinical documentation in the light of the state of scientific knowledge at the
time the application is subJ;nitted together with a detailed ·summary of the results of the
tests and trials submitted ~d precise bibliographic references.
                                                      97
 ---pagebreak---                                           TITLED                                            · 81/852/EEC
                                                                                             .Aimex
             REQ~ FORIMMUNOLOGI~ VElERINARY                                                  (as amcilded by
                                 MEPtCINAL PRODUCTS                                          92/18/EEC Art. 1)
                                                                                             (adapteci) .
WithoUt prejudice to the specific reqUirements ·iaid doWn by Community legislation tor
the contrQI and eradication of animal desease; tbefolk>wing ~enf:S sball BJ)ply tb
immunological veterinary medicinal products.
PARTS
SlJMMARY OF 'l'lm·DOSSIER
A. ADMINISTRATIVE DATA
The immunological veterinary medicinal product which is the subject of the application
shall be ·identified by name and by name. of the active substances, together with the
strength and pharmaceutical form, the method and route of administration, and a·
description of the final sales presentation of the product.
The name and address of the applicant shall be given, together with the name and address
of the manufacturer and· the sites involved in the different ·scages of manufacture
(including the manufacturer of the finished product and the manufacturer(s) of the active
substance(s)) and where relevant the name and address .of the importer.
The applicant sball identify the number and tides of volumes of documentation submitted
in support of the application and indicate what samples, if any, are also provided.
Annexed to the administrative data shall be copies of a document showing that the
manufacturer is authorized to produce immunological veterinary medicinal products, as
                                                            .          I
defined in Article 44 (with a brie( description of the production site). Moreover, the list
of organisms bandied at the production site shall be given.
The applicant shall submit a list of countries in which authorization has been granted, .
copies of all the summaries of product characteristics in accordance with Article 14 as
approved by Member States and a list of countries in which an application has been
submitted.                ·                    ·
B. SUMMARY OF PRODUcr CBARACI'ERISTICS
The applicant shall propose a summary of the product characteristics, in accordance with
Article 14.
In addition the applicant shall provide one or more specimens or mock-ups of the sales
presentation of the immunological veterinary medicinal product,. together· with a package
insert, where one is required.
                                                     98
 ---pagebreak--- . All important data shall be summarised in an appendix to the expert report, whenever
  possible in tabular or graphic form. The expert report and the summaries .shall contain
  prec~ cross references to the information containc;d in the main documentation.
  Each expert report sball be prepared by ·a suitably qualified and experienced ·person. It
  shall be signed and dated by tbe expert, ,and attached to the report shall be brief
  information about the ed~onal background, training and occupational experience of
  the expert. The professional relationship of the expert to the applicant shall be declared.
  PART6
  ANALYTICAL (PHYSICo-cHEMICAL, BIOLOGICAL OR
  MICROBIOLOGICAL) TESTS OF IMMUNOLOGICAL .VETERINARY
  MEDICINAL PRODUCfS
  All test procedures used shall correspond to the state of scientific progress at the time and
  shall be validated procedures; results of the validation studies shall be proVided.
  All the test procedure(s) shall be described in sufficiently precise detail so as to be
  reproducible in control tests, carried out at the request of the competent authority; any
  special apparatus and equipment which may be used shall be described in adequate
  detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall
  be supplemente~ if necessary, by the manufacturing method. In the case of test
  procedures included in the European Pharlnllcopoeia or the pharmacopoeia of a Member
  State, this description may be replaced by a detailed reference to the pharmacopoeia in
  question.
                                                       99
 ---pagebreak---   A. QUALITATIVE· AND · QUANTITATIVE                           PARTI~              . OF   THE 81/852/EEC
       CONSTITUENTS                                                                               Annex
                                                                                                  (as amended by
  The    Particulars  and . documents which . must accOmpany applications for marketing 92/18/EEC Art. I)
  authorization, pursuant to. Article 12 (3) {c), shall be submitted in accordance· with the (adapted)
  following requirements.                        ·
  1. Qualitative partieulan
  '·Qualitative particulars' of all the constituents of the· immunological veterinary medicinal ·
  product shall mean the designation or description of:
       the active substance(s),
       the constituents of the adjuvants,
       the constituent(s) of the excipients, whatever their nat\U'e or the quantity used,
       including preservatives, stabilizers, emulsifiers, colouring matter, flavouring,
       aromatic substances, markers, etc.,
       the constituents of the phannaceutical form administered to animals.
  These particulars shall be supplemented by any relevant data concerning ~e container
· and, where appropriate, its manner of cloSW'e, together with details of devices with
  which the immunological veterinary medicinal product will be used or administered and
  which will be delivered with the medicinal product.
  2. The 'usual terminology', to be used in describing the constituents of immunological
  veterinary medicinal products, shall mean, notwithstanding the application of the other
  provisions of Article 12 (3) (c):
       in respect of substances which appear in the European Pharmacopoeia or, failing
       this, in the national pharmacopoeia of one of the Member States, the main title of the
       monograph in question, which will be obligatory for all such substances, with
       reference to the phannacopoeia concerned,
       in respect of other substances, the international non-proprietary name recommended
       by the World Health Organization, which may be accompanied· by another non-
       proprietary name or, failing these, the exact scientific designation; substances not
      having an international non-proprietary name or an exact scientific designation shall
       be described. by a statement of how and from ·what they were prepared,
      supplemented, where cq)propriate, by any other relevant details,
      in respect of colouring matter, designation by the 'E' code assigned to them in
      Directive 78/25/EEC.
                                                         100
 ---pagebreak---  3. ·Qaatitative particulars . ·                                                                 811852/EEC .
                                                                                                 Annex
.ID older ..to    give.· dle 'quantitative particUlars• of the activ~ subS.ces of· an (as amended by
 immunological veterinary medicinal product, it is necessary to specify whenever possible 92/1.81EEC Art. 1)
the number.     of   organisms, the specific proteiD content, the mass, the number of (adapted)
 lntemational Units ·(IU) or units· of biological activity,· either per ~sage-unit or volume,
 and with regard to the adjuvant and to the constituents of the eicipients, .the mass or the
 volume of each of them, with due allowance for the details provided in section B.            ·
 Where an International Unit of biological activity has been· defined, this sbaU be used. .
 The units of biological activity for which no pUblished data exist shaD ·be expressed in
 such a way as io provide unambiguous information on the activity of the ingredients, e.g.
 by :StatiJig the immunological ·effect on which the method of determining the dose is
 based..,          . .                   .
 4.   Development pharmaceutics
 An explanation ·sbaU be provided with regard to t"Qe composition, components and
 containers, supported by scientific data on development pharmaceutics. ~ overage,
 with justification thereof: sball be stated.. The efli:cacy of any preservative system shall be
 dem9nstrated.                                                                     .
 B. DESCRIPTION OF MANUFACI'URING MEmOD OF THE FINISHED
     PRODUCf
The description of the manufacturing method accompanying the application for
marketm.g authorization pursuant to Article 12 (3) (d), shall be drafted in such a way as to
give an adequate description of the nature of the operations employed.
For this purpose the description shall include at least:
     the various stages of manufacture (including ·purification procedures) so that an
     assessment can be made of the reproducibility of the manufacturing procedure and of
     the risks of adverse effects on the finished prod~cts, such as microbiological
     contamination,
     in the case of continuous manufacture, full details concerning precautions taken to
     ensure the homogeneity and consistency of each batch ~f the finished product,
     mention of substances which cannot be recovered in the course of manufacture,
     the details of the blending, with the quantitative particulars of all ~e substances used,
     a statement of the stage of manufacture at which sampling is carried out for in-
     process control tests.                            ·
                                                         101
 ---pagebreak---  C. .PRODUCTION AND CONTROL OF STARTJNG.Ml\TERIALS .                                          811852/EEC
                                                                                             .Annex
 For ·the purposes of this paragraph 'stBrting materials' means all components Used. in the (as -.nended by
 production of the immunological veterinary medicinal prodilCt. Culture media- used for 92/18/EEC Art. .I)
 the: production
         .
                  of the active substance.are
                                .    .  ..    considered as .·one single s1artiJlg
                                                                             ..
                                                                                   material.  (adapted) .
 ln~eca5eof
       ~ active.· substance not ·describCd in the European Pharmacopoeia or in the
       pharmacopoeia of a Member State,
       or
 .-    an active substance described in the European Pharmacopoeia or in the
       pharmacopoeia of a Member State when prepared_ by a method liable to leave
       impurities not mentioned in the pharmacopoeial monograph. and for which the
       monograph is inappropnate to adequately control its quality,
 which is manu&ctured by a person different from the applicant, the latter may mange for
 the detailed description of the manufacturing method, quality control during manufacture
  and process validation to be supplied directly to· the ~mpetent authorities by the
 manufacturer of t11e active substance. In this case, the manufacturer · shall however
 provide the applicant with all the data which may be necessary for the latter to take
 responsibility for the medicinal product. The manufacturer shall confirm in writing to the
 applicant .that he slW1 ensure batch-to-batch . consistency and not modify the
 manufacturing process or specifications without informing the applicant Documents and
 particulars supporting .the application for such a change shall be supplied to the
 competent authorities.                     ·
 The particulars and documents accompanying the application for marketing authorization
 pursuant to·Article 12 (3) (i) and 0) and Article 13 (1) shall include the results of the
 tests relating to quality control of all the components "USed and shall be submitted in
 accordanc~ with the following provisions.
 1. Starting materials listed in pharmacopoeias
 The monographs of the European Pharmacopoeia shall be applicable to all substances
.appearing in it
 In respect of other substances, each Member State may require observance of its own
 national pharmacopoeia with regard to products manufactured in jts territory.
 Components ful.tilling the requim;nents of the European Pharmacopoeia or the
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with
 Article 12 (3) (i). In this case the description of the analytical methods may be replaced
 by a detailed reference to the pharmacopoeia in question.          ·
                                                      102
 ---pagebreak---  Reference ·to  pharmacopoeia~. of third ~untries may be permitted in cases ~ere the 81/852/EEC
 substan~ is described neither m the··Eurapean ·Pharmacopoeia. nor in the national            Annex,
 p~ia concerned; in .that ~ the monograph shall be sUbmitted, acconipanied                    (as amended ~Y
 where·necessary by a tranSlation for whi~h the applicant Win be responsibl~.                 92/18/EEC Art. 1)
                                                                                              (adapted) .
 Colouring matter shall, in all· cases, satisfy the requirements· of Council Directive
 78/25/EEC.                                                                                 .
 The routine tests  caniea  out on each batch of starting materials must be as stated in the
·application for mirketing author.izaiion. If tests o~ than those mentioned in the
 pharmacopoeia are used, proof must be .supplied that the starting materials meet. the
 quality requirements oftbat pharmacopoeia.           · ·
 In cases  Wtiere a specification or other provisions contained in a monograph of the'
 European Pharmacopoeia or in the national pharmacopoeia of a Member State might be
 insufficient to ensure the quality of the substance, th~ competent authorities may request
 more appropriate specifications from the marketing authorization holder.
 The competent authorities shall inform the authoriti~ reSponsible for the pharmacopoeia
 in question.· The marekting auth9rization holder shall provide the authorities of that
 pharmacopoeia With the details of the alleged insutliciency and the additional
 specifications applied.
 In cases where a starting material is described neither in the .European Pharmacopoeia
 nor in the pharmacopoeia of a Member State, compliance with the monograph of a third
 country pharmac:opoeia can be accepted; in such ~s, the applicant shall submit a copy
 of the monograph accompanied where necessary by the validation of the test procedures
 contained in the monograph and by a translation ·where appropriate. For active
 ingredients, demonstration of the ability of the monograph adequately to control their
 quality shall be presented.
 l. Starting materials not listed in a pharmacopoeia
2.1. Starting materials ofbiological origin
 The description shall be given in the form of a monograph. ·
 Whenever possible, Vaccine production shall be based on a seed lot system and on
 established cell banks. For the production of immunological veterinary medicinal
 products consisting of serums, the origin, general health and immunological status of the
producing animals shall be indicated; defined pools of source materials shall be used.
The origin and history of starting materials shall be described .and documented. For
genetically engineered starting materials this information shall include details such as the
description of the starting cells or strains, the construction ·of the expression vector
(name, origin, function of the replicon, promoter enhancer and other regulator elements),
control ofthe,sequence of DNA or RNA effectively inserted, oligonucleotid.ic sequences
of plasmid vector in cells, plasmid used .for cotransfection, added or deleted genes,
biological properties of the final construct and the genes expressed, copy number and
gen~c stability.
                                                    103
 ---pagebreak--- Seed .materials, mcluding, Cell binks and raw serum for anti~serum production shall be Jl/852/EEC
tested f~ identity ~d adventitious agents. ·                                                    Annex
                                                                                                (as amended by
Information sball be provided OD all substances of biologiCal origin used at any stage in 92/18/EEC Art. 1)
the manufacturing procedure.
                      .
                                  The information- shall include:                               {adapted)
      details.ofthe source of the materials,
      details of any processing,· purifi~on and inactivation applied, With data on the
      validation of these process and in-process controls, ·
      details of any tests for contamination canicd out..on each batch of the sUbstance.
If the presence of adventitious agents is detected or suspected, tb:e corresponding material
shall be discarded ·or. used in very exceptional circumstances only when further
processing of the produCt ensilres their elimination and/or inactivation; elimination and/or
inactivation of such adventitious agents shall be demonstrated
When cell banks are used, the cell characteristics shall be shown to have remained
unchanged up to the highest passage level used for the production.
For live attenuated vaccines, proof of the stability of the attenuation characteristics of the
seed has to be given.
When required, samples of the biological starting material or reagents used in the testing
procedures shall be provided to enable the competent authority to arrange for check tests
to be carried out.
2.2. Starting materials ofnon-biological or.igin
The description shall be given in th~ form of a rqonograph under the following headings:
      the name of the starting material meeting the requirements of point 2 of Section A
    · shall be supplement~ by any trade or scientific synonyms,
      the description of the starting material, set down in a form similar to that used in a
      descriptive item mthe European Pharmacopoeia,
      the function of the starting material,
      methods of identification,
      purity shall be described in relation to the sum total of predictable impurities,
      especially those which may have a harmful effect and, if necessary, those which,
      having regard to the. combination of substances to which the application ref~ may
      adversely effect the stability of the medicinal product or distort analytical. results. A
      brief description shall be provided of the tests undertaken to establish the pmity of
      each batch of the starting material,
                                                     104
 ---pagebreak---       any· special Precautious ·which may ~ necessary .during storage· of the SWting S·118S21EEC
      ~ and,. ifnecessary, its storQe life shall be given.                                ·      Annex
                                                                                                 (is amended by
D. CONTRO~. TESTS DURING ~RODUCI'ION                                                             92/18/EEC Art. 1)
                                                                                                 (adapted)
 1. The particulars' and documents accompanying · an application for marketing
      authorization, ·pursuant to Article 12 (3) (i) and (j) and Article 13. (1 ), shall include
      particulars ~lating to the controJ tests which are. canied out on intermediate products
      with a view ta verifying the consistency of the production process and the final
   .~                                                                        '
2. For inactivated or detoxified vaccines, inactivation or detoxification shall be tested
      during each production run .immediately~ after the inactivation or detoxification
      process.
E. CONTROL TESTS ON THE FINISHED PRODUCI'
The particulars and documents acCompanying the application for marketing authorization
 pursuant to Article 12 (3) (i) and (j) and Article 13 (1), shall include particulars relating
to control tests on the finished product. Where appropriate monographs .exist, if
test procedures and limits other than those mentioned in the monographs of the
Emopean PharmaCopoeia, or failing this, in the national pharmacopoeia of a Member
State, are used, proof must be supplied that the finished product would, if tested in
accordance with those monographs, meet the quality requirements of that pharmacopoeia
for the pharmaceutical form concerned. The application for marketing authorization shall
list those tests which are. carried out on representative samples of each batch of finished
produ~ The frequency of the teSts which are not carried out on each batch shall be
stated. Release limits shall be indicated.
1. General characteristics of the finished product
Certain tests of the gene~ characteristics of a product shall be included among the tests
on the finished product, even if they have been carried out in the course of the
manufacturing process.
These tests shall, wherever applicable, relate to the control of average masses and
maximum deviations, to mechanical, physical, chemical or microbiological tests, physical
characteristics such· as density, pH, refractive index, etc. For each of these characteristics,
specifications, with appropriate confidence limits, shall be established by the applicant in
each particular case.
2. Identification and assay of active substance(s)
For all tests, the description of the techniques for analyzing the finished product shall be
set out in s~ciently precise detail, so that they  can  be reprodu~d readily.
The assay of biological activity of the active substance(s) shall be carried out either in a
representative sample from the production batch or in a number of dosage-units analysed
individually.
                                                      10S
 ---pagebreak---  Wh~:nccessacy, a specific test for identification sliall also be ·canied o~                    81/852/EEC
                                                                                                Annex
 ~ certain exCCJrti:onal cases where assay of active· substances which are very numerous or (as amended by
 present in very low. ampunts would necessitate an. ~cate investigation difficult to cany._ 92/18/EEC Art. 1) .
.out in respect of each pociuctioh batch, the assay of one or more active substances· in. the (adapted)
 finished product may ·be omitied, OQ the express condition tb8t SUCh assays are made at
 intermediate stages as late as possible in the production process. This relaxation may not
 be extended to the chara:cterization of the .substanCes concerned. This simplified
 technique shall be supplemented by a method of quantitative ~evaluation,· enabling the
 com~t. authority to verify that the immunological veterinary medicinal product iS in
 accordance with ~ts formula after it has been placed on the market
 3. ldentifieation
                 .
                      and assay of adjuvaats
                                          ~
 In so far as testing Pr-ocedures are available, the quantity and natw:e of the adjuvant and
 its components shall be verified on the finished product.
 4: Identification and assay of excipient components
 In so far as is necessary, the excipient(s) shall be subject at least to identification tests.
 The test procedure proposed for identifying coloming matters must enable a verification
 to be made that such matters are permitted under Directive 78/25/EEC.
 An upper and lower limit. test shall be obligatory in respect of preserving agents; an upper
 limit test for any other excipient components liable to give rise to an adverse reaction
 shall be obligatory.
 5. Safety tests
 Apart from the results of tests submitted in accordance with Part 7 of this Annex,
·particulars of safety tests shall be submitted. These tests shall preferably be overdosage
 studies carried out in at least ·one of the most sensitivcr target species and by at least the
 recommended route of administration posing the· greatest risk.
 6. Sterility and purity test
 Appropriate tests to demonstrate the absence of contamination by adventitious agents or
 other substances shall be carried out according to the nature- of the immunological
 veterinary medicinal product, the method and the conditions of manufacture.
                                                       106
 ---pagebreak---  -7. IDactivaUOD                                                                              :81/852/EEC
                                                                                               Annex
  Where ·.ppncable~ a test to verify iDadivation sball ~ carried_ out on the product in the (as amended by '
  final ~er.                                                                 ·                 9Z/.t81£EC An. 1)
                                                                                               (adapted)
  ~ Residual hllllli~
  Each batch of lyophilized ~et sball-~ tested for residual hilmi~ _. ·
  9. Bateh-•bateh .eoaslsteney
  In order to eusure that efficacy of the product is reproduCible from batch to batch and to
  demonstrate conformity with specifications, potency tests based upon in vitro or in vivo
  ~~;~ethods, including appropriate .reference materials whenever available, shall be carried
  out on ead1 final bulk or each batch of finished product, with apprOpriate confidence
  limits; in . exCeptional circumstances, · potency testing may be carried out at an
  intermediate stage, as late as possible in the production process.
· F. .STABD.JTY TESTS
  The particulars and documents accompanying the application for marketing authorization
  pursuant to Article 12 (3) (f) and (i) shall be submitted in accordance with the following
  requirements.
  A description shall be given of the tests uodertaken to supJ)ort the shelf life proposed by
 the applicant. These tests shall always be real-time studies; they shall be carried out on a
 sufficient number of batches prl?duced according to the described production process and
  on products stored in the final container(s); these. tests include biological and physico-
  chemical stability tests.
 The conclusions shall contain the results of analyses, justifying the proposed shelf-life
 under all proposed storage conditions.                             '
 In the case of products administered in the feed, information shall also be given as
 necessary on the shelf-life of the product, at the different stages of mixing, when mixed in
 accordance with the recommended instructions.
 Where a finished product requires reconstitution prior to administration, details of the
 proposed shelf-life are reqWrec:l for the prodUct reconstituted as recommended. Data in
 support of the proposed shelf-life for the reconstituted product shall be submitted.
                                                                  '                  '
                                                      107
 ---pagebreak--- PAR.T7                                                                                     81/852/EEC ·.
                                                                                           Annex
SAFETY TESTING ·                                                                           (as amended by
                      ,•  I
                                                                                           92/18/EEC Art. 1)
A. INTRODUCI10N                                                                            (adapted) .
1. The safety ~ shall show the po•tial risks from the immunol~gical veterinaly
    ·medicinal prOdw:t which may occur under the proposed conditions of use in animals:
     these sbal1 be ·evaluated in relation to-the potentiaJ benefits of the product.    ·
     Where immunologic81 ·veteriiwy· medicinal. products consist of live. organisms,
     especially those which could be shed by vaccinated animals; the potential risk to
     unvaccinated animals of the same or of any other potentially exposed species shall be
     evaluated.
2. nie particulars and documents which shall aceompany the application for marketing
     authorization purSuant to Article 12 (3j (j) and 13 (1) shall be submitted in
     accordance with the requirements of section B.
3. Member States shall ensure that the laboratory tests are cmied out in conformity
     with the ·principles of good laboratory practice laid down in Council Directives
     87118/EEC and 88/320/EEC.
B. GENERAL REQ~MENTS
1.. The safety tests shall be carped out in the target species.
2. The dose to be used shall be that quantity of the product to be recommended for use
     and containing the maximum titre or potency for which the application is submitted.
3. The sample used for safety testing shall be taken from a batch or batches produced
     according to the manufacturing process descnDed in the application for marketing
     authorization.
                                                      108
 ---pagebreak--- C•.LABORATORY~                                                                              81/852/.EEC :.
                                                                                            Annex·
1. ··Safety of the admiDJstration of. one dose                                              (as· imended by
                                                                                            92/18/EEC Art. 1) ·
The immunologi'* .. veterinary' medicinal product ~ be administered at the (adapted)
~ended.dose and by each recommended route ~fadu;linistration to animals of each.
species and category. in which it is intended for use, including anjmals of the minimum
age of administration. The animaJs sbal1 be obserVed and examined for signs of systemic
m,d local reactions. Where appropriate, these studies shall· include detailed post-mortem
macroscopic and microscopic examinations of tbe .injection site. Other objective criteria
shall be~ such as-~ temperat1D'e and performance ineasurements.
The anjmals sball be o~served and examined until reactions may no "longer be expected,
but in all cases, the observation and examination period shall be at least 14 days after
administration.
2. Safety of o~e admi.Distration of an overdose
An overdose of the immunological veterinary medicinal product shall be administered by
each recommended route of administration to animals of the most sensitive categories of
the target species. The animals shall be observed and examined for signs of systemic and
local reactions. Other objective criteria shall be recorded, such as rectal temperature and
performance measurements.
The animals shall be observed and examined for at least 14 days after administration.
3. Safety of the repeated administration of one dose
Repeated administration of one dose may be required to reveal any adverse effeets
induced by such administration. These tests shall be carried out on the most sensitive
categories of the target species, using the recommended route of administration.
The animals shall be observed and examined for at least 14 days after the last
administration for signs of systemic and local reactions. Other objective criteria shall be
recorded, such as rectal temperature and performance measurements.
4. Examination of reproductive performance
Examination of reproductive performance shall be considered when data suggest that the
starting material from which the product is derived may be a potential risk factor.
Reproductive performance of males and non-pregnant. and pregnant females shall be
investigated with the recommended dose and by each of the recommended routes of
administration. In addition, harmful effects on the progeny, as well as teratogenic and
abortifacient effects, shall be investigated.
These studies may form part of the safety. studies described in paragraph I.
                                                    109
 ---pagebreak--- 5. · Eumiaatlon of lmmuaoJopcal fDDctioDJ                                                    ll/IS21EEC
                                                                                             Annex
Where the imDiunologic8l veterinary medicinil. produCt· might adv~IY 8tfect the (as amended by
immune respouse .of the vaccinated animal or· of. its oroRenv. suitable tests on the 92/18/EEC Art. 1)
immunological f_unctiQDS sblll be cmied out                                                  (adapted)
~·   S~l      require10ents for live vaeeines:
6.1. Spread ofthe vaccine strain
Spread of the vaccine strain from vacc~ to unvaccinated target animals sball be
investigated, using the recommended route of administration most likely to result in the
spread. Moreover, it may be necessary to investigate the spread to non target species
which could be highly susceptible to a live vaccine strain.               ·
6.2. Dissemination in the vaccinated animal
Faeces, urine, milk, eggs, oral, nasal and other secretions shall be tested for the presence
of the organism. Moreover, studies may be required of the dissemination of the vaccine
strain in the body, with particulir attention being paid to the j,redilection sites for
replication of the organism. In the case of live vaccines for well established zoonotic
diseases for food producing animals, these studies must be undertaken.
6.3. Reversion to virulence ofattenuatedvaccines
Reversion to virulence shall be investigated with material from the passage level which is
least attenuated between the master seed and the final product. The initial vaccination
shall be carried out using the recommended route of administration most .likely to lead to.
reversion to virulence. At least five serial passages through animals of the target species
shall be undertaken. Where ~ is not technically possible due to fiilure of the organism
io replicate adequately, as many passages as possible shall be carried out in the target
species. If necessary, in vitro propagation of the organism may be carried out between
passages in vivo. The passages shall be undertaken by 1;he route of administration most
likely to lead to revers~on to virulence.
6.4. Biological properties ofthe vaccine strain
Other tests may be necessary to determine as precisely as possible the intrinsic biological
properties of the vaccine strain (e.g. neurotropism).
6.5. Recombination or genomic reassortmenl ofstrains
The probability of recombination or genomic reassortment with field or other strains shall
be discussed
                                                    110
 ---pagebreak---  7. Study of fesidues                                                                         811$52/EEC
                                                                                              Annex
 For imDlunological veterinary medicinal products, it will normally not be ·necessary to .(as amended by
 undertake a study ofresidues. However, where adjuvants and/or preservimves are used in 92/18/EEC M 1)
 the manufacture of immuiaological veterinary medicinal prod~, consideration shall be (adapted)
 given. to ·the possibility of any ·residue remaining .in .the foodstuffs~ .If necessary, the
 effects of such residues shaD be investigated. Moreover, in the case ofli~e, vaccines for
 zoonotJc diselses, the· determinat:ion.of residues at the injection site may be required in
 ~on to the-studies described m· paragraph 6.2.
                     .                .
 A proposal f~ ·a withdrawal period shall be made and its adequacy shall be_ discussed in
 relation to any·resid_ue studies which have· been undertaken.
 8. lateractioas
 Any known interactions with other products shall be .indicated.
 D. FIELD STUDIES
 Unless justified, results from laboratory studies shall be supplemented with supportive
 data from field studies.
 E. ECOTOXICITY
 The purpose of the study of the ecotoxicity of an immunological veterinary medicinal
.product is to assess the potential harmful effects which the use of the product may cause
 to the environment and to identify any precautionary measures which may be necessary
 to reduce such risks.
 An assessment of ecotoxicity shall be compUlsory for any application for marketing
 authorization for an immunological veterinary medicinal product other than applications
 submitted in accordance with Article 12 (3}0) and 13 (I).
                                                     111
 ---pagebreak---     ·This assessment shall ~o~ be~~ in two p~.                                                   . 811852/EEC
                                                                                                   Annex
     The first phase of the assessment shall always be carried out the inv~gator shall assess · (u amended by
     the.potential extent of exposure of the environment to the prOduct, its ~ve substances, ·.92/1.8/EEC Art. 1)
     or relevant metabolites, taking into accouD.~                                                 (adapted) ·
           the target species and the proposed pattern of use (for example, mass medication or
           individual animal medi~on), .               ·
         · the method of ~on, in particular th~ llkely extent to which the prOduC:t will
           enter directly into environmental system, ·
           the possible excretion of the product, its active substances or relevant metabolites
           into the environment by treated animals, persistence in such excretia,              ·
           the disposal of unused or waste product
     Where the conclusions of the first phase indicate potential exposure of the environment
     to the. product, the applicant shall proceed to the second phase and evaluate the potential
     ecotoxicity of the product. For this purpose, he shall consider the extent and duration of
     exposure of the environment to the product, and. the information about the
     physical/chemical, pharmacological and/or toxicological properties of the compound
     obtained during the conduct of the other tests and trials required by this Directive. Where
     necessary, further investigations on the impact of the product (soil, w~r, air, aquatic
     systems, non-target organisms) shall be carried out.
     These further investigations shall be carried out in accordance with the te~ protocols laid
     down in Annex V to Council Directive 67/548/EEC or where an end point is not
     adequately covered by these protocols, in accordance with other internationally
     recognised protocols on the immunological veterinary medicinal product and/or the
     active substances and/or the excreted metabolites as appropriate. The number and types
     of tests and the criteria for their evaluation shall depend upon the state of scientific
     knowledge at the time the application is submitted.
                                                          112
(8)
 ---pagebreak--- PAllTI ··                                                                                          81/852/EEC
                                                                                                  -Annex.
EmCACY TRIALS.                                                                                     (as amend~ by
                                                                                                   92/18/EEC Art. 1)
A. .INTRODUCTION.                                                                                 ·(adapted)
1. The purpose of .the trials described in this Part· ·is to demonstrate or to confirm the
     efficacy of  the immunological veterinary .m~cinal product. All claims made· by the
   . appliCant with regard to the properties, effects and use of the product, shall be fully
     supported by· results of ~itic trials contained in the application for· marketing
     authorization. ·                 ·                                                  ·
2. The particulars and· documents which ~ accompany -applications for rilarketing
     authorizations pursuant ·to Article 12 .(3) (j) and 13 (1) sball be submitted· in
     accordance~ -the provisions below.                             · ,
3.    All veterinary clinical tri8ls shall be condu~~ in accordance with a. fully considered
     detailed trial protocol which shall be recorded in w.ritlng prior to commencement of
     the trial. The welfare of the trial animals shall be subject· to veterinary supervision
     and shall be taken fully into consideration during the elaboration of any trial protocol
     and throughout the conduct of the trial. .
     Pre-established systematic written procedures for the organization, conduct, data
     c~llection, docmnentation and verification of clinical trials shall be required.
4. Before the commencement of any trial, the informed ·consent of the owner of the
     animals to be used in the trial shall be obtained and documented. In particular, the
     animal owner shall be informed in writins of the COJl.Sequences of participation in the
     trial for the subsequent disposal of treated animals or for the taking of foodstuffs
     from treated animals. A copy of this notification, countersigned and dated by the
     animal owner, shall be included in the trial documentation.
5. Unless the trial is conducted with a blind design, the provisions of Articles 55, 56
     and 57 shall apply by analogy to the labelling of formulations intended for use in
     veterinary clinical trials. In all cases, the words 'for veterinary clinical trial use only'
     shall appear prominently and indelibly upon the labelling.
B. GENERAL REQUIRE~
1. The choice of vaccine strains shall be justified on the ba:sis of epizoological data.
2. Efficacy trials carried out in the laboratory shall be controlled trials, including
     untreated control animals.
                                                       113
 ---pagebreak---     In general, these 1rai1s shaD be supported by trials canied out hi .field. conditions, 81/852/EEC ·
    including untreated control animals•.                                                      AnneX ..
                             .                         .                                       (as amtmded by
    All trials Shall be described in sufficiently precise details so as to be reproducible in 92/18/EECM 1)
    control trials, carried out at the request of the competent authorities. The investigator (~)
   ·shall demonStrate the validity .of all the techniques involved. All results shall be
    plesented as p~isely as possible. ·
    All Rsults obtained,. whether favoUrable or unfavourable, shall be reported.
3. The efficacy .of an immunological veterin8ry . memcinal product shall be
    deDtonstrated for each category of each species recommended for vaccinatio~ by
    each recommended route of administration and using the proposed schedule of
    administration. The influence of passively acquired -and maternally derived
    antibodies on the efficacy of a vaccb:ie shall be adequately evaluated. Any claims
   ·regarding the onset and duration of protection shall be supported by data froi:n trials. .
4.   The efficacy of e8ch of the components of multivalent and combined immunological
     veterinary medicinal products shall be demonstrated. If the product is recommended
    for administration in combination with or at the Sam.e time as another veterinary
    medicinal product, they shall be shown to be eompatible.
S. Whenever a product forms part of a vaccination scheme recommended by the
    applicant, the priming or booster effect or the contribution of the p~duct to the
    efficacy of the scheme as a whole shall be demo~.
6. The dose to be used shall ~ that quantity of the product to be recommended for use
    and containing the minimum titre or potency for which the ~plication is submitted.
7. The samples used for efficacy trials shall be taken from a batch or batches produced
    according to the manufacturing process described in the application for marketing
    authorization.
8. For diagnostic immunological veterinary medicinal products administered to
    animals, the applicant shall indicate how -reactions to the product are to be
    interpreted.
1. In principle, demonstration of efficacy shall be undertaken under well controlled
    laboratory conditions by challenge after administration of the immunological
    veterinary medicinal product to the species animal under the recommended
    conditions of use. In so far as possible, the conditions under which the challenge is
    carried out shall mimic the natural conditions for infection, for example with regard
    to the_ amount of cllallenge organism and the route of ~on of the cllallenge.
2. If possible, the immune mechanism (cell-mediated/humoral, locaJ/general classes of
    immunoglobulin) which is initiated after the administration of the immunological
    veterinary medicinal product to target -inimals by the rccon;unend~ roUte of
    administration shall be specified -and documented.                              ·
                                                     114
 ---pagebreak---   D. F1ELD TRIALs                                                                               81/852/EEC ·
                   · ·                                                                          Annex
  1.- Unlessjustified, resuits ftopl Jaboratoey trials shall· be supplemented with data from (as amended by
 . . field 1rials.                                                      ·                     · 92/18/EEC Art. 1)
                                                                                                (adapted)         .
  2. ·Where laboratory trials cannot be supportive of efficacy, the peiforinance of field
     · trials ·alone may be acCeptable.
  PAR.T9'
  PARTICULARS·AND DOCUMENTS CONcERNING SAFETY TESTING AND
  EmCACY. TRIALS ·OF IMMUNOLOGIC~ VETERINARY MEDICINAL
  PRODUCfS·
  A. INTRODUCI'ION
  As in any scientific work, the dossier of safety and efficacy studies shall include an
· introduction defining the subject and in~cating the tests ~hich have been carried out in
  compliance with Parts 7 and 8, as well as a summary, with references to the published
  literature. Omission of any tests or trials listed in Parts 7 and 8 shall be indicated and
  discussed.
 B. LABORATORY STUDIES
 The following shall be. provided for all studies:
 2. the niune of the body having carried out the studies;
 3. a detailed experimental protocol giving a description of the methods, apparatus and
       materials used, details such as species, breed or strain of animals, categories of
       animals~ where they were .obtained, their identification and number, the conditions
       under which they were housed and fed (stating inter. alia whether they were free from
       any specified pathogens and/or specified antibodies, the nature and quantity of any
       additives contained in the feed), dose, route, schedule and dates of administration, a
       description of the statistical methods used;
 4.    in the case of control animals, whether they received a placebo or no treatment;
                                            I
                                                      llS
 ---pagebreak---                                          •                        •t                .
·S. ·all geoeral.and individual obserVations and results obtained (wbh averages and· 811852/EEC.
        staDdard . deviations), whether favOmable or unfavourable.·       ·ne    datA sball· be Annex· · ·
        described in ..Jumcient detail to· allow the resUlts to be critically evaluatei:l (as amended. by
      · independently of their~ by the author•.ne raw data Sball be presented in · 92/li!EEC ~ 1)
        tabuJar:form. By way of explanltion and illus1ration, the results ~Y be acccmipai;iied (adapted)
        by reproductions of reccmtings, photomicrographs, etc.;
                              .               .
 6. · the nature, frequency and duration of obser:ved sido-e1fects~
 7. the number of animals ~wn prematurely ftom the studies and reasons for sUch
        withdrawal;                .
 8. a· statistical milYsis of the ~, where such is called ·for by the test· programme,
        mdwrlm~~~the~                                            ·                    ·
 9. OCCWTence and course of any intercuri'ent disease;
 10. all details concerning medicinal products (other than the product under study), the-
        administration ofwhi~h was n~cessaey during the course of the study;
 11. an objective discussion of the results obtained, 1Qdmg. to conclusions on the .safety
      ·.and efficacy of the product.
 C.· FIELD STUDIES
 Particulars concerning field studies shall be sufficiently detailed to enable an objective
judgement to be made. ·They shall include the following:
 I. a summary;
2. name, address, function and qualifications of the investigator in charge;
3. place and date of administration, name and address of the owner of the animal(s);
4. details of the trial protocol, giving a description of the methods, apparatus and
        materials. used, details such as the route of administration, the schedule of
        administration, the dose, the categories of animals, the duration of observation, the
        serological response and other investigations carried out on the animals after
        administration;                     ·                   ·
                                                                 ...
S.      in the case of control animals, whether they received a placebo or no treatment;
6. identification of the treated and control animals (collective or individual, as
                  .
     · appro~}, such as species, breeds or strains, age, weight,. sex, physiological status;
 ---pagebreak--- 7. •· brief clesclipion of the. ·mel;hod of rearing .and feeding, ~ the            nature and 81/852/EEC.
        quantity of any additives ccmtained in the feed;            ·                         Annex .
        .                                       .                                             (as amended by ·
·a.     all· the. particulars on observations,. performances· and results-(~ av«ages and 92/18/EEC Art. 1)
  · ... stiodard deviation); individual da1a shall be. ilidicated When tests and measurements (adapted)
      . OD in~ have been CIJried out;
9. all obserVations and results of the studies, whether filvo~le or unfavourable~ With
        a tWl statement of the observati~ and the results of the objective tests of activity
       required to evaluate the product; the techniques -used must be specified and the
        significance of any variations in the results explained;
 10. effect on the animals' performances· (e.g. egg laying. milk production,· reproductive
    · performance);                     ·                           ·
 11. the number of animals       withdrawn prematurely from the studies and reasons for ~eh
       withdrawal;
 12. the nature, frequency and duration of ob~ed adverse reactions;
13. oecurrence and course of any intercmrent disease;
14. all details concerning medicinal products (other than the product 1mder study) which
       have been administered either prior to or concmrently with the test prOduct or during
       the observation period; details of any interactions observed;
IS. an objective discussion of the results obtained, leading to conclusions on the safety
       and efficacy of th~ product.
D. GENERAL CONCLUSIONS
General conclusions on all results of tests and trials canied out in compliance with Pans
7 and 8 shall be given. They shall contain an objective discussion of all the results
obtained and lead to a· conclusion on the safety and efficacy of the immunological
veterinary medicinil product.
E. BmLIOGRAPHICAL REFERENCES
The bibliographical references cited in the summary mentioned under Section A shall be
~inde~.                                                           .
                                                        117
 ---pagebreak---                                      ·ANNEXn
                                       Pan A
                                Repealed DireetiVes
                             (referred to by 1\rti~le 98)
Council Directive 81/851/EEC (OJNo L 3i7, 6. 11.1981~ p.l)
   Council Directive 90/676/EEC (OJ L 373,31.12.1990, p. 15)
  .Council Directive 90/677/EEC (OJ L 373, 31.12.1990, p. 26)
   Council Directive 92f74/EEC (OJ L 297, 13.10.1992, p. 12)
   Council Directive 93/40/EEC (OJ L 214,24.8.1993, p. 31)
Council ~irective 81/852/EEC (OJ L 317, 6.11.1981, p. 16)
   Council Directive 87/20/EEC (OJ L 15, 17.1.1987, p. 34)
   Council.Directive 92/18/EEC (OJ L 97, 10.4.1992, ·p. 1)
   Council Directive 93/40/EEC (OJ L 214,24.8.1993, p. 31)
                                         118
 ---pagebreak---                                                  ~art B.
                                      .                            . .
                         ~~·_for tnmspositioo into oatioullaw
                                   '.. (referred to by Article 94)
                          Directive
   Directive 81/851/EEC                                      9 October 1983
 · Directive 81/852/EEC.                                     9 October 1983
· Directive· 87/20/EEC                                      l July 1987
   Directive 90/676/EEC                                      1J~1992·
   Directive 90/677/EEC                                      1 January 1992
   Directive 92/18/EEC                                       1 Aprill993
  .Directive 92174/EEC                                       31 December 1993
   Directive
         '
             93/40/EEC
                  .                                          1 January 1995
                                                             1 January 1998 (An. I. 7)
                                                   119
 ---pagebreak---                                                                            ANNEX Ill
                                                                  CORRELATION TABLE
This Directive      Dir. 6S/6SIEEC       Dir. 81/85 I!EEC                         Dir. 81/852/EEC   Dir. 90/677/EEC   Dii:.
                                                                                                                      92174/EEC
                                                                                                  ;
Art. I (1) and {2)  Art. I (I) and (2) · Art.  I (I)
Art. I ~ 3)                   )          Art.  1.1 2).- 2nd indent                                                               ..
                                                                                                                            •.
Art. I~ 4)          Art. I. point 3      Art.  11 IT-
Art. I I S)and(6)                        Art.  I I 2). 3rd and 4th indents
Art. I~ 7)                                                                                          Art. I (2} ·
Art. I~ 8)                                                                                                            Art. I
Art. I~ 9)                               Art. S. 3rd suboara21'8Ph. point 8                                                             I
Art. I (10) to (13)                      Art.42b
Art. I (14)                              Art. SOa (If 2nd SUL             h                                                             I
Art. I (IS)                              Art.l6 (I) ..
                                                                                                                                        I
                                                                                                                                        I
Art. I (16)                              Art. 18 (I), footnote
Art.2                 ,                  Art.. 2 I)                                                                            '
Art. 3 (I), 1st                          Art. 2 (2), 1st indent
sub          h                                                                                      ..
                                                                                                                   ..
Art. 3 (I}, 2nd                          Art. 2 (3)                                                                                    l
sub          h                                                                                                                          I
Art.                                                                                                                                ..
Art. 3 (2)                                                                                          Art. I (3) · .
                                                                              120
 ---pagebreak--- This Directive         · Dir. 65/65/EEC .. Dir. 81/85 I!EEC                                Dir. 81/852/EEC Dir. 90/677/BEC    Dir. 92174/BEC
Art. 3 (3) and (4)       Art. I (4}_ and 1SJ   Art. I (I)
Art. 3 (5)                                   - Art. 2 (2), 3rd indent
Art. 3 ~ 6)                                    Art. 1 (4)
Art. 4 ~ I)                                                                                                Art. I (4)
Art. 4 ~ 2)                                    Art.3
Art. 5                                         Art. 4_(1 ), 1st sub_parag.raph                                             -·
Art.6                                          Art. 4 (2), 1st subparagraph
Art. 7                                         Art. 4 ( 1), 2nd subparagraph                 ..
Art. 8                                         Art. 4 (I),_ 3rd sub_paragraph
Art.9                                          Art. 4 (3)f. 1st subparagraph
Art. 10 (I) and (2),                           Art. 4 (4), 1st and 2nd subparagraphs
                                                                                                                .  -
lstand 2nd.
subparagraphs
                                                             "'                                                                     -
Art. 10 (2),                                                                                                                  Art. 2 ·(I), 2nd .
3rd subparagraph                                                                                                              subparagraph
Art. 11                                        Art. 4 (4), 3rd subparagraph
Art. 12 (I)                                    Art. S, 1st subparagraph
Art. 12 {2)                                    Art. s, 2rid subparagraph
Art. 12 {3) {a) to {i)                         Art. S, 3rd subpargraph, points I to 9      Art. 1, 1st                                           .I
                                                                                           subparagral)h                                          I
Art. 12 (3) (j)                                Art. S, 3rd subpargraph, points 10, Jst
                                               subparagt¥h                                                                                    . I
Art, 12 {3) (k) to                             Art. S, 3rd subpargraph, poirits 11 to 14                                                          I
(n)
Art. 13 (I)                                    Art. S, 3rd subpargraph, points I 0, 2nd
                                               subparagraph                                                         ~                             1
                                                                                         121
 ---pagebreak--- This Directive        Dir. 6S/6SIEEC Dir. 81/8S I/EEC Dir. 81/8S2/EEC    Dir. 90/677/EEC    Dir. 92174/EEC
Art. 13 (2)                                           Art. I, 2nd sub 'h
                                                                          ..
Art. 14                              Art. Sa
Art. IS (I)                          Art.6
                                                                                            ,.
Art. IS (2) and (3) .                Art. 7
Art. 16                                                                                     -Art. 6 .
Art. 17 (1)                                                                                 M 7(1) .
Art. 17 (2)                                                           ,.                    Art. 7 (3)
Art. 17 (3) .                                                                               Art. ~. 2rid - .
                                                                                            sub        . h
                                                                                         ..
Art. 18                                                                                     Art. 8
Art. 19                                                                                     Art.9                .I
Art. 20                                                                                     Art. 2 (3) .
Art. 21                              Art. 8
Art. 22                              Art.8a                                                                        !
Art.23                               Art.9
Art. 24                              Art. 10
Art. 2S                              Art. Sb
Art. 26 (I) and (2)                  Art. "12                                                                • -   I
Art. 26 (3)                          Art. IS {2)                                  ------
                                                           122
 ---pagebreak--- This Directive      Dir. 65/65/EEC Dir. 811851/EEC                 · Dir. 81/852/EEC Dir. 90/677/EBC      Dir. 92174/EBC
Art. 27 (I)                        Art 14 (I), I st subparagraph ·
Art. 27 (2)                        Art. 14 ( 1). 2nd subparagraph
Art. 27 (3)                        Art. 14 (2)                                                         ..
Art. 27 (4) and (S)                Art. 14(j) and(4)
Art. 28                            Art. IS (I)
Art. 29                            Art. 13                                                           -
Art. 30                            Art. 11
Art. 31 (1)                        Art. 16(1)
Art. 31 (2)                        Art. 16(il
Art. 31 (3)                        Art. 16 (3)
Art. 32 (I) .                      Art. 17 (3)                                                                            .
Art. 32 {2)                        Art. 17 (I)
Art.32(3)                          ~. 17-(2)
Art. 32 (4                         Art. 17 (4)                                                                            .
Art. 33                            Art. 18
)U1.34                             Art. 19
Art.3S                             Art.20
Art. 36                            Art, 21 I
Art. 37                            Art. 2fln
 Art. 38                           Art. 22 {2). {3) and {4)                                                             .
 Art. 39                           Art. 23                                             _
                                                                     123
 ---pagebreak--- This Directive     Dir. 65/65/EEC   Dir. 81/851/EEC               Dir. 81/852/EEC      Dir. 90/677/EEC · ' Dir. 92174/EBC
Art. 40                             Art.23a                                                                               .
Art. 41                             Art. 23b
Art.42                              Art.23c
Art. 43                             Art. 22 (5)
Art. 44                             Art.24                                                                           :
Ait.45                              Art.25
Art. 46.                            Art. 26                                                                                  ·-
Art.47                              Art. 28{1)                                                                        • 0
Art.48                              Art. 28 (2)
Art. 49      .                      Art. 28(3)-
                                                                                                                               ..
Art. so                             Art.27
Art. 51                             Art.27a
Art. 52                             Art. 29.
                                                                                                       ..
Art. 53                             Art. 31
Art. 54                             Art.32
Art. ss (I)
                                                                                  ..
                                    M· .~0 (1 ), 1st and 2nd
                                  - su"          hs                                                  :
                                                                                                                                  '
Art. ss (2)                         Art. 30 (1).3rd subpara~h
                                                                                     ~
                                                                                                                          ..
Art. ss (3)                         Art. 30 (2).
                                                                          :
Art. 56                             Art.33                                                                          ..
Art. 57                                                                                                    Art.3
Art. 58 (I) to (3)                  Art.43                                                                              '
                                                              124
 ---pagebreak--- This Directive            Dir. 65/65/EEC Dir. 81/851/EEC                       Dir. 81/852/EEC Dir. 90/677/EEC     ..     Dir. 92!14/BEC
Art. 58 (4)                              Art. 47
Art. 59 I)                               Art. 44                                                                \.
Art. 59 2)                               Art. 45
Art. 59 3)                               Art.47
Art.60                                   Art.46                                                         ~
Art. 61 (I)                              Art.48(1)
Art. 61 (2)'                             Art. 48 (2)
Art. 61 3)                               Art. 48 (3)
Art.62                                   Art. 49. 1st paragraph
                                                            ,
Art.63                                   Art. 50
Art. 64 I)                                                                                                                Art. 2 (2}
Art. 64 ~2) .                                                                                                             Art. 7(2)-
Art. 65 ~ I)                             Art. SOa(l~ 1st and 3rd subparagraphs
Art. 65 ~ 2). (3) and (4)                Art. SOa (2), (3) and (4}_
Art. 66                                  Art. SOb
Art.67                                   Art. 4· (3 ), 3rd subparagraph                                        ...
Art.68                                   Art. I (5)
Art. 69                                  Art.SOc
Art. 70                                  Art. 4 (S)
Art. 71                                                                                        Art.4
Art. 72                                  Art.42e
Art. 73         -                        Art. 42a                                                                     - L______
                                                                        12S
 ---pagebreak---                                                                                      ..
This Directive Dir. 65/65/EEC   Dir. 81/851/EEC                       Dir. 81/852/EEC   Dir. 90/677/EEC         Dir. 92r/4/EBC
Art. 74                         Art.42c                                                     '
Art. 15 .                       Art. 42d                                                                     ..
Art. 76                         Art.42f                                                            .                                 '
Art. 77                         Art. 422                                                                                               I
Art. 78                         Art. 42h
Art. 79               ..        Art. 42i                                                                                    ~
                                                                                                                          ~
Art. 80 (I)                     Art. 34, 1st and 2nd subparagraphs ·
Art. 80 (2)                                                                             Art. 3 (I) . .                             r
Art. 80 {3)                     Art. 34, 3rd subparagraph
Art. 81 {1)                     Art. 35
Art. 81 (2)                                                                             Art. 3 (2)
                                                                                                                                ..
Art. 82 .                                                                               Art. 3 (3)              ..
Art.83                          Art.36                                                                                        I
Art. 84                         Art.37                     ..
Art.8S                          Art. 38
Art.86                                                                                                          Art. 4, lst.
                                                                                                                 subparagraph
Art. 87                         Art. 38a
Art.88                                                                Art. 2b
Art. 89
Art.90                        . Art. 42_i
                                                                      Art.2a
                                                                                                       ..
                                                                                                          '.
Art. 91· .                      Art.42k
Art.92                          Art.39
                                                                  126
 ---pagebreak--- 'Ibis Directive Dir. 65/65/EEC Dir. 81/85 I!EEC                 Dir. 81/852/EEC · Dir. 90/677/EEC. Dir. 92!74/EBC
                                                                                                               ..
Art. 93           I            Art. 42
Art.94.                                                                                            Art. 5        ..
Art. 95                        Art.24a                                                                            ..
                                                                                                               .
                                                                                                               ..
Art. 96                        Art. 40 and 41
Art. 91                        Art. 4 (2), 2nd subparagraph
Art. 98         -              -                                -                 -                --                -
Art. 99         -              -                                -                 -                   .
'Art. lOO       -              -                                -                 -                 -       ,
 Annex I                                                        Annex
 Annexll        -              -                                -                 -                 ~             •·
 Annex Ill      -              -                                -                 -                 -            ~-
                                                            127